Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins.

The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.

Mouse models susceptible to HCoV-229E and HCoV-NL63 and cross protection from challenge with SARS-CoV-2.

Human coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63) are endemic causes of upper respiratory infections such as the "common cold" but may occasionally cause severe lower respiratory tract disease in the elderly and immunocompromised patients. There are no approved antiviral drugs or vaccines for these common cold coronaviruses (CCCoV). The recent emergence of COVID-19 and the possible cross-reactive antibody and T cell responses between these CCCoV and SARS-CoV-2 emphasize the need to develop experimental animal models for CCCoV. Mice are an ideal experimental animal model for such studies, but are resistant to HCoV-229E and HCoV-NL63 infections. Here, we generated 229E and NL63 mouse models by exogenous delivery of their receptors, human hAPN and hACE2 using replication-deficient adenoviruses (Ad5-hAPN and Ad5-hACE2), respectively. Ad5-hAPN- and Ad5-hACE2-sensitized IFNAR-/- and STAT1-/- mice developed pneumonia characterized by inflammatory cell infiltration with virus clearance occurring 7 d post infection. Ad5-hAPN- and Ad5-hACE2-sensitized mice generated virus-specific T cells and neutralizing antibodies after 229E or NL63 infection, respectively. Remdesivir and a vaccine candidate targeting spike protein of 229E and NL63 accelerated viral clearance of virus in these mice. 229E- and NL63-infected mice were partially protected from SARS-CoV-2 infection, likely mediated by cross-reactive T cell responses. Ad5-hAPN- and Ad5-hACE2-transduced mice are useful for studying pathogenesis and immune responses induced by HCoV-229E and HCoV-NL63 infections and for validation of broadly protective vaccines, antibodies, and therapeutics against human respiratory coronaviruses including SARS-CoV-2.

Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure.

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.

Oxygen-Vacancy-Reinforced Vanadium Oxide/Graphene Heterojunction for Accelerated Zinc Storage with Long Life Span.

Vanadium trioxide (V6 O13 ) cathode has recently aroused intensive interest for aqueous zinc-ion batteries (AZIBs) due to their structural and electrochemical diversities. However, it undergoes sluggish reaction kinetics and significant capacity decay during prolonged cycling. Herein, an oxygen-vacancy-reinforced heterojunction in V6 O13- x /reduced graphene oxide (rGO) cathode is designed through electrostatic assembly and annealing strategy. The abundant oxygen vacancies existing in V6 O13- x weaken the electrostatic attraction with the inserted Zn2+ ; the external electric field constructed by the heterointerfaces between V6 O13- x and rGO provides additional built-in driving force for Zn2+ migration; the oxygen-vacancy-enriched V6 O13- x highly dispersed on rGO fabricates the interconnected conductive network, which achieves rapid Zn2+ migration from heterointerfaces to lattice. Consequently, the obtained 2D heterostructure exhibits a remarkable capacity of 424.5 mAh g-1 at 0.1 A g-1 , and a stable capacity retention (96% after 5800 cycles) at the fast discharge rate of 10 A g-1 . Besides, a flexible pouch-type AZIB with real-life practicability is fabricated, which can successfully power commercial products, and maintain stable zinc-ion storage performances even under bending, heavy strikes, and pressure condition. A series of quantitative investigation of pouch batteries demonstrates the possibility of pushing pouch-type AZIBs to realistic energy storage market.

Small Extracellular Vesicles From Brown Adipose Tissue Mediate Exercise Cardioprotection.

