Building health research systems to achieve better health

Health research systems can link knowledge generation with practical concerns to improve health and health equity. Interest in health research, and in how health research systems should best be organised, is moving up the agenda of bodies such as the World Health Organisation. Pioneering health research systems, for example those in Canada and the UK, show that progress is possible. However, radical steps are required to achieve this. Such steps should be based on evidence not anecdotes. Health Research Policy and Systems (HARPS) provides a vehicle for the publication of research, and informed opinion, on a range of topics related to the organisation of health research systems and the enormous benefits that can be achieved. Following the Mexico ministerial summit on health research, WHO has been identifying ways in which it could itself improve the use of research evidence. The results from this activity are soon to be published as a series of articles in HARPS. This editorial provides an account of some of these recent key developments in health research systems but places them in the context of a distinguished tradition of debate about the role of science in society. It also identifies some of the main issues on which 'research on health research' has already been conducted and published, in some cases in HARPS. Finding and retaining adequate financial and human resources to conduct health research is a major problem, especially in low and middle income countries where the need is often greatest. Research ethics and agenda-setting that responds to the demands of the public are issues of growing concern. Innovative and collaborative ways are being found to organise the conduct and utilisation of research so as to inform policy, and improve health and health equity. This is crucial, not least to achieve the health-related Millennium Development Goals. But much more progress is needed. The editorial ends by listing a wide range of topics related to the above priorities on which we hope to feature further articles in HARPS and thus contribute to an informed debate on how best to achieve such progress

The utilisation of health research in policy-making: Concepts, examples, and methods of assessment

Chapter 1: Introduction and Background • The importance of utilising health research in policy-making, and therefore the need to understand the mechanisms involved, is increasingly recognised. Recent reports calling for more resources to improve health in developing countries, and global pressures for accountability, draw greater attention to research-informed policy-making. • For at least twenty years there has been recognition of the multiple meanings or models of research utilisation in policy-making. It has similarly been long recognised that a range of factors is involved in the interactions between health research and policy-makers. • The emerging focus on Health Research Systems (HRS) has identified additional mechanisms through which greater utilisation of research could be achieved. Assessment of the role of health research in policy-making is best undertaken as part of a wider study that also includes the utilisation of health research by industry, medical practitioners, and the public. Chapter 2: The Nature of Policy-Making, Types of Research and Utilisation Models • Policy-making broadly interpreted includes national health policies made by government ministers and officials, policies made by local health service managers, and clinical guidelines from professional bodies. In this report, however, the main focus is on public policy-making rather than that conducted by professional bodies. The utilisation of health research in policy-making should eventually lead to desired outcomes, including health gains. Research can make a contribution in at least three phases of the policy-making process: agenda setting; policy formulation; and implementation. Descriptions of these processes, however, can over-estimate the degree of rationality in policy-making. Therefore, the analysis is informed by a review of the full range of policy-making models. These include rational and incrementalist models. • Various categories of research are likely to