Efekti piretroidnog insekticida deltametrina na parametre oksidativnog stresa u različitim tkivima zelene krastave žabe (Bufotes viridis)

One of the main causes of declining frog populations is the increased use of pesticides. The toxicity mechanisms for most pesticides in non-target organisms are associated with oxidative stress. The present doctoral thesis examines acute and chronic Bufotes viridis exposure to pyrethroid insecticide deltamethrin (DM). In the part of experiment that examined acute exposure to DM oral application (96 h) was used, while chronic exposure (7, 14 and 21 days) included oral, dermal and combined oral-dermal application. The following oxidative stress, biotransformation and neurotoxicity parameters were analyzed: the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST); the concentrations of glutathione (GSH), sulfhydryl groups (-SH) and thiobarbituric reactive substances (TBARS); the activity of neurotoxicity biomarker-cholinesterase (ChE) and the expression of phase I biotransformation enzyme cytochrome P4501A (CYP1A). The effects of DM were examined on the liver, muscle, gastrointestinal tissue and skin of adult individuals. The obtained results suggest that DM (although it does not tend to accumulate in tissues) can be hazardous to amphibians and that pesticide exposure modulates the parameters of oxidative stress in selected toad tissues. The data show that the DM-induced systemic toxicity was dose-, route of application- and time-dependent. Toads exposed to this insecticide respond by producing tissue-specific adaptive responses in the course of establishing cell defense to the resulting oxidative stress. The present investigation supports the hypothesis that oxidative stress is one of the steps of pesticide-induced toxicity and that further examination are required to elucidate the entire mechanism.Jedan od glavnih uzroka opadanja populacije žaba u svetu je povećana upotreba pesticida. Mehanizmi toksičnosti za većinu pesticida u non-target organizmima su povezani sa oksidativnim stresom. U ovoj doktorskoj disertaciji ispitivan je efekat akutne i hronične izloženosti zelene krastave žabe Bufotes viridis piretroidnom pesticidu deltametrinu (DM). U delu eksperimenta koji se bavio akutnim izlaganjem DM (96 h), primenjen je oralni način aplikacije, dok je hronično izlaganje (7, 14 i 21 dan) uključivalo oralnu, dermalnu i kombinovanu oralno-dermalnu aplikaciju. Analizirani su sledeći parametri oksidativnog stresa, biotransformacije i neurotoksičnosti: aktivnosti superoksid dismutaze (SOD), katalaze (CAT), glutation-peroksidaze (GSH-Px), glutation-reduktaze (GR) i glutation-S-transferaze (GST); koncentracije glutationa (GSH), sulfhidrilnih grupa (-SH) i tiobarbiturnih reaktivnih supstanci (TBARS); aktivnost biomarkera neurotoksičnosti-holinesteraze (ChE) i ekspresija biotransformacionog enzima faze I-citohroma P4501A (CIP1A). Efekti DM ispitivani su na jetri, mišiću, gastrointestinalnom tkivu i koži adultnih jedinki. Rezultati ove doktorske disertacije sugerišu da deltametrin (iako nema tendenciju akumuliranja u tkivima) može biti opasan za vodozemce i da izloženost pesticidima modulira ispitivane parametre oksidativnog stresa u tkivima zelenih krastavih žaba. Dobijeni podaci pokazuju da je sistemska toksičnost izazvana deltametrinom zavisila od doze, načina i vremena aplikacije pesticida. Jedinke izložene ovom insekticidu su stvorile specifične adaptivne reakcije tkiva u cilju odbrane ćelija od rezultirajućeg oksidativnog stresa. Sadašnje istraživanje podržava hipotezu da je nastanak oksidativnog stresa jedan od razloga toksičnosti pesticida, ali potrebno je dalje ispitivanje da bi se ceo mehanizam u potpunosti rasvetlio

Study the correlation between the activity of investment funds and the market value of stocks listed in the fina

