Design optimisation of additively manufactured titanium lattice structures for biomedical implants

A key advantage of additive manufacturing (AM) is that it allows the fabrication of lattice structures for customised biomedical implants with high performance. This paper presents the use of statistical approaches in design optimisation of additively manufactured titanium lattice structures for biomedical implants. Design of experiments using response surface and analysis of variance were carried out to study the effect design parameters on the properties of the AM lattice structures such as ultimate compression strength, specific compressive strength, elastic modulus, and porosity. In addition, the lattice dimensions were optimized to fabricate a diamond cellular structure with properties that match human bones. The study found that the length of a diamond-shaped unit cell strut is the most significant design parameter. In particular, the porosity of the unit cell increases as the strut length increases, while it had a significant reverse effect on the specific compressive strength, elastic modulus and ultimate compression strength. On the other hands, increasing the orientation angle was found to reduce both the specific compressive strength and modulus of elasticity of the lattice structure. An optimised lattice structure with strut diameter of 0.84 mm, length of 3.29 mm and orientation angle of 47° was shown to have specific compressive strength, elastic modulus, ultimate compression strength and porosity of 37.8 kN.m/kg, 1 GPa, 49.5 MPa and 85.7%, respectively. A cellular structure with the obtained properties could be effectively applied for trabecular bones replacement surgeries

Dynamic assembly of Hda and the sliding clamp in the regulation of replication licensing

Regulatory inactivation of DnaA (RIDA) is one of the major regulatory mechanisms of prokaryotic replication licensing. In RIDA, the Hda-sliding clamp complex loaded onto DNA directly interacts with adenosine triphosphate (ATP)-bound DnaA and stimulates the hydrolysis of ATP to inactivate DnaA. A prediction is that the activity of Hda is tightly controlled to ensure that replication initiation occurs only once per cell cycle. Here, we determined the crystal structure of the Hda-�� clamp complex. This complex contains two pairs of Hda dimers sandwiched between two �� clamp rings to form an octamer that is stabilized by three discrete interfaces. Two separate surfaces of Hda make contact with the �� clamp, which is essential for Hda function in RIDA. The third interface between Hda monomers occludes the active site arginine finger, blocking its access to DnaA. Taken together, our structural and mutational analyses of the Hda-�� clamp complex indicate that the interaction of the �� clamp with Hda controls the ability of Hda to interact with DnaA. In the octameric Hda-�� clamp complex, the inability of Hda to interact with DnaA is a novel mechanism that may regulate Hda function. ? The Author(s) 2017.113Ysciescopu

Validated spectrophotometric approach for the estimation of an antiepileptic drug: retigabine in pure form and pharmaceutical formulations utilizing N-Bromosuccinimide as an oxidant

A spectrophotometric method that is sensitive, easy, accurate, exact, reproducible, and verified has been developed for quantifying a new antiepileptic medication called retigabine in both its pure form and pharmaceutical formulations. The techniques employ N-bromosuccinimide (NBS) as an oxidizing agent and three dyes, namely amaranth, methylene blue, and indigo carmine. The three methods rely on the oxidation reaction of retigabine with an excess of N-bromosuccinimide (NBS) in an acidic environment. The unreacted NBS is then quantified by reacting it with fixed amounts of dyes, specifically amaranth, methylene blue, and indigo carmine. The absorbance at 520 nm, 664 nm, and 610 nm is measured for each respective dye. Linear relationships with high correlation coefficients (0.9992-0.9997) were observed under optimal conditions across concentration ranges of 0.5-12, 0.5-16, and 0.5–10 µg/ml. The limit of detection (LOD) for amaranth, methylene blue, and indigo carmine methods were determined to be 0.15, 0.15, and 0.14 µg/ml, respectively. The accuracy and precision of the approaches have been assessed for both intra-day and inter-day measurements. There was no observable interference caused by the typical tablet excipients. The proposed methodologies were verified in compliance with ICH recommendations and effectively utilized for the analysis of retigabine in pharmaceutical formulations. The reliability of the approaches was confirmed by conducting recovery studies employing the usual addition method. The findings produced by the proposed methods were statistically compared to those of the described approach using the student's t-test and F-test, which showed a significant level of agreement

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world. FundingBill & Melinda Gates Foundation