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Tubular NiTi is a promising candidate refrigerant for eco-friendly elastocaloric cooling, but its severe functional degradation during cyclic phase transition (PT) is a key concern in the technology development. Here, plastic deformation of 6.7% is applied to NiTi tube by overstress training under 1900 MPa for five cycles to improve the cyclic PT stability without losing cooling efficiency. It is found that after 106 compressive cycles under 1000 MPa, the overstress-trained NiTi tube exhibits small residual strain (0.5%), stable adiabatic temperature drop (ΔT = 11K) and improved coefficient of performance (COP = 55), showing high functional stability and good cooling performance. Transmission electron microscopy (TEM) observations show that the microstructure of the overstress-trained NiTi tube consists of 5–10 nm sized austenite (B2) and martensite (B19′) nanodomains with near-saturated dislocation density (ρ ≈ 5.153 × 1016 m−2). Such dislocation-enriched nanostructure effectively suppresses further formation and motion of dislocation during subsequent cyclic compression, thereby significantly enhancing the cyclic stability of the NiTi tube. The residual B19′ nanodomains and dense dislocations change the PT mode from nucleation-growth of the B19′ phase to direct growth of residual B19′ nanodomains, thereby reducing the dissipation of the PT process and increasing the COP of the NiTi tube. Our study provides an economic and effective method for to enhance the cyclic stability of bulk NiTi tubes for solid-state refrigeration.

Atherosclerotic cardiovascular disease is closely correlated with elevated low density lipoprotein-cholesterol. In feeding state, glucose and insulin activate mammalian target of rapamycin 1 that phosphorylates the deubiquitylase ubiquitin-specific peptidase 20 (USP20). USP20 then stabilizes HMG-CoA reductase, thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity, and increased energy expenditure through elevating UCP1. In Ldlr−/− mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

Aging increases the risks of various diseases and the vulnerability to death. Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases. This study demonstrates that extracellular vesicles from human urine-derived stem cells (USC-EVs) efficiently inhibit cellular senescence in vitro and in vivo. The intravenous injection of USC-EVs improves cognitive function, increases physical fitness and bone quality, and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice. The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ ages, genders, or health status. Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase (PLAU) and tissue inhibitor of metalloproteinases 1 (TIMP1). These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

Objectives: FGFR4-variant and wild-type colorectal cancer (CRC) organoids were developed to investigate the effects of FGFR4-targeted drugs, including FGFR4-IN and erdafitinib, on CRC and their possible molecular mechanism. Methods: Clinical CRC tissues were collected, seven CRC organoids were developed, and whole exome sequencing (WES) was performed. CRC organoids were cultured and organoid drug sensitivity studies were conducted. Finally, an FGFR4-variant (no wild-type) CRC patient-derived orthotopic xenograft mouse model was developed. Western blot measured ERK/AKT/STAT3 pathway-related protein levels. Results: WES results revealed the presence of FGFR4-variants in 5 of the 7 CRC organoids. The structural organization and integrity of organoids were significantly altered under the influence of targeted drugs (FGFR4-IN-1 and erdafitinib). The effects of FGFR4 targeted drugs were not selective for FGFR4 genotypes. FGFR4-IN-1 and erdafitinib significantly reduced the growth, diameter, and Adenosine Triphosphate (ATP) activity of organoids. Furthermore, chemotherapeutic drugs, including 5-fluorouracil and cisplatin, inhibited FGFR4-variant and wild-type CRC organoid activity. Moreover, the tumor volume of mice was significantly reduced at week 6, and p-ERK1/2, p-AKT, and p-STAT3 levels were down-regulated following FGFR4-IN-1 and erdafitinib treatment. Conclusions: FGFR4-targeted and chemotherapeutic drugs inhibited the activity of FGFR4-variant and wild-type CRC organoids, and targeted drugs were more effective than chemotherapeutic drugs at the same concentration. Additionally, FGFR4 inhibitors hindered tumorigenesis in FGFR4-variant CRC organoids through ERK1/2, AKT, and STAT3 pathways. However, no wild-type control was tested in this experiment, which need further confirmation in the next study.

Background: The prevalence of breast cancer (BRCA), which is common among women, is on the rise. This study applied network pharmacology to explore the potential mechanism of action of herba sarcandrae in BRCA and construct a prognostic signature composed of inflammation-related genes. Methods: The active ingredients of herba sarcandrae were screened using the SymMap, TCMID, and TCMSP platforms, and the molecular targets were determined in the UniProt database. The “drug-active compound-potential target” network was established with Cytoscape 3.7.2. The molecular targets were subjected to disease ontology, gene ontology (GO), and Kyoto Encyclopedia of Genes (KEGG) analyses. AutoDock software was used for molecular docking. Differentially expressed genes (DEGs) related to inflammation were obtained from the BRCA Cancer Genome Atlas (TCGA) database. In the training cohort, the univariate Cox regression model was applied to preliminarily screen prognostic genes. A multigene signature was built by the least absolute shrinkage and selection operator (LASSO) regression model, followed by validation through Kaplan‒Meier, Cox, and receiver operating characteristic (ROC) analyses. Results: Forty-one active compounds were identified, and 265 therapeutic targets for herba sarcandrae were predicted. GO enrichment results revealed significant enrichment of biological processes, such as response to xenobiotic stimuli, response to nutrient levels, and response to lipopolysaccharide. KEGG analysis revealed significant enrichment of pathways such as AGE-RAGE and chemical carcinogenesis receptor activation signaling pathways. In addition, the herbs Marc-Andre and rutin were shown to mediate BRCA cell proliferation and apoptosis via the interferon regulatory factor 1 (IRF1)/signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) pathway. Sixteen inflammatory signatures, including BST2, GPR132, IL12B, IL18, IL1R1, IL2RB, IRF1, and others, were constructed, and the risk score was found to be a strong independent prognostic factor for overall survival in BRCA patients. The 16-inflammation signature was associated with several clinical features (age, clinical stage, T, and N classifications) and could reflect immune cell infiltration in tumor microenvironments with different immune cells. Conclusions: Herba sarcandrae and rutin were shown to mediate BRCA cell proliferation and apoptosis via the IRF1/STAT3/PD-L1 pathway, and the 16-member inflammatory signature might be a novel biomarker for predicting BRCA patient prognosis, providing more accurate guidance for clinical treatment prognosis evaluation and having important reference value for individualized treatment selection.