    في إطار تلبية رغبات المستثمرين والمدخرين على حد سواء ومواكبة الأسواق المالية العالمية في استخدام الأدوات المالية الحديثة ظهرت فكرة إنشاء صناديق الاستثمار، فأنشأت المملكة العربية السعودية أول صندوق استثماري على مستوى الدول العربية عام 1979، ونجحت المملكة في هذه التجربة ليبلغ عدد الصناديق الاستثمارية فيها 273 صندوق عام 2017 حيث امتازت هذه الصناديق بتنوعها وشمولها، وفي هذا السياق تهدف الدراسة الى اظهار الدور الذي يمكن أن تؤديه صناديق الاستثمار في تعزيز القيمة السوقية لما لها من دور في إزالة التخوف من استخدام هذه الأداة المالية وإعطاء الثقة للمستثمر بهذه الصناديق، وذلك باستخدام المنهج الكمي لمعرفة هذا الأثر، وتم الحصول على بيانات سنوية إحصائية من مؤسسة النقد العربي السعودي, وبناء النموذج القياسي عن طريق برنامج Eviews10)) واستخدام أسلوب الانحدار الخطي المتعدد والمربعات الصغرى، وقد توصلت الدراسة إلى وجود علاقة طردية بين كل من عدد الصناديق، إجمالي الأصول وعدد المشتركين من جهة والقيمة السوقية من جهة أخرى في سوق الأسهم السعودي خلال الفترة السابقة.   In the context of satisfying the wishes of investors and savers alike and keeping abreast of global financial markets in the use of modern financial tools, the idea of ​​establishing investment funds emerged. The Kingdom of Saudi Arabia established the first investment fund at the level of Arab countries in 1979, and the Kingdom succeeded in this experiment, bringing the number of investment funds to 273 funds In 2017, as these funds were distinguished by their diversity and coverage, and in this context the study aims to show the role that investment funds can play in enhancing the market value because of their role in removing fear of using this financial instrument and giving confidence to touch. Fruit of these boxes, using the quantitative method to know this effect, and annual statistical data were obtained from the Saudi Arabian Monetary Agency, and the construction of the standard model through the Eviews10 program) and the use of the multiple linear regression method and the least squares, and the study concluded that there is a direct relationship between each From the number of funds, total assets, number of subscribers on one side, and market value on the other hand in the Saudi stock market during the previous period

Aberrometry from Astronomy to Vision Science

Aberrometry is a branch from optical metrology and more directly from astronomy. Applied to the science of vision, it allows for dramatic improvements in human vision research, such as refining the visual capabilities of healthy and diseased subjects beyond physiological limits. In retinal imaging, it permits observing with very high resolution, photoreceptors allowing glimpsing an earlier diagnosis of some retinal pathologies as well as the observation and assessment of more effective treatments. They rely on the ocular wave front collection with the help of an aberrometer which allows establishing the precise and quantitative record of the various optical aberrations of the human eye, whether low or high degree. In this work, we draw our approach to apply these concepts to refractive surgery and contact lenses adaptation, to relate the changes in higher-order aberrations (HOAs) following wavefront-guided femtosecond laser-assisted (WFG FS-LASIK), and to explore the correlations between preoperative spherical equivalence (SE) and mechanisms of HOAs affecting the visual quality

Study protocol for a phase 1/2, single-centre, double-blind, double-dummy, randomized, active-controlled, age de-escalation trial to assess the safety, tolerability and immunogenicity of a measles and rubella vaccine delivered by a microneedle patch in healthy adults (18 to 40 years), measles and rubella vaccine-primed toddlers (15 to 18 months) and measles and rubella vaccine-naïve infants (9 to 10 months) in The Gambia [Measles and Rubella Vaccine Microneedle Patch Phase 1/2 Age De-escalation Trial].

BACKGROUND: New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants. METHODS: This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18-40 years] followed by 120 toddlers [15-18 months] and 120 infants [9-10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee. DISCUSSION: This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination. TRIAL REGISTRATION: Pan-African Clinical Trials Registry 202008836432905 . CLINICALTRIALS: gov NCT04394689

A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial.

BACKGROUND: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children. METHODS: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18-40 years for the adult cohort, 15-18 months for toddlers, or 9-10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete. FINDINGS: Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0-97·2) seroconverted to measles and 100% (58/58; 93·8-100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2-95·2) and 100% (59/59; 93·9-100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events. INTERPRETATION: The safety and immunogenicity data support the accelerated development of the MRV-MNP. FUNDING: Bill & Melinda Gates Foundation

Prevention and treatment for COVID-19 associated severe pneumonia in the Gambia (PaTS-COVID-19), a single-blinded randomized clinical trial: study protocol

Background: The coronavirus disease (COVID-19) pandemic resulted in an unprecedent global response for the development of COVID-19 vaccines. However, as viral mutations continue to occur, potentially decreasing the efficacy of currently available vaccines, and inequity of vaccine access continues, identifying safe and effective drugs to minimise severity of COVID-19 disease remains a priority. Methods: We designed an adaptive individually randomised single blinded non identical placebo-controlled trial to evaluate the safety and efficacy of repurposing licenced treatments for COVID-19 patients in an African setting. The trial has two cohorts: Cohort 1 recruits mild and moderate COVID-19 cases and their household contacts. Cases are actively followed up for 14 days, with a final visit at day 28. There are two co-primary endpoints: clinical progression to severe-pneumonia and persistence of the virus at day 14. The primary endpoint for household contacts is infection during a 14-day follow-up period. Cohort 2 recruits hospitalized patients with severe COVID-19 associated pneumonia followed up actively until discharge or death, and passively until day 90, with a final visit. The primary endpoint is clinical progression or death. Conclusions: This randomised trial will contribute African-specific data to the global response to COVID-19. Besides the efficacy of drugs on clinical progression, the trial will provide information on the dynamics of intra-household transmission. Trial registration: This study is registered with Clinical Trials.gov with registration number NCT04703608 and with Pan African clinical trials registry with registration number PACTR202101544570971

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer

Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations

Trade Balance and Oil Shocks in African Oil Exporting Countries: A Panel Threshold Regression

This paper is driven by the vast influence oil money have on the current account balance of major oil producing countries in Africa and the role policy measures could play to soften these effects. Dwelling on the nonlinear techniques, two types of Threshold Regression were used to estimate data on 8 African countries from 1995-2019. The results show evidence of nonlinear impacts of oil revenue on the current account balances of the 8 countries. The nature of the impact relies significantly on the levels of the threshold variable. Precisely, the estimated threshold benchmark for financial development was 33.34; below this threshold the sensitivity of current account balance to crude-oil shocks is higher and the probability of policy measures to mitigate the effects is low and, beyond the threshold the sensitivity of current account balance to crude-oil shocks is low and the probability of policy measure to mitigate the effects is higher. The finding suggested among others that crude-oil shocks is not the primary problem of the current account imbalance of oil-exporting countries rather the nature of the domestic economic policy environment

Successful Control of Ebola Virus Disease: Analysis of Service Based Data from Rural Sierra Leone

Introduction: The scale and geographical distribution of the current outbreak in West Africa raised doubts as to the effectiveness of established methods of control. Ebola Virus Disease (EVD) was first detected in Sierra Leone in May 2014 in Kailahun district. Despite high case numbers elsewhere in the country, transmission was eliminated in the district by December 2014. We describe interventions underpinning successful EVD control in Kailahun and implications for EVD control in other areas. Methods Internal service data and published reports from response agencies were analysed to describe the structure and type of response activities, EVD case numbers and epidemic characteristics. This included daily national situation reports and District-level data and reports of the Sierra Leone Ministry of Health and Sanitation, and Médecins Sans Frontières (MSF) patient data and internal epidemiological reports. We used EVD case definitions provided by the World Health Organisation over the course of the outbreak. Characteristics assessed included level of response activities and epidemiological features such as reported exposure (funeral-related or not), time interval between onset of illness and admission to the EVD Management Centre (EMC), work-related exposures (health worker or not) and mortality. We compared these characteristics between two time periods—June to July (the early period of response), and August to December (when coverage and quality of response had improved). A stochastic model was used to predict case numbers per generation with different numbers of beds and a varying percentage of community cases detected. Results There were 652 probable/confirmed EVD cases from June-December 2014 in Kailahun. An EMC providing patient care opened in June. By August 2014 an integrated detection, treatment, and prevention strategy was in place across the district catchment zone. From June-July to August-December 2014 surveillance and contact tracing staff increased from 1.0 to 8.8 per confirmed EVD case, EMC capacity increased from 32 to 100 beds, the number of burial teams doubled, and health promotion activities increased in coverage. These improvements in response were associated with the following changes between the same periods: the proportion of confirmed/probable cases admitted to the EMC increased from 35% to 83% (χ2 p-value<0·001), the proportion of confirmed patients admitted to the EMC <3 days of symptom onset increased from 19% to 37% (χ2 p-value <0·001), and reported funeral contact in those admitted decreased from 33% to 16% (χ2 p-value <0·001). Mathematical modelling confirmed the importance of both patient management capacity and surveillance and contact tracing for EVD control. Discussion Our findings demonstrate that control of EVD can be achieved using established interventions based on identification and appropriate management of those who are at risk of and develop EVD, including in the context of ongoing transmission in surrounding regions. Key attributes in achieving control were sufficient patient care capacity (including admission to specialist facilities of suspect and probable cases for assessment), integrated with adequate staffing and resourcing of community-based case detection and prevention activities. The response structure and coverage targets we present are of value in informing effective control in current and future EVD outbreaks