RATIONALE: Long-term exercise provides reliable cardioprotection via mechanisms still incompletely understood. Although traditionally considered a thermogenic tissue, brown adipose tissue (BAT) communicates with remote organs (eg, the heart) through its endocrine function. BAT expands in response to exercise, but its involvement in exercise cardioprotection remains undefined. OBJECTIVE: This study investigated whether small extracellular vesicles (sEVs) secreted by BAT and their contained microRNAs (miRNAs) regulate cardiomyocyte survival and participate in exercise cardioprotection in the context of myocardial ischemia/reperfusion (MI/R) injury. METHODS AND RESULTS: Four weeks of exercise resulted in a significant BAT expansion in mice. Surgical BAT ablation before MI/R weakened the salutary effects of exercise. Adeno-associated virus 9 vectors carrying short hairpin RNA targeting Rab27a (a GTPase required for sEV secretion) or control viruses were injected in situ into the interscapular BAT. Exercise-mediated protection against MI/R injury was greatly attenuated in mice whose BAT sEV secretion was suppressed by Rab27a silencing. Intramyocardial injection of the BAT sEVs ameliorated MI/R injury, revealing the cardioprotective potential of BAT sEVs. Discovery-driven experiments identified miR-125b-5p, miR-128-3p, and miR-30d-5p (referred to as the BAT miRNAs) as essential BAT sEV components for mediating cardioprotection. BAT-specific inhibition of the BAT miRNAs prevented their upregulation in plasma sEVs and hearts of exercised mice and attenuated exercise cardioprotection. Mechanistically, the BAT miRNAs cooperatively suppressed the proapoptotic MAPK (mitogen-associated protein kinase) pathway by targeting a series of molecules (eg, Map3k5, Map2k7, and Map2k4) in the signaling cascade. Delivery of BAT sEVs into hearts or cardiomyocytes suppressed MI/R-related MAPK pathway activation, an effect that disappeared with the combined use of the BAT miRNA inhibitors. CONCLUSIONS: The sEVs secreted by BAT participate in exercise cardioprotection via delivering the cardioprotective miRNAs into the heart. These results provide novel insights into the mechanisms underlying the BAT-cardiomyocyte interaction and highlight BAT sEVs and their contained miRNAs as alternative candidates for exercise cardioprotection.

Global burden of diabetes mellitus from 1990 to 2019 attributable to dietary factors: An analysis of the Global Burden of Disease Study 2019.

AIMS: To analyse spatial and temporal changes in the global burden of diabetes mellitus (DM) attributable to dietary factors from 1990 to 2019. MATERIALS AND METHODS: The burden of DM was analysed in terms of age-standardized disability-adjusted life-year (DALY) rates and age-standardized death rates (ASDRs), which were obtained from the Global Burden of Disease Study 2019, and their corresponding estimated annual percentage changes (EAPCs). RESULTS: The ASDR exhibited a decreasing trend (EAPC = -0.02), while the age-standardized DALY rate exhibited an increasing trend (EAPC = 0.65). Forty-four percent of the burden of DM was attributable to dietary factors, with the three largest contributors being high intake of red meat, high intake of processed meat, and low intake of fruit. Residence in a region with a high sociodemographic index (SDI) was associated with a diet low in whole grains and high in red meat and processed meat, while residence in a low-SDI region was associated with a diet low in whole grains and fruits, and high in red meat. CONCLUSIONS: The age-standardized DALYs of DM attributable to dietary factors increased between 1990 and 2019 but differed among areas. The three largest dietary contributors to the burden of DM were high intake of red meat, high intake of processed meat, and low intake of fruit.

Epithelial thickness remodeling after small incision lenticule intrastromal keratoplasty in correcting hyperopia measured by RTVue OCT.

