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This study was investigated to assess the effects of different traditional and commercial aqua feed on proximate composition, growth performance and survival rate of Labeo rohita reared in the composite semi-intensive culture system. The aqua feeds of various companies (AMG, Supreme, Aqua, Star Floating, Hi-Pro and Punjab feed) used as commercial feed. Farm made feeds were maize gluten and rice polish. For confidentiality, these feeds were randomly given code labels T1, T2, T3, T4, T5, T6, T7 and T8 which were only known to investigating staffs. There were two replicates for each treatment. In this experiment, higher growth rate was observed in T3 as compared to other treatments. Lesser weight gain was observed in the T1 ( 270.30 ± 0.5 ). The maximum body length ( 19.25 ± 2.19) was found in T3. Similarly, the minimum body length (5.97 ± 2.94) was seen in T2. FCR ratio (2.36 ± 0.01 ) was recorded in T3. Simultaneously, FCR (1.86 ± 0.002 ) was also recorded in T4 that is the perfect ratio for farmers. Higher SGR was noted in T3 (1.62 ± 0.05 ). Overall, T4 showed lesser SGR (1.05 ± 0.001 ). T4 showed the higher crude protein ( 28.66 ± 0.24 % ). In the body composition higher level of fat content was recorded in T3 ( 5.46 ± 0.33 %). These outcomes also proved that the rise in the dietary protein level and lipid content can improve the fish’s body crude fats and protein level. Thus, based on growth performance, survival and proximate composition. It is concluded that T3 and T4 may be recommended for commercial culture of L. rohita.

Robotic assisted surgery (RAS) has become increasingly adopted in colorectal cancer surgery. This study aims to compare robotic and laparoscopic approaches to left sided colorectal resections in terms of surgical outcomeswith no formal enhanced recovery programme. All patients undergoing robotic or laparoscopic left sided or rectal (high and low anterior resection) cancer surgery at a single tertiary referral centre over 3 years were included.A total of 184 consecutive patients from July 2017 to December 2020 were included in this study, with 40.2% (n=74/184) undergoing RAS. The median age at time of surgery was 68 years (IQR 60-73 years). RAS had a significantly shorter length of median stay of 3 days, compared to 5 days in the conventional laparoscopic surgery (CLS) group (p

We study the phase-field model with the elasticity energy arising from the coherency stress across the two-phase interface for lithium-ion batteries by using olivine LiFePO4 as a model system. The existence of global solutions about this model which is a coupled system of elliptic and parabolic equations with the singular points in the case of a logarithmic nonlinear term [Formula: see text] is proved. We demonstrate the model satisfies the second law of thermodynamics, and numerical simulations are given to show that the evolution of lithium concentration and the motion of interfaces are consistent with the experiments results of Laffont et al.

The usage of Brush-Less Direct Current (BLDC) motor has been increased in the industry especially in the field of Aerospace and electric bikes. The requirements for motion control were generated from the human eye features. The settling time and % overshoot were the desired features and design parameters. Based on desired features, values of  and ωn were found. The root-locus technique was applied to the uncompensated and compensated system, the results were not satisfactory. The % overshoot was very high, and the steady-state error was also very high. The state feedback controller was applied to the system. The % overshoot was controlled successfully but the steady-state error was still very high. To reduce the steady-state error to zero the integral control was applied. The comparison of results is presented in tabular form in the last section.

