A novel approach towards therapeutic optimization of diclofenac

Con objeto de obtener compuestos con menor toxicidad gástrica que el diclofenaco, se sintetizaron y evaluaron cinco ésteres derivados aminoetílicos N,N-sustituidos derivados del diclofenaco. Estos ésteres se diseñaron para satisfacer el requisito estructural de disponer de una actividad anticolinérgica intacta antes de la separación. Además de bloquear el grupo carboxilo ácido mediante esterificación, esta actividad se incorporó a los ésteres sintetizados, con el beneficio adicional esperado de la reducción de la secreción de ácido gástrico y la consecuente eliminación de la irritación local mediante un mecanismo dual. En este estudio se describen la síntesis, la cinética de la hidrólisis y la actividad biológica de estos ésteres. Todos los derivados de éster permanecieron estables en tampones de pH 2,0 y 7,4 durante un período de tiempo suficiente, lo que aseguró su absorción en estado intacto y la eliminación de la irritación gástrica local producida por el fármaco principal. Se observó una rápida hidrólisis enzimática de todos los derivados en un 80% de suero humano combinado. Se descubrió que los ésteres sintetizados poseían la actividad anticolinérgica propuesta. Se mantuvo la actividad antiinflamatoria en la mayoría de los compuestos y se logró una significativa reducción del potencial ulcerogénico en comparación con el diclofenaco.In an effort for obtaining compounds with lower gastric toxicity than diclofenac, five different N,Ndisubstitutedaminoethyl ester derivatives of diclofenac were synthesized and evaluated. These esters were designed so as to satisfy the structural requirement for them to possess the anticholinergic activity in intact form before cleavage. Besides blocking the acidic carboxyl group by esterification this activity was incorporated into the synthesized esters with an expected additional benefit of having reduced gastric acid secretion and thereby abolishing the local irritation by a dual mechanism. This report describes the synthesis, hydrolysis kinetics and the biological activity of these esters. All the ester derivatives were found to be stable in buffers (pH 2.0 and 7.4) for sufficient time period, assuring them to be absorbed intact and to successfully overcome the local gastric irritation of the parent drug. A fast enzymatic hydrolysis was observed for all the derivatives in 80% pooled human serum. The synthesized esters were found to possess the proposed anticholinergic activity. The anti-inflammatory activity for most of the compounds was retained with a significant reduction in the ulcerogenic potential compared to diclofenac

ANN-based energy reconstruction procedure for TACTIC gamma-ray telescope and its comparison with other conventional methods

The energy estimation procedures employed by different groups, for determining the energy of the primary $\gamma$-ray using a single atmospheric Cherenkov imaging telescope, include methods like polynomial fitting in SIZE and DISTANCE, general least square fitting and look-up table based interpolation. A novel energy reconstruction procedure, based on the utilization of Artificial Neural Network (ANN), has been developed for the TACTIC atmospheric Cherenkov imaging telescope. The procedure uses a 3:30:1 ANN configuration with resilient backpropagation algorithm to estimate the energy of a $\gamma$-ray like event on the basis of its image SIZE, DISTANCE and zenith angle. The new ANN-based energy reconstruction method, apart from yielding an energy resolution of $\sim$ 26%, which is comparable to that of other single imaging telescopes, has the added advantage that it considers zenith angle dependence as well. Details of the ANN-based energy estimation procedure along with its comparative performance with other conventional energy reconstruction methods are presented in the paper and the results indicate that amongst all the methods considered in this work, ANN method yields the best results. The performance of the ANN-based energy reconstruction has also been validated by determining the energy spectrum of the Crab Nebula in the energy range 1-16 TeV, as measured by the TACTIC telescope.Comment: 23pages, 9 figures Accepted for publication in NIM

