The role of Actovegin in muscle injuries

Muscle injuries are one of the most common sports related injuries. An audit published by The Football Association (FA) in 2004, suggested that 12% of all injuries were hamstring injuries, which are 2.5 times more common than quadriceps injuries (Woods et al., 2004). Recent figures published by Ekstrand et al suggested that, in a professional male football team of 25 players, about 5 hamstring injuries occur each season, equivalent to more than 80 lost football days (Ekstrand et al., 2011). In terms of professional elite athletes, shortened recovery time could mean continuing with training, increased game play and benefit to the team and club. Therefore, further research is needed to analyse the new techniques in treating muscle injuries. In 2008, an article in the British Journal of Sports Medicine titled "The early management of muscle strains in the elite athlete: Best practice in the world with a limited evidence", summarised that currently almost all our socalled knowledge has a basis of level 4 or level 5 (Orchard et al., 2008a). The panel of experts continued to highlight the importance of Dr. Mueller- Wohlfahrt's injection treatment regimen for treating muscle injuries. In brief, the treatment protocol involves multiple local injections and associated back injections with a mixture of a homeopathic and pharmacological cocktail (Wohlfahrt, 2008). Therefore, the biochemical property, pharmacodynamics and pharmacokinetics of each drug are altered and unpredictable. The only potential “active” substance in Dr. Mueller-Wohlfahrt’s cocktail could be a drug called “Actovegin” which is a licenced clinically used drug with a track record of over 60 years. Therefore in this PhD thesis, in order to avoid the unpredictable nature of poly-pharmacy as discussed above, only Actovegin will be investigated. In order to investigate the potential therapeutic effect or efficacy of Actovegin on muscle injury, basic muscle structures, histology and pathophysiology of the healing process were discussed. The biochemical 10 events following skeletal muscle injuries and repair are driven by cytokines, monocytes and leukocytes. The speed and quality of muscle healing are dependent on the inflammatory process. In order to alter the speed or quality of muscle repair, Actovegin must be able to modulate the inflammatory process. The in-vitro study in this PhD thesis was the first study to investigate the role of Actovegin in the inflammatory process and demonstrated significant results. It confirmed that Actovegin could modulate the inflammatory process by influencing the CD68+ and CD163+ macrophages and CD163+ THP-1 cells, which could influence the muscle healing process. Based on the findings from the in vitro studies and data from previous literature, a stand-alone single drug intramuscular Actovegin injection therapy regimen was developed to treat acute muscle injuries. The first clinical study using this stand-alone Actovegin treatment regimen was conducted in this PhD in professional footballer players and translated the in vitro findings to clinical practice, which confirmed that Actovegin could influence clinical outcome in treating acute muscle injuries. This thesis summarises the current evidence on Actovegin. Compared with conventional conservative RICE and NSAID therapy, Actovegin proposes an exciting and legal alternative for high performance athletes. From the studies, Actovegin injection therapy seems safe and well tolerated. Overall, this PhD has suggested that Actovegin has an active role in the treatment of muscle strain injuries biochemically and clinically

Should we treat soft tissue injuries with Actovegin

Actovegin is a biological drug produced from deproteinised hemodialysate of calf serum with over 50 years of history for its clinical use. There have been many in vitro studies to speculate its potential role and mechanism of action in cells; due to the nature of this drug and serum based culture techniques for most in vitro experiments, presumptuous conclusions and claims from these studies on performance enhancement should be cautiously interpreted. There have been well-designed human in vivo studies suggesting it does not enhance human performance, and has potentially good clinical applications to treat injuries, strokes and diabetes. Recently, evidence has emerged suggesting Actovegin has anti-inflammatory and anti apoptotic effects on injured tissues; further clinical research is needed to define these effects. This article also provides a narrative review of Actovegin summarizing outcomes from recent publications

The Atacama Large Millimeter/submillimeter Array (ALMA) Band-1 Receiver

The Atacama Large Millimeter/submillimeter Array(ALMA) Band 1 receiver covers the 35-50 GHz frequency band. Development of prototype receivers, including the key components and subsystems has been completed and two sets of prototype receivers were fully tested. We will provide an overview of the ALMA Band 1 science goals, and its requirements and design for use on the ALMA. The receiver development status will also be discussed and the infrastructure, integration, evaluation of fully-assembled band 1 receiver system will be covered. Finally, a discussion of the technical and management challenges encountered will be presented

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Long-term results with the Atlas IIIp elastic cementless acetabular component in total hip replacement

Purpose Modular cementless elastic acetabular systems have advantages over cemented and hard shell cementless acetabular systems. There are few reports on the medium-term and long-term follow up of this particular type of implant. This study describes our experience with the Atlas IIIp modular acetabular system, which is a thin shell cementless elastic acetabular implant for total hip replacement commercialized under this name in many countries. Methods We prospectively followed 244 patients treated with Atlas IIIp acetabular system between 2001 and 2004. Minimum ten year follow up was available for 148 hips (139 patients) from the original cohort of 263 hips (244 patients). One hundred five patients had died from unrelated causes and were excluded from the results. Post-operative and follow up radiographs of patients were assessed; and Harris hip scores were used as clinical outcome. Revision for any reason was defined as the end point for survivorship analysis. Results The mean pre-operative Harris hip score was 48 (S.D. 16) and the average post-operative score was 82 (S.D. 12). The mean follow up in our series was 11.5 years, ranging from ten to 13.5 years. Thirteen hips required further surgery in our cohort; of which ten cases required cup revision. The 13-years cumulative implant survival was 91.2 % and the risk of implant revision was 8.8 % at 13 years in 148 hips (139 patients). Kaplan-Meier analysis showed the implant survival rate of 95.2 % at ten years for revision for any reason and 99.4 % for aseptic loosening. Conclusions Our clinical experience with this acetabular cup suggests good long-term survival rates that are similar to other cups on the market. The clinical experience in this study shows long-term survival rates that are consistent, acceptable and good results achieved with a low revision rate

Long-term results with the Atlas IIIp elastic cementless acetabular component in total hip replacement

Purpose Modular cementless elastic acetabular systems have advantages over cemented and hard shell cementless acetabular systems. There are few reports on the medium-term and long-term follow up of this particular type of implant. This study describes our experience with the Atlas IIIp modular acetabular system, which is a thin shell cementless elastic acetabular implant for total hip replacement commercialized under this name in many countries. Methods We prospectively followed 244 patients treated with Atlas IIIp acetabular system between 2001 and 2004. Minimum ten year follow up was available for 148 hips (139 patients) from the original cohort of 263 hips (244 patients). One hundred five patients had died from unrelated causes and were excluded from the results. Post-operative and follow up radiographs of patients were assessed; and Harris hip scores were used as clinical outcome. Revision for any reason was defined as the end point for survivorship analysis. Results The mean pre-operative Harris hip score was 48 (S.D. 16) and the average post-operative score was 82 (S.D. 12). The mean follow up in our series was 11.5 years, ranging from ten to 13.5 years. Thirteen hips required further surgery in our cohort; of which ten cases required cup revision. The 13-years cumulative implant survival was 91.2 % and the risk of implant revision was 8.8 % at 13 years in 148 hips (139 patients). Kaplan-Meier analysis showed the implant survival rate of 95.2 % at ten years for revision for any reason and 99.4 % for aseptic loosening. Conclusions Our clinical experience with this acetabular cup suggests good long-term survival rates that are similar to other cups on the market. The clinical experience in this study shows long-term survival rates that are consistent, acceptable and good results achieved with a low revision rate