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A progressive erosion of the democratic space appears as one of the emerging challenges in global health today. Such delimitation of the political interplay has a particularly evident impact on the unique public interest function of the World Health Organization (WHO). This paper aims to identify some obstacles for a truly democratic functioning of the UN specialized agency for health. The development of civil society's engagement with the WHO, including in the current reform proposals, is described. The paper also analyses how today's financing of the WHO - primarily through multi-bi financing mechanisms -- risks to choke the agency's role in global health. Democratizing the public debate on global health, and therefore the role of the WHO, requires a debate on its future role and engagement at the country level. This desirable process can only be linked to national debates on public health, and the re-definition of health as a primary political and societal concern. [ABSTRACT FROM AUTHOR]

Comprehensive Genomic Profiling (CGP) allows for the identification of many targets. Reimbursement decision-making is, however, challenging because besides the health benefits of on-label treatments and costs, other factors related to diagnostic and treatment pathways may also play a role. The aim of this study was to identify which other factors are relevant for the technology assessment of CGP and to summarize the available evidence for these factors. After a scoping search and two expert sessions, five factors were identified: feasibility, test journey, wider implications of diagnostic results, organisation of laboratories, and "scientific spillover". Subsequently, a systematic search identified 83 studies collecting mainly evidence for the factors "test journey" and "wider implications of diagnostic results". Its nature was, however, of limited value for decision-making. We recommend the use of comparative strategies, uniformity in outcome definitions, and the inclusion of a comprehensive set of factors in future evidence generation., Competing Interests: Declaration of Competing Interest L.F. van Schaik, E.G. Engelhardt, E.A. Wilthagen, A. Fernández Coves, M.A. Joore, W.H. van Harten and V.P. Retèl declare no competing interests. N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, Luszana. N Steeghs received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The aim of this study is to gain insight in the cardiorespiratory fitness of persons with lower limb amputation (LLA) during rehabilitation, and in potential factors influencing their cardiorespiratory fitness. We performed a retrospective cohort study using data from cardiopulmonary exercise tests. Included participants were adults with LLA. Main outcome was cardiorespiratory fitness expressed as O 2 peak (ml/min/kg) and was directly determined using breath-by-breath gas analysis. O 2 peak was compared to reference values for able-bodied controls. Multivariate regression analysis was performed to investigate potential factors related to O 2 peak in persons with LLA. Potential factors were age, BMI adjusted, gender, level of amputation, aetiology of amputation, unilateral/bilateral, type of ergometry and use of beta blockers. Data of 74 participants with LLA are presented; 84% male (n = 62), mean age 58.9 (SD 11.6), mean BMI 26.7 (SD 5.6), 44 participants have a LLA above the knee, 30 below the knee. Overall O 2 peak was lower in persons with LLA compared to reference values for able-bodied controls, with mean O 2 peak for the total LLA group of 14.6 ± 4.1 ml/kg/min. In the multivariate regression analysis, only age was a significant predictor for