Tensile Response of Adhesively Bonded Composite-to-composite Single-lap Joints in the Presence of Bond Deficiency

This paper studies the quasi-static tensile response of adhesively bonded composite-to-composite single-lap joints in the presence of weak and kissing bonds, as an attempt for characterisation of bond deficiencies likely to occur in polymer composite bonded repair. Cytec FM®94 adhesive film (0.25 mm nominal thickness) was used for all joints to bond two 2mm-thickness carbon fibre polymer composite laminates manufactured from unidirectional Hexcel M21/T800S pre-pregs. Peel-ply surface treatment was used for all joints. The bonds were deteriorated via five methods: pre-curing the centre of bond area prior to the cure of the bond edges, increasing the curing temperature rate, reducing the curing time, and embedding PTFE films over the centre of the bond. For the last method, the studies were carried out by embedding PTFE films on one and two sides of the adhesive film. The bond deterioration was followed by non-destructive inspections using ultrasound C-scanning. The ultimate failure load of the joints with defected bonds (i.e. weak and kissing bonds) was measured and compared to that of the joints with no defect (i.e. good bonds). It was found that rapid curing and short-time curing reduces more than 50% of the load carrying capacity of the single-lap joins in tension while the joints with weak bonds introduced by pre-curing of a large area of the bond (>60%) can take up more than 65% of the ultimate load of the joint with good bond. Also, optical microscopy of the bond surfaces after failure showed changes in failure type for the rapid and short-time cure, strongly correlated with their significant failure load reduction

Antipsychotic dose escalation as a trigger for Neuroleptic Malignant Syndrome (NMS): literature review and case series report

Background: “Neuroleptic malignant syndrome” (NMS) is a potentially fatal idiosyncratic reaction to any medication which affects the central dopaminergic system. Between 0.5% and 1% of patients exposed to antipsychotics develop the condition. Mortality rates may be as high as 55% and many risk factors have been reported. Although rapid escalation of antipsychotic dose is thought to be an important risk factor, to date it has not been the focus of a published case series or scientifically defined. <p/>Aims: To identify cases of NMS and review risk factors for its development with a particular focus on rapid dose escalation in the 30 days prior to onset. <p/>Methodology: A review of the literature on rapid dose escalation was undertaken and a pragmatic definition of “rapid dose escalation” was made. NMS cases were defined using DSM-IV criteria and systematically identified within a secondary care mental health service. A ratio of titration rate was calculated for each NMS patient and “rapid escalators” and “non rapid escalators” were compared. <p/>Results: 13 cases of NMS were identified. A progressive mean dose increase 15 days prior to the confirmed episode of NMS was observed (241.7mg/day during days 1-15 to 346.9mg/day during days 16-30) and the mean ratio of dose escalation for NMS patients was 1.4. Rapid dose escalation was seen in 5/13 cases and non rapid escalators had markedly higher daily cumulative antipsychotic dose compared to rapid escalators. <p/>Conclusions: Rapid dose escalation occurred in less than half of this case series (n=5, 38.5%), although there is currently no consensus on the precise definition of rapid dose escalation. Cumulative antipsychotic dose – alongside other known risk factors - may also be important in the development of NMS

Bridging the gap from medical to psychological safety assessment: consensus study in a digital mental health context

Background: Digital Mental Health Interventions (DMHIs) that meet the definition of a medical device are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The MHRA uses procedures that were originally developed for pharmaceuticals to assess the safety of DMHIs. There is recognition that this may not be ideal, as is evident by an ongoing consultation for reform led by the MHRA and the National Institute for Health and Care Excellence. Aims: The aim of this study was to generate an experts’ consensus on how the medical regulatory method used for assessing safety could best be adapted for DMHIs. Method: An online Delphi study containing three rounds was conducted with an international panel of 20 experts with experience/knowledge in the field of UK digital mental health. Results: Sixty-four items were generated, of which 41 achieved consensus (64%). Consensus emerged around ten recommendations, falling into five main themes: Enhancing the quality of adverse events data in DMHIs; Re-defining serious adverse events for DMHIs; Reassessing short-term symptom deterioration in psychological interventions as a therapeutic risk; Maximising the benefit of the Yellow Card Scheme; and Developing a harmonised approach for assessing the safety of psychological interventions in general. Conclusion: The implementation of the recommendations provided by this consensus could improve the assessment of safety of DMHIs, making them more effective in detecting and mitigating risk

