34 research outputs found
Selective targeting of proteins by hybrid polyoxometalates: Interaction between a bis-biotinylated hybrid conjugate and avidin
The Keggin-type polyoxometalate [\u3b3-SiW10O36]8 12 was covalently modified to obtain a bis-biotinylated conjugate able to bind avidin. Spectroscopic studies such as UV-vis, fluorimetry, circular dichroism, coupled to surface plasmon resonance technique were used to highlight the unique interplay of supramolecular interactions between the homotetrameric protein and the bis-functionalized polyanion. In particular, the dual recognition mechanism of the avidin encompasses (i) a complementary electrostatic
association between the anionic surface of the polyoxotungstate and each positively charged avidin subunit and (ii) specific host-guest interactions between each biotinylated arm and a corresponding pocket on the tetramer subunits. The assembly exhibits peroxidase-like reactivity and it was used in aqueous solution for L-methionine methyl ester oxidation by H2O2. The recognition phenomenon was then exploited for the preparation of layer-by-layer films, whose structural evolution was monitored in situ by
ATR-FTIR spectroscopy. Finally, cell tracking studies were performed by exploiting the specific interactions with a labeled streptavidin
Early clinical experience of radiotherapy of prostate cancer with volumetric modulated arc therapy
<p>Abstract</p> <p>Background</p> <p>To report about initial clinical experience in radiation treatment of carcinoma of prostate with volumetric modulated arcs with the RapidArc (RA) technology.</p> <p>Methods</p> <p>Forty-five patients with a median age of 72 ± 3, affected by prostate carcinoma (T1c: 22 patients, T2a-b: 17 patients, T3a-b: 6 patients. N0: 43 patients, N1-Nx: 2 patients, all M0), with initial PSA of 10.0 ± 3.0 ng/mL, were treated with RapidArc in a feasibility study. All patients were treated with single arc using 6MV photons. Dose prescription ranged between 76 (7 patients) and 78 Gy (38 patients) in 2Gy/fraction. Plan quality was assessed by means of Dose Volume Histogram (DVH) analysis. Technical parameters of arcs and pre-treatment quality assurance results (Gamma Agreement Index, GAI) are reported to describe delivery features. Early toxicity was scored (according to the Common Terminology Criteria of Adverse Effects scale, CTCAE, scale) at the end of treatment together with biochemical outcome (PSA).</p> <p>Results</p> <p>From DVH data, target coverage was fulfilling planning objectives: V<sub>95% </sub>was in average higher than 98% and V<sub>107%</sub>~0.0% (D<sub>2%</sub>~104.0% in average). Homogeneity D<sub>5%</sub>-D<sub>95% </sub>ranged between 6.2 ± 1.0% to 6.7 ± 1.3%. For rectum, all planning objectives were largely met (e.g. V<sub>70Gy </sub>= 10.7 ± 5.5% against an objective of < 25%) similarly for bladder (e.g. D<sub>2% </sub>= 79.4 ± 1.2Gy against an objective of 80.0Gy). Maximum dose to femurs was D<sub>2% </sub>= 36.7 ± 5.4Gy against an objective of 47Gy. Monitor Units resulted: MU/Gy = 239 ± 37. Average beam on time was 1.24 ± 0.0 minutes. Pre-treatment GAI resulted in 98.1 ± 1.1%. Clinical data were recorded as PSA at 6 weeks after RT, with median values of 0.4 ± 0.4 ng/mL. Concerning acute toxicity, no patient showed grade 2-3 rectal toxicity; 5/42 (12%) patients experienced grade 2 dysuria; 18/41 (44%) patients preserved complete or partial erectile function.</p> <p>Conclusion</p> <p>RapidArc proved to be a safe, qualitative and advantageous treatment modality for prostate cancer.</p
Mycobacterial ESAT-6 and katG are Recognized by Sarcoidosis CD4+ T Cells When Presented by the American Sarcoidosis Susceptibility Allele, DRB1*1101
Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019
Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of
social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries,
and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key
indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational
locations from 1950 to 2019.
Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other
sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR)
was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to
age groups 10â14 and 50â54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific
fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult
mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured
as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling
histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5
and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed agespecific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality
generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other
sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of
net migration and population for each country and territory were generated using a Bayesian hierarchical cohort
component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and
747 population registry years. We classified location-years into seven categories on the basis of the natural rate of
increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration
rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and
standard demographic methods. Uncertainty was propagated throughout the demographic estimation process,
including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric.
Findings The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66â2·79) in 2000 to 2·31 (2·17â2·46) in
2019. Global annual livebirths increased from 134·5 million (131·5â137·8) in 2000 to a peak of 139·6 million
(133·0â146·9) in 2016. Global livebirths then declined to 135·3 million (127·2â144·1) in 2019. Of the 204 countries and
territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of
replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted
for 27·1% (95% UI 26·4â27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI
66·8â67·6) in 2000 to 73·5 years (72·8â74·3) in 2019. The total number of deaths increased from 50·7 million
(49·5â51·9) in 2000 to 56·5 million (53·7â59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1â10·3) in 2000
to 5·0 million (4·3â6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0â6·3) in 2000 to
7·7 billion (7·5â8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population
declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased
from 58·6 years (56·1â60·8) in 2000 to 63·5 years (60·8â66·1) in 2019. HALE increased in 202 of 204 countries and
territories between 2000 and 2019.
Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing,
with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such
as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries
have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more
populations into the late stages of the demographic transition. Tracking demographic change and the emergence of
new patterns will be essential for global health monitorin
Global burden of 369 diseases and injuries in 204 countries and territories, 1990â2019: a systematic analysis for the Global Burden of Disease Study 2019
Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990â2010 time period, with the greatest annualised rate of decline occurring in the 0â9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10â24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10â24 years were also in the top ten in the 25â49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50â74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
Size-segregated aerosol in a hot-spot pollution urban area: Chemical composition and three-way source apportionment
In this work, a comprehensive characterisation and source apportionment of size-segregated aerosol collected using a multistage cascade impactor was performed. The samples were collected during wintertime in Milan (Italy), which is located in the Po Valley, one of the main pollution hot-spot areas in Europe. For every sampling, size-segregated mass concentration, elemental and ionic composition, and levoglucosan concentration were determined. Size-segregated data were inverted using the program MICRON to identify and quantify modal contributions of all the measured components. The detailed chemical characterisation allowed the application of a three-way (3-D) receptor model (implemented using Multilinear Engine) for size-segregated source apportionment and chemical profiles identification. It is noteworthy that - as far as we know - this is the first time that three-way source apportionment is attempted using data of aerosol collected by traditional cascade impactors. Seven factors were identified: wood burning, industry, resuspended dust, regional aerosol, construction works, traffic 1, and traffic 2. Further insights into size-segregated factor profiles suggested that the traffic 1 factor can be associated to diesel vehicles and traffic 2 to gasoline vehicles. The regional aerosol factor resulted to be the main contributor (nearly 50%) to the droplet mode (accumulation sub-mode with modal diameter in the range 0.5\ue2\u80\u931 \uce\ubcm), whereas the overall contribution from the two factors related to traffic was the most important one in the other size modes (34\ue2\u80\u9341%). The results showed that applying a 3-D receptor model to size-segregated samples allows identifying factors of local and regional origin while receptor modelling on integrated PM fractions usually singles out factors characterised by primary (e.g. industry, traffic, soil dust) and secondary (e.g. ammonium sulphate and nitrate) origin. Furthermore, the results suggested that the information on size-segregated chemical composition in different size classes was exploited by the model to relate primary emissions to rapidly-formed secondary compounds