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PURPOSE The ideal location for mesh placement in minimally invasive ventral hernia repair (VHR) is still up for debate. We undertook a systematic review and meta-analysis (SRMA) to evaluate the outcomes of patients who received intraperitoneal mesh versus those that received extraperitoneal mesh in minimally invasive VHR. METHODS We searched PubMed, EMBASE, Cochrane, and Scopus from inception to May 3, 2021. We selected studies comparing intraperitoneal mesh versus extraperitoneal mesh placement in minimally invasive VHR. A meta-analysis was done for the outcomes of surgical site infection (SSI), seroma, hematoma, readmission, and recurrence. A subgroup analysis was conducted for a subset of studies comparing patients who have undergone intraperitoneal onlay mesh (IPOM) versus extended totally extraperitoneal approach (e-TEP). RESULTS A total of 11 studies (2320 patients) were identified. We found no statistically significant difference between patients who received intraperitoneal versus extraperitoneal mesh for outcomes of SSI, seroma, hematoma, readmission, and recurrence [(RR 1.60, 95% CI 0.60-4.27), (RR 1.39, 95% CI 0.68-2.81), (RR 1.29, 95% CI 0.45-3.72), (RR 1.40, 95% CI 0.69-2.86), and (RR 1.22, 95% CI 0.22-6.63), respectively]. The subgroup analysis had findings similar to the overall analysis. CONCLUSION Based on short-term results, extraperitoneal mesh does not appear to be superior to intraperitoneal mesh in minimally invasive ventral hernia repair. The choice of mesh location should be based on the current evidence, surgeon, and center experience as well as individualized to each patient.

There has not been a consensus on the superiority of a surgical approach for minimally invasive ventral hernia repair. This systematic review and meta-analysis (SRMA) aims to compare clinical, and patient-reported outcomes of robotic-assisted ventral hernia repair (rVHR) to traditional endo-laparoscopic ventral hernia repair (lapVHR). We searched PubMed, EMBASE, Cochrane and Scopus from inception to 16th March 2021. We selected randomised controlled trials and propensity score matched studies comparing rVHR to lapVHR. A meta-analysis was done for the outcomes of operative time, length of hospital stay, open conversion, recurrence, surgical site occurrence and cost. A total of 5 studies (3732 patients) were included in the qualitative and quantitative synthesis. Significantly shorter operative times were reported with the lapVHR as compared to rVHR (weighted mean difference (WMD): 62.52, 95% CI: 50.84–74.19). There was also significantly less rates of open conversion with rVHR as compared to lapVHR (WMD: 0.22, 95% CI: 0.09–0.54). No significant differences in patient-reported outcomes that was discernible from the two papers that reported them. Overall, rVHR is comparable to lapVHR with longer operative times but less open conversion. It is, therefore, important to have proper patient selection to maximise the utility of rVHR.

Background The potential protective role of eosinophils in the COVID-19 pandemic has aroused great interest, given their potential virus clearance function and the infection resistance of asthma patients to this coronavirus. However, it is unknown whether eosinophil counts could serve as a predictor of the severity of COVID-19. Methods A total of 1004 patients with confirmed COVID-19 who were admitted to Leishenshan Hospital in Wuhan, China, were enrolled in this study, including 905 patients in the general ward and 99 patients in the intensive care unit (ICU). We reviewed their medical data to analyze the association between eosinophils and ICU admission and death. Results Of our 1004 patients with COVID-19, low eosinophil counts/ratios were observed in severe cases. After adjusting for confounders that could have affected the outcome, we found that eosinophil counts might not be a predictor of ICU admission. In 99 ICU patients, 58 of whom survived and 41 of whom died, low eosinophil level was an indicator of death in severe COVID-19 patients with a cutoff value of 0.04 × 109/L, which had an area under the curve of 0.665 (95% CI = 1.089-17.839; P = .045) with sensitivity and specificity of 0.569 and 0.7317, respectively. Conclusion Our research revealed that a low eosinophil level is a predictor of death in ICU patients rather than a cause of ICU admission.

Background Substantial studies have demonstrated that fasting therapy (FT) can inhibit the inflammatory response and improve insulin resistance (IR); however, the underlying mechanisms are still unclear. This study aimed to explore the related mechanisms of intermittent FT for the treatment of IR. Methods A rat IR model was established through collaboration of a high-fat diet with streptozotocin (STZ) injection. 8 rats were treated with intermittent FT. A positive control group was treated with metformin (MET). Mouse 3T3-L1 pre-adipocytes were cultured and induced into adipocytes in vitro, and were used as the cellular IR model. Blood insulin, glucose, and homeostatic model assessment (HOMA)-IR index were determined. Enzyme-linked immunosorbent assay (ELISA) and western blotting were used to detect inflammatory markers. Oil Red O staining determined the lipid accumulation. An NLRP3 inflammasome agonist served to investigate the effects of FT on IR in 3T3-L1 adipocytes. Results The high levels of blood insulin, glucose, and HOMA-IR induced by high-fat diet and STZ were significantly decreased by FT. The FT also reduced the level of C-reactive protein (CRP), interleukin (IL)-1β, IL-18, caspase-1, and increased the expression of glucose transporter 1 (GLUT1), insulin receptor substrate 1 (IRS1), and IRS2 in both the rat models and 3T3-L1 adipocytes. In addition, FT significantly relieved lipid accumulation in the liver of rats. Application of NLRP3 inflammasome agonist weakened the effect of FT on IR in the IR 3T3-L1 adipocytes. Conclusions These results suggest that FT can ameliorate the high-fat diet-and STZ-induced IR in rats through inhibition of NLRP3 inflammasome.

Background Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR). Aims To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX. Methods Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing. Results Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing. Conclusion Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped.

Critical aortic stenosis (AS) of the fetal heart causes a drastic change in the cardiac biomechanical environment. Consequently, a substantial proportion of such cases will lead to a single-ventricular birth outcome. However, the biomechanics of the disease is not well understood. To address this, we performed Finite Element (FE) modelling of the healthy fetal left ventricle (LV) based on patient-specific 4D ultrasound imaging, and simulated various disease features observed in clinical fetal AS to understand their biomechanical impact. These features included aortic stenosis, mitral regurgitation (MR) and LV hypertrophy, reduced contractility, and increased myocardial stiffness. AS was found to elevate LV pressures and myocardial stresses, and depending on severity, can drastically decrease stroke volume and myocardial strains. These effects are moderated by MR. AS alone did not lead to MR velocities above 3 m/s unless LV hypertrophy was included, suggesting that hypertrophy may be involved in clinical cases with high MR velocities. LV hypertrophy substantially elevated LV pressure, valve flow velocities and stroke volume, while reducing LV contractility resulted in diminished LV pressure, stroke volume and wall strains. Typical extent of hypertrophy during fetal AS in the clinic, however, led to excessive LV pressure and valve velocity in the FE model, suggesting that reduced contractility is typically associated with hypertrophy. Increased LV passive stiffness, which might represent fibroelastosis, was found to have minimal impact on LV pressures, stroke volume, and wall strain. This suggested that fibroelastosis could be a by-product of the disease progression and does not significantly impede cardiac function. Our study demonstrates that FE modelling is a valuable tool for elucidating the biomechanics of congenital heart disease and can calculate parameters which are difficult to measure, such as intraventricular pressure and myocardial stresses. Electronic supplementary material The online version of this article (10.1007/s10439-020-02683-x) contains supplementary material, which is available to authorized users.

Pancreatic cancer is one of the deadliest types of cancer and its prognosis is extremely poor in the present scenario. Automatic pancreatic tumor image segmentation is often provided by computer-aided screening (CAD), diagnosis and quantitative evaluations in radiology images such as CT and MRI. Tumor classification through these methods can also help to track, predict and endorse customized therapy as a part of effective treatment, without invasions of cancer. Nowadays, neural networks (NN) have shown promising results for precise pancreatic image segmentation. This paper presents a deep learning-based Hierarchical Convolutional Neural Network (HCNN) for pancreatic tumor detection. A recurrent neural network (RNN) is provided to meet the issue of spatial discrepancy segmentation across slices of adjacent images. The recurrent neural network generates CNN results and fine-tunes its segmentation by enhancing the smoothness and shape. Furthermore, the HCNN training and configurations objectives have been illustrated to the performance of pancreatic tumor image segmentation. The experimental results demonstrate that the proposed approach can improve the performance of the classifier and reduce the cost on the Internet of medical things platform (IoMT).

