Severe acute respiratory syndrome coronavirus 2 was isolated from feces of a patient in China with coronavirus disease who died. Confirmation of infectious virus in feces affirms the potential for ...fecal-oral or fecal-respiratory transmission and warrants further study.
Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to ...increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.
Bioprinting as an enabling technology for tissue engineering possesses the promises to fabricate highly mimicked tissue or organs with digital control. As one of the biofabrication approaches, ...bioprinting has the advantages of high throughput and precise control of both scaffold and cells. Therefore, this technology is not only ideal for translational medicine but also for basic research applications. Bioprinting has already been widely applied to construct functional tissues such as vasculature, muscle, cartilage, and bone. In this review, the authors introduce the most popular techniques currently applied in bioprinting, as well as the various bioprinting processes. In addition, the composition of bioink including scaffolds and cells are described. Furthermore, the most current applications in organ and tissue bioprinting are introduced. The authors also discuss the challenges we are currently facing and the great potential of bioprinting. This technology has the capacity not only in complex tissue structure fabrication based on the converted medical images, but also as an efficient tool for drug discovery and preclinical testing. One of the most promising future advances of bioprinting is to develop a standard medical device with the capacity of treating patients directly on the repairing site, which requires the development of automation and robotic technology, as well as our further understanding of biomaterials and stem cell biology to integrate various printing mechanisms for multi‐phasic tissue engineering.
Bioprinting as an enabling technology for tissue engineering possesses the promises of fabricating highly mimicked tissue or organs with digital control. Here we present the bioprinting techniques in our aspect of review and the current successful applications in tissue engineering.
Background and Aims
Hepatic ischemia‐reperfusion (IR) injury is a major complication of liver transplantation, resection, and hemorrhagic shock. Hypoxia is a key pathological event associated with IR ...injury. MicroRNA‐210 (miR‐210) has been characterized as a micromanager of hypoxia pathway. However, its function and mechanism in hepatic IR injury is unknown.
Approach and Results
In this study, we found miR‐210 was induced in liver tissues from patients subjected to IR‐related surgeries. In a murine model of hepatic IR, the level of miR‐210 was increased in hepatocytes but not in nonparenchymal cells. miR‐210 deficiency remarkably alleviated liver injury, cell inflammatory responses, and cell death in a mouse hepatic IR model. In vitro, inhibition of miR‐210 decreased hypoxia/reoxygenation (HR)–induced cell apoptosis of primary hepatocytes and LO2 cells, whereas overexpression of miR‐210 increased cells apoptosis during HR. Mechanistically, miR‐210 directly suppressed mothers against decapentaplegic homolog 4 (SMAD4) expression under normoxia and hypoxia condition by directly binding to the 3′ UTR of SMAD4. The pro‐apoptotic effect of miR‐210 was alleviated by SMAD4, whereas short hairpin SMAD4 abrogated the anti‐apoptotic role of miR‐210 inhibition in primary hepatocytes. Further studies demonstrated that hypoxia‐induced SMAD4 transported into nucleus, in which SMAD4 directly bound to the promoter of miR‐210 and transcriptionally induced miR‐210, thus forming a negative feedback loop with miR‐210.
Conclusions
Our study implicates a crucial role of miR‐210‐SMAD4 interaction in hepatic IR‐induced cell death and provides a promising therapeutic approach for liver IR injury.
Fluoroalkylated enaminones, such as trifluridine and 5-trifluoromethyluracil, have widespread applications in pharmaceuticals and agrochemicals. Although these kinds of pharmaceutical agent often ...bear CF3 and perfluoroalkyl motifs in the core structure, access to such analogues typically requires multi-step synthesis. Here, we report a mild, metal-free and operationally simple strategy for the direct perfluoroalkylation of uracils, cytosines and pyridinones through a visible-light induced pathway from perfluoroalkyl iodides. This photochemical transformation features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance, providing a facile route for applications in medicinal chemistry.
Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II–IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with ...EGFR-mutant stage IB–IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II–IIIA (N1–N2) NSCLC.
We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18–75 years with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079.
Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8–44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months 95% CI 24·9–32·5) than with vinorelbine plus cisplatin (18·0 months 13·6–22·3; hazard ratio HR 0·60, 95% CI 0·42–0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two 2% patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 34% patients vs none with gefitinib), leucopenia (14 16% vs none), and vomiting (eight 9% vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related.
Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II–IIIA (N1–N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature.
Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.
The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II-IIIA non-small cell lung cancer (NSCLC). ...However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.
Background
Overweight and obesity are related to maternal and infant physical health, such as gestational diabetes, preeclampsia, and macrosomia. The purpose of this meta‐analysis was to assess the ...effect of physical exercise on maternal and infant outcomes in overweight and obese pregnant women.
Methods
Two researchers independently searched Cochrane Library, Embase, PubMed, Web of Science, and ClinicalTrials.gov. for English‐language articles based on randomized controlled trials examining physical exercise in overweight and obese pregnant women and its effect on maternal and infant outcomes. Primary outcomes were gestational weight gain and a relative risk of gestational diabetes. Secondary outcomes were gestational hypertension, preeclampsia, cesarean delivery, birthweight, large for gestational age, small for gestational age, macrosomia, and preterm birth. Risk bias was evaluated by Cochrane Collaboration's tool. The results of integration were reported as relative risks (RR), mean difference, or standard mean difference with 95% confidence intervals (CI). This meta‐analysis was registered on PROSPERO on November 18, 2017, with registration number CRD42017081565.
Results
Thirteen studies involving 1439 participants were included. Physical exercise reduced gestational weight gain (mean difference = −1.14 kg, 95% CI = −1.67 to −0.62, P < 0.0001) and the risk of gestational diabetes (RR = 0.71, 95% CI = 0.57‐0.89, P = 0.004) in overweight and obese pregnant women. There were no significant differences in other outcomes such as gestational hypertension, preeclampsia, cesarean delivery, birthweight, large for gestational age, small for gestational age, macrosomia, and preterm birth.
Conclusions
Prenatal exercise interventions reduced gestational weight gain and the risk of gestational diabetes for overweight and obese pregnant women, which reinforced the benefits of exercise during pregnancy. However, no evidence was found with respect to benefits and/or harm for infants. Consideration should be taken when interpreting these findings as a result of the relative small sample size in this meta‐analysis. Further larger well‐designed randomized trials may be helpful to assess the short‐term and long‐term effects of prenatal exercise on maternal and infant outcomes.
ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus ...vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor (
) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.
From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and
-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat ITT population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.
Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio HR, 0.92; 95% CI, 0.62 to 1.36;
= .674); respective 5-year OS rates were 53.2% and 51.2% (
= .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP (
= .316) and 5y DFS rates were 22. 6% and 23.2% (
= .928), respectively.
Adjuvant therapy with gefitinib in patients with early-stage NSCLC and
mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
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