COVID-19 and Clinical Trials: Current Challenges and Future Directions.

BACKGROUND: The outbreak of coronavirus disease (COVID-19) has posed a major threat to people's lives across the globe. It has drastically changed the way we perceive this world. A paradigm shift was observed globally as the world's emphasis shifted to testing, diagnosis, treatment, and developing a coronavirus cure. Clinical trials were also not untouched by this. The coronavirus pandemic has abhorrently affected the day-to-day clinical trial activities at sites. METHODS: The status of various ongoing clinical trials was assessed through a literature search, which also includes clinical trial portals. Our evaluations were based on these observations. RESULTS: Multiple challenges were present in clinical trials as recruitment, retention, the safety of trial subjects, protocol compliance, and this made the world to re-think to incorporate newer strategies and to cope with this untoward situation. CONCLUSION: Digitalization of clinical trials as virtual management of adverse events, remote monitoring visits, and web-based consulting with trial subjects are potential directions that can be applied to better manage clinical trials worldwide.

Pulmonary lymphangitis carcinomatosis: systematic review and meta-analysis of case reports, 1970-2018.

Pulmonary lymphangitis carcinomatosis (PLC) is a life-threating complication in patients suffering from malignancies. Misleading and nonspecific symptoms often result in a delayed diagnosis. This review was aimed at evaluating epidemiology, clinical manifestations, and survival of patients with PLC reported in the literature. According to our knowledge, this study is the first such extensive analysis of PLC. We searched for the literature in the PubMed database for articles published from 1970 to 2018 using keywords: lung, pulmonary, lymphangitic, carcinoma, carcinomatosis. Pulmonary lymphangitis carcinomatosis rarely occurs, thus all data were extracted from case reports and case series consisted of a method for identifying individual-level patient data. In the final analysis, 108 articles (139 individual patient cases) were included. The mean age of PLC occurrence is 49.21 years. There is no difference in the prevalence between men and women. The most common underlying primary tumors coexisting with PLC are breast (17.3%), lung (10.8%), and gastric cancers (10.8%). Dyspnea and dry cough were the most common symptoms occurring in 59.0% and 33.8% of patients, respectively. In half the patients, PLC developed in fewer than ten months after first diagnosis of cancer. Pulmonary lymphangitis carcinomatosis diagnosis is associated with a poor prognosis: approximately half of patients die within two months of their first respiratory symptoms and three weeks from admission to hospital. Regarding survival time, we observed better results achieved in patients described between 2000 and 2018 compared to 1970 through 1999. In the presence of progressive dyspnea, cough, and lesions comparable to interstitial lung disease, diagnosis of PLC should be considered. Pulmonary lymphangitis carcinomatosis can be the first manifestation of primary occult neoplasm and may occur at any age. Adenocarcinoma, especially primary lung, breast, and gastric cancers is the most common cancer coexisting with PLC.

Fluid therapy in non-septic, refractory acute decompensated heart failure patients - The cautious role of central venous pressure.

PURPOSE: Fluid therapy in congestive acute decompensated heart failure (ADHF) patients might be inappropriate and worsening the prognosis. The aim of our study was to analyze the effect of fluid administration on mortality in non-septic, ADHF patients with reduced ejection fraction. MATERIAL AND METHODS: We analyzed 41 ADHF consecutive 'cold-wet' patients (mean age 69.3 ± 14.9 years, 27 men, LVEF 22.8 ± 11.1%, lactates 2.2 ± 1.6 mmol/L) without sepsis. At admission central venous pressure (CVP) was measured (17.6 ± 7.2 cm H2O), and ultrasound examination of inferior vena cava (IVC) was performed (IVC min. 18.6 ± 7.3 mm and IVC max. 24.6 ± 4.3 mm). Moreover, the groups were compared (survivors vs. non-survivors as well as 1st and 4th quartile of CVP). RESULTS: Altogether 17 (41%) patients died: 16 (39%) during a mean of 11.2 ± 7.8 days of hospitalization and 1 during a 30-day follow up. Patients in the lowest CVP quartile (<13 cm H2O) had significantly worse in-hospital survival as compared to patients in the highest quartile (>24 cm H2O), P = 0.012. Higher intravenous fluid volumes within the first 24 h were infused in patients in the lowest CVP quartile as compared to the highest CVP quartile (1791.7 ± 1357.8 mL vs. 754.5 ± 631.4 mL, P = 0.046). Moreover, more fluids were infused in a group of patients who died during a hospital stay and at 30-day follow up (1362.8 ± 752.7 mL vs. 722.7 ± 1046.5 mL, P = 0.004; 1348.8 ± 731.0 mL vs. 703.6 ± 1068.4 mL, P = 0.002, respectively). CONCLUSIONS: CVP-guided intravenous fluid therapy is a common practice which in high risk ADHF 'cold-wet' patients might be harmful and should rather be avoided. Lower CVP seems to be related with worse prognosis.

Hydroxyflutamide affects connexin 43 via the activation of PI3K/Akt-dependent pathway but has no effect on the crosstalk between PI3K/Akt and ERK1/2 pathways at the Raf-1 kinase level in primary rat Sertoli cells.

We investigated the effects of 2-hydroxyflutamide (HF), an active metabolite of the anti-androgen flutamide, on the activation of the phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) in rat Sertoli cells. Sertoli cells, isolated from 20-day-old rat testes, were cultured in vitro and treated with HF, testosterone, or HF+testosterone. Studies by western blotting demonstrated that HF inhibited the testosterone-mediated increase in c-Src activity (p<0.05). In contrast, Akt phosphorylation was augmented within 5 min after HF treatment (p<0.01). This effect was accompanied by a rapid upregulation in PTEN phosphorylation (p<0.001). Despite no changes in Raf-1 phosphorylation, HF increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation (p<0.001), indicating that the effect of the anti-androgen on ERK1/2 was independent of PI3K/Akt-pathway activation at this level. Since HF inhibited the testosterone-mediated increase in c-Src activity, it is likely that activation of both Akt and ERK1/2 occurred in a p-Src independent manner. Activation of PI3K/Akt-pathway by HF resulted in the reduced level of Sertoli cell functional marker, connexin 43 (p<0.01). Collectively, these data provide evidence that HF rapidly and transiently affects the protein kinase-dependent signaling pathways, acting both as an antagonist and agonist. Moreover, using testes of flutamide-treated rats for 7 days, we demonstrated that the anti-androgen can modulate the protein kinase-dependent pathways in long term by enhancing Akt and ERK1/2 protein expression (p<0.05).