Objective Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood‐brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti‐inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA‐induced HT after stroke. Methods and results We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA‐induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA‐treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA‐treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA‐alone‐treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down‐regulated in microglia of the RSG‐treated mice. We further found that the expression of Arg‐1 was also upregulated in those tPA and RSG‐treated stroke mice and the protection against tPA‐induced HT and BBB disruption in these mice were abolished in the presence of PPAR‐γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). Conclusions RSG treatment protects against BBB damage and ameliorates HT in delayed tPA‐treated stroke mice by activating PPAR‐γ and favoring microglial polarization toward anti‐inflammatory phenotype.

Background Spontaneous bacterial peritonitis (SBP) is a common and potentially fatal complication of liver cirrhosis. This study aims to analyze the prevalence of SBP among liver cirrhotic patients according to geographical location and income level, and risk factors and outcomes of SBP. Methods A systematic search for articles describing prevalence, risk factors and outcomes of SBP was conducted. A single-arm meta-analysis was performed using generalized linear mix model (GLMM) with Clopper-Pearson intervals. Results 99 articles, comprising a total of 5,861,142 individuals with cirrhosis were included (IDDF2021-ABS-0019 Figure 1. Summary of Findings). Pooled prevalence of SBP was found to be 17.12% globally (CI: 13.63% - 21.30%), highest in Africa (68.20%; CI: 12.17% - 97.08%), and lowest in North America (10.81%; CI: 5.32% - 20.73%; IDDF2021-ABS-0019 Figure 2. Summary of SBP prevalence by region). The summary of the global prevalence is found in figure 1. Prevalence of community-acquired SBP was 6.05% (CI: 4.32% - 8.40%), and 11.11% (CI: 5.84% - 20.11%,) for healthcare-associated SBP. Antibiotic-resistant microorganisms were found in 11.51% (CI: 7.28% - 17.74%) of SBP patients. Of which, methicillin-resistant Staphylococcus aureus was most common (6.23%; CI: 3.83% – 9.97%), followed by extended-spectrum beta-lactamase producing organisms (6.19%; CI: 3.32% - 11.26%), and lastly vancomycin-resistant enterococci (1.91%; CI: 0.41% - 8.46%). A subgroup analysis was conducted to compare the rate of resistant SBP based on continent and summarized in figure 2. Subgroup analysis comparing prevalence, antibiotic resistance and outcomes between income groups. Conclusions SBP remains a frequent complication of liver cirrhosis worldwide. The drawn link between income level and SBP in liver cirrhosis may enable further insight on actions necessary to tackle the disease on a global scale.

Background Endoscopic variceal ligation (EVL) is a common procedure for primary and secondary prevention of variceal bleeding in cirrhosis patients. As portal vein thrombosis is associated with a higher risk of variceal bleeding and decompensation in cirrhosis patients, anticoagulation may be considered in these patients. However, it is uncertain if continuing anticoagulation during EVL may significantly increase the risk of bleeding. To address this gap, we performed a systematic review and meta-analysis to evaluate the safety of continuing anticoagulation during EVL. The primary outcome was the bleeding risk following EVL. Secondary outcomes were mortality following EVL and length of stay (LOS). Methods We performed a systematic search of 4 electronic databases (PubMed/MEDLINE, EMBASE, Cochrane library, and ClinicalTrial.gov) up to May 21, 2021 using both free text and MeSH terms. We included all studies that reported the 4-week rebleeding rate in cirrhosis patients during EVL, regardless of study design, language, publication types or status. The pooled relative risk (RR), mean difference (MD) and 95% confidence interval (95%CI) of study outcomes were estimated using Review Manager in a random-effect model. Results A total of six studies (5,102 subjects, 1,028 received anticoagulation) fulfilled our inclusion criteria. The mean (standard deviation) MELD and Child-Pugh score were 18 (5.5) and 7 (1.6), respectively. Follow-up duration ranged from 6 to 196 weeks. The overall pooled risk of bleeding and mortality was 8.2% (95%CI: 6.6%-10.0%) and 8.6% (95%CI: 4.2%-15.3%), respectively. Mean number of bands deployed per session was similar between the anticoagulation and control group. Continuation of anticoagulants during EVL was not associated with a higher pooled risk of bleeding (RR: 0.90, 95%CI: 0.71-1.15, I2 =0%) and mortality (RR: 1.16, 95%CI: 0.22-6.19) following EVL. However, continuing anticoagulation was associated with a shorter LOS (3.9 days, 95%CI: -7.35 to -0.48 days, I2 =0%). All studies had a low risk of bias except for one. Conclusions In cirrhosis patients undergoing EVL, continuing anticoagulation was safe without a significant increase in bleeding and mortality.

Caffeine is one of the most widely used psychostimulants in the world and possesses central excitative, anti-depressive, and neuroprotective properties. However, excessive ingestion or abuse of caffeine can lead to intoxication. Many toxic effects are attributed to oxidative damage, and nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical intracellular regulator of the oxidative stress response. Here, we investigated the neurotoxicity of caffeine in rat pheochromocytoma PC12 cells and zebrafish larvae. It was found that caffeine inhibited the viability of PC12 cells in a dose- and time-dependent manner. Furthermore, it induced PC12 cell apoptosis and elevated reactive oxygen species (ROS) production. Quantitative polymerase chain reaction (qPCR) and western blotting revealed that caffeine also inhibited the expression levels of Nrf2 mRNA and protein and its target genes (e.g., NADPH quinone oxidoreductase 1 [NQO1]). Furthermore, Nrf2 silencing attenuated the toxic effects of caffeine. In addition, zebrafish larvae were treated with different doses of caffeine. Behavioral experiments showed that a low dose of caffeine (0.05 to 0.3 mM) increased the average distance of movement and promoted excitation. Survivorship curves showed that caffeine (0.2 to 1.5 mM) caused lethality. Finally, qPCR revealed that a higher dose of caffeine inhibited mRNA levels in the Nrf2 pathway. Based on these results, this study identified for the first time that overuse of caffeine can induce neurotoxicity by inhibiting the Nrf2 pathway. These results will provide a new perspective for studies on caffeine toxicity.

Diabetic nephropathy (DN) is one of the most serious and major renal complications of diabetes. Previously, Six-transmembrane Protein of Prostate 2 (STAMP2) was reported to contribute to nutritional stress. The purpose of this study is to investigate whether overexpression of STAMP2 attenuates diabetic renal injuries in DN rats. We induced the DN rat model by high-fat diet and low-dose streptozotocin and evaluated the metabolite and urine albumin/creatinine. Recombinant adeno-associated virus vectors were injected for overexpression of STAMP2. Pathophysiologic and ultrastructure features of DN by histochemical stain and transmission electron microscope, autophagy-related proteins and signaling pathway by western blotting were assessed. We found the expression of STAMP2 was decreased and autophagy was blunted in DN rat kidneys. Overexpressing STAMP2 significantly ameliorated metabolic disturbance, insulin resistance, and specifically restoring diabetic renal injury. Furthermore, overexpressing STAMP2 improved the autophagy deficiency in DN rats, as revealed by changes in the expressions of Beclin1, p62, and LC3. Furthermore, STAMP2 overexpressing promoted autophagy by inhibiting the mTOR and activating the AMPK/SIRT1 signaling pathway. Our results suggested that STAMP2 overexpression attenuated renal injuries via upregulating autophagy in DN rats. STAMP2 overexpressing promoted autophagy may been involved with inhibition of the mTOR/ULK1 and activation of the AMPK/SIRT1 signaling pathway.