Synthesis, biological evaluation, and molecular docking of novel 1,3,4-substituted-thiadiazole derivatives as potential anticancer agent

In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides (4b-g), were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the hepatocellular carcinoma (HEPG-2), human lung carcinoma (A549), human breast carcinoma (MCF-7) and pseudo-normal human embryonic liver (L02) cancer cell lines by an MTT assay. Among all synthesized compounds, compound 8d showed the potent anti-cancer activities with GI50 values of 2.98, 2.85 and 2.53 μM against MCF-7, A549 and HepG-2 cell lines respectively as compared to standard drug Doxorubicin. Furthermore, molecular modelling studies have spotlighted the anchoring role of 1,3,4-substituted-thiadiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. Therefore, these results can provide promising starting points for further development of best anti-cancer agents.Graphical Abstrac

Quality of life in purely ocular myasthenia in Japan

Background: Since there has been no conclusive evidence regarding the treatment of ocular myasthenia, treatment guidelines were recently issued by the European Federation of Neurological Societies/European Neurological Society (EFNS/ENS). However, the therapeutic outcomes concerning the quality-of-life (QOL) of patients with ocular myasthenia are not yet fully understood.Methods: We investigated the therapeutic outcomes of patients with purely ocular myasthenia in a multicenter cross-sectional survey in Japan. To evaluate the severity of ocular symptoms, we used the ocular-quantitative MG (QMG) score advocated by Myasthenia Gravis Foundation of America. We used the Japanese translated version of the MG-QOL15, a self-appraised scoring system.Results: Of 607 myasthenia gravis (MG) patients with an observation-duration of illness ? 2 years, the cases of 123 patients (20%) were limited to ocular muscles (purely ocular myasthenia). During the entire clinical course, 81 patients experienced both ptosis and diplopia, 36 had ptosis alone, and six had diplopia alone. Acetyl-cholinesterase inhibitors and prednisolone were used in 98 and 52 patients, respectively. Treatment improved ocular symptoms, with the mean reduction in ocular-QMG score of 2.3 ± 1.8 points. However, 47 patients (38%) failed to gain minimal manifestation or a better status. Patients with unfavorable outcomes also self-reported severe QOL impairment. Multivariate analyses showed that the pretreatment ocular-QMG score was associated with unfavorable outcomes, but not associated with the patient\u27s QOL.Conclusion: A treatment strategy designed in accord with a patient\u27s ocular presentation must be considered in order to improve ocular symptoms and the patient\u27s QOL

Global age-sex-specific all-cause mortality and life expectancy estimates for 204 countries and territories and 660 subnational locations, 1950–2023: a demographic analysis for the Global Burden of Disease Study 2023

Background: Comprehensive, comparable, and timely estimates of demographic metrics—including life expectancy and age-specific mortality—are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study—part of the latest GBD release, GBD 2023—aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time. Methods: We used 24 025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950–2023. For the first time, we used complete birth history data for ages 5–14 years, age-specific sibling history data for ages 15–49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: In 2023, 60·1 million (95% UI 59·0–61·1) deaths occurred globally, of which 4·67 million (4·59–4·75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35·2% (32·2–38·4) over the 1950–2023 study period, during which the global age-standardised all-cause mortality rate declined by 66·6% (65·8–67·3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67·7% decrease); the largest increases in mortality for those aged 5–14 years, 25–29 years, and 30–39 years occurring in high-income North America (11·5%, 31·7%, and 49·9%, respectively); and the largest increases in mortality for those aged 15–19 years and 20–24 years occurring in Eastern Europe (53·9% and 40·1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5–14 years (87·3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950–2021 period) and for females aged 15–29 years (61·2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13·2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51·2 (50·6–51·7) years for females and 47·9 (47·4–48·4) years for males in 1950 to 76·3 (76·2–76·4) years for females and 71·4 (71·3–71·5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74·7 (74·6–74·8) years for females and 69·3 (69·2–69·4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76·3 [76·0–76·6] years for females and 71·5 [71·2–71·8] years for males). 194 (95·1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61·8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally. Interpretation: This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020–23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950–2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world