lower O 2 peak (regression coefficient: -0.15, 95% CI [0.23-0.069], r 2  = 0.166). These results indicate that the cardiorespiratory fitness in persons with LLA is low, while they actually need more energy to walk and perform other daily activities. Cardiorespiratory fitness is not closely associated with the analysed demographic or clinical factors and will have to be determined on an individual basis for use in daily practice., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: There is now strong evidence to support the positive impact of place-based medical education on the recruitment and retention of the rural health workforce in Australia. Much of this work, however, has been undertaken in the context of 'extended rural clinical placement' - students undertaking part of their medical degree in a rural location. Until recently, there were only a few places in Australia in which students could undertake the entirety of their medical degree in a rural area. With the introduction of the Murray-Darling Medical Schools Network (MDMSN) initiative, this dynamic is changing. The MDMSN is part of the Stronger Rural Health Strategy and builds on the Australian Government's existing Rural Health Multidisciplinary Training Program to establish a network of rurally based medical programs in the Murray-Darling region. The MDMSN offers a unique opportunity to explore the effect of complete rural immersion during medical school on subsequent rural practice. This article describes the establishment of a research collaboration intended to ensure the harmonisation of research data collection from the outset of the MDMSN program., Methods: The MDMSN research collaboration is a longitudinal, multi-university program of work to explore the effect of rurally based medical school programs in the Murray-Darling region. Initially it has been agreed that administrative student data will be collected from existing university datasets to help characterise this novel student cohort. Each university will then distribute an entry survey to all first-year MDMSN students. The survey will collect demographic information as well as information regarding rural background, preferences and future practice intention. Questions have been aligned with and adapted from the Medical Schools Outcomes Database survey, the Australian Bureau of Statistics, and from the literature. This information will be combined with graduate information from the Australian Health Practitioner Regulation Agency., Results: The MDMSN research collaboration will work toward the co-design of research projects, to facilitate and progress multi-site research addressing nationally relevant research questions. Early research efforts are focused on our ability to better understand the new cohort of students embarking on rurally based medical education, their practice intentions and realisation. Subsequent work of the collaboration may lead to deeper understanding of the rural student experience, any effect of 'place', changes in student professional identity over time, and their relationship to subsequent rural practice., Conclusion: The MDMSN research collaboration is a proactive initiative that brings together data and experience from five new rurally based medical programs, and answers calls for multi-institution and longitudinal studies. It is uniquely placed to capture the impact of the MDMSN program, including the effect of complete rural immersion on the future practice location of these graduates. Ultimately, the combined research efforts of the MDMSN research collaboration will add knowledge to address the known rural workforce maldistribution, particularly how to attract and retain medical workforce.