Background and Aims: Spontaneous bacterial peritonitis (SBP) is a common and potentially fatal complication of liver cirrhosis. This study aims to analyze the prevalence of SBP among liver cirrhotic patients according to geographical location and income level, and risk factors and outcomes of SBP.Methods: A systematic search for articles describing prevalence, risk factors and outcomes of SBP was conducted. A single-arm meta-analysis was performed using generalized linear mix model (GLMM) with Clopper-Pearson intervals.Results: Ninety-Nine articles, comprising a total of 5,861,142 individuals with cirrhosis were included. Pooled prevalence of SBP was found to be 17.12% globally (CI: 13.63–21.30%), highest in Africa (68.20%; CI: 12.17–97.08%), and lowest in North America (10.81%; CI: 5.32–20.73%). Prevalence of community-acquired SBP was 6.05% (CI: 4.32–8.40%), and 11.11% (CI: 5.84–20.11%,) for healthcare-associated SBP. Antibiotic-resistant microorganisms were found in 11.77% (CI: 7.63–17.73%) of SBP patients. Of which, methicillin-resistant Staphylococcus aureus was most common (6.23%; CI: 3.83–9.97%), followed by extended-spectrum beta-lactamase producing organisms (6.19%; CI: 3.32–11.26%), and lastly vancomycin-resistant enterococci (1.91%; CI: 0.41–8.46%). Subgroup analysis comparing prevalence, antibiotic resistance, and outcomes between income groups was conducted to explore a link between socioeconomic status and SBP, which revealed decreased risk of SBP and negative outcomes in high-income countries.Conclusion: SBP remains a frequent complication of liver cirrhosis worldwide. The drawn link between income level and SBP in liver cirrhosis may enable further insight on actions necessary to tackle the disease on a global scale.

Background There is controversy about the proactive clinical application of therapeutic drug monitoring (TDM) of biologic drugs in Crohn’s disease (CD). One way to practically assess this is to examine how TDM influences management decisions. We examined how knowledge of proactive and reactive antitumor necrosis factor (anti-TNF) drug levels changes management in a variety of clinical scenarios. Methods In this retrospective cohort study, all adults with CD having trough level infliximab or adalimumab measurements at Liverpool Hospital between June 2013 and July 2016 were included. Demographics, indications for testing, anti-TNF drug levels, and treatment details were collected along with subsequent management decisions. The decision made by the treating clinician after receiving the drug level was compared to a consensus decision from a panel of 3 gastroenterologists based on the clinical, laboratory, imaging, and/or endoscopic results without the drug level. When these 2 decisions were discrepant, the anti-TNF drug level was deemed to have changed management. Results One hundred and eighty-seven trough levels of infliximab or adalimumab from 108 patients were analyzed. Overall, assessment of anti-TNF levels affected management in 46.9% of the instances. Knowledge of the drug level was also more likely to result in management change when the test was performed for reactive TDM compared to proactive TDM (63% vs 36%, P = .001). Conclusions The addition of TDM of anti-TNF agents to routine investigations alters management decisions in adult CD patients on anti-TNF therapy in both proactive and reactive settings.

Background Ejection Fraction (EF) has been an important parameter describing cardiac function, because of earlier work demonstrating its correlation with outcomes. However, during conditions such as Heart Failure preserved ejection fraction (HFpEF), EF fails to distinguish HFpEF from healthy patients. There are further reports that EF can be skewed by the geometry of the heart, and Heart Failure (HF) can present a wide variety of cardiac morphologies due to remodelling. The reason for the poor performance of EF and its dependency on geometry is unclear, and it is further unclear if such geometric changes from HF remodelling affects cardiac function. We strive to address this here, and derive an improve and simple EF parameter to resolve this. Methods We developed a simple discretized numerical model to relate incompressible myocardial strains to stroke volume. We used data from two porcine animal models of heart failure, one for HFpEF and one for HF reduced EF (HFrEF), and literature clinical measurements to inform our model. We used the model to test the effects of geometric changes relevant to HF on the ability of the heart to convert myocardial strains to flow function. Results Our animal models showed that cardiac dilation and wall thickening are primary features relevant to HF. Further investigation via our numerical model showed that wall thickening with no change to strain artificially increased EF, while cardiac dilation with no change to strain artificially decreased EF, demonstrating that EF can be skewed by geometric changes during HF remodelling, and is an inaccurate representation of cardiac function. We further showed that this is because EF is calculated using the endocardial boundary rather than the mid-wall layer, because a corrected EF parameter (CEF) that uses the mid-wall layer for quantification resolves this shortcoming. This CEF became independent of cardiac geometry, and could successfully distinguish HFpEF and healthy heart in our animal models, where EF could not. The CEF can be calculated easily with measurements of EF, wall thickness, and LV inner diameter. We further showed that the myocardial strains at the endocardial and epicardial boundary deviated significantly from each other and from the strains at the mid-wall layer, and this magnitude of deviation depended on the cardiac geometry, suggesting that any quantification of cardiac function using the epi- or endo- boundaries can be skewed by geometric changes to the heart, and will be ineffective. Finally, we tested specific types of HF morphologies, namely, eccentric hypertrophy, concentric hypertrophy, and concentric remodelling with our numerical model. We found that the concentric remodelling morphology is the most inefficient in converting myocardial strains to stroke volume, while eccentric hypertrophy is the most efficient. This may explain why HFpEF hearts, which are likely have wall thickening similar to concentric remodelling, have exercise intolerant, and our results suggest that cardiac dilation during HFrEF is providing advantages to help with flow function. Conclusion We demonstrated that geometric changes during HF remodeling can significantly impact cardiac function, and can skews functional parameters like EF. We further showed that the reason for EF’s shortcoming is due to a flawed reliance on quantification using the endocardial boundary of the heart rather than the mid-wall layer. We proposed a new CEF parameter to replace EF that can resolve the shortcoming, and that can distinguish HFpEF from healthy hearts. Conflict of Interest None to declare

Left atrial ligation (LAL) of the chick embryonic heart at HH21 is a model of the hypoplastic left heart syndrome (HLHS) disease, demonstrating morphological and hemodynamic features similar to human HLHS cases. Since it relies on mechanical intervention without genetic or pharmacological manipulations, it is a good model for understanding the biomechanics origins of such HLHS malformations. To date, however, the fluid mechanical environment of this model is poorly understood. In the current study, we performed 4D ultrasound imaging of LAL and normal chick embryonic hearts and 4D cardiac flow simulations to help shed light on the mechanical environment that may lead to the HLHS morphology. Results showed that the HH25 LAL atrial function was compromised, and velocities in the ventricle were reduced. The HH25 LAL ventricles developed a more triangular shape with a sharper apex, and in some cases, the atrioventricular junction shifted medially. These changes led to more sluggish flow near the ventricular free wall and apex, where more fluid particles moved in an oscillatory manner with the motion of the ventricular wall, while slowly being washed out, resulting in lower wall shear stresses and higher oscillatory indices. Consequent to these flow conditions, at HH28, even before septation is complete, the left ventricle was found to be hypoplastic while the right ventricle was found to be larger in compensation. Our results suggest that the low and oscillatory flow near the left side of the heart may play a role in causing the HLHS morphology in the LAL model. Supplementary Information The online version contains supplementary material available at 10.1007/s10237-021-01447-3.

About 10 million people in China are infected with hepatitis C virus (HCV), with the seroprevalence of anti-HCV in the general population estimated at 0.6%. Delaying effective treatment of chronic hepatitis C (CHC) is associated with liver disease progression, cirrhosis, hepatocellular carcinoma, and liver-related mortality. The extrahepatic manifestations of CHC further add to the disease burden of patients. Managing CHC-related advanced liver diseases and systemic manifestations are costly for both the healthcare system and society. Loss of work productivity due to reduced well-being and quality of life in CHC patients further compounds the economic burden of the disease. Traditionally, pegylated-interferon plus ribavirin (PR) was the standard of care. However, a substantial number of patients are ineligible for PR treatment, and only 40%-75% achieved sustained virologic response. Furthermore, PR is associated with impairment of patient-reported outcomes (PROs), high rates of adverse events, and poor adherence. With the advent of direct acting antivirals (DAAs), the treatment of CHC patients has been revolutionized. DAAs have broader eligible patient populations, higher efficacy, better PRO profiles, fewer adverse events, and better adherence rates, thereby making it possible to cure a large proportion of all CHC patients. This article aims to provide a comprehensive evaluation on the value of effective, curative hepatitis C treatment from the clinical, economic, societal, and patient experience perspectives, with a focus on recent data from China, supplemented with other Asian and international experiences where China data are not available.

