Aquatic surface respiration improves survival during hypoxia in zebrafish ( Danio rerio ) lacking hypoxia-inducible factor 1-α

Hypoxia-inducible factor 1-α (Hif-1α), an important transcription factor regulating cellular responses to reductions in O 2 , previously was shown to improve hypoxia tolerance in zebrafish ( Danio rerio ). Here, we examined the contribution of Hif-1α to hypoxic survival, focusing on the benefit of aquatic surface respiration (ASR). Wild-type and Hif-1α knockout lines of adult zebrafish were exposed to two levels (moderate or severe) of intermittent hypoxia. Survival was significantly compromised in Hif-1α knockout zebrafish prevented from accessing the surface during severe (16 mmHg) but not moderate (23 mmHg) hypoxia. When allowed access to the surface in severe hypoxia, survival times did not differ between wild-type and Hif-1α knockouts. Performing ASR mitigated the negative effects of the loss of Hif-1α with the knockouts initiating ASR at a higher P O 2 threshold and performing ASR for longer than wild-types. The loss of Hif-1α had little impact on survival in fish between 1 and 5 days post-fertilization, but as the larvae aged, their reliance on Hif-1α increased. Similar to adult fish, ASR compensated for the loss of Hif-1α on survival. Together, these results demonstrate that age, hypoxia severity and, in particular, the ability to perform ASR significantly modulate the impact of Hif-1α on survival in hypoxic zebrafish.

Use of endoscopic ultrasound for pancreatic cancer from 2000 to 2016

Background and study aims Pancreatic cancer (PC) is the fourth most common cause of cancer death in the United States. Previous studies have suggested a survival benefit for endoscopic ultrasound (EUS), an important tool for diagnosis and staging of PC. This study aims to describe EUS use over time and identify factors associated with EUS use and its impact on survival. Patients and methods This was a retrospective review of the Surveillance, Epidemiology and End Results (SEER) database linked with Medicare claims. EUS use, clinical and demographic characteristics were evaluated. Chi-squared analysis, Cochran-Armitage test for trend, and logistic regression were used to identify associations between sociodemographic and clinical factors and EUS. Kaplan-Meier and Cox proportional hazard ratios were used for survival analysis. Results EUS use rose during the time period, from 7.4 % of patients in 2000 to 32.4 % in 2015. Patient diversity increased, with a rising share of older, non-White patients with higher Charlson comorbidity scores. Both clinical (receipt of other therapies, PC stage) and nonclinical factors (region of country, year of diagnosis) were associated with receipt of EUS. While EUS was associated with a survival improvement early in the study period, this effect did not persist for PC patients diagnosed in 2012 to 2015 (median survival 3 month ± standard deviation [SD] 9.8 months without vs. 4 months ± SD 8 months with EUS). Conclusions Our data support previous studies, which suggest a survival benefit for EUS when it was infrequently used, but finds that benefit was attenuated as EUS became more widely available.

Maternal high-fat diet consumption programs male offspring to mitigate complications in liver regeneration

In the last decades, obesity and nonalcoholic fatty liver disease (NAFLD) have become increasingly prevalent in wide world. Fatty liver can be detrimental to liver regeneration (LR) and offspring of obese dams (HFD-O) are susceptible to NAFLD development. Here we evaluated LR capacity in HFD-O after partial hepatectomy (PHx). HFD-O re-exposed or not to HFD in later life were evaluated for metabolic parameters, inflammation, proliferation, tissue repair markers and survival rate after PHx. Increasing adiposity and fatty liver were observed in HFD-O. Despite lower IL-6 levels, Ki67 labeling, cells in S phase and Ciclin D1/PCNA protein content, a lower impact on survival rate was found after PHx, even when re-exposed to HFD. However, no difference was observed between offspring of control dams (SC-O) and HFD-O after surgery. Although LR impairment is dependent of steatosis development, offspring of obese dams are programmed to be protected from the damage promoted by HFD.

255 Tricuspid regurgitation in the community by routine echocardiography

Aims Tricuspid Regurgitation (TR) is quite frequent in the community and often overlooked in routine clinical practice. This study aims to convey the TR rate of diagnosis and impact on survival in a geographically defined population of an Italian referral centre, considering five different clinical contexts. Methods The study included consecutive outpatients with comprehensive echocardiography and complete clinical evaluation over 7 years of practice. Outpatients with TR greater than moderate were included, and the different clinical contexts evaluated: patients with concomitant significant mitral regurgitation (MR-TR), heart failure (HF-TR), previous open-heart surgery (postop-TR), pulmonary hypertension (PHTN-TR) and isolated TR (isolated-TR). Results Among all consecutive echocardiograms performed in routine practice (N=6797) in a geographically defined community, moderate or severe TR was found in 4.8% (N = 327; mean age 76±10, 56% female). Median follow-up was 6.1 [2.2–8.9] years. TR severity was an independent determinant of survival: risk ratio for mortality of severe TR vs. moderate was 1.72 [95% CI 1.06–2.77; P = 0.03] univariate and 1.76 [95% CI 1.02–3.01; P = 0.04] after adjusted for age, sex, MR, PHTN and EF. Only 2.8% of patients underwent tricuspid valve surgery during follow-up. Outpatients with MR-TR or HF-TR held the worst prognosis (Figure). As compared to isolated-TR, the mortality risk was 2.67 [95% CI 1.05–6.78; P = 0.04] for HF-TR and 2.04 [95% CI 1.00–4.14; P = 0.05] for MR-TR. Risk ratios for mortality vs. postop-TR were 3.66 [95% CI 1.19–11.26; P= 0.02] for HF-TR and 2.79 [95% CI 1.08–7.21; P = 0.03] for MR-TR. There was no interaction between the TR clinical context and the survival impact of TR (P=0.09). Conclusions Significant TR is frequent in our community, comparable to key epidemiological studies. TR severity independently impacts survival in all clinical settings, and it is associated with an absolute high event-rate when present with concomitant MR or HF. These results give importance to early diagnosis with grading to be performed through accurate echocardiography and renew the interest in new and safe, less invasive percutaneous intervention to improve patients' survival.