Health care accounts for 9–10% of greenhouse gas (GHG) emissions in the United States. Strategies for monitoring these emissions at the hospital level are needed to decarbonize the sector. However, data collection to estimate emissions is challenging. We explored the potential of gradient boosting machines (GBM) to impute missing data on resource consumption in the 2020 survey of a consortium of 283 hospitals participating in Practice Greenhealth. GBM imputed missing values for selected variables in order to predict electricity use (R2 = 0.82) and beef consumption (R2 = 0.82) and anesthetic gas desflurane use (R2 = 0.51), using administrative and financial data readily available for most hospitals. After imputing missing consumption data, estimated GHG emissions associated with these three examples totaled over 3 million metric tons of CO2 equivalent emissions (MTCO2e). Specifically, electricity consumption had the largest total carbon footprint (2.4 MTCO2e), followed by beef (0.6 million MTCO2e) and desflurane consumption (0.03 million MTCO2e) across the 283 hospitals. The approach should be applicable to other sources of hospital GHGs in order to estimate total emissions of individual hospitals and to refine survey questions to help develop better intervention strategies.

Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.

CRISPR-Cas12a has been used for genome editing and molecular diagnosis. The well-studied Cas12a orthologs have a T-rich PAM and are usually categorized as non-thermally stable enzymes. Here, we identified a new Cas12a ortholog from Clostridium thermobutyricum, which survives at 60 °C. This Cas12a ortholog is named as CtCas12a and exhibits low sequence similarity to the known Cas12a family members. CtCas12a is active in a wide temperature range from 17 to 77 °C. Moreover, this ortholog has a relaxed PAM of YYV (Y=C or T, V = A or C or G). We optimized the conditions for trans-cleavage and enabled its detection of nucleic acids. CtCas12a executed genome editing in human cells and generated up to 26% indel formation in the EGFP locus. With the ability to be active at high temperatures as well as having a relaxed PAM sequence, CtCas12a holds potential to be further engineered for pathogen detection and editing a wide range of genomic sequences.

Chemical vapor deposition tungsten (CVD-W) is a promising material for plasma-facing materials. This work evaluated CVD-W samples with a large grain size (CVD-L) and a small grain size (CVD-S) together with rolled W (ND-W) and recrystallized (Rec-W) samples for their performance under deuterium (D) plasma exposure with a flux of 1021 D m−2 s−1 and fluences up to 2 × 1025 D m−2 at a surface temperature of 500 K. Both CVD-L and CVD-S samples featured a columnar grain structure with a preferred orientation close to 〈001〉 || Z, with a more preferred orientation in CVD-L samples. Both CVD-L and CVD-S samples show good resistance to blistering and only few micron-diameter blisters were observed at fluences. In ND-W and Rec-W samples, the number and size of blisters increased with fluence. The D desorption spectra show two desorption peaks in both CVD-W samples at 520 K and 570–604 K. Whereas in ND-W and Rec-W samples, two peaks were at 520 K and 607–700 K. The total D retention in both CVD-L and CVD-S samples was less than 30 % of that in ND-W and Rec-W samples. The low D retention in CVD-W samples was attributed to the low desorption intensities with the peak at 570–604 K. It is suggested that the microstructure of the columnar grain and the 〈001〉 texture in CVD-W samples helps suppressing plasma-induced blistering, therefore reducing D retention. In terms of the stability of the surface integrity and hydrogen isotopes retention, CVD-W demonstrates a significant potential as a wall material for future fusion reactors.

Long-term observations of the volume mixing ratio (VMR) profiles and total columns of key atmospheric constituents are significant for understanding climate change and the impact of the carbon budget in China. This study provides an overview of the first ground-based high-resolution Fourier-transform spectrometry (FTS) observation station in China, which is located in Hefei, east China. The FTS observation station can observe the total columns and VMR profiles of more than 30 atmospheric constituents. Time series of some key atmospheric constituents observed at the Hefei station since 2014 have been released to the public. The major scientific achievements obtained to date at this station include spectral retrieval characterization and harmonization, investigation of the overall characteristics of key atmospheric constituents, emission estimates, satellite and chemical transport model (CTM) evaluations, and a summary of pollutant sources and transport patterns. An outlook is also presented of the envisaged plan for observations, scientific studies, and data usage at the Hefei station. China has explicitly proposed reaching a peak in its CO2 emissions by 2030 and realizing carbon neutrality by 2060. The Hefei station will provide scientific assistance to the Chinese Government for developing green economy policies and achieving carbon neutrality and the goals of the Paris Agreement.

Objectives: Physical frailty is one of the major concerns among older people living with HIV (PLWH). This meta-analysis aimed to explore the association between physical frailty and negative health outcomes among PLWH. Methods: We systematically searched six electronic databases including PubMed, Embase, Web of Science, the Cochrane Library, and Chinese databases up to April 10, 2022, for studies examining the association between physical frailty and risk of negative health outcomes among PLWH. Risk ratios (RRs), odds ratios, and hazard ratios with 95% CIs were extracted, and meta-analyses were conducted by using a fixed or random-effects model. Results: In total, 10 studies incorporating 7755 HIV–seropositive patients (mean age 49.4 years) were included in the meta-analysis. Overall, five studies with 3434 participants reported the effect of physical frailty on falls. Results showed that physical frailty in HIV–seropositive individuals demonstrated a higher risk of future falls (pooled RR 3.74, 95% CI 1.42-9.86) compared with robust HIV–seropositive patients. In addition, a meta-analysis of five studies (4321 participants) reporting the frailty-mortality association showed that physical frailty was significantly associated with a higher risk of all-cause mortality (RR 1.70, 95% CI 1.32-2.19) among PLWH. Conclusion: Physical frailty is a significant risk factor for negative health outcomes in PLWH, including falls and all-cause mortality, underscoring the need for routine screening and early intervention of physical frailty among PLWH.

CRISPR-Cas12a based one-pot detection system has been used in nucleic acid detection and diagnosis. However, it is not sensitive enough to distinguish single nucleotide polymorphisms (SNP), which has greatly restricted its application. To overcome these limitations, we engineered a LbCas12a variant with enhanced sensitivity against SNP, named seCas12a (sensitive Cas12a). SeCas12a-based one-pot SNP detection system is a versatile platform that could use both canonical and non-canonical PAM, and was almost not limited by mutation types to distinguish SNPs located between position 1 to 17. The use of truncated crRNA further improved SNP specificity of seCas12a. Mechanistically, we found only when the cis-cleavage was at low level between 0.01min−1 and 0.0006 min−1, a good signal-to-noise ratio can be achieved in one-pot test. SeCas12a-based one-pot SNP detection system was applied to detect pharmacogenomic SNPs in human clinical samples. Of thirteen donors tested in two different SNPs, the seCas12a mediated one-pot system could faithfully detect the SNPs in 30 min with 100% accuracy.