Background Intercostal chest catheter (ICC) insertion is a common hospital procedure with attendant risks including life‐threatening complications such as pneumothorax and visceral damage. Aim To investigate the effect of a quality improvement (QI) initiative on complications associated with inpatient thoracostomy tube insertion. Methods Following an audit of ICC complications in inpatients over a 2‐year period we implemented a comprehensive QI programme. This involved formal training in and mandatory use of thoracic ultrasound, standardisation of the procedure and documentation, a dedicated procedure room with nurses trained in assisting ICC insertion and senior supervision for medical staff. An audit over 2 years post‐implementation of the QI protocol was compared with pre‐implementation results. Results A total of 103 cases were reviewed pre‐implementation and 105 cases were reviewed post‐implementation of the QI programme. All procedures following the QI initiative were image guided compared to 23.3% of cases pre‐implementation. The rate of developing a pneumothorax requiring intervention post‐implementation was less than pre‐implementation (1.9% vs 5.8% (P = 0.023). Post‐implementation, there were no instances of dry taps, viscera perforation, clinically significant bleeding or wrong side ICC insertion and documentation improved. Conclusion QI initiative applied to thoracostomy tube insertion in hospital inpatients can reduce complications and improve procedure documentation.

Stroke is the world's leading cause of disability with limited brain repair treatments which effectively improve long‐term neurological deficits. The neuroinflammatory responses persist into the late repair phase of stroke and participate in all brain repair elements, including neurogenesis, angiogenesis, synaptogenesis, remyelination and axonal sprouting, shedding new light on post–stroke brain recovery. Resident brain glial cells, such as astrocytes not only contribute to neuroinflammation after stroke, but also secrete a wide range of trophic factors that can promote post–stroke brain repair. Alternatively, activated microglia, monocytes, and neutrophils in the innate immune system, traditionally considered as major damaging factors after stroke, have been suggested to be extensively involved in brain repair after stroke. The adaptive immune system may also have its bright side during the late regenerative phase, affecting the immune suppressive regulatory T cells and B cells. This review summarizes the recent findings in the evolving role of neuroinflammation in multiple post–stroke brain repair mechanisms and poses unanswered questions that may generate new directions for future research and give rise to novel therapeutic targets to improve stroke recovery.

Middle East respiratory syndrome (MERS) is a lethal respiratory disease with its first case reported back in 2012 (Jeddah, Saudi Arabia). It is a novel, single-stranded, positive-sense RNA beta coronavirus (MERS-CoV) that was isolated from a patient who died from a severe respiratory illness. Later, it was found that this patient was infected with MERS. MERS is endemic to countries in the Middle East regions, such as Saudi Arabia, Jordan, Qatar, Oman, Kuwait and the United Arab Emirates. It has been reported that the MERS virus originated from bats and dromedary camels, the natural hosts of MERS-CoV. The transmission of the virus to humans has been thought to be either direct or indirect. Few camel-to-human transmissions were reported earlier. However, the mode of transmission of how the virus affects humans remains unanswered. Moreover, outbreaks in either family-based or hospital-based settings were observed with high mortality rates, especially in individuals who did not receive proper management or those with underlying comorbidities, such as diabetes and renal failure. Since then, there have been numerous reports hypothesising complications in fatal cases of MERS. Over the years, various diagnostic methods, treatment strategies and preventive measures have been strategised in containing the MERS infection. Evidence from multiple sources implicated that no treatment options and vaccines have been developed in specific, for the direct management of MERS-CoV infection. Nevertheless, there are supportive measures outlined in response to symptom-related management. Health authorities should stress more on infection and prevention control measures, to ensure that MERS remains as a low-level threat to public health.

Zika virus was first discovered in the Zika Forest of Uganda in 1947 and was until recently believed to be an infection of mild clinical significance. Infection with Zika virus presents with mild clinical symptoms including fever, headache, rash, conjunctivitis, arthralgia, and myalgia—only a small proportion of laboratory-confirmed infections manifested clinically detectable features. In 2016 the World Health Organization declared Zika virus infection and its associated congenital malformations and neurological disorders as a Public Health Emergency of International Concern, following a large-scale outbreak of microcephaly in Brazil. Molecularly confirmed or serologically confirmed acute Zika virus infection was associated with an increased incidence of a spectrum of significant neurological manifestations including Guillain-Barre syndrome, encephalitis, and transverse myelitis. Zika virus infection during the perinatal period results in congenital Zika syndrome, a condition characterized by microcephaly, reduced head circumference, and significant craniofacial disproportion. Although Zika virus is no longer a Public Health Emergency of International Concern, Zika virus screening during pregnancy in endemic regions remains relevant and necessary, due to the severe long-term sequelae and cost to the healthcare systems involved.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells in the pancreas. Consequently, T1D patients produce little to no insulin, resulting in absolute insulin deficiency and an inability to regulate blood glucose levels effectively. Insulin replacement is the mainstream treatment for T1D, but it comes with a major drawback—the risk of hypoglycemia unawareness. As such, replenishment of glucose-sensing and insulin-producing beta cells via cell replacement therapy is believed to have great therapeutic value for T1D patients. Human pluripotent stem cells (hPSCs) are considered an attractive source for the derivation of insulin-producing beta-like cells for cell replacement therapy. However, several challenges need to be addressed before hPSC-derived beta-like cells can be used for T1D treatment. In this chapter, we provide a snapshot of the current progress of hPSC therapy with an emphasis on T1D, discuss some of the clinical considerations and technical strategies in the generation of current good manufacturing practice (cGMP)-compliant hPSC-derived beta-like cells and the future outlook for T1D hPSC therapy.

Background Total hip and total knee replacement (THR/TKR) are common and effective surgeries to reduce the pain and disability associated with arthritis but are associated with small but significant risks of preventable complications such as surgical site infection (SSI) and venous-thrombo-embolism (VTE). This study aims to determine the degree to which hospital care was compliant with clinical guidelines for the prevention of SSI and VTE after THR/TKR; and whether non-compliant prophylaxis is associated with increased risk of complications. Methods and findings A prospective multi-centre cohort study was undertaken in consenting adults with osteoarthritis undergoing elective primary TKR/THR at one of 19 high-volume Australian public or private hospitals. Data were collected prior to surgery and for one-year post-surgery. Four adjusted logistic regression analyses were undertaken to explore associations between binary non-compliance and the risk of surgical complications: (1) composite (simultaneous) non-compliance with both (VTE and antibiotic) guidelines and composite complications [all-cause mortality, VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35-days)], (2) VTE non-compliance and VTE outcomes, (3) antibiotic non-compliance and any SSI, and (4) antibiotic non-compliance and deep SSI. Data were analysed for 1875 participants. Guideline non-compliance rates were high: 65% (VTE), 87% (antibiotics) and 95% (composite guideline). Composite non-compliance was not associated with composite complication (12.8% vs 8.3%, adjusted odds ratio [AOR] = 1.41, 95%CI 0.68–3.45, p = 0.40). Non-compliance with VTE guidelines was associated with VTE outcomes (5% vs 2.4%, AOR = 2.83, 95%CI 1.59–5.28,p < 0.001). Non-compliance with antibiotic guidelines was associated with any SSI (14.8% vs 6.1%, AOR = 1.98, 95%CI 1.17–3.62,p = 0.02) but not deep infection (3.7% vs 1.2%,AOR = 2.39, 95%CI 0.85–10.00, p = 0.15). Conclusions We found high rates of clinical variation and statistically significant associations between non-compliance with VTE and antibiotic guidelines and increased risk of VTE and SSI, respectively. Complications after THR/TKR surgery may be decreased by improving compliance with clinical guidelines.