The present study was conducted to isolate and characterize bacteria from water and soil sample taken from the Lahore Canal at different sites i.e. Mall Road, Mohlanwal and Khera site. Isolated bacterial strains were identified on the basis of morphological and biochemical tests. Identification was confirmed by culturing bacteria on selective media. Antibiotic resistance test was also performed to observe the resistance of bacteria against different antibiotics. Blood agar test was performed for identification of different pathogenic bacteria. The result revealed that water and soil samples of Lahore Canal Lahore from different sites were contaminated with Escherichia coli, Salmonella sp., Vibrio sp., Bacillus spp., Enterococcus sp. and Staphylococcus spp. Due to presence of these pathogens, this water is not suitable for any domestic and irrigation use. Study also revealed that water of the Lahore Canal is harmful for human health as it is contaminated with bacteria that can cause severe disease e.g., Escherichia coli can cause gastroenteritis, Bacillus spp. can cause nausea and vomiting, Enterococcus may infect urinary tract, Salmonella sp. is responsible for Bacteremia, Staphylococcus spp. can cause mild fever and Vibrio sp. can be the reason of cholera. Thus it is rendered unfit for any kind of human use even other than drinking like swimming, bathing, washing etc., until and unless some remedial measures are employed to eradicate pathogenic microorganisms by WASA and LWMS according to standards of WHO. Similarly, it is quite harmful, when and where ever it is used for irrigation without proper treatment. Resumo O presente estudo foi realizado para isolar e caracterizar bactérias de amostras de água e solo retiradas do Canal Lahore, em Lahore, em diferentes locais, ou seja, Mall Road, Mohlanwal e Khera. As cepas bacterianas isoladas foram identificadas com base em testes morfológicos e bioquímicos. A identificação foi confirmada por cultura de bactérias em testes de meios seletivos. O teste de resistência aos antibióticos também foi realizado para observar a resistência das bactérias a diferentes antibióticos. Foi realizado o teste de ágar sangue para identificar diferentes bactérias patogênicas. O resultado revelou que amostras de água e solo do Canal Lahore, Lahore, de diferentes localidades estavam contaminadas com Escherichia coli, Salmonella sp., Vibrio sp., Bacillus spp., Enterococcus sp. e Staphylococcus spp. Por causa da presença desses patógenos, essa água não é adequada para qualquer uso doméstico e de irrigação. O estudo revelou que a água do Canal Lahore é prejudicial à saúde humana, pois está contaminada com bactérias que podem causar doenças graves, por exemplo: Escherichia coli pode ocasionar gastroenterite; Bacillus spp. pode causar náuseas e vômitos; Enterococcus sp. pode infectar o trato urinário; Salmonella sp. é responsável pela bacteremia; Staphylococcus spp. pode causar febre leve; e Vibrio sp. pode ser a razão da cólera. Assim, torna-se imprópria para uso humano, como natação, banho, lavagem etc., até que algumas medidas corretivas sejam empregadas para erradicar microrganismos patogênicos por WASA e LWMS de acordo com os padrões da OMS. Da mesma forma, é bastante prejudicial, quando usada para irrigação sem tratamento adequado.

Background: Autopsy can lead to the cause of death most accurately in both natural as well as unnatural deaths. Aim: To determine the correlation between gender and different parameters like cause of death, region involved and manner of death seen on autopsies in government hospitals of Pakistan. Study design: Retrospective study. Methodology: Patients (n=186) were enrolled in present study held at Forensic department, Sheikh Zaid Hospital, Rahim-yar Khan-Pakistan. Cases were included irrespective of gender in present study. Data analyzed by SPSS 22.0v. Results: Males were 67.9% while females were 32.1% in present study. Among these 186 cases of autopsy, manner of death was homicidal in 83(44.6%) autopsies, accidental in 49(26.3%) and suicidal deaths was in 54(29%). There was no correlation between gender & cause of death by weapon. There was correlation between gender & manner of death. There was correlation between area & cause of death by weapon. Conclusion: This study concluded that mostly males of our population were involved in medico-legal cases and criminal activities. Major cause of death remained to be firearms. Gender was correlated with manner of death but not related with cause of death by weapon. However, government needs to play its due role in-order to stop criminal acts through law enforcement. Keywords: Autopsy, Audit, Manner of Death and Cause of Death.

Aims Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of hypoglycemic agents for type 2 diabetes mellitus (T2DM), which act independently of insulin to selectively inhibit renal glucose reabsorption, thereby increasing urinary excretion of glucose. Several studies have demonstrated the cardioprotective effects of SGLT2-i in patients with heart failure (HF), with and without diabetes mellitus. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of left or right ventricular function in patients affected by HF with T2DM. Evaluate the effect of SGLT2 inhibitors on left and right ventricular function by conventional and advanced echocardiographic parameters, focusing on speckle tracking echocardiography, in patients with HF and T2DM. Methods and results BEGIN-HF is an international multi-centre registry enrolling outpatients affected by HF and T2DM. Inclusion criteria are HbA1c> 6.5%, eGFR [MDRD] > 45 ml/min/1.73 m2, age > 18 years, FE Conclusions This is the first international multicentre registry evaluating biventricular function by conventional and advanced echocardiography in patients with HF and T2DM starting and no-starting SGLT2i therapy.