PURPOSE: To characterize the in vivo corneal epithelial thickness (CET) remodeling profile in a population of eyes after small incision lenticule intrastromal keratoplasty (SMI-LIKE) for hyperopia. METHODS: The CET profile was measured by RTVue-100 Fourier-domain OCT system across the central 6-mm diameter of the cornea of 17 eyes from 12 subjects (five males and seven females) who accepted corneal stromal lens implantation surgery for correcting hyperopia. The CET were measured at positions with a radius of 0-1.0 mm, 1.0-2.5 mm (divided into eight quadrants) and 2.5-3.0 mm (divided into eight quadrants) from the corneal center. Corneal maximum simulated keratometry (Km) was measured by Pentacam HR anterior segment analyzer to analyze CET changes. The examination data of subjects were collected in four time periods, which were preoperative, short-term postoperative (one week after surgery), mid-term postoperative (the last review within 3-6 months after surgery), and long-term postoperative (the last review over 1-2.5 years after surgery). The changes of CET were compared and analyzed in the four time periods. RESULTS: Mean CET in 0-1.0 mm, 1.0-2.5 mm and 2.5-3.0 mm of the cornea decreased in one week after surgery, respectively, as compared to CET in the preoperative period, which turned from 55.06 ± 0.82 µm、54.42 ± 0.75 µm、53.46 ± 0.60 µm to 51.18 ± 1.05 µm (P = 0.005), 49.38 ± 0.70 µm (P = 0.000), 51.29 ± 0.59 µm (P = 0.025). In the mid-term postoperative period, mean CET in 0-1.0 mm and 1.0-2.5 mm areas kept thinner than mean CET in the preoperative period, CET in 0-1.0 mm is 50.59 ± 0.76 µm (P = 0.000),CET in 1.0-2.5 mm is 50.23 ± 0.57 µm (P = 0.000), while mean CET in 2.5-3.0 mm area recovered to the same thickness as the preoperative level, which is 54.36 ± 0.66 µm (P = 1.000), until the long-term period, CET stabilized in the above doughnut pattern. CONCLUSIONS: After stromal lenticule implantation for hyperopia, CET showed a remodeled form of thinning in the 0-2.5 mm area and thickening in the 2.5-3.0 mm area, and remained stable within one year after surgery.

Blocking the utilization of carbon sources via two pathways to induce tumor starvation for cancer treatment.

Glucose oxidase (GOx) is often used to starvation therapy. However, only consuming glucose cannot completely block the energy metabolism of tumor cells. Lactate can support tumor cell survival in the absence of glucose. Here, we constructed a nanoplatform (Met@HMnO2-GOx/HA) that can deplete glucose while inhibiting the compensatory use of lactate by cells to enhance the effect of tumor starvation therapy. GOx can catalyze glucose into gluconic acid and H2O2, and then HMnO2 catalyzes H2O2 into O2 to compensate for the oxygen consumed by GOx, allowing the reaction to proceed sustainably. Furthermore, metformin (Met) can inhibit the conversion of lactate to pyruvate in a redox-dependent manner and reduce the utilization of lactate by tumor cells. Met@HMnO2-GOx/HA nanoparticles maximize the efficacy of tumor starvation therapy by simultaneously inhibiting cellular utilization of two carbon sources. Therefore, this platform is expected to provide new strategies for tumor treatment.

The adaptive evolution of Euryale ferox to the aquatic environment through paleo-hexaploidization.

Occupation of living space is one of the main driving forces of adaptive evolution, especially for aquatic plants whose leaves float on the water surface and thus have limited living space. Euryale ferox, from the angiosperm basal family Nymphaeaceae, develops large, rapidly expanding leaves to compete for space on the water surface. Microscopic observation found that the cell proliferation of leaves is almost completed underwater, while the cell expansion occurs rapidly after they grow above water. To explore the mechanism underlying the specific development of leaves, we performed sequences assembly and analyzed the genome and transcriptome dynamics of E. ferox. Through reconstruction of the three sub-genomes generated from the paleo-hexaploidization event in E. ferox, we revealed that one sub-genome was phylogenetically closer to Victoria cruziana, which also exhibits gigantic floating leaves. Further analysis revealed that while all three sub-genomes promoted the evolution of the specific leaf development in E. ferox, the genes from the sub-genome closer to V. cruziana contributed more to this adaptive evolution. Moreover, we found that genes involved in cell proliferation and expansion, photosynthesis, and energy transportation were over-retained and showed strong expression association with the leaf development stages, such as the expression divergence of SWEET orthologs as energy uploaders and unloaders in the sink and source leaf organs of E. ferox. These findings provide novel insights into the genome evolution through polyploidization, as well as the adaptive evolution regarding the leaf development accomplished through biased gene retention and expression sub-functionalization of multi-copy genes in E. ferox.

DNA methylation and histone post-translational modifications in atherosclerosis and a novel perspective for epigenetic therapy.