BACKGROUND Colonoscopy remains the gold standard for detection of colonic disease. An optimal evaluation depends on adequate bowel cleansing. Patients with inflammatory bowel disease (IBD), require frequent endoscopic assessment for both activity and dysplasia assessment. Two commonly used bowel preparations in Australia are Prep Kit-C (Pc) and Moviprep (Mp). Little is known about tolerability, efficacy and safety of split protocols of Mp and Pc in both IBD and non-IBD patients. AIM To primary aim was to compare the tolerability, efficacy and safety of split protocols of Mp and Pc in patients having a colonoscopy. The secondary aim was to compare the efficacy, tolerability and safety of either preparation in patients with or without IBD. METHODS Patients were randomized to Pc or Mp bowel preparation. Patients completed a questionnaire to assess tolerability. Efficacy was assessed using the Ottawa Bowel Preparation Score. Serum electrolytes and renal function were collected one week prior to colonoscopy and on the day of colonoscopy. RESULTS Of 338 patients met the inclusion criteria. Of 168 patients randomized to Mp and 170 to Pc. The efficacy of bowel preparation (mean Ottawa Bowel Preparation Score) was similar between Mp (5.4 ± 2.4) and Pc (5.1 ± 2.1) (P = 0.3). Mean tolerability scores were similar in Mp (11.84 ± 5.4) and Pc (10.99 ± 5.2; P = 0.17). 125 patients had IBD (73 had Crohn's Disease and 52 had Ulcerative colitis). Sixty-four IBD patients were allocated to Mp and 61 to Pc. In non-IBD patients, 104 were allocated to Mp and 109 to Pc. The mean tolerability score in the IBD group was lower than the non-IBD group (mean tolerability scores: IBD: 10.3 ± 5.1 and non-IBD: 12.0 ± 5.3; P = 0.01). IBD patients described more abdominal pain with Mp when compared with Pc; (Mp: 5.7 ± 4.4 vs Pc: 3.6 ± 2.6, P = 0.046). Serum magnesium level increased with Pc compared with Mp in all patients (mean increase in mmol/L: Mp: 0.03 ± 0.117 and Pc: 0.11 ± 0.106; P < 0.0001). CONCLUSION In this study, the efficacy, tolerability and safety of Mp and Pc were similar in all patients. However, patients with IBD reported lower tolerability with both preparations. Specifically, IBD patients had more abdominal pain with Mp. These results should be considered when recommending bowel preparation especially to IBD patients.

Objective Clinical grading scales used for prognostication in spontaneous intracerebral hemorrhage facilitate informed-decision making for resource-intensive interventions. Numerous clinical prognostic scores are available for spontaneous intracerebral hemorrhage. However, these have not been validated well in Asian patients, and the most appropriate scoring system remains debatable. We evaluated the utility of clinical scores in prognosticating 30-day mortality and 90-day functional outcome in patients with spontaneous intracerebral hemorrhage. Materials and Methods We conducted a retrospective review of all patients with spontaneous intracerebral hemorrhage admitted to our tertiary center from December 2014 to May 2016. Data on clinical presentation, imaging, and outcomes were extracted from electronic medical records using a standardized form. The data were analyzed for predictors of outcomes. Performance of prognostic scales was compared using receiver-operator characteristic statistics. Results A total of 297 patients were included in the study. Mean age was 60.1 (SD 15.2) years and 190 (64.0%) were male. Thirty-two (10.8%) cases died within 30 days and 177 (62.8%) cases had poor functional outcome (modified Rankin scale of 3 or more) at 90 days. Dialysis dependency (OR=33.54, 95%CI=4.21–325.26, p=0.002), Glasgow coma scale (OR=0.76, 95%CI=0.64–0.88, p=0.001), hematoma volume (OR=1.02, 95%CI=1.00–1.04, p=0.027), and surgical evacuation (OR=0.15, 95%CI=0.02–0.66, p=0.024) were independent predictors for 30-day mortality. The original ICH score (0.862) and the ICH-Grading Scale (0.781) had the highest c-statistic for 30-day mortality and 90-day poor functional outcome respectively. Conclusions Current prognostic scores performed acceptable-to-good in our patient cohort. Future studies may be useful to investigate the utility of these scores in clinical decision-making.

Purpose Neutrophil-to-lymphocyte ratio (NLR) has been reported to predict adverse survival outcomes among patients with colorectal cancer (CRC). This study evaluates the prognostic value of NLR among patients with obstructing CRC who successfully underwent stenting before curative surgery. Methods We retrospectively reviewed patients who underwent stenting before surgery. Patient demographics, tumor characteristics, perioperative outcomes, recurrence-free survival (RFS), and overall survival (OS) were analyzed. NLR was calculated from the differential white blood cell counts at least 4 days after successful stenting, before elective surgery. Optimal cutoff to dichotomize NLR was obtained by maximizing log-rank test statistic with recursive partitioning of Kaplan-Meier RFS and OS curves. The optimal cutoff for high NLR was ≥ 5 at presentation before stenting, and ≥ 4 after stenting. Results Fifty-seven patients with localized obstructing CRC underwent successful endoscopic stenting before curative surgery. High NLR was associated with lymphovascular invasion (P = 0.006) and apical lymph node involvement (P = 0.034). Major perioperative complication(s) (hazard ratio [HR], 11.34; 95% confidence interval [CI], 2.49 to 51.56; P < 0.01) and high NLR (HR, 3.69; 95% CI, 1.46 to 9.35; P < 0.01) negatively impacted OS on univariate and multivariate analyses. High NLR negatively impacted RFS on univariate analysis (HR, 2.91; 95% CI, 1.29 to 6.60; P = 0.01). Conclusion NLR of ≥ 4 after stenting is an independent prognostic factor among patients with obstructing localized CRC who are successfully decompressed by endoscopic stenting before curative surgery.

Importance The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. Objective To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. Design, Setting, and Participants This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. Main Outcomes and Measures Disease-free survival and overall survival. Results Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjustedP = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjustedP = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjustedP = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjustedP = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjustedP = .04). Conclusions and Relevance This study’s findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status.

High-risk human papillomavirus (HPV) types 16/18 have been associated with Barrett's dysplasia (BD)/esophageal adenocarcinoma (EAC). Nevertheless, no data exist in relation to serological analysis for HPV antibodies in BD/EAC with site-specific viral DNA status. We prospectively examined antibodies to multiple HPV types in 438 patients representing hospital/reflux controls and Barrett's metaplasia (BM)/BD/intramucosal EAC. Antibody responses to HPV6/11/16/18/31/33/45/52/58 were analyzed using multiplex serology, including antibodies to E6/E7/E1/E2 and L1 antigens. Seropositivity for individual HPV proteins was infrequent in both cases and controls and was ≤10.2%. There was no difference in the seroprevalence of antibodies to any HPV antigen/antibody combination between reclassified cases (BD/EAC) and controls (hospital/reflux/BM) or between HPV16 or HPV18 DNA cases and controls, respectively. Among HPV16 DNA-positive BD/EAC cases, antibodies to HPV16 E7 were significantly more prevalent (3/26, 11.5%) than in hospital and reflux controls plus BM (5/328, 1.5%) (adjusted OR = 10.12, 95% CI: 1.61-63.73, P = 0.014). Among HPV18 DNA-positive cases, antibodies to HPV18 E1 were present in 3/6 (50%) cases versus 5/328 (1.5%) controls (adjusted OR = 44.28, 95% CI: 6.10-321.47, P = 0.0002). Although antibodies against HPV were generally uncommon in cases and controls, immune responses against two early proteins of HPV16/18 were significantly more frequent in viral DNA-positive BD/intramucosal EAC.

Objective Although angiogenesis plays an important role in coronary collateral circulation (CCC) formation and there are many determinants of coronary angiogenesis, they cannot fully explain the mechanism of CCC formation or as potent biomarker for CCC status. Therefore, there is of great clinical significance to identify the novel molecules associated with CCC. Previously, miR-503 exerts anti-angiogenesis effect via inhibition of VEGF-A and its expression is associated with many angiogenesis-related factors. Thus, we aimed to investigate the relationship of plasma miR-503 with CCC formation as well as its predictive power for CCC status in patients with coronary artery disease. Methods Among patients who underwent coronary angiography with coronary artery disease and a stenosis of ≥90% were included in our study. Collateral degree was graded according to Rentrop Cohen classification. The patients were divided to good CCC group (grade 2 or 3) and poor CCC group (grade 0 or 1) according to Rentrop grade. We investigated the plasma levels of miR-503 and VEGF-A by ELISA or q RT-PCR, respectively. In addition, we assayed the correlations of plasma miR-503 with VEGF-A or Rentrop grade using the spearman correlation test and its predictive power by receiver operating characteristic (ROC) and binary logistical regression analysis. Results Our data showed that plasma VEGF-A was significantly higher in good CCC group than that in poor group. Plasma miR-503 was lower in CAD patients with good CCC or poor CCC compared with control subjects and lowest in good CCC group. In addition, miR-503 negatively correlated with VEGF-A and Rentrop grade, respectively. Moreover, miR-503 displayed more potent predictive power for CCC status than VEGF-A, but its sensitivity and specificity for CCC status were only 72.4 or 60.9%, respectively. Conclusions Lower plasma miR-503 level was related to better CCC formation, accompanied by up-regulation of VEGF-A. In addition, miR-503 displayed potent predictive power for CCC status, but its sensitivity and specificity were not high enough, indicating that miR-503 might be as an additional prognosis biomarker for CCC.