Cisplatin (CP) is a commonly used, powerful antineoplastic drug, having numerous side effects. Casticin (CAS) is considered as a free radical scavenger and a potent antioxidant. The present research was planned to assess the curative potential of CAS on CP persuaded renal injury in male albino rats. Twenty four male albino rats were distributed into four equal groups. Group-1 was considered as a control group. Animals of Group-2 were injected with 5mg/kg of CP intraperitoneally. Group-3 was co-treated with CAS (50mg/kg) orally and injection of CP (5mg/kg). Group-4 was treated with CAS (50mg/kg) orally throughout the experiment. CP administration substantially reduced the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione S-transferase (GST), glutathione reductase (GSR), glutathione (GSH) content while increased thiobarbituric acid reactive substances (TBARS), and hydrogen peroxide (H2O2) levels. Urea, urinary creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, albumin and creatinine clearance was significantly reduced in CP treated group. The results demonstrated that CP significantly increased the inflammation indicators including nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activity and histopathological damages. However, the administration of CAS displayed a palliative effect against CP-generated renal toxicity and recovered all parameters by bringing them to a normal level. These results revealed that the CAS is an effective compound having the curative potential to counter the CP-induced renal damage. Resumo A cisplatina (CP) é uma droga antineoplásica poderosa, comumente usada, com vários efeitos colaterais. Casticin (CAS) é considerado um eliminador de radicais livres e um potente antioxidante. A presente pesquisa foi planejada para avaliar o potencial curativo da CAS em lesão renal induzida por PC em ratos albinos machos. Vinte e quatro ratos albinos machos foram distribuídos em quatro grupos iguais. O Grupo 1 foi considerado grupo controle. Os animais do Grupo 2 foram injetados com 5 mg / kg de PB por via intraperitoneal. O Grupo 3 foi cotratado com CAS (50 mg / kg) por via oral e injeção de CP (5 mg / kg). O Grupo 4 foi tratado com CAS (50 mg / kg) por via oral durante todo o experimento. A administração de CP reduziu substancialmente as atividades de catalase (CAT), superóxido dismutase (SOD), peroxidase (POD), glutationa S-transferase (GST), glutationa redutase (GSR), glutationa (GSH), enquanto aumentou as substâncias reativas ao ácido tiobarbitúrico (TBARS) e níveis de peróxido de hidrogênio (H2O2). Os níveis de ureia, creatinina urinária, urobilinogênio, proteínas urinárias, molécula 1 de lesão renal (KIM-1) e lipocalina associada à gelatinase de neutrófilos (NGAL) aumentaram substancialmente. Em contraste, a albumina e a depuração da creatinina foram significativamente reduzidas no grupo tratado com PC. Os resultados demonstraram que a CP aumentou significativamente os indicadores de inflamação, incluindo fator nuclear kappa-B (NF-κB), fator de necrose tumoral-α (TNF-α), interleucina-1β (IL-1β), interleucina-6 (IL-6) níveis e atividade da ciclooxigenase-2 (COX-2) e danos histopatológicos. No entanto, a administração de CAS apresentou um efeito paliativo contra a toxicidade renal gerada por CP e recuperou todos os parâmetros, trazendo-os a um nível normal. Estes resultados revelaram que o CAS é um composto eficaz com potencial curativo para combater o dano renal induzido por CP.

Patient selection for critical care admission must balance patient safety with optimal resource allocation. This study aimed to determine the relationship between critical care admission, and postoperative mortality after abdominal surgery.This prespecified secondary analysis of a multicentre, prospective, observational study included consecutive patients enrolled in the DISCOVER study from UK and Republic of Ireland undergoing major gastrointestinal and liver surgery between October and December 2014. The primary outcome was 30-day mortality. Multivariate logistic regression was used to explore associations between critical care admission (planned and unplanned) and mortality, and inter-centre variation in critical care admission after emergency laparotomy.Of 4529 patients included, 37.8% (n=1713) underwent planned critical care admissions from theatre. Some 3.1% (n=86/2816) admitted to ward-level care subsequently underwent unplanned critical care admission. Overall 30-day mortality was 2.9% (n=133/4519), and the risk-adjusted association between 30-day mortality and critical care admission was higher in unplanned [odds ratio (OR): 8.65, 95% confidence interval (CI): 3.51-19.97) than planned admissions (OR: 2.32, 95% CI: 1.43-3.85). Some 26.7% of patients (n=1210/4529) underwent emergency laparotomies. After adjustment, 49.3% (95% CI: 46.8-51.9%, P0.001) were predicted to have planned critical care admissions, with 7% (n=10/145) of centres outside the 95% CI.After risk adjustment, no 30-day survival benefit was identified for either planned or unplanned postoperative admissions to critical care within this cohort. This likely represents appropriate admission of the highest-risk patients. Planned admissions in selected, intermediate-risk patients may present a strategy to mitigate the risk of unplanned admission. Substantial inter-centre variation exists in planned critical care admissions after emergency laparotomies.