Atherosclerosis, which is a vascular pathology characterized by inflammation and plaque build-up within arterial vessel walls, acts as the important cause of most cardiovascular diseases. Except for a lipid-depository and chronic inflammatory, increasing evidences propose that epigenetic modifications are increasingly associated with atherosclerosis and are of interest from both therapeutic and biomarker perspectives. The chronic progressive nature of atherosclerosis has highlighted atherosclerosis heterogeneity and the fact that specific cell types in the complex milieu of the plaque are, by far, not the only initiators and drivers of atherosclerosis. Instead, the ubiquitous effects of cell type are tightly controlled and directed by the epigenetic signature, which, in turn, is affected by many proatherogenic stimuli, including low-density lipoprotein, proinflammatory, and physical forces of blood circulation. In this review, we summarize the role of DNA methylation and histone post-translational modifications in atherosclerosis. The future research directions and potential therapy for the management of atherosclerosis are also discussed. Video Abstract.

Visualization of Activated Fibroblasts in Heart Failure with Preserved Ejection Fraction with [18F]AlF-NOTA-FAPI-04 PET/CT Imaging.

During the pathogenesis of heart failure with preserved ejection fraction (HFpEF), fibroblasts are activated and express the fibroblast activation protein (FAP). Targeted imaging of FAP can qualitatively and quantitatively assess the fibroblast activity. This study aimed to use [18F]AlF-NOTA-FAPI-04 (AlF = aluminum fluoride; NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid; FAPI = FAP inhibitor) positron emission tomography/computed tomography (PET/CT) imaging to detect activated fibroblasts in a rat HFpEF model. The rat HfpEF model was established by feeding a high-fat diet plus l-NAME (Nω-nitro-l-arginine methyl ester) for 10 weeks. Blood pressure, echocardiography, and [18F]AlF-NOTA-FAPI-04 PET/CT were used to assess the progression of HfpEF. The biodistribution of [18F]AlF-NOTA-FAPI-04 in healthy rats was obtained. Cardiac tissue sections were also analyzed using Masson's, hematoxylin and eosin (H&E), and FAP immunohistochemistry (IHC) staining. The echocardiography and blood pressure data indicated that the rat HfpEF model was successfully established. [18F]AlF-NOTA-FAPI-04 PET/CT imaging showed obvious radiotracer accumulation in the left ventricular wall of the HfpEF rats from the seventh week. A biodistribution test showed that the tracer was cleared mainly via renal and intestinal excretion. Percentage of injected dose per gram tissue (% ID) of the heart and its surrounding organs was lower in normal rats, which was conducive to image analysis. Masson's and H&E stainings showed large areas of vascular and interstitial fibrosis in the HfpEF rat hearts. IHC staining also confirmed the presence of FAP-positive cardiac fibroblasts of the HfpEF rat hearts, with a good correlation with FAPI PET. Thus, [18F]AlF-NOTA-FAPI-04 PET/CT is a promising and non-invasive method to assess the progression of fibrosis in HfpEF to facilitate the clinical management.

Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating ß-Hydroxybutyrate-activated Citrate Synthase.

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing ß-hydroxybutyric acid (ß-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of ß-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.

Development and validation of a new risk assessment model for immunomodulatory drug-associated venous thrombosis among Chinese patients with multiple myeloma.

BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

Predicting the impact of the COVID-19 pandemic on globalization.

The COVID-19 pandemic has significantly influenced the global economy, international travel, global supply chains, and how people interact, and subsequently affect globalization in coming years. In order to understand the impact of COVID-19 on globalization and provide potential guidance to policymakers, the present study predicted the globalization level of the world average and 14 specific countries in scenarios with and without COVID-19 based on a new Composite Indicator method which contains 15 indicators. Our results revealed that the world average globalization level is expected to decrease from 2017 to 2025 under the scenario without COVID-19 by -5.99%, while the decrease of globalization under the COVID-19 scenario is predicted to reach -4.76% in 2025. This finding implies that the impact of COVID-19 on globalization will not be as severe as expected in 2025. Nevertheless, the downward trend of globalization without COVID-19 is due to the decline of the Environmental indicators, whereas the decline under the COVID-19 scenario is attributed to Economic aspects (almost -50%). The impact of COVID-19 on globalization varies across individual countries. Among the countries investigated, COVID-19 had a positive impact on the globalization of Japan, Australia, the United States, the Russian Federation, Brazil, India and Togo. In contrast, the globalization in the United Kingdom, Switzerland, Qatar, Egypt, China and Gabon are expected to decrease. The variation of impact induced by COVID-19 on those countries is attributed to the weighting of economic, environmental and political aspects of globalization is different across these countries. Our results can help governments take suitable measures to balance economic, environmental and political policies, which may better support their decision-making.