Background/Aims: Osteoarthritis is a degenerative joint disease characterized by cartilage degeneration and a chondrocyte inflammatory response that induces an inflammatory environment closely linked to extracellular matrix (ECM) degradation. Ligustilide (LIG) is a major component of the herb Radix Angelicae Sinensis, with demonstrated anti-inflammatory effects. To confirm whether LIG has an equally inhibitory effect on inflammation in human osteoarthritis chondrocytes, we performed in vivo and in vitro experiments to validate the above conjectures and determine the relevant mechanisms. Methods: Quantitative realtime PCR and western blotting were performed to evaluate the expression of MMP-3, MMP-13, ADAMTS-5, iNOS, and COX-2 at both gene and protein levels. An enzyme-linked immunosorbent assay was used to evaluate the levels of other inflammatory factors (PGE2, TNF-α, and IL-6). The PI3K/AKT and nuclear factor kappa B (NF-κB) signaling pathways were also analyzed by western blotting, whereas immunofluorescence was used to assess the expression of collagen II and aggrecan. The in vitro effect of LIG was evaluated by intraperitoneal injection into a mouse osteoarthritis model induced by destabilization of the medial meniscus. Results: LIG lowered the phosphorylation levels of p65, IκBα, and IKKα/β and suppressed the IL-1β-induced expression of MMP-3, ADAMTS-5, iNOS, and COX-2 and the inflammatory factors PGE2, TNF-α, and IL-6. LIG markedly decreased IL-1β-induced degradation of collagen II and aggrecan. In vivo results showed that LIG-treated mouse cartilage showed less damage than the control group; the Osteoarthritis Research Society International (OARSI) score was also lower. LIG further reduced the thickness of the subchondral bone plate and alleviated the synovitis. Conclusion: LIG may act as a promising therapeutic agent for osteoarthritis by attenuating IL-1β-induced inflammation in chondrocytes and ECM degradation via suppression of NF-κB activation by the PI3K/AKT pathway.

ObjectiveInconsistent findings in regard to association between different concentrations of vitamin D, calcium or their combination and the risk of fracture have been reported during the past decade in community-dwelling older people. This study was designed to compare the fracture risk using different concentrations of vitamin D, calcium or their combination.DesignA systematic review and network meta-analysis.Data sourcesRandomised controlled trials in PubMed, Cochrane library and Embase databases were systematically searched from the inception dates to 31 December 2017.OutcomesTotal fracture was defined as the primary outcome. Secondary outcomes were hip fracture and vertebral fracture. Due to the consistency of the original studies, a consistency model was adopted.ResultsA total of 25 randomised controlled trials involving 43 510 participants fulfilled the inclusion criteria. There was no evidence that the risk of total fracture was reduced using different concentrations of vitamin D, calcium or their combination compared with placebo or no treatment. No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of hip or vertebral fractures.ConclusionsThe use of supplements that included calcium, vitamin D or both was not found to be better than placebo or no treatment in terms of risk of fractures among community-dwelling older adults. It means the routine use of these supplements in community-dwelling older people should be treated more carefully.PROSPERO registration numberCRD42017079624.

Neuropilin-2 (NRP-2) not only functions as a receptor for semaphorins, a family of neural axon guidance factors, but also interacts with VEGFs, a family of vascular endothelial growth factors. As an independent receptor or a co-receptor, NRP-2 binds to ligands VEGF-C/D, activates the VEGF-C/D-NRP-2 signaling axis, and further regulates lymphangiogenesis-associated factors in both lymphatic endothelial cells (LECs) and some tumor cells during tumor progression. Via VEGF-C/D-NRP-2 axis, NRP-2 induces LEC proliferation, reconstruction and lymphangiogenesis and subsequently promotes tumor cell migration, invasion and lymphatic metastasis. There are similarities and differences among NRP-1, NRP-2 and VEGFR-3 in chemical structure, ligand specificity, chromosomal location, soluble protein forms, cellular functions and expression profiles. High expression of NRP-2 in LECs and tumor cells has been observed in different anatomic sites, histological patterns and progression stages of various tumors, especially during tumor lymphangiogenesis and lymphatic metastasis, and therefore the NRP-2 and VEGF-C/D-NRP-2 axis are closely related to tumor development, progression, invasion, and metastasis. In addition, it is important for prognosis of tumor. The studies on NRP-2 targeted therapy have recently achieved some successes, utilizing NRP-2 blocking antibodies, NRP-2 inhibitory peptides, soluble NRP-2 antagonists, small molecule inhibitors and various NRP-2 gene therapeutic strategies.

Portal hypertension can lead to ectopic varices, which occur most frequently in the rectum. Rectal variceal bleeding in patients with portal hypertension is rare but can be life-threatening if not diagnosed and treated in a timely manner. However, no specific treatment guidelines have been established for rectal variceal bleeding. We herein report a case involving a woman with portal hypertension due to autoimmune liver disease who was successfully treated with a transjugular intrahepatic portosystemic stent shunt and variceal embolization. We recommend treatment of refractory ectopic variceal bleeding with a transjugular intrahepatic portosystemic stent shunt in combination with embolization.

Our previous study (Oncotarget 2016; 7:46) demonstrated that the over-expression of sulfatase-1 in murine hepatocarcinoma Hca-F cell line (a murine HCC cell with lymph node metastatic [LNM] rate of >75%) downregulates mesothelin and leads to reduction in lymphatic metastasis, both in vitro and in vivo. In current work, we investigated the effects of Sulf-1 knockdown on mesothelin (Msln) and it’s effects on the in vitro cell proliferation, migration, invasion, and in vivo tumor growth and LNM rate for Hca-P cells (a murine HCC cell with LNM rate of

OBJECTIVE To compare the effectiveness of rehabilitation after total knee arthroplasty (TKA) in models with or without an inpatient rehabilitation component. DESIGN, SETTING AND PARTICIPANTS A propensity score-matched cohort of privately insured patients with osteoarthritis who underwent primary, unilateral TKA in one of 12 Australian hospitals between August 2013 and January 2015 were included. Those discharged to an inpatient facility because of poor progress or who experienced significant complications within 90 days of surgery were excluded. INTERVENTION Discharge after surgery to an inpatient rehabilitation facility or home. MAIN OUTCOME MEASURES Patient-reported knee pain and function (Oxford Knee Score; at 90 and 365 days after surgery) and health rating (EuroQol "today" health scale; at 35, 90 and 365 days). Inpatient and community-based rehabilitation provider charges were also assessed. RESULTS 258 patients (129 pairs) from a sample of 332 were matched according to their propensity scores for receiving inpatient rehabilitation; covariates used in the matching included age, sex, body mass index, and markers of health and impairment. The only significant difference in outcomes was that EuroQol health scores were better on Day 35 for patients not undergoing inpatient rehabilitation (median difference, 5; IQR, -10 to 19; P = 0.01). Median rehabilitation provider charges were significantly higher for those discharged to inpatient therapy (total costs: median difference, $9500; IQR, $7000-11 497; P < 0.001; community therapy costs: median difference, $749; IQR, $0-1980; P < 0.001). CONCLUSIONS Rehabilitation pathways incorporating inpatient rehabilitation did not achieve better joint-specific outcomes or health scores than alternatives not including inpatient rehabilitation. Given the substantial cost differences, better value alternatives should be considered for patients after uncomplicated TKA.

We have previously demonstrated that transcriptionally active high-risk HPV (hr-HPV) is strongly incriminated in Barrett's dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett's metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway which are targets for the viral oncoproteins, E6/E7 respectively. Prospectively, BM(n=81)/BD(n=72)/OAC(n=65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A, cyclin D1, p53 and RNA in-situ hybridization (ISH) for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was also performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n=42), 18 (n=13), 6 (n=1)]. Viral load was low. Transcriptionally active HPV (DNA+/RNA+) was only found in the dysplastic and adenocarcinoma group (n=21). The majority of HPV DNA+/RNA+ BD/OAC were characterized by p16INK4Ahigh (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA-/RNA- (n=94) and HPV DNA+/RNA- cohorts (n=22)]. p53low had the strongest association with DNA+/RNA+ oesophageal lesions (OR=23.5, 95% CI=2.94-187.8, p=0.0029). Seventeen HPV DNA+/RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow/p53low provided the best balance of strength of association (OR=8.0, 95% CI=2.6-25.0, p=0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+/RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway. This article is protected by copyright. All rights reserved.

