Design, Synthesis and Evaluation of Hybrid Intracellularly Targeted Anticancer and Antimicrobial Agents

One of the most important barriers to the success of anticancer therapy is the dysregulation of apoptotic pathways that limit effectiveness of current chemotherapy. A long-term objective seeks to exploit links between apoptosis and the functions of mitochondria to favour apoptosis and thus circumvent mechanisms of multi-drug resistance.The specific aims of this research are the synthesis, characterisation and evaluation of a series of novel anthraquinone-based, tri-partite hybrid DCA-ciprofloxacin-TPP compounds to repurpose clinically useful antibiotics as non-genotoxic anticancer agents; and towards the design of dual anticancer and antibacterial agents.These hybrid compounds consist of 3 components: ciprofloxacin (a broad-spectrum clinically useful 2nd generation fluoroquinolone antibiotic), dichloroacetate (DCA, a metabolic inhibitor of mitochondrial oxidation), and a triphenylphosphonium (TPP) cationic group, a hydrophobic carrier group with delocalised charge, capable of passing through mitochondrial membranes and accumulating in this organelle.Dichloroacetate (DCA) is characterised as an apoptosis inducer in cancer cells; specifically, its clean mechanism of action to inhibit the critical mitochondrial enzyme pyruvate dehydrogenase kinase 2 (PDK2).Four members of the series code-named Aq-Pip-DCA, Aq-Pip-Lys(TFA)-NH-TPP, Aq-Pip-Lys(Cp-TFA)-NH-TPP, and Aq-Pip-Lys(Cp-DCA)-NH-TPP hybrids showed good antibacterial activity. Ciprofloxacin (CIPRO) conjugate Aq-Pip-Lys(Cp-TFA)-NH-TPP was the most potent agent to inhibit bacterial growth in both sensitive (ATCC47055) and resistant (LIB213) strains of Escherichia coli (MIC 0.5 and 8 mg/L, respectively), and in Staphylococcus aureus both sensitive (82) and resistant (83) strains with MIC values 4 and 64 mg/L. In preliminary experiments, compounds from the series have shown cytotoxic activity against the resistant HCT15 colon carcinoma cell line at micromolar concentrations. Ciprofloxacin-TPP-DCA hybrids could provide multi-targeted leads for the design of biologically active agents with dual anticancer and antimicrobial activities

IMPACT OF GRAVITY MODEL ON TRADE BETWEEN CHINA AND PAKISTAN: A CASE OF CPEC BETWEEN CHINA AND PAKISTAN

To find out the trade flow among different economies, the gravity model has been applied in various researches in different regions of the world. The present study has applied the Gravity model to analyze the bilateral trade patterns between China and Pakistan. The secondary panel data was collected from 2009 and 2018. The variables used in the study were Distance, Inflation, Gross Domestic Product (GDP), and GDP per capita, Exchange Rate. The data was collected from the official websites of State Bank of Pakistan, the Pakistan Economic Survey, and the Pakistan Stock Exchange.  The fixed effect regression model was used for analysis. The results showed that the Distance, GDP growth, GDP per capita had an insignificant impact on the Trade Flow between China and Pakistan. The Exchange Rate and Inflation showed a positive and significant effect on trade between China and Pakistan. The results recommended that further studies should be done targeting other potential variables with different mediating and non-mediating roles. Keywords:Gravity Model Trade, CPE