In mammals, brown adipose tissue (BAT) is activated rapidly in response to cold in order to maintain body temperature. Although BAT has been studied greatly in small animals, it is difficult to measure the activity of BAT in humans. Therefore, little is known about the heat-generating capacity and physiological significance of BAT in humans, including the degree to which components of the diet can activate BAT. This is due to the limitations in the currently most used method to assess the activation of BAT-radiolabeled glucose (fluorodeoxyglucose or 18 FDG) measured by positron emission tomography-computerized tomography (PET-CT). This method is usually performed in fasted subjects, as feeding induces glucose uptake by the muscles, which can mask the glucose uptake into the BAT. This paper describes a detailed protocol for quantifying total-body human energy expenditure and substrate utilization from BAT thermogenesis by combining indirect calorimetry, infrared thermography, and blood glucose monitoring in carbohydrate-loaded adult males. To characterize the physiological significance of BAT, measures of the impact of BAT activity on human health are critical. We demonstrate a protocol to achieve this by combining carbohydrate loading and indirect calorimetry with measurements of supraclavicular changes in temperature. This novel approach will help to understand the physiology and pharmacology of BAT thermogenesis in humans.

Using a combination of respiratory gas exchange, infrared thermography, and blood glucose (BGL) analysis, we have investigated the impact of Capsicum annuum (C. annuum) fruit powder (475 mg) or caffeine (100 mg) on metabolic activity in a placebo controlled (lactose, 100 mg) double-blinded three-way cross-over-design experiment. Metabolic measurements were made on day 1 and day 7 of supplementation in eight adult male participants (22.2 ± 2 years of age, BMI 23 ± 2 kg/m 2 , x̅ ± SD). Participants arrived fasted overnight and were fed a high carbohydrate meal (90 g glucose), raising BGL from fasting baseline (4.4 ± 0.3 mmol/L) to peak BGL (8.5 ± 0.3 mmol/L) 45 min after the meal. Participants consumed the supplement 45 min after the meal, and both caffeine and C. annuum fruit powder restored BGL (F (8,178) = 2.2, p = 0.02) to near fasting levels within 15 min of supplementation compared to placebo (120 min). In parallel both supplements increased energy expenditure (F (2, 21) = 175.6, p < 0.001) over the 120-min test period (caffeine = 50.74 ± 2 kcal/kg/min, C. annuum fruit = 50.95 ± 1 kcal/kg/min, placebo = 29.34 ± 1 kcal/kg/min). Both caffeine and C. annuum fruit powder increased supraclavicular fossa temperature (F (2,42) = 32, p < 0.001) on both day 1 and day 7 of testing over the 120-min test period. No statistical difference in core temperature or reference point temperature, mean arterial pressure or heart rate was observed due to supplementation nor was any statistical difference seen between day 1 and day 7 of intervention. This is important for implementing dietary ingredients as potential metabolism increasing supplements. Together the results imply that through dietary supplements such as caffeine and C. annuum , mechanisms for increasing metabolism can be potentially targeted to improve metabolic homeostasis in people., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Schaik, Kettle, Green, Wundersitz, Gordon, Irving and Rathner.)

Earthworms are an important soil taxon as ecosystem engineers, providing a variety of crucial ecosystem functions and services. Little is known about their diversity and distribution at large spatial scales, despite the availability of considerable amounts of local-scale data. Earthworm diversity data, obtained from the primary literature or provided directly by authors, were collated with information on site locations, including coordinates, habitat cover, and soil properties. Datasets were required, at a minimum, to include abundance or biomass of earthworms at a site. Where possible, site-level species lists were included, as well as the abundance and biomass of individual species and ecological groups. This global dataset contains 10,840 sites, with 184 species, from 60 countries and all continents except Antarctica. The data were obtained from 182 published articles, published between 1973 and 2017, and 17 unpublished datasets. Amalgamating data into a single global database will assist researchers in investigating and answering a wide variety of pressing questions, for example, jointly assessing aboveground and belowground biodiversity distributions and drivers of biodiversity change.

The impact of brown adipose tissue (BAT) metabolism on understanding energy balance in humans is a relatively new and exciting field of research. The pathogenesis of obesity can be largely explained by an imbalance between caloric intake and energy expenditure, but the underlying mechanisms are far more complex. Traditional non-selective sympathetic activators have been used to artificially elevate energy utilization, or suppress appetite, however undesirable side effects are apparent with the use of these pharmacological interventions. Understanding the role of BAT, in relation to human energy homeostasis has the potential to dramatically offset the energy imbalance associated with obesity. This review discusses paradoxical effects of caffeine on peripheral adenosine receptors and the possible role of adenosine in increasing metabolism is highlighted, with consideration to the potential of central rather than peripheral mechanisms for caffeine mediated BAT thermogenesis and energy expenditure. Research on the complex physiology of adipose tissue, the embryonic lineage and function of the different types of adipocytes is summarized. In addition, the effect of BAT on overall human metabolism and the extent of the associated increase in energy expenditure are discussed. The controversy surrounding the primary β-adrenoceptor involved in human BAT activation is examined, and suggestions as to the lack of translational findings from animal to human physiology and human in vitro to in vivo models are provided. This review compares and distinguishes human and rodent BAT effects, thus developing an understanding of human BAT thermogenesis to aid lifestyle interventions targeting obesity and metabolic syndrome. The focus of this review is on the effect of BAT thermogenesis on overall metabolism, and the potential therapeutic effects of caffeine in increasing metabolism via its effects on BAT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Van Schaik, Kettle, Green, Irving and Rathner.)