Hepatocellular carcinoma (HCC) ranks in the top of cancers leading to death. Early diagnosis is the big challenge in the case of HCC. Our in vitro study showed that Ezrin expression in lymphatic metastasis hepatocellular carcinoma (LNM-HCC) was associated with the metastatic rate. Here we aim to evaluate Ezrin expression as diagnostic and/or prognostic biomarker of LNM-HCC in mice. Chinese inbred 615 mice, Hca-F and Hca-P cell lines were used in the study. Histological changes were determined by Hematoxylin and Eosin, while Ezrin expression was assessed by qRT-PCR, western blot, immunohistochemistry, and enzyme-linked immunosorbent assay. Ezrin expression in this study gives credit to our in vitro study which Ezrin expression was positively correlated with LNM-HCC and negatively with Annexin7 (A7) expression. The highest histological changes were observed in high metastatic primary/secondary tumors combined with high Ezrin expression. Ezrin and A7 are higher in total primary tumors than in total secondary tumors (P = 0.0001, P = 0.021), respectively. Ezrin expression was enhanced in Hca-P A7 down-regulated primary/secondary tumors (P = 0.004), whereas, Ezrin expression was suppressed in Hca-F A7 upregulated primary/secondary tumors. Serum ELISA indicated differential expression of Ezrin among the study groups (P ≤ 0.0001). Ezrin expression was higher in NC-Hca-F than NC-Hca-P (P ≤ 0.0001), suppressed in Hca-F A7 upregulation (P ≤ 0.0001) and in enhanced in Hca-P A7 down-regulation (P = 0.0001). In conclusion, Ezrin level may serve as a differential diagnostic and/or prognostic biomarker for high and low LNM-HCC and may be beneficial in the diagnosis of HCC disease. © 2017 BioFactors, 43(5):662-672, 2017.

Summary Background The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis. Methods We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4–10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov, number NCT01896635. The trial has ended; this report presents the final analysis. Findings From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1–11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission. Interpretation Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor–recipient matching based on microbial profiles. Funding Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales.

Background Anti-TNF α agents, including infliximab (IFX) and adalimumab (ADA), are arguably the most effective medical therapies for fistulising perianal Crohn’s disease (CD). Increased rates of perianal fistula healing have been reported with increased IFX trough levels. Our study aimed to determine the correlation between perianal fistula healing and closure with IFX and ADA trough levels in fistulising perianal CD patients on maintenance therapy. Methods In this multi-centre retrospective cross-sectional study, we identified CD patients with perianal fistulae on maintenance IFX or ADA who had an IFX or ADA trough level within 3 months of clinical assessment. Data collected included demographics, serum IFX and ADA trough levels (mg/l) and concomitant medical and surgical therapy. The primary outcome was fistula healing, defined as a cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing as well as closure of all external fistula openings. Receiver operating characteristic (ROC) curve analysis was performed to identify the IFX and ADA concentration cut-off points with combined maximal sensitivity and specificity that corresponded to fistula healing. Results A total of 123 patients (IFX = 72; ADA = 51) were included. Fifty-four (75.0%) patients on maintenance IFX achieved fistula healing and 22 (30.6%) achieved fistula closure. Patients who achieved fistula healing had significantly higher median IFX trough levels compared with patients who did not [6.2 (interquartile range 3.1 - 9.6) vs. 3.0 (0.3 - 6.2), (p = 0.007)]. The median IFX trough levels for patients with and without fistula closure were not significantly different [6.4 (2.9 - 9.8) vs. 4.9 (2.5 - 8.9), (p = 0.277)]. Forty (78.4%) patients on maintenance ADA achieved fistula healing and eighteen (35.3%) fistula closure. Patients who achieved fistula healing had a significantly higher median ADA level compared with those who did not [8.7 (6.6 - 12.0) vs. 5.4 (2.5 - 8.3), p = 0.007]. The median ADA trough levels for patients with fistula closure and without fistula closure were not significantly different [9.6 (6.7 – 12.0) vs. 7.7 (4.4–9.8), p = 0.098]. An IFX cut off point of 6.10mg/l was associated with healing (sensitivity 52%; specificity 78%; area under the curve (AUC) 0.72). An ADA cut off point of 7.05mg/l was associated with healing (sensitivity 70%; specificity 73%; AUC 0.77). Conclusion Higher IFX and ADA trough levels are associated with fistula healing. No association between IFX and ADA trough levels and fistula closure was seen, although larger numbers may be required. To the best our knowledge, this is the first study to demonstrate a significant association with both higher IFX and ADA levels with fistula healing in perianal CD.

// Salma Mahmoud 1 , Mohammed Ibrahim 1, 2 , Ahmed Hago 1 , Yuhong Huang 1 , Yuanyi Wei 1 , Jun Zhang 1 , Qingqing Zhang 1 , Yu Xiao 1 , Jingwen Wang 1 , Munkaila Adam 2 , Yu Guo 1 , Li Wang 1 , Shuting Zhou 1 , Boyi Xin 1 , Wei Xuan 1 , Jianwu Tang 1 1 Department of Pathology, Dalian Medical University, Dalian 116044, China 2 Department of Pathology, School of Medicine and Health Sciences, University for Development Studies, Tamale, Ghana Correspondence to: Jianwu Tang, email: jianwutang@163.com Keywords: sulfatase-1, mesothelin, hepatocellular carcinoma, migration and invasion, lymph node metastasis Received: June 17, 2016 Accepted: August 26, 2016 Published: September 10, 2016 ABSTRACT Lymphatic vessels function as transport channels for tumor cells to metastasize from the primary site into the lymph nodes. In this experiment we evaluated the effect of Sulfatase-1 (Sulf-1) on metastasis by upregulating it in murine hepatocarcinoma cell line Hca-F with high lymph node metastatic rate of >75%. The study in vitro showed that upregulation of Sulf-1 in Hca-F cells significantly reduced cell proliferation, migration and invasion (p

Background Despite the advances of cardiac surgery in the last decades, the incidence of acute kidney insufficiency (AKI) post isolated coronary artery bypass grafting surgery (iCABG) is increasing. The purpose of this study was to identify the potential predictors of postoperative AKI in iCABG in order to implement measures to reduce its incidence. Results We reviewed the data of 1914 patients who had on-pump iCABG from January 2008 to December 2015, using the cardiothoracic surgery unit database of Liverpool Hospital, Sydney, New South Wales, Australia. Patients were divided into two groups according to the occurrence of postoperative AKI. The incidence of postoperative AKI was 5.3% in 8 years (n = 101/1914 patients). Multivariable analysis has identified the following independent predictors of postoperative AKI; age older than 80 years (OR 4.27; 95% CI 1.6–11.81) (p

SUMMARY There is evidence to suggest that human papillomaviruses (HPV) are associated with Barrett's dysplasia and esophageal adenocarcinoma. In other HPV-linked cancers such as cervical and oropharyngeal cancer, circulating HPV DNA is a potential biomarker to assist in tumor diagnosis and management. This study aimed to determine whether circulating HPV DNA was detectable in patients with Barrett's dysplasia and esophageal adenocarcinoma, and if so, whether there is any correlation with esophageal tissue HPV status. Plasma from 138 patients representing esophageal adenocarcinoma (N = 41), Barrett's dysplasia (N = 48) and hospital controls (N = 49) were analyzed for the presence of circulating HPV DNA using droplet-digital PCR targeting the E7 gene of HPV types 16 and 18. Circulating HPV DNA was detected in 11/138 (8.0%) study subjects including 1/49 (2.0%) hospital controls, 4/48 (8.3%) Barrett's dysplasia patients, and 6/41 (14.6%) esophageal adenocarcinoma patients. Detection of circulating HPV DNA was higher in patients with HPV-positive esophageal tissue (6/35, 17.1%) compared to those with HPV-negative specimens (5/103; 4.9%) (OR = 4.06; 95% CI 1.15–14.25; P = 0.020). The highest rates of detection occurred in esophageal adenocarcinoma patients, particularly those with invasive tumors that had breached the esophageal submucosa, had regional lymph node involvement or metastatic disease. Circulating HPV DNA was detectable in a subset of Barrett's dysplasia and esophageal adenocarcinoma patients. Detection was associated with tissue HPV positivity and possibly disease severity.