Ramucirumab for Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha Fetoprotein Following Non-Sorafenib Systemic Therapy: An Expansion Cohort of REACH-2.

BACKGROUND: Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies. MATERIALS AND METHODS: This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment. RESULTS: Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months. CONCLUSION: Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib.

One-year renal outcome in lupus nephritis patients with acute kidney injury: a nomogram model.

OBJECTIVE: To develop a short-term renal outcome prediction model for acute kidney injury (AKI) in patients with LN. METHODS: Two lupus AKI cohorts from two independent centres during 2013-2019 were included: a derivation cohort from a rheumatology centre and a validation cohort from a nephrology centre. Clinical characteristics and renal histologic features were obtained. The outcome measurement was the recovery of kidney function within 12 months. Lasso regression was used for feature selection. Prediction models with or without pathology were built and a nomogram was plotted. Model evaluation including calibration curve and decision curve analysis was performed. RESULTS: A total of 130 patients were included in the derivation cohort and 96 patients in the validation cohort, of which 82 and 73 patients received a renal biopsy, respectively. The prognostic nomogram model without pathology included determinants of SLE duration, days from AKI onset to treatment and baseline creatinine level [C-index 0.85 (95% CI 0.78, 0.91) and 0.79 (95% CI 0.70, 0.88) for the two cohorts]. A combination of histologic tubulointerstitial (TI) fibrosis in the nomogram gave an incremental predictive performance (C-index 0.93 vs 0.85; P = 0.039) in the derivation cohort but failed to improve the performance in the validation cohort (C-index 0.81 vs 0.79; P = 0.78). Decision curve analysis suggested clinical benefit of the prediction models. CONCLUSION: The predictive nomogram models might facilitate more accurate management for lupus patients with AKI.

Impact of in vitro fertilization-embryo transfer on mother-to-infant transmission in women with chronic HBV infection.

BACKGROUND AND AIMS: In vitro fertilization-embryo transfer (IVF-ET) may increase the risk of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). The purpose of this study was to investigate the impact and safety of IVF-ET on MTCT in women with chronic HBV infection (CHB). METHODS: The data of 298 women who got pregnant by IVF-ET and their 375 children were collected retrospectively. Mothers were divided into the CHB group (n = 224) and the control group (HBsAg negative, n = 74). After birth, newborns were routinely vaccinated with the hepatitis B vaccine, and infants in the CHB group were injected with hepatitis B immunoglobulin within 2 h after birth. Demographic information, clinical data and laboratory test results were collected. The primary outcome measures were the MTCT rate of HBV, and the secondary outcome measures were the safety of the mother and infant. RESULTS: There was no case of HBV MTCT in all 282 newborns born in the CHB group and 93 neonates born in the control group. Of the two groups, the birth weight (3056.74 ± 601.65 vs. 2926.24 ± 704.86, P = .083), length (49.22 ± 1.97 vs. 48.74 ± 3.09, P = .167), 5-min Apgar score (9.97 ± 0.21 vs. 9.90 ± 0.51, P = .212), days of pregnancy (265.70 ± 12.73 vs. 262.02 ± 17.50, P = .064) and neonatal malformation rate (0.71% vs. 0, P = 1.000) were similar. Two cases of neonatal malformation occurred in the CHB group. The incidences of pregnancy and childbirth complications were similar between the two groups. CONCLUSION: IVF-ET does not increase the risk of MTCT in women with chronic HBV infection, and it is safe for mothers and infants.

Attaining treat-to-target endpoints with metformin in lupus patients: a pooled analysis.