Screening Antibacterial Activity of Vinegar & Olive Oil on Enteric Bacteria

Food-borne infection is the health problem related to food borne diseases. The majority of reported food-borne disease outbreak was caused by pathogenic bacteria. The important handling & uncooked or raw foods are risk of contamination which is unfit for human consumption & leads to food-borne infection. In the present study, the antimicrobial activity of olive oil & vinegar has been suggested that both the natural preservatives were effective & shown effective bacterial reduction & used as an inhibitors of food-borne pathogens. In this study we screened the chicken meat samples. The isolated micro-organisms were E. coli, Klebsiella, Salmonella & Shigella. Further antimicrobial activity of olive oil & vinegar were screened against these micro-organisms from our findings, it’s suggested that both the natural preservatives were effective & shown effective bacterial reduction & used as a inhibitors of food-borne pathogens. The growth of bacterial isolates was inhibited by vinegar. The vinegar & olive oil both exhibited a broad range of antimicrobial activity tested by agar-well diffusion methods & zone of inhibitions (mm) were then measured. Antibiotics sensitivity test against these microbial isolates compared with Gentamicin, Nalidixic acid & Chloramphenicol. These compounds therefore possess potential to be used as food bio-preservatives

A Novel Dynamic Appliance Clustering Scheme in a Community Home Energy Management System for Improved Stability and Resiliency of Microgrids

Power scheduling of domestic appliances is a vital preference for bridging the gap between demand and generation of electricity in a microgrid. For a stable microgrid, an acceptable mechanism must reduce the peak to average ratio (PAR) of power demand with supplementary benefits for consumers as reduced electricity charges. Recent studies have focused on PAR and cost reduction for a small consumer population. Furthermore, researchers have mainly considered homogeneous consumer loads. This study focuses on residential power scheduling for electricity cost reduction for consumers and load profile PAR curtailment for a relatively large consumer population with non-homogeneous loads. A sample population of 1000 consumers from various classes of society is considered. The proposed dynamic clustered community home energy management system (DCCHEMS) allows the clustering of appliances based on time overlap criteria. Comparatively flatter power demand is attained by utilizing the clustered appliances in conjunction with particle swarm optimization under the influence of user-defined constraints. Modified inclined block rates with real-time electricity pricing strategies are deployed to minimize the electricity costs. DCCHEMS achieved higher efficiency rates in contrast to the traditional non-clustering and static clustering optimization schemes. An improvement of 21% in peak to average ratio, 4% in cost reduction, and 19% in variance to mean ratio is obtained

Comparisons and Recommendations

For the last decade a major trend within tax administrations has been to shift from a roughly one size fits all approach—where close to all taxpayers experience a deterrence approach—to a more responsive and collaborative approach as in co-operative compliance programmes. Such programmes build on the idea that the participating corporations disclose relevant information including their tax risks and are transparent to the tax administrations and in return will tax administrations provide real-time predictability and clarity concerning taxation issues of relevance for the corporation. In brief, co-operative compliance builds on the slogan: “…certainty in exchange for transparency” (OECD 2016, 7). Co-operative compliance has increasingly become a core concern and way of organizing the relation between tax authorities and large corporate tax payers when it comes to securing tax compliance. This working paper is the result of research by Work Package 6 in EU’s Horizon 2020 funded programme FairTax that has been running for the four-year period 2015-2019. Our research in Work Package 6 addresses how proactive engagements with large corporate taxpayers have affected regulation of tax collection and administrative processes, changed relationships between stakeholders and tax administrations, and influenced tax compliance in the Nordic countries. The aim of this working paper is to provide a comparison of the experiences in four of the Nordic countries: Denmark, Finland, Norway and Sweden and to propose recommendations. The Nordic countries are considered similar and so were the co-operative compliance programmes that were implemented in each country, yet the outcomes were very different. We thus dealt with various case characteristics (Flyvbjerg 2006) where the outcomes hinged on a complexity of elements. We argue that the Swedish case is an extreme case due to its turbulent life and concomitantly with only a handful of participants that have very little activity. The Norwegian case, in contrast, is an example of a maximum variation case because of the much longer history of collaborative relationships and the outcome of the work with tax risk. The combination of a collaborative way of working and systematic risk management and monitoring may either reflect a most likely scenario of future tax administration—or perhaps the least likely. Lastly, we argue that the Danish and Finnish cases represent paradigmatic cases because both of these align largely with the standards set by the OECD and because they therefore present more ordinary or regular ways of working with co-operative compliance. Analyzing a wide variety of case characteristics means that our findings can be of general interest, beyond the Nordic countries