Antiviral therapy has been shown to improve the prognosis of hepatitis B virus (HBV) DNA-positive hepatocellular carcinoma (HCC) after radical treatment, but antiviral treatments require further optimization. This study aimed to evaluate the efficacies of different antiviral strategies with HCC patients after hepatectomy/ablation. This prospective, randomized, controlled and multi-centre trial enrolled HBV DNA-positive primary HCC patients after hepatectomy/ablation between January 2007 and January 2009. Patients were divided into four groups: early combination (entecavir plus Peg-interferon [IFN]α-2a co-administration during year 1); late combination (addition of Peg-IFNα-2a for 48 weeks after 1 year of entecavir); nucleos(t)ide analogue[NA] monotherapy; and non-antiviral treatment. Primary endpoints included recurrence-free survival and overall survival. A total of 447 patients were enrolled. The 2-year and 8-year recurrence-free survival and 8-year overall survival rates were significantly higher in the early combination group than in the other two antiviral groups (P .05). After 48-week treatment, more patients achieved an HBsAg reduction1500 IU/mL and the mean HBsAg level was significantly lower in the early combination group compared with the late combination and NA monotherapy groups (P .05). Multivariate analysis showed that early combination therapy and a reduction in HBsAg by1500 IU/mL after 48 weeks of therapy correlated with reduced mortality and disease recurrence. Early introduction of combination antiviral treatment may represent a more effective therapeutic strategy for patients with HBV DNA-positive HCC after hepatectomy/ablation. A reduction in HBsAg by1500 IU/mL after 48-week treatment is associated with reduced mortality and disease recurrence of HBV DNA-positive HCC patients after hepatectomy/ablation.

AIMS This study aimed to compare outcomes in unselected patients undergoing cardiac catheterisation via transradial versus transfemoral access and standard versus ultrasound-guided arterial access. METHODS AND RESULTS This was a prospective, randomised (radial vs. femoral and standard vs. ultrasound), 2x2 factorial trial of 1,388 patients undergoing coronary angiography and percutaneous coronary intervention. The primary outcome was a composite of ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) major bleeding, MACE (death, stroke, myocardial infarction or urgent target lesion revascularisation) and vascular complications at 30 days. Transradial access reduced the primary outcome (RR 0.37, 95% CI: 0.17-0.81; p=0.013), mostly driven by ACUITY major bleeding (RR 0.343, 95% CI: 0.123-0.959; p=0.041) when compared with the transfemoral approach. There was no difference in the primary outcome between standard and ultrasound guidance (p=0.76). Ultrasound guidance, however, reduced mean access time (93 sec vs. 111 sec; p=0.009), attempts (1.47 vs. 1.9; p

Objectives Following total knee or total hip arthroplasty (TKA, THA), up to 31% of recipients experience significant weight gain while up to 14% experience significant weight loss. Factors associated with significant weight change (≥5% of baseline weight) have not been comprehensively explored. This study aimed to identify pre- and post-surgical (including current) patient factors associated with significant weight change three years after surgery. Methods A pre-existing nationally-acquired cohort who underwent TKA or THA for osteoarthritis participated in 3-year telephone follow-up. Updated weight, comorbidity, and complication data were collected along with ongoing index joint problems and other patient-reported outcomes including global improvement. These data, along with body mass index (BMI) pre-surgery and post-surgery rehabilitation received, were incorporated into two multivariable logistic regression models to determine separately the factors associated with ≥5% weight gain and ≥5% loss at 3-years post-surgery. Results 73.4% (1289/1757) participated in the follow-up; 1191 (n = 663 TKA) provided updated weight data. Patterns of weight change were similar for both surgeries (TKA: 16.1% gained ≥5%, 19.6% lost ≥5%; THA: 15.8% gained ≥5%, 17.8% lost ≥5%). In multivariable modelling, younger age and lower pre-surgery BMI were significantly associated with weight gain; female gender and an absence of ongoing index joint issues were associated with weight loss. Conclusion Different mechanisms are likely associated with significant weight gain or loss at 3-years post-surgery. Cogent weight management entails consideration of both outcomes. Many post-surgical factors appear not to be importantly associated with weight change.

Internationally, use of lidocaine infusions to treat cancer pain varies by center. Existing systematic reviews do not adequately inform use of lidocaine in cancer pain.To assess the effects of systemic sodium channel blockers on cancer pain in adults, review the dose protocols for administration, and assess toxicity.Databases CENTRAL, MEDLINE, Embase, LILACS, CareSearch, and OpenGrey were searched from inception to 2016. Conference abstracts and reference lists were handsearched, and the lead investigators of included trials and Australian manufacturers were contacted. Included studies were randomized controlled trials evaluating one or more of lidocaine via intravenous or subcutaneous route, or mexiletine, flecainide, or tocainide via oral route; delivered at a site distant to the pain locus. The methodological quality of studies was assessed using the "risk of bias" domain-based evaluation by Jadad. Protocol is available on PROSPERO:CRD42016047092.One positive (n = 50) and three negative (n = 10 each) crossover trials evaluated lidocaine versus placebo, and one trial (n = 16) compared lidocaine with dexmedetomidine. Meta-analysis of pooled data in 60 patients demonstrated a significant benefit of lidocaine infusion of 4-5 mg/kg over 30-80 minutes compared with placebo for50% reduction in cancer pain. Secondary outcomes did not show a significant difference.Based on the current available evidence, lidocaine infusion could be considered in refractory cancer pain where agents with level 1 evidence are ineffective. Further research is necessary to understand the protocol and population in which lidocaine may improve cancer pain and capitalize on the promising opportunities identified.

Discovery and development of gene targets for cancer therapeutics are lengthy and highly costly processes. Identification and evaluation of candidate gene targets are of fundamental importance. RNA interference allows candidate genes to be specifically and effectively knocked down in cancer cells. This tool can be easily incorporated into a loss-of-function approach in the initial evaluation of candidate gene targets for cancer treatment prior to moving on to animal studies and clinical trials. This chapter describes a relatively simple and straightforward protocol that makes use of small interfering RNA to achieve knockdown of the candidate gene target and to evaluate the resultant effects on four aspects of cancer cell behavior: migration, invasion, proliferation, and adhesion.

Diabetic cardiomyopathy (DCM) is a form of idiopathic heart disease, with signs including hypertrophy of myocardial cells, hypertension-independent fibrosis and coronary artery disease. Considering the involvement of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in diabetes, it was hypothesized that DDAH2 may be beneficial to cardiac function and myocardial fibrosis during the progression of DCM with involvement of the DDAH/asymmetric NG, NGdimethyl-L-arginine (ADMA)/nitric oxide synthase (NOS)/nitric oxide (NO) signaling pathway. Following establishment of diabetic rat models, diabetes-related blood biochemical indices and cardiac function were measured in diabetic rats treated with lentivirus expressing DDAH2, short hairpin RNA against DDAH2, or L-NNA (inhibitor of NOS) to identify the roles of DDAH2 in DCM. The functional roles of DDAH2 in DCM were further determined through detection of the levels of collagen I, matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 2 (TIMP2). The H9C2 myocardial cell line was selected for in vitro experiments. The effects of DDAH2 on the migration of myocardial cells under high glucose conditions were also examined. To further investigate the underlying regulatory mechanism of DDAH2 in DCM, the contents of ADMA and NO, and the activities of DDAH and NOS were observed. The DCM model rats treated with DDAH2 exhibited reduced left ventricular end-diastolic pressure, and decreased blood glucose, total cholesterol, triglyceride, fasting blood glucose, and fasting insulin levels, but exhibited increased left ventricular systolic pressure and maximum rate of left ventricular pressure rise/fall levels in myocardial tissues. Myocardial cells under high glucose conditions treated with DDAH2 showed reductions in collagen I, MMP2 and TIMP2, indicating that DDAH2 reduced cell migration. Decreased levels of ADMA and NO but increased levels of DDAH and NOS were observed following treatment with DDAH2, indicating that the DDAH/ADMA/NOS/NO pathway was activated. These results reveal that the overexpression of DDAH2 attenuates myocardial fibrosis and protects against DCM through activation of the DDAH/ADMA/NOS/NO pathway in DCM rats. These results indicate that DDAH2 is a potential therapeutic candidate for the treatment of DCM.