OBJECTIVES: Low disease activity status and remission are crucial treat-to-target (T2T) endpoints in systemic lupus erythematosus (SLE). To evaluate the efficacy of metformin add-on in attaining T2T among Chinese patients with mild-to-moderate lupus, a post-hoc analysis combining our previous two randomised trials was carried out. METHODS: Data from the open-labeled proof-of-concept trial (ChiCTR-TRC-12002419) and placebo-controlled trial (NCT02741960) were integrated together. Disease flares were compared between patients attaining T2T or not at baseline. The efficacy of metformin versus placebo/nil add-on to standard therapy in SLE patients who did not meet the T2T criteria at baseline was evaluated in terms of attaining T2T at 12-month follow-up. RESULTS: Of 253 SLE patients, 43.8% (n=89) attained T2T at baseline. During the 12 months, 15 patients flared in the T2T group, which was significantly lower than that in the non-T2T group (16.9% vs. 36.0%, p=0.001). For 164 patients who did not meet the T2T criteria at entry, 59.0% and 43.6% of the 78 patients taking metformin in this population attained the lupus low disease activity status (LLDAS) and remission endpoints at last visit, respectively, as compared to 37.2% and 24.4% of the 86 patients in the placebo/nil group (LLDAS p=0.008; remission p=0.013). Over time, metformin helped patients achieving T2T earlier and maintain longer T2T duration over placebo/nil (LLDAS duration: 44.9% vs. 26.4%, p=0.002; remission duration:19.1% vs. 10.7%, p=0.014). CONCLUSIONS: This post-hoc analysis suggested that metformin might be an adjuvant therapy in achieving treat-to-target in SLE patients.

Ferroptosis-based molecular prognostic model for adrenocortical carcinoma based on least absolute shrinkage and selection operator regression.

BACKGROUND: This study aimed to find ferroptosis-related genes linked to clinical outcomes of adrenocortical carcinoma (ACC) and assess the prognostic value of the model. METHODS: We downloaded the mRNA sequencing data and patient clinical data of 78 ACC patients from the TCGA data portal. Candidate ferroptosis-related genes were screened by univariate regression analysis, machine-learning least absolute shrinkage, and selection operator (LASSO). A ferroptosis-related gene-based prognostic model was constructed. The effectiveness of the prediction model was accessed by KM and ROC analysis. External validation was done using the GSE19750 cohort. A nomogram was generated. The prognostic accuracy was measured and compared with conventional staging systems (TNM stage). Functional analysis was conducted to identify biological characterization of survival-associated ferroptosis-related genes. RESULTS: Seventy genes were identified as survival-associated ferroptosis-related genes. The prognostic model was constructed with 17 ferroptosis-related genes including STMN1, RRM2, HELLS, FANCD2, AURKA, GABARAPL2, SLC7A11, KRAS, ACSL4, MAPK3, HMGB1, CXCL2, ATG7, DDIT4, NOX1, PLIN4, and STEAP3. A RiskScore was calculated for each patient. KM curve indicated good prognostic performance. The AUC of the ROC curve for predicting 1-, 3-, and 5- year(s) survival time was 0.975, 0.913, and 0.915 respectively. The nomogram prognostic evaluation model showed better predictive ability than conventional staging systems. CONCLUSION: We constructed a prognosis model of ACC based on ferroptosis-related genes with better predictive value than the conventional staging system. These efforts provided candidate targets for revealing the molecular basis of ACC, as well as novel targets for drug development.

Digital fabrication of an adult speech aid prosthesis by using a 3-dimensionally printed polyetheretherketone framework.

This article presents a digital fabrication method for a speech aid prosthesis by using a 3D-printed polyetheretherketone (PEEK) framework. The computer-aided design (CAD) of the speech aid prosthesis framework was based on oral scan data. The framework was printed with PEEK filament material supplemented with nanoTiO2 powder by fused deposition modeling (FDM). A resin preliminary cast was 3D printed, and an altered cast technique was adopted to fabricate the definitive cast. The PEEK framework exhibited precise fit, toothlike color, excellent mechanical properties, and reduced weight as compared with a typical metal framework. This technique describes the successful clinical application of 3D-printed PEEK material for the fabrication of an adult speech aid prosthesis.