Anomalous characteristics of the atmospheric water cycle structure are highly significant to the mechanisms of seasonal-scale meteorological droughts. They also play an important role in the identification of indicative predictors of droughts. To better understand the causes of seasonal meteorological droughts in the middle and lower reaches of the Yangtze River (MLRYR), characteristics of the atmospheric water cycle structure at different drought stages were determined using standardized anomalies. The results showed that the total column water vapor (TCWV) was anomalously low during drought occurrence periods. In contrast, there were no anomalous signals at the drought persistence and recovery stages in the MLRYR. Moreover, there was no significant temporal correlation between the TCWV anomaly and seasonal-scale drought index (the 3-month standardized precipitation index (SPI3)). During drought events, water vapor that mainly originated from the Bay of Bengal was transported southwest of the MLRYR. Meanwhile, the anomalous signal of water vapor transport was negative at the drought appearance stage. At the drought persistence stage, the negative anomalous signal was the most significant. Water vapor flux divergence in the MLRYR showed significant positive anomalous signals during drought events, and the signal intensity shifted from an increasing to a decreasing trend at different drought stages. In addition, a significant positive correlation existed between the anomaly of water vapor flux divergence and regional SPI3. Overall, water vapor flux divergence is more predictive of droughts in the MLRYR.

In vitro preparation of mRNA is a key step for mRNA therapeutics. The widely used T7 RNA polymerase (RNAP) was shown to have many by-products during in vitro transcription (IVT) process, among which double-stranded RNA (dsRNA) is the major by-product to activate the intracellular immune response. Here, we describe the use of a new VSW-3 RNAP that reduced dsRNA production during IVT and the resulting mRNA exhibited low inflammatory stimulation in cells. Compared to T7 RNAP transcripts, these mRNA exhibited superior protein expression levels, with an average of 14-fold increase in Hela cells and 5-fold increase in mice. In addition, we found that VSW-3 RNAP did not require modified nucleotides to improve protein production of IVT products. Our data suggest that VSW-3 RNAP could be a useful tool for mRNA therapeutics.

Summary: The DSB machinery, which induces the programmed DNA double-strand breaks (DSBs) in the leptotene and zygotene stages during meiosis, is suppressed before the onset of the pachytene stage. However, the biological significance and underlying mechanisms remain largely unclear. Here, we report that ZFP541 is indispensable for the suppression of DSB formation after mid-pachytene. The deletion of Zfp541 in mice causes the aberrant recruitment of DSB machinery to chromosome axes and generation of massive DSBs in late pachytene and diplotene spermatocytes, leading to meiotic arrest at the diplotene stage. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data indicate that ZFP541 predominantly binds to promoters of pre-pachytene genes, including meiotic DSB formation-related genes (e.g., Prdm9 and Mei1) and their upstream activators (e.g., Meiosin and Rxra), and maintains their repression in pachytene spermatocytes. Our results reveal that ZFP541 functions as a transcriptional regulator in pachytene spermatocytes, orchestrating the transcriptome to ensure meiosis progression.

In recent years, the damage caused by soil nematodes has become increasingly serious; however, the varieties and structures of the nematicides available on the market are deficient. Fluopyram, a succinate dehydrogenase inhibitor (SDHI) fungicide developed by Bayer AG in Germany, has been widely used in the prevention and control of soil nematodes due to its high efficiency and novel mechanism of action. In this paper, two series of novel target compounds were designed and synthesized with nematicidal and fungicidal fluopyram as the molecular skeleton in order to introduce sulfide and sulfone substructures. The structures were identified and characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, and high-resolution mass spectrometer (HRMS). The bioassays revealed that most of the compounds showed excellent nematicidal activities at 200 µg·mL−1 in comparison with fluopyram, while the nematode mortality rate dropped sharply at 100 µg·mL−1, except for compounds I-11 and II-6. In terms of fungicidal activity, compound I-9 was discovered to have an excellent inhibitory rate, and a molecular docking simulation was performed that can provide important guidance for the design and exploration of efficient fungicidal lead compounds.

Background: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. Methods: We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. Findings: We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermre, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. Interpretation: We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel “seno-destructive” SMC phenotype could open new opportunities for managing BAV aortopathy. Fund: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair. Keywords: Bicuspid aortic valve, Aortic aneurysm, Smooth muscle cells, Cellular senescence, Collagenase

Chitobiose (OC)and chitotriose (TOC)were used to simulate the in vitro fermentation of feces samples from nonalcoholic fatty liver disease (NAFLD) patients to evaluate their effects on gut microorganisms and metabolites. The results indicated that OC and TOC shifted the gut microbial community of NAFLD patients to that of healthy volunteers. Specifically, OC and TOC increased the relative abundance of Fusobacteria, while reducing Actinobacteria and the ratio of Firmicutes to Bacteroidetes. OC's targeted bacteria were Fusobacterium, Clostridium sensu stricto 13 and Parabacteroides, while TOC's targeted bacteria were Clostridium sensu stricto 1, Enterococcus. The content of total short-chain fatty acids, propionic acid and butyric acid in the OC and TOC groups increased significantly, which was closely related to the increase in the abundance of the targeted flora. Although the non-targeted metabolites of OC and TOC had a high degree of similarity in the positive ion mode and a large difference in the negative ion mode. The up-regulated metabolites of the OC and TOC groups include bile acids (7-ketodeoxycholic acid, docosahexaenoic acid ethyl ester, deoxycholic acid, cholic acid), amino acids (succinyl proline, cys-tyr, L-β-leucine), antibiotics (fortimicin FU-10, kanoamine), and down-regulated metabolites include xanthine, hypoxanthine, L-glutamic acid, acetophenone, etc. The biomarker metabolites of OC and TOC may reveal the probiotic effect on gut microecological health on the biosynthesis of amino acids, butyric and bile acid metabolism pathways. The results can be helpful for the further development of COS as a functional food.