Chinese Salvia Species also called as “sages” are known as full of polyphenols that are rich source of natural antioxidants which are used to decrease levels of free radicals. Caffeic acid is an antioxidant present in Salvia as a secondary metabolite in plant metabolism. Many species of this plant are used in the treatment of degenerative disorders like cancer due to its anti-inflammatory, anti-oxygenation, anti-tumor and cytotoxic properties. Because of these specific properties of salvia species it is used in food, cosmetics and pharmaceutical industries.

Poultry industry is amongst highly developed industries of Pakistan, fulfilling the protein demand of rapidly increasing population. On the other hand, the untreated poultry waste is causing several health and environmental problems. The current study was designed to check the potential of keratinolytic fungal species for the conversion of chicken-feather waste into biofortified compost. For the purpose, three fungal species were isolated from soil samples. These strains were pure cultured and then characterized phenotypically and genotypically. BLAST searches of 18S rDNA nucleotide sequence of the fungal isolates revealed that the two fungal isolates belonged to genus Aspergillus and one belonged to genus Chrysosporium. Optimum temperature for Aspergillus flavus, Aspergillus niger and Chrysosporium queenslandicum was 29, 26 and 25 oC, respectively. A. flavus showed maximum (53%) feather degradation, A. niger degraded feather waste up to 37%, while C. queenslandicum showed 21% keratinolytic activity on chicken feathers at their respective temperature optima. The degradation potential of these fungal species showed their ability to form compost that has agro-industrial importance.

Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company. © 2020 Elsevier Ltd

This paper presents an analytical solver which is known as a generalization of types methodologies. With the proposed method, one of the old but at the same time popular problem is considered, which is known as nonlinear Zoomeron equation, and its analytical solutions are tried to obtain. Moreover, the known solutions, many new analytical solutions are obtained via the proposed method. Plotting some simulations of the solutions, we can present a conclusion.

In chemical reaction process, mathematical modeling of certain experiments lead to Brusselator system of equations. In this article, the dynamical behaviors of reaction Brusselator system with fractional Caputo derivative is studied. Also, Its stability and chaotic attractors of the commensurate fractional dynamical Brussleator system are discussed. The fractional derivative operators are nonlocal and having weak singularity as compare to the classical derivative operators. To find the analytical solutions of fractional dynamical systems is a big challenge, therefore, new techniques are worth demanding to solve such problems. To overcome this difficulty, the optimal homotopy asymptotic method is extended in this study to the system of fractional partial differential equations. A numerical example is presented as well to investigate the convergence, performance, and effectiveness of this method.

Optimal homotopy asymptotic method (OHAM), a semi-analytical process is employed, for solving singular partial differential equations of fractional order to authenticate the usefulness and competen...

Introduction Lower respiratory tract secretions from lung transplant recipients are known on rare occasions to yield a low inoculum of non-tuberculous mycobacteria. However, despite the intense systemic immunosuppression required in these recipients, disseminated mycobacterial disease has rarely been reported. Case Report A 66-year-old male with history of right total knee arthroplasty in 2007 and bilateral lung transplant in 2019 (cytomegalovirus [CMV] donor seropositive/recipient negative) was admitted with two days of fevers, chills, and dyspnea. Immunosuppression therapy included basilixumab induction and maintenance immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. A CT chest demonstrated patchy opacities in the left lung allograft and right middle lobe with a moderate partially loculated left pleural effusion. A bronchoscopy with bronchoalveolar lavage (BAL) was performed and cultures demonstrated Veillonella parvula, anaerobic gram negative bacilli, and M. fortuitum. Two months earlier, BAL cultures had demonstarted M. fortuitum, but treatment had been deferred at that time as recipient was asymptomatic. Now, with rapid improvement on cephalosporin therapy, treatment for M. fortuitum was again not pursued. The recipient was readmitted one month later with left knee pain, fever, and diarrhea, and was diagnosed with hemarthrosis and CMV colitis. Four weeks later the recipient experienced right knee pain and when joint aspiration demonstrated M. fortuitum he underwent two stage revision at which time intraoperative cultures again yielded M. fortuitum. Following this surgery the recipient then was found to have a chest wall abscess, which when incised also yielded M. fortuitum. Treatment with imipenem and ciprofloxacin for six weeks was initiated, with transition to oral ciprofloxacin for one year. Summary This case illustrates the potential for M. fortuitum pulmonary infections to result in disseminated disease in lung transplant recipients. While rarely reported in the literature, non-tuberculous mycobacterium infections have been associated with bronchiolitis obliterans syndrome and mortality in lung transplant recipients. Dissemination of M. fortuitum is uncommon and prompt recognition is crucial for appropriate source control and antibiotic therapy initiation.