The aim of this study is to determine the 15 most important daily activities according to persons with lower limb amputation (LLA) and healthcare professionals. Persons with LLA (n = 125) and healthcare professionals (n = 44) filled in a questionnaire. Participants had to select 10 items out of a list of 40 items on the domains activity and/or participation. Selection criterion was what they considered to be most important to perform independently and order the selected 10 items from most to least important. Mean rank scores of the 15 highest scored items according to participants with LLA were compared with the mean rank scores given by professionals, using the Mann-Whitney U test with a Hochberg adjustment for multiple testing. Participants with LLA rated five activities as significantly more important compared to professionals: 'driving a car', 'bicycling', 'ascending/descending stairs', 'heavy exercise', and 'preparing meals'. Healthcare professionals rated four activities as significantly more important compared to persons with LLA: 'going to the toilet', 'getting in and out bed', 'walking around outdoors', and 'walking around indoors'. A significant difference in rating importance was present in 9 out of 15 activities between persons with LLA and healthcare professionals. This result makes it all the more clear how complex shared decision making can be and how important it is for healthcare professionals to communicate with the person with LLA.

Soil organisms, including earthworms, are a key component of terrestrial ecosystems. However, little is known about their diversity, their distribution, and the threats affecting them. We compiled a global dataset of sampled earthworm communities from 6928 sites in 57 countries as a basis for predicting patterns in earthworm diversity, abundance, and biomass. We found that local species richness and abundance typically peaked at higher latitudes, displaying patterns opposite to those observed in aboveground organisms. However, high species dissimilarity across tropical locations may cause diversity across the entirety of the tropics to be higher than elsewhere. Climate variables were found to be more important in shaping earthworm communities than soil properties or habitat cover. These findings suggest that climate change may have serious implications for earthworm communities and for the functions they provide., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To systematically review the literature on the metabolic costs of activities of daily living (ADL) in persons with a lower limb amputation (LLA)., Data Sources: A literature search was undertaken in the Pubmed, Embase, CINAHL, CENTRAL, and PsycINFO databases using keywords and synonyms for LLA, metabolic costs, and ADL. The last search was performed on November 29th, 2017., Study Selection: Studies were included if they met the following 2 criteria: participants were adults with a (unilateral or bilateral) LLA and metabolic costs were measured while participants performed a physical activity or ADL., Data Extraction and Synthesis: Data of 1,912 participants from 61 studies were included in the systematic review and meta-analysis. The studies used different terms to describe metabolic costs. Participants were recruited in different settings, relatively healthy, with few comorbidities. Limited data were available on metabolic costs of other activities than walking with a prosthesis. A linear mixed model analysis was performed based on the means reported, with study as unit of analysis and test results of different groups and measurement conditions as repeated measures within the unit of analysis. Predictors entered in the analysis were e.g. level and reason of amputation, age, weight, and height. During walking, oxygen consumption (ml O2/kg/min) and heart rate (beats/min) increased with a higher walking speed and a more proximal amputation. Additionally, oxygen consumption was determined by the interaction terms walking speed x amputation level and walking speed squared. Heart rate was determined by the interaction term walking speed squared., Conclusion: During walking, oxygen consumption (ml O2/kg/min) and heart rate (beats/min) increased with a higher walking speed and a more proximal amputation. Data on metabolic costs of other activities were limited. The poor quality of the studies and the relatively healthy participants limited generalizability of the results of the meta-analysis., Competing Interests: The authors have declared that no competing interests exist.

We investigated expression of genes involved in the proteolytic process during epileptogenesis in a rat model of temporal lobe epilepsy (TLE). In a previous microarray study we found prominent activation of this process, which reached highest expression during the acute and latent phase (1 week after SE) in CA3 and entorhinal cortex (EC). Detailed analysis shows differences in dynamics of the changes of several protease genes such as cathepsins, caspases, matrix metalloproteinases, and plasminogen activators. Most genes were acutely upregulated while others were mainly activated during the latent phase. Interestingly several proteolytic genes were still elevated in the chronic epileptic phase. Various protease inhibitors followed a similar time course. The identification of changes in the activation of genes involved in proteolysis at critical phases during epileptogenesis could point to potential time specific targets for intervention. The fact that several proteolytic genes were still activated in the chronic epileptic phase makes them interesting candidates to modify and slow down seizure progression.