Summary: Critical limb ischemia (CLI) is a hazardous manifestation of atherosclerosis and treatment failure is common. Abnormalities in the arterioles might underlie this failure but the cellular pathobiology of microvessels in CLI is poorly understood. We analyzed 349 intramuscular arterioles in lower limb specimens from individuals with and without CLI. Arteriolar densities were 1.8-fold higher in CLI muscles. However, 33% of small (

Summary: Adipose tissue browning and systemic energy expenditure provide a defense mechanism against obesity and associated metabolic diseases. In high-cholesterol Western diet-fed mice, mast cell (MC) inactivation ameliorates obesity and insulin resistance and improves the metabolic rate, but a direct role of adipose tissue MCs in thermogenesis and browning remains unproven. Here, we report that adrenoceptor agonist norepinephrine-stimulated metabolic rate and subcutaneous adipose tissue (SAT) browning are enhanced in MC-deficient Kitw-sh/w-sh mice and MC-stabilized wild-type mice on a chow diet. MC reconstitution to SAT in Kitw-sh/w-sh mice blocks these changes. Mechanistic studies demonstrate that MC inactivation elevates SAT platelet-derived growth factor receptor A (PDGFRα+) adipocyte precursor proliferation and accelerates beige adipocyte differentiation. Using the tryptophan hydroxylase 1 (TPH1) inhibitor and TPH1-deficient MCs, we show that MC-derived serotonin inhibits SAT browning and systemic energy expenditure. Functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice. : Zhang et al. report that mast cell deficiency or pharmacological inhibition in mice increases subcutaneous adipose tissue (SAT) adipocyte browning and metabolic rate by increasing SAT PDGFRα+ adipocyte precursor proliferation and beige adipocyte differentiation. Mechanistic analysis demonstrates that MC-derived serotonin inhibits SAT browning and systemic energy expenditure. Keywords: mast cell, beige adipocyte, brown adipocyte, serotonin, subcutaneous adipose tissue, energy expenditure

Background: Progesterone can inhibit intestinal smooth muscle contraction; however, the specific mechanism remains unclear. Besides smooth muscle cells, smooth muscle has two important mesenchymal cells, namely interstitial cells of Cajal (ICC) and PDGFRα+ cells, which induce the contraction and relaxation of smooth muscles. We aimed to explore the regulation of PDGFRα+ cells and ICC in progesterone-mediated colon slow transit in pregnant mice. Methods: Colon transit experiments were performed in vivo and in vitro to observe slow colon transit. The expression of PDGFRα and c-KIT was detected by Western blot, RT-PCR, and immunofluorescence. An isometric tension experiment was performed to investigate smooth muscle contractions. Results: The colon transit time in pregnant mice was longer than that in non-pregnant mice. Progesterone significantly blocks colonic smooth muscle contractions. However, when the relaxation and contraction of PDGFRα+ cells and ICC are blocked, progesterone cannot inhibit smooth muscle contraction. When the function of only PDGFRα+ cells are blocked, progesterone has a more obvious inhibitory effect on smooth muscle in the non-pregnant group than that in the pregnant group. However, when ICC alone was blocked, progesterone inhibited smooth muscle contractions more clearly in pregnant mice. The protein and mRNA expression of PDGFRα was higher and c-KIT was lower in pregnant mice. PDGFRα+ cells and ICC from smooth muscle all co-localize progesterone receptors. Conclusions: Under the regulation of progesterone, the relaxation function of PDGFRα+ cells is enhanced and the contraction function of ICC is weakened, leading to the slow colon transit of pregnant mice.

In recent years, the application of Laser powder bed fusion (LPBF) technology in the manufacturing industry has become increasingly widespread. Compared to traditional casting processes, LPBF technology allows for the production of complex-shaped and structurally unique components made of 2507 duplex stainless steel (2507DSS), thus improving production efficiency and product quality. This article focuses on determining the LPBF parameters required for printing 2507DSS, successfully fabricating samples with a density of 98.71% and subjecting them to solution treatment followed by tensile testing. The results show that the LPBF-prepared samples exhibit a strength of 1173 MPa and an elongation of 18%. The presence of island-like structures enables excellent mechanical performance in the horizontal direction. The samples subjected to solution treatment at 1100 °C exhibit a strength of 860 MPa and an elongation of 45%. It is observed that when 2507DSS undergoes solution treatment from a single-phase state, the formation of large-angle grain boundaries and residual stresses within the austenite phase occurs, and a reasonable explanation is provided. Furthermore, the article conducts electrochemical tests on the samples. The results indicate that the LPBF-prepared samples possess the same electrochemical properties as the samples treated at 1100 °C, and both outperform the cast samples. Thus, this study reveals that the proportion of phases is not the sole determining factor for the corrosion resistance of DSS, providing valuable insights for the future development of more corrosion-resistant 2507DSS materials.

Objectives: This study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines. Methods: The Cochrane Library, Embase, PubMed, Web of Science, ClinicalKey, and other COVID-19 datasets were searched from December 2019 to May 2022. Case-control studies and prospective cohort studies of COVID-19 vaccine effectiveness and safety in pregnant women were included. Results: From day 11 to day 13, after the first dose of the COVID-19 messenger RNA vaccine, the effectiveness was 54% (95% confidence interval: 0.33-0.69). On days 14 to 27, the effectiveness was 59%. There was a 14% increase in vaccine effectiveness 28 days after the first dose was given. The inactivated vaccines showed similar effectiveness. The proportions of placental abruptions, postpartum hemorrhages, miscarriages, stillbirths, premature births, and small for gestational age infants were not significantly different between vaccinated and nonvaccinated pregnant women. Fatigue and fever were also not associated with pregnancy. Conclusion: Our findings affirm that the effectiveness varies for different types of vaccines and is significantly and positively correlated with time in the pregnant population. COVID-19 vaccines have also been deemed safe for pregnant women. Thus, we developed a comprehensive understanding of the role of vaccines in pregnant women.

It is important to quickly strengthen and repair earthquake-damaged buildings to restore the normal life after earthquake. Therefore, it is necessary to study the seismic performance of widely-used assembled buildings repaired with different approaches. In this paper, two different methods are designed to repair seismically damaged shear walls assembled with grouted sleeves. Based on different damage scenarios, the first method uses high-strength grout to replace damaged concrete, and the second method uses grout jacketing with reinforcement implantation and reinforcing mesh to enhance the damaged cross-section. The repaired walls are compared with the original walls on the damage mode, bearing capacity, ductility, energy dissipation capacity, and stiffness degradation. The test results verify that both repair methods can restore the load-bearing capacity of the assembled shear walls. Further, the seismic performance of the two repaired seismic-damaged shear walls with different axial pressure ratios is analyzed using finite element analysis. The seismic loss indices of the original assembled and the repaired shear walls are calculated using the Park-Ang two-parameter seismic damage model based on the results of the experimental studies and the finite element analysis.