Big data technologies and a range of Government open data initiatives provide the basis for discovering new insights into cities; how they are planned, how they managed and the day-to-day challenges they face in health, transport and changing population profiles. The Australian Urban Research Infrastructure Network (AURIN --- www.aurin.org.au) project is one example of such a big data initiative that is currently running across Australia. AURIN provides a single gateway providing online (live) programmatic access to over 2000 data sets from over 70 major and typically definitive data-driven organizations across federal and State government, across industry and across academia. However whilst open (public) data is useful to bring data-driven intelligence to cities, more often than not, it is the data that is not-publicly accessible that is essential to understand city challenges and needs. Such sensitive (unit-level) data has unique requirements on access and usage to meet the privacy and confidentiality demands of the associated organizations. In this paper we highlight a novel geo-privacy supporting solution implemented as part of the AURIN project that provides seamless and secure access to individual (unit-level) data from the Department of Health in Victoria. We illustrate this solution across a range of typical city challenges in localized contexts around Melbourne. We show how unit level data can be combined with other data in a privacy-protecting manner. Unlike other secure data access and usage solutions that have been developed/deployed, the AURIN solution allows any researcher to access and use the data in a manner that meets all of the associated privacy and confidentiality concerns, without obliging them to obtain ethical approval or any other hurdles that are normally put in place on access to and use of sensitive data. This provides a paradigm shift in secure access to sensitive data with geospatial content.

This paper deals with the investigation of the analytical approximate solutions for two-term fractional-order diffusion, wave-diffusion, and telegraph equations. The fractional derivatives are defined in the Caputo sense, whose orders belong to the intervals [0,1], (1,2), and [1,2], respectively. In this paper, we extended optimal homotopy asymptotic method (OHAM) for two-term fractional-order wave-diffusion equations. Highly approximate solution is obtained in series form using this extended method. Approximate solution obtained by OHAM is compared with the exact solution. It is observed that OHAM is a prevailing and convergent method for the solutions of nonlinear-fractional-order time-dependent partial differential problems. The numerical results rendering that the applied method is explicit, effective, and easy to use, for handling more general fractional-order wave diffusion, diffusion, and telegraph problems.

A visible bremsstrahlung detector array diagnostic system has been developed on the Korea Superconducting Tokamak Advanced Research (KSTAR) to view the whole minor radius in a narrow region of the continuum free of spectral lines. The interference filters coupled with photomultiplier tubes have been employed to determine the effective charge Z

Optimal homotopy asymptotic method (OHAM) is prolifically implemented to find the optimal solutions of fractional order heat- and wave-like equations. We inspect the competence of the method by examining fractional order time dependent partial differential equations. It is observed that OHAM is a prevailing and convergent method for the solutions of linear and nonlinear fractional order time dependent partial differential problems. The numerical results rendering that the applied method is explicit, effective and easy to use, for handling more general fractional order heat- and wave-like models.

Hyperkalemia can be a life-threatening disorder, especially for at-risk patients with heart failure, chronic kidney disease, with diabetes, and patients on certain drugs like renin-angiotensin-aldosterone system antagonists and mineralocorticoid receptor antagonists. There are limited therapeutic options available for hyperkalemia, and they have narrow effectiveness because of their unfavorable side effects profile in long-term and high cost utilization requiring inpatient care. Patiromersorbitex calcium and sodium zirconium cyclosilicate are novel potassium-lowering compounds for the treatment and prevention of hyperkalemia in at-risk population. These therapeutic agents have shown encouraging results in early phase II and phase III clinical trials. However, there is need to further study their efficacy and safety in heart failure population in order to establish their clinical use. The focus of this chapter will be to promote better understanding of potassium homeostasis in heart failure patients and the mechanistic overview of novel drugs, with emphasis on heart failure population.

Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. © 2017 Elsevier Ltd