230 Antiplatelet therapy and outcome in COVID-19. Results from a multi-centre international prospective registry (HOPE-COVID)

Aims Standard therapy for Corona-virus-19 disease (COVID-19) is mainly developed for critical ill patients. Autopsy studies showed high prevalence of platelet-fibrin rich micro-thrombi in several organs. Aim of the study was to evaluate safety and efficacy of antiplatelet therapy (APT) in COVID-19 hospitalized patients and its impact on survival. Methods and results 7824 consecutive patients with COVID-19 were enrolled in a multicentre-international prospective registry (HOPE-COVID-19). Clinical data and in-hospital complications were recorded. Antiplatelet (AP) regimen, including aspirin and other antiplatelet drugs, was obtained for each patient. During hospitalization 730 (9%) patients received AP drugs with single (93%, n = 680) or dual APT (7%, n = 50). Patients treated with APT were older (74 ± 12 vs. 63 ± 17 years, P < 0.01), more frequently male (68% vs. 57%, P < 0.01) and had higher prevalence of diabetes (39% vs. 16%, P < 0.01). Patients treated with APT compared with no APT showed no differences in terms of in-hospital mortality (18% vs. 19%, P = 0.64, Log Rank P = 0.23), need of invasive ventilation (8.7% vs. 8.5%, P = 0.88), embolic events (2.9% vs. 2.5% P = 0.34) and bleeding (2.1% vs. 2.4%, P = 0.43) but shorter duration of mechanical ventilation (8 ± 5 vs. 11 ± 7 days, P = 0.01); however, when comparing patients with APT vs. no APT and no anticoagulation therapy, APT was associated with lower mortality rates (Log Rank P < 0.01, relative risk 0.79, 95% CI: 0.70–0.94). At multivariable analysis in-hospital APT was associated with a lower mortality risk (relative risk 0.39, 95% CI: 0.32–0.48, P < 0.01). Conclusions APT during hospitalization for COVID-19 could be associated with lower mortality risk and shorter duration of mechanical ventilation, without increased risk of bleeding.

A REVIEW ON BIOACTIVE PHYTOCHEMICALS AND IT’S MECHANISM ON CANCER TREATMENT AND PREVENTION BY TARGETING MULTIPLE CELLULAR SIGNALING PATHWAYS

In developing and developed countries, cancer is a significant health problem in people. Cancer becomes the second greatest cause of death in human after cardiovascular disease. However, significant advancements in modern cancer therapies have a beneficial impact on survival, chemotherapy and radiation therapy. Plants fulfill our basic needs to continue life and provide natural products that help to cure disease. The medicinal plants are readily available and have no toxicity as compared to modern drugs. Phytochemicals act on metabolic pathways and inhibit tumor growth, the development of cancerous cells, and replication by different mechanisms. Apigenin's chemo-preventive and anticancer activities have been demonstrating in numerous studies. Curcumin is a polyphenolic compound isolated from the Curcuma longa plant. EGCG, a polyphenol in black, white, and green tea is a chemo-preventive effect against many cancers by targeting multiple pathways. Normal cell growth and cell proliferation are closely regulated processes. The JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway controls gene expression during different processes, including proliferation, initiation, and apoptosis. The transcription factors are associated with the growth of cancer cells and control a cellular function in the disease. Mitogen-activated protein kinase (MAPK) is a class of serine and threonine kinase that includes ERK (extracellular regulated kinase), JNK (c-Jun N-terminal kinases), and p38. This review paper describes natural phytochemical compounds, their molecular targets and mechanisms of action.

123 Prophylactic anticoagulation and aspirin therapy for hospitalized patients with COVID-19: a propensity score-matched analysis of the hope-COVID-19 registry

Aims No standard therapy is currently recommended for moderately ill Corona-virus-19 disease (COVID-19) patients. Potential benefit in terms of survival for anticoagulation were found only in this subset of patients. Aim of this study was to evaluate safety and efficacy of add-on antiplatelet therapy with aspirin over prophylactic anticoagulation (PAC) in COVID-19 hospitalized patients and its impact on survival. Methods and results 7824 consecutive patients with COVID-19 were enrolled in a multicentre-international prospective registry (HOPE-COVID-19). Clinical data and in-hospital complications, including mortality, were recorded. Study population included only patients treated with aspirin and/or PAC. A comparison of clinical outcomes between add-on antiplatelet therapy and PAC and patients treated with PAC only was performed using an adjusted analysis with propensity score (PS) matching. Of 7824 patients, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC only. Propensity-score matching yielded 298 patients from each group. Mean age was 73 ± 11 years, 67% were male, prevalence of hypertension and diabetes was 79% and 33%, respectively, and 7.5 % underwent invasive ventilation. In the propensity score-matched population, cumulative incidence curves of in-hospital mortality were lower in patients treated with PAC and Aspirin vs. PAC only (15% vs. 21%, Log Rank P = 0.01). At multivariable analysis in propensity matched population of COVID-19 patients, including age, sex, hypertension, diabetes, kidney failure and invasive ventilation, aspirin treatment was associated with lower risk of in-hospital mortality (HR: 0.62, CI: 95% 0.42–0.92, P = 0.018). Conclusions Add-on anti-platelet therapy with aspirin over PAC in COVID-19 hospitalized patients was associated with lower mortality risk in a propensity score matched population.