Objectives: We sought to assess the incidence of hungry bone syndrome (HBS) following parathyroidectomy (PTX) for primary hyperparathyroidism (PHPT) in a cohort of multi-ethnic patients from a developed country in the Asia Pacific. Methods: One hundred and sixty-four patients who underwent PTX for PHPT between 2012 and 2019 at the 2 largest public hospitals in Singapore were identified. HBS was defined as serum albumin-adjusted calcium ≤ 2.1 mmol/L with normal or raised serum intact parathyroid hormone (iPTH) levels, manifesting on or after the 3rd day, or persisting for more than 3 days post-operatively. Results: Chinese constituted 73.8%, Malays 12.2%, Indians 9.8%, and other races 4.3%. HBS developed in 4 patients (2.4%) (95% CI, 0.8%–6.5%). HBS patients had significantly longer in-hospital stays; 20 days [IQR:15–22] vs 2 days [IQR:1–3]; P

Graphene/hexagonal boron nitride (h-BN) heterostructures have attracted a lot of research interests due to their superior electronic properties in field effect transistor devices and the novel physical properties such as fractional fractal quantum hall effect and massive Dirac fermions. Chemical vapor deposition (CVD) is the most common method to synthesize h-BN and graphene, however, the directly growth of graphene/h-BN heterostructures remains challenging. Here we report the crucial impact of hydrogen on the nucleation density, growth rate and etching rate in the h-BN CVD growth. It is found that the nucleation density increases monotonically, whereas the growth rate and etching rate first increases and then decreases with the increasing hydrogen partial pressure. Benefitting from the understanding of the crucial role of hydrogen, we successfully grow the graphene/h-BN vertical heterostructures by low pressure CVD in one-pot through the modulation of hydrogen partial pressure. The field effect transistor (FET) fabricated using graphene/h-BN heterostructure shows better performance with higher carrier mobility and lower level of doping than the one without h-BN. Our direct synthesis approach paves a new pathway for large-scale production of graphene/h-BN heterostructures and could be applied for the synthesis of other van der Waals heterostructures.

Objective: c-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood. Methods: We generated liver-specific c-Jun knock-out (c-jun△li) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature. Primary hepatocytes were also used to explore a direct regulation of c-Jun in gluconeogenesis. Results: c-jun△li mice showed higher hepatic gluconeogenic capacity compared with control mice, and similar results were obtained in vitro. In addition, fibroblast growth factor 21 (FGF21) expression was directly inhibited by c-Jun knockdown and adenovirus-mediated hepatic FGF21 over-expression blocked the effect of c-Jun on gluconeogenesis in c-jun△li mice. Interestingly, c-jun△li mice also exhibited higher body temperature, with induced thermogenesis and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). Furthermore, the body temperature became comparable between c-jun△li and control mice at thermoneutral temperature (30 °C). Moreover, the activity of sympathetic nervous system (SNS) was increased in c-jun△li mice and the higher body temperature was inhibited by beta-adrenergic receptor blocker injection. Finally, the activated SNS and increased body temperature in c-jun△li mice was most likely caused by the signals from the brain and hepatic vagus nerve, as the expression of c-Fos (the molecular marker of neuronal activation) was changed in several brain areas controlling body temperature and body temperature was decreased by selective hepatic vagotomy. Conclusions: These data demonstrate a novel function of hepatic c-Jun in the regulation of gluconeogenesis and body temperature via FGF21 and neural signals. Our results also provide novel insights into the organ crosstalk in the regulation of the whole-body physiology. Keywords: Gluconeogenesis, Temperature, Organ crosstalk

Objective: Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders. Methods: We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice. Intracerebroventricular (ICV) cannulation of insulin was used to test the hypothalamic insulin sensitivity in the mice. Hypothalamic primary neurons were used to investigate the mechanism of Smad7 regulating hypothalamic insulin signaling. Results: We found that Smad7 expression was increased in POMC neurons in the hypothalamic ARC of HFD-fed or middle-aged mice. Furthermore, overexpression of Smad7 in POMC neurons disrupted the glucose balance, and deletion of Smad7 in POMC neurons prevented diet- or age-induced glucose disorders, which was likely to be independent of changes in body weight or food intake. Moreover, the effect of Smad7 was reversed by overexpression of AKT in the ARC. Finally, Smad7 decreased AKT phosphorylation by activating protein phosphatase 1c in hypothalamic primary neurons. Conclusions: Our results demonstrated that an excess of central Smad7 in POMC neurons disrupts glucose balance by attenuating hypothalamic insulin signaling. In addition, we found that this regulation was mediated by the activity of protein phosphatase 1c.

Introduction and aim. Salidroside and curcumin (SC) formula could alleviate lipid deposition in high fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the mechanisms are still unknown, and the magnitude of potential therapeutic benefit remains understudied.Material and methods. The rats were treated with high fat diet for 14 weeks to induce NAFLD. The experiment was divided into control, model (NAFLD), SC formula and rosiglitazone groups (n = 7 in each group). Hematoxylin-eosin (H&E) staining was applied to detect liver morphological changes. Biochemical, metabolic indices and inflammation factors in liver tissue and serum were detected. Additionally, the activities of related enzymes were detected by enzyme-linked immunosorbent assay.Results. In the established rat model, typical lipid deposition and liver steatosis were observed. Liver triglyceride, free fatty acids, sera alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, fasting insulin, fasting blood glucose and homeostasis model assessment of insulin resistance were elevated in model group. Liver malondialdehyde was significantly elevated, while superoxide dismutase was significantly decreased in model group, compared with control. Moreover, tumor necrosis factor-α and Interleukin-1 were significantly prod uced in model group, compared with control. As a mechanism, high fat diet decreased tissue AMP-activated protein kinase (AMPK), phosphorylated AMPK, carnitine palmitoyltransferase 1 and increased inacetyl-CoA carboxylase (ACCase), phosphorylated ACCase. Importantly, these abnormal changes caused by high fat diet were reduced by SC formula administration.Conclusion. SC formula could ameliorate the injury caused by high fat diet. The effect was likely mediated via its influence on insulin resistance, lipid peroxidation injury and AMPK signaling pathway.

Background: Twin growth discordance is one of the leading causes of perinatal mortality in twin pregnancies. Whether prenatal exposure to fine particle (PM2.5) air pollution is associated with twin growth discordance have not been studied yet. Objective: To evaluate the associations of prenatal exposure to PM2.5 and its chemical constituents with twin growth discordance. Methods: This study included 1917 twin pairs and their mothers drawn from a previous twin birth cohort at the Shanghai First Maternity and Infant hospital in Shanghai, China. Exposure to PM2.5 total mass and 6 key chemical constituents during the whole pregnancy and each trimester of pregnancy was represented by satellite-based models. Results: Maternal exposures to PM2.5 total mass and chemical constituents of sulfate (SO42−) and ammonium (NH4+) during the third trimester were significantly associated with increased within-pair birth weight difference and intertwin birth weight discordance. The within-pair birth weight difference increased by 30.6 g (β = 30.6, 95% CI, 4.4–56.9), 19.2 g (β = 19.2, 95% CI, 0.2–38.1) and 33.2 g (β = 33.2, 95% CI, 7.9–58.6) for an IQR increase in PM2.5 total mass, SO42− and NH4+ exposure, respectively. While the intertwin birth weight discordance increased by 1.3% (β = 1.3, 95% CI, 0.3–2.2), 0.9% (β = 0.9, 95% CI, 0.2–1.6) and 1.4% (β = 1.4, 95% CI, 0.4–2.3) for the same exposure metrics. Moreover, higher SO42− and NH4+ exposure was also associated with increased risk of twin growth discordance in linear dose-response manners. Compared to the lowest quartile of SO42− (OR = 2.51, 95% CI, 1.08–5.82) and NH4+ (OR = 2.97, 95% CI, 1.16–7.58) exposure, the odds of twin growth discordance were doubled in highest quartile of exposure. Conclusion: Our results suggest that fine particle air pollution may be a risk factor for twin growth discordance. Late pregnancy seems to be a critical window for the effects of PM2.5 exposure on fetal growth in twins. Keywords: Ambient air pollution, PM2.5, Chemical constituents, Within-pair birth weight difference, Twin growth discordance

Summary: Hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) offer a promising cell resource for disease modeling and transplantation. However, differentiated HLCs exhibit an immature phenotype and comprise a heterogeneous population. Thus, a better understanding of HLC differentiation will improve the likelihood of future application. Here, by taking advantage of CRISPR-Cas9-based genome-wide screening technology and a high-throughput hPSC screening platform with a reporter readout, we identified several potential genetic regulators of HLC differentiation. By using a chemical screening approach within our platform, we also identified compounds that can further promote HLC differentiation and preserve the characteristics of in vitro cultured primary hepatocytes. Remarkably, both screenings identified histone deacetylase 3 (HDAC3) as a key regulator in hepatic differentiation. Mechanistically, HDAC3 formed a complex with liver transcriptional factors, e.g., HNF4, and co-regulated the transcriptional program during hepatic differentiation. This study highlights a broadly useful approach for studying and optimizing hPSC differentiation. : Ding and colleagues developed a broadly useful approach to study novel regulators involved in hepatic differentiation of human pluripotent stem cells, with a combination of reporter system construction, genome-wide CRISPR-Cas9-based genetic screening, and targeted chemical screening. Studies revealed HDAC3 as a key regulator in hepatic lineage determination. Keywords: human pluripotent stem cells, hepatic differentiation, genome-wide CRISPR/Cas9 screening, histone deacetylase 3, histone deacetylase inhibitor CI-994

Fibrosis is common after skeletal muscle injury, undermining tissue regeneration and function. The mechanism underlying skeletal muscle fibrosis remains unveiled. Transforming growth factor-β/Smad signaling pathway is supposed to play a pivotal role. However, how microRNAs interact with transforming growth factor-β/Smad-related muscle fibrosis remains unclear. We showed that microRNA (miR)-24-3p and miR-122-5p declined in skeletal muscle fibrosis, which was a consequence of transforming growth factor-β. Upregulating Smad4 suppressed two microRNAs, whereas inhibiting Smad4 elevated microRNAs. Luciferase reporter assay and chromatin immunoprecipitation confirmed that Smad4 directly inhibited two microRNAs. On the other hand, overexpression of these two miRs retarded fibrotic process. We further identified that Smad2 was a direct target of miR-24-3p, whereas miR-122-5p targeted transforming growth factor-β receptor-II. Both targets were important participants in transforming growth factor-β/Smad signaling. Taken together, a positive feedback loop in transforming growth factor-β/Smad4 signaling pathway in skeletal muscle fibrosis was identified. Transforming growth factor-β/Smad axis could be downregulated by microRNAs. This effect, however, was suppressed by Smad4, the downstream of transforming growth factor-β.

Cognitive decline is common and increases mortality risk in hemodialysis patients. Intradialytic interventions like cognitive training (CT) and exercise training (ET) may preserve cognitive function. Methods: We conducted a pilot randomized controlled trial of 20 hemodialysis patients to study the impact of 3 months of intradialytic CT (tablet-based brain games) (n = 7), ET (foot peddlers) (n = 6), or standard of care (SC) (n = 7) on cognitive function. Global cognitive function was measured by the Modified Mini Mental Status Exam (3MS), psychomotor speed was measured by Trail Making Tests A and B (TMTA and TMTB), and executive function was assessed by subtracting (TMTB − TMTA). Lower 3MS scores and slower TMTA and TMTB times reflected worse cognitive function. P values for differences were generated using analysis of variance, and 95% confidence intervals (CIs) and P values were generated from linear regression. Results: Patients with SC experienced a decrease in psychomotor speed and executive function by 3 months (TMTA: 15 seconds; P = 0.055; TMTB: 47.4 seconds; P = 0.006; TMTB − TMTA; 31.7 seconds; P = 0.052); this decline was not seen among those with CT or ET (all P > 0.05). Compared with SC, the difference in the mean change in 3MS score was −3.29 points (95% CI: −11.70 to 5.12; P = 0.42) for CT and 4.48 points (95% CI: −4.27 to 13.22; P = 0.30) for ET. Compared with SC, the difference in mean change for TMTA was −15.13 seconds (95% CI: −37.64 to 7.39; P = 0.17) for CT and −17.48 seconds (95% CI: −41.18 to 6.22; P = 0.14) for ET, for TMTB, the difference was −46.72 seconds (95% CI: −91.12 to −2.31; P = 0.04) for CT and −56.21 seconds (95% CI: −105.86 to −6.56; P = 0.03) for ET, and for TMTB – TMTA, the difference was −30.88 seconds (95% CI: −76.05 to 14.28; P = 0.16) for CT and −34.93 seconds (95% CI: −85.43 to 15.56; P = 0.16) for ET. Conclusion: Preliminary findings of our pilot study suggested that cognitive decline in psychomotor speed and executive function is possibly prevented by intradialytic CT and ET. These preliminary pilot findings should be replicated.

RIPK3 mediates cell death and regulates inflammatory responses. Although genetic studies have suggested that RIPK3-MLKL-mediated necroptosis leads to embryonic lethality in Fadd or Caspase-8-deficient mice, the exact mechanisms are not fully understood. Here, we generated Ripk3 mutant mice by altering the RIPK3 kinase domain (Ripk3Δ/Δ mice), thus abolishing its kinase activity. Ripk3Δ/Δ cells were resistant to necroptosis stimulation in vitro, and Ripk3Δ/Δ mice were protected from necroptotic diseases. Although the Ripk3Δ/Δ mutation rescued embryonic lethality in Fadd−/− embryos, Fadd−/− Ripk3Δ/Δ mice died within 1 day after birth due to massive inflammation. These results indicate that Ripk3 ablation rescues embryonic lethality in Fadd-deficient mice by suppressing two RIPK3-mediating processes: necroptosis during embryogenesis and inflammation during postnatal development in Fadd−/− mice.

Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

Introduction: Early enteral nutrition (EN) is a nutritional strategy for reducing the incidence of in-hospital infections. However, the benefits of early EN, under targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA), remain unclear. We aimed to evaluate the effect of early EN on the infective complications of OHCA patients who underwent TTM. Methods: We retrospectively searched the clinical databases of two adult emergency tertiary referral hospitals in southern Taiwan and identified patients admitted for OHCA who underwent TTM between 2017 and 2022. The 85 enrolled patients were divided into two groups based on timing: early EN (EN within 48 h of admission) and delayed EN (EN > 48 h after admission). Clinical outcomes of 7-day infective complications between the two groups were analyzed. Results: Early EN was provided to 57 (67 %) of 85 patients and delayed EN was provided to the remaining 28 (33 %) patients. No significant differences in baseline patient characteristics were observed between the two groups. In addition, no differences in clinical outcomes were observed, except that the early EN group had a lower 7-day bacteremia rate (5.3 % vs. 26.9 %, p = 0.013). Gram-negative bacteria were the major pathogen among the 7-day infective complications. Conclusion: In OHCA patients treated with TTM, early EN was associated with a lower 7-day bacteremia rate. Furthermore, the application of early EN in this population was well tolerated without significant adverse events.

Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for Duchenne muscular dystrophy (DMD) patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the serum levels of six muscle-specific miRNAs (miR-1/206/133/499/208a/208b, also known as myomiRs) were all elevated in DMD patients (P < 0.01). The receiver operating characteristic curves of circulating miR-206, miR-499, miR-208b, and miR-133 levels reflected strong separation between Becker's muscular dystrophy (BMD) and DMD patients (P < 0.05). miR-206, miR-499, and miR-208b levels were positively correlated with both age and type IIc muscle fiber content in DMD patients (2–6 years), indicating that they might represent the stage of disease as well as the process of regeneration. miR-499 and miR-208b levels were correlated with slow and fast fiber content and might reflect the ratio of slow to fast fibers in DMD patient (>6 years). Fibroblast growth factor, transforming growth factor-β, and tumor necrosis factor-α could affect the secretion of myomiRs, suggesting that circulating myomiRs might reflect the effects of cytokines and growth factors on degenerating and regenerating muscles. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for DMD diagnosis and disease progression.

Background: This study aimed to compare the efficacy of mycophenolic acid (MPA) and cyclophosphamide (CYC) for treating pediatric lupus nephritis (pLN). Methods: Data on patients with pLN class III, IV, and V, diagnosed by renal biopsy, were collected from the Databank of Kaohsiung Veterans General Hospital between February 2005 and December 2020. The study included 31 pLN patients. Of these, 15 received MPA (MPA group) and 16 received CYC (CYC group). Systemic lupus erythematosus disease activity index score, laboratory findings, complete remission (CR), and partial remission (PR) were assessed at 6, 12, and 24 months. Results: In the MPA group, CR occurred in 7/15 (47%) patients at month 6 and in 11/15 (73%) at months 12 and 24. In the CYC group, CR was reached in 5/16 (31%) patients at month 6, in 8/16 (50%) at month 12, and in 9/16 (56%) at month 24. PR was seen in 3/15 (20%) patients in the MPA group and in 3/16 (19%) in the CYC group at month 24. The cumulative probability of CR and PR showed no statistically significant difference between the two groups. However, the estimated glomerular filtration rate (eGFR) improved significantly in the MPA group at months 6, 12 and 24 compared to that in the CYC group (p

Importance: Previous investigations have found that time to positive blood culture (TTP) is a prognostic factor for clinical outcomes. In fact, what the emergency physician sees from the medical information system is TAT (turnaround time) defined as time required to post a bacterial culture report. We propose a definition of blood culture TAT that more closely aligns with clinical considerations by measuring the time from starting specimen culture to the release of an official blood culture report.We were curious to know whether the duration of TAT is as intricately linked to the prognosis of bacteremia as TTP. Objectives: To examine the association between TAT and outcomes of adult patients who present to the ED with community acquired bacteremia. Design: Setting, and Participants: This retrospective study utilized electronic medical records from Kaohsiung Veterans General Hospital (KVGH), a 1000-bed tertiary medical center in Taiwan. Patients were adults aged 18 years and older who presented to ED (Emergency department) for initial diagnosis of community acquired bacteremia from January 1, 2016 to March 31, 2021. Data analysis was performed from December 2022 to January 2023.Main outcomes and measures.The primary outcomes included mortality in the ED, all-cause in-hospital mortality, length of hospital stay, and all-cause 30-day mortality in relation to the individual first report of positive blood culture TAT. Results: A total of 4011 eligible patients with bacteremia were evaluated, of which 207 patients had a blood culture TAT of ≤48 h. The overall 30-day all-cause mortality rate was 13%. Contrary to expectation, no statistically significant differences were observed in clinical prognosis between the TAT groups (≤48 versus >48 h). Subgroup analyses indicated that the length of TAT did not have a significant effect on clinical prognosis in patients who underwent lactate level assessment. Furthermore, no difference in clinical outcome was noted between TAT groups (≤48 versus >48 h) in terms of Gram-negative bacilli or Gram-positive cocci bacteremia. However, in patients with delayed antibiotic treatment (>3 h), a shorter TAT was significantly associated with a fatal outcome. Conclusion: In adults with community-acquired bacteremia, this study did not observe a significant association between blood culture TAT and clinical prognosis, except in cases of delayed antibiotic treatment.

Background: Aminophylline use and the association between clinical outcomes and therapy timing have been less investigated. The objective of this study was to determine the efficacy of early aminophylline use (within the first two days of life) in premature infants. Method: A retrospective observational cohort of infants weighing

Background: Serious bacterial infections (SBIs) could lead to mortality or severe long-term sequelae in neonates and infants aged 2.5 mg/dL, and pyuria were associated with an increased risk of SBIs. Accordingly, these four factors were used to develop a nomogram for SBI prediction, which exhibited significantly high performance (area under curve = 0.848, p < 0.001) in predicting SBI risk. Conclusion: We developed a nomogram combining clinical appearance, serum myelocyte/metamyelocyte presence, CRP, and pyuria for predicting SBI risk in febrile neonates. This tool can assist clinicians in making early diagnoses and delivering the appropriate treatment.