Variation of hepatic enzymes with Vitamin B12 and D3 levels in cirrhotic patients

OBJECTIVE: To determine variation of hepatic enzymes Vitamin B12 and D3 levels in cirrhotic patients.DESIGN: Cross sectional study.SETTING: Cirrhotic patients in Abbasi Shaheed Hospital.PARTICIPANTS: 250 patients in Abbasi Shaheed Hospital with diagnosis of cirrhosis including 141 males and 109 females.VARIABLE PARAMETERS: They include mean ALT, GGT, Alkaline phosphatase levels along with Vitamin B12 and D3 levels in blood.RESULTS: Vitamin B12 levels were 1249.59±487.01pg/ml and 1422.28±627.75pg/ml in males and females respectively while Vitamin D3 levels were found to be 17.15±10.45 nmol/L in males and 14.80±14.24 nmol/L in females. Vitamin B12 levels were found to be positively correlated with the elevation of ALT and were negatively correlated with elevation of ALT, GGT and Alkaline Phosphatase. The ALT levels were 50.0±21.88 in males and 14.80±14.24 in females, Alkaline phosphatase to be 311.46±107.98 in males while female Alkaline phosphatase were 346.47±101.60. GGT levels to be 41.70±10.62 in males and 45.01±13.74 in females.CONCLUSION: Cirrhotic patients suffering from severe hepatocellular damage have their elevated levels of Vitamin B12 and depressed Vitamin D3 levels in plasma accompanied by a positive association with elevated ALT and GGT plasma level

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Threat of antimicrobial resistance among pilgrims with infectious diseases during Hajj : lessons learnt from COVID-19 pandemic

Hajj pilgrimage is a large mass gathering global event that may facilitate the spread and emergence of various infectious diseases as well as antimicrobial resistance (AMR) in a local and global scenario. Planning and preparing for these public health issues is a challenging and complex process for the Kingdom of Saudi Arabia (KSA) health authorities. Despite multiple efforts for the prevention and treatment of infectious diseases through longtime funding in education and medical care, the prevalence of infectious disease is still high among Hajj pilgrims. The commonly observed infectious diseases during Hajj include respiratory tract infections (influenza and pneumonia), urinary tract infections and skin infections that may necessitate the use of antimicrobials. Beta-lactams are used as a first-line treatment for hospital acquired infections as well as community acquired infections due to their broad-spectrum activity. However, most of the bacterial isolates such as Staphylococcus spp., Pseudomonas spp. and E. coli are resistant to beta-lactams. Irrational use of anti-microbials, lack of infection prevention practices and suboptimal healthcare access further exacerbate the risk of spreading AMR among Hajj pilgrims. Enhanced collaboration between countries, sharing of best practices and international cooperation are crucial in addressing AMR threats among pilgrims. Consequently, robust surveillance systems for early detection and monitoring of AMR, collaboration with national as well as international healthcare agencies, effective infection prevention and control measures, public awareness, and rational use of antimicrobials via antimicrobial stewardship programs are required to mitigate the risk of AMR and ensure the health and well-being of pilgrims during Hajj

Contemporary Management of Locally Advanced and Recurrent Rectal Cancer: Views from the PelvEx Collaborative

Pelvic exenteration is a complex operation performed for locally advanced and recurrent pelvic cancers. The goal of surgery is to achieve clear margins, therefore identifying adjacent or involved organs, bone, muscle, nerves and/or vascular structures that may need resection. While these extensive resections are potentially curative, they can be associated with substantial morbidity. Recently, there has been a move to centralize care to specialized units, as this facilitates better multi-disciplinary care input. Advancements in pelvic oncology and surgical innovation have redefined the boundaries of pelvic exenterative surgery. Combined with improved neoadjuvant therapies, advances in diagnostics, and better reconstructive techniques have provided quicker recovery and better quality of life outcomes, with improved survival This article provides highlights of the current management of advanced pelvic cancers in terms of surgical strategy and potential future developments

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication