Multifunctional Silver-based Nanomaterials for Non-conventional Oral Cancer Therapy through Simultaneous LOX and Selective COX-2 inhibition

Neoplastic cells have co-opted inflammatory receptors and signaling molecules that potentiate inflammation. Activated inflammatory pathways lead to neo-angiogenesis, lymph-angiogenesis, immunosuppression, tumor growth, proliferation and metastasis. This cancer-sustaining inflammation is a critical target to arrest cancer growth. Multiple drug resistance, high cost, low oral bioavailability and serious side effects have rendered conventional cytotoxic chemotherapeutics less impressive. The aim of this research was to achieve cancer debulking and proliferation prevention by limiting ‘cancer-sustaining’ tumor niche inflammation through non-conventional oral approach employing anti-inflammatory agents and avoiding conventional cytotoxic agents. Synergistic anti-inflammatory agents, i.e. celecoxib as selective COX-2 inhibitor and montelukast as cysteinyl leukotriene receptor antagonist, were selected. Silver nanoparticles (AgNPs) were used as nanocarriers because of their efficient synergistic anti-neoplastic effects and excellent oral drug delivery potential. Specifically, selected drugs were co-conjugated onto AgNPs. Synthesized nanoparticles were then surface-modified with poly (vinyl alcohol) to control particle size, avoid opsonization/preferred cellular uptake and improve dispersion. Surface plasmon resonance analysis, particle size analysis, DSC, TGA, XRD, FTIR and LIBS analysis confirmed the successful conjugation of drugs and efficient polymer coating with high loading efficiency. In-vitro, the nanoparticles manifested best and sustained release in moderately acidic (pH 4.5) milieu enabling passive tumor targeting potential. In-vivo, synthesized nanoparticles exhibited efficient dose-dependent anti-inflammatory activity reducing the dose up to 25-fold. The formulation also manifested hemo-compatibility, potent anti-denaturation activity and dose-dependent in-vitro and in-vivo anti-cancer potential against MCF-7 breast cancer and Hep-G2 liver cancer cell lines in both orthotopic and subcutaneous xenograft cancer models. The anti-inflammatory nanoparticles manifested tumor specific release potential exhibiting selective cytotoxicity at cancerous milieu with slightly acidic environment and activated inflammatory pathways. The formulation displayed impressive oral bioavailability, sustained release, negligible cytotoxicity against THLE-2 normal human hepatocytes, low toxicity (high LD50) and wide therapeutic window. Results suggest promise of developed nanomaterials as hemo-compatible, potent, cheaper, less-toxic oral anti-inflammatory and non-conventional anti-cancer agents

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Endovascular Treatment of a Traumatic Pseudo Aneurysm of the Middle Meningeal Artery

AbstractWe describe a case of traumatic pseudoaneurysm of middle meningeal artery in a patient after a head trauma. The aneurysm was associated with epidural hemorrhage and was treated successfully with coil embolization

Endovascular Treatment of a Traumatic Pseudo Aneurysm of the Middle Meningeal Artery

We describe a case of traumatic pseudoaneurysm of middle meningeal artery in a patient after a head trauma. The aneurysm was associated with epidural hemorrhage and was treated successfully with coil embolization