Background: For risk stratification and individualized treatment for children with urinary tract infection (UTI), they must be assessed for the presence of acute pyelonephritis (APN). Our study aimed to combine variables that can predict APN and establish a nomogram for clinical use. Methods: In total, 111 children 39 °C, serum procalcitonin (PCT) ≥ 0.52 pg/mL, C-reactive protein (CRP) ≥ 2.86 mg/dL, and abnormal RUBS findings were independent variables for predicting APN in children. The nomogram established using the aforementioned variables had an area under the receiver operating characteristic curve (AUC) of 0.89, which was higher than those of PCT and CRP alone (0.776 and 0.774, respectively). Conclusion: The combination of four variables had the highest power in predicting APN in children with UTI. The established nomogram is practical for clinical use.

Summary: Background: Identifying patients with clinically significant prostate cancer (csPCa) before biopsy helps reduce unnecessary biopsies and improve patient prognosis. The diagnostic performance of traditional transrectal ultrasound (TRUS) for csPCa is relatively limited. This study was aimed to develop a high-performance convolutional neural network (CNN) model (P-Net) based on a TRUS video of the entire prostate and investigate its efficacy in identifying csPCa. Methods: Between January 2021 and December 2022, this study prospectively evaluated 832 patients from four centres who underwent prostate biopsy and/or radical prostatectomy. All patients had a standardised TRUS video of the whole prostate. A two-dimensional CNN (2D P-Net) and three-dimensional CNN (3D P-Net) were constructed using the training cohort (559 patients) and tested on the internal validation cohort (140 patients) as well as on the external validation cohort (133 patients). The performance of 2D P-Net and 3D P-Net in predicting csPCa was assessed in terms of the area under the receiver operating characteristic curve (AUC), biopsy rate, and unnecessary biopsy rate, and compared with the TRUS 5-point Likert score system as well as multiparametric magnetic resonance imaging (mp-MRI) prostate imaging reporting and data system (PI-RADS) v2.1. Decision curve analyses (DCAs) were used to determine the net benefits associated with their use. The study is registered at https://www.chictr.org.cn with the unique identifier ChiCTR2200064545. Findings: The diagnostic performance of 3D P-Net (AUC: 0.85–0.89) was superior to TRUS 5-point Likert score system (AUC: 0.71–0.78, P = 0.003–0.040), and similar to mp-MRI PI-RADS v2.1 score system interpreted by experienced radiologists (AUC: 0.83–0.86, P = 0.460–0.732) and 2D P-Net (AUC: 0.79–0.86, P = 0.066–0.678) in the internal and external validation cohorts. The biopsy rate decreased from 40.3% (TRUS 5-point Likert score system) and 47.6% (mp-MRI PI-RADS v2.1 score system) to 35.5% (2D P-Net) and 34.0% (3D P-Net). The unnecessary biopsy rate decreased from 38.1% (TRUS 5-point Likert score system) and 35.2% (mp-MRI PI-RADS v2.1 score system) to 32.0% (2D P-Net) and 25.8% (3D P-Net). 3D P-Net yielded the highest net benefit according to the DCAs. Interpretation: 3D P-Net based on a prostate grayscale TRUS video achieved satisfactory performance in identifying csPCa and potentially reducing unnecessary biopsies. More studies to determine how AI models better integrate into routine practice and randomized controlled trials to show the values of these models in real clinical applications are warranted. Funding: The National Natural Science Foundation of China (Grants 82202174 and 82202153), the Science and Technology Commission of Shanghai Municipality (Grants 18441905500 and 19DZ2251100), Shanghai Municipal Health Commission (Grants 2019LJ21 and SHSLCZDZK03502), Shanghai Science and Technology Innovation Action Plan (21Y11911200), and Fundamental Research Funds for the Central Universities (ZD-11-202151), Scientific Research and Development Fund of Zhongshan Hospital of Fudan University (Grant 2022ZSQD07).

Summary: Previous studies have explored the role of laparoscopic surgery (LS) in the surgical management of gallbladder carcinoma (GBC) and obtained satisfactory outcomes versus conventional open surgery. However, most of them either included a small number of patients or mainly focused on the early-staged lesions. Therefore, their results were less statistical powerful and a more comprehensive evaluation on the role of LS in GBC is warranted. A thorough database searching was performed in PubMed, EMBASE and Cochrane Library for comparative studies between the laparoscopic and open approach in the surgical management of GBC and 18 comparative studies were finally identified. RevMan 5.3 and Stata 13.0 software were used for statistical analyses. Pooled results revealed that patients in the laparoscopic group recovered faster with less intraoperative hemorrhage and less postoperative morbidity. Comparable operative time, overall recurrence rate, R0 resection rate, lymph node yield, intraoperative gallbladder violation rate and postoperative survival outcomes were also acquired. Regarding the debating issue of port-site recurrence, a significantly higher incidence of port-site recurrence was observed in laparoscopic group. However, having excluded studies on incidental gallbladder carcinoma, the subsequent pooled result showed no significant difference. Considering the inherent inconsistency of the surgical indication between laparoscopic and open surgeries and the deficiency of advanced lesions, we drew a conclusion that laparoscopic surgery seems to be only safe and feasible for early- or middle-staged lesions. Upcoming random controlled trials or comparative studies with equivalent surgical indication focused on advanced lesions are warranted for further evaluation.

Background: Preoperative determination of breast cancer molecular subtypes facilitates individualized treatment plan-making and improves patient prognosis. We aimed to develop an assembled convolutional neural network (ACNN) model for the preoperative prediction of molecular subtypes using multimodal ultrasound (US) images. Methods: This multicentre study prospectively evaluated a dataset of greyscale US, colour Doppler flow imaging (CDFI), and shear-wave elastography (SWE) images in 807 patients with 818 breast cancers from November 2016 to February 2021. The St. Gallen molecular subtypes of breast cancer were confirmed by postoperative immunohistochemical examination. The monomodal ACNN model based on greyscale US images, the dual-modal ACNN model based on greyscale US and CDFI images, and the multimodal ACNN model based on greyscale US and CDFI as well as SWE images were constructed in the training cohort. The performances of three ACNN models in predicting four- and five-classification molecular subtypes and identifying triple negative from non-triple negative subtypes were assessed and compared. The performance of the multimodal ACNN was also compared with preoperative core needle biopsy (CNB). Finding: The performance of the multimodal ACNN model (macroaverage area under the curve [AUC]: 0.89–0.96) was superior to that of the dual-modal ACNN model (macroaverage AUC: 0.81–0.84) and the monomodal ACNN model (macroaverage AUC: 0.73–0.75) in predicting four-classification breast cancer molecular subtypes, which was also better than that of preoperative CNB (AUC: 0.89–0.99 vs. 0.67–0.82, p