Investigation of trends in basin-scale temperature variables

This research paper presents an analysis of temperature variables over the West Banas basin in order to detect the presence of underlying trends employing historical temperature data for three points viz., Abu Road, Mount Abu and Pindwara obtained for a period of 40 years (1981 – 2020) from MERRA-2 database. The study aims to investigate the long-term changes in temperature trends and identify any significant patterns or anomalies in mean, maximum and minimum temperatures at monthly, seasonal and annual timescales at the three locations amounting to a total of 162 series. The trends were evaluated using the Mann-Kendall test, a popular and powerful statistical technique formulated for analysing abnormal distributions. Prior to the application of the trend test, autocorrelated time series were identified and the trend test was modified using a variance correction approach to incorporate the influence of autocorrelations upon the resultant trends. The findings of autocorrelation analysis revealed that 11 of the 162 series were autocorrelated, a majority of which were associated with the temperature series at Abu Road. The results of the trend test showed that 27 out of the 162 series possessed significant trends with the mean and maximum monsoon temperatures in most of the series exhibiting a reducing trend while the minimum temperature appeared to be rising. Overall, the research highlights the importance of monitoring temperature trends, particularly in regions that may be more vulnerable to the impacts of climate change. The findings of this study can inform future climate adaptation strategies and support decision-making processes aimed at mitigating the effects of global warming on the natural and built environment

Observations of TeV gamma-rays from Mrk 421 during Dec. 2005 to Apr. 2006 with the TACTIC telescope

The TACTIC $\gamma$-ray telescope has observed Mrk 421 on 66 clear nights from Dec. 07, 2005 to Apr. 30, 2006, totalling $\sim$ 202 hours of on-source observations. Here, we report the detection of flaring activity from the source at $\geq$ 1 TeV energy and the time-averaged differential $\gamma$-ray spectrum in the energy range 1-11 TeV for the data taken between Dec. 27, 2005 to Feb. 07, 2006 when the source was in a relatively higher state as compared to the rest of the observation period. Analysis of this data spell, comprising about $\sim$97h reveals the presence of a $\sim 12.0 \sigma$ $\gamma$-ray signal with daily flux of $>$ 1 Crab unit on several days. A pure power law spectrum with exponent $-3.11\pm0.11$ as well as a power law spectrum with an exponential cutoff $(\Gamma = -2.51\pm0.26$ and $E_0=(4.7\pm2.1) TeV)$ are found to provide reasonable fits to the inferred differential spectrum within statistical uncertainties. We believe that the TeV light curve presented here, for nearly 5 months of extensive coverage, as well as the spectral information at $\gamma$-ray energies of $>$ 5 TeV provide a useful input for other groups working in the field of $\gamma$-ray astronomy.Comment: 13pages,4figures; Accepted for publication in Astroparticle Physic

Spallation reactions. A successful interplay between modeling and applications

The spallation reactions are a type of nuclear reaction which occur in space by interaction of the cosmic rays with interstellar bodies. The first spallation reactions induced with an accelerator took place in 1947 at the Berkeley cyclotron (University of California) with 200 MeV deuterons and 400 MeV alpha beams. They highlighted the multiple emission of neutrons and charged particles and the production of a large number of residual nuclei far different from the target nuclei. The same year R. Serber describes the reaction in two steps: a first and fast one with high-energy particle emission leading to an excited remnant nucleus, and a second one, much slower, the de-excitation of the remnant. In 2010 IAEA organized a worskhop to present the results of the most widely used spallation codes within a benchmark of spallation models. If one of the goals was to understand the deficiencies, if any, in each code, one remarkable outcome points out the overall high-quality level of some models and so the great improvements achieved since Serber. Particle transport codes can then rely on such spallation models to treat the reactions between a light particle and an atomic nucleus with energies spanning from few tens of MeV up to some GeV. An overview of the spallation reactions modeling is presented in order to point out the incomparable contribution of models based on basic physics to numerous applications where such reactions occur. Validations or benchmarks, which are necessary steps in the improvement process, are also addressed, as well as the potential future domains of development. Spallation reactions modeling is a representative case of continuous studies aiming at understanding a reaction mechanism and which end up in a powerful tool.Comment: 59 pages, 54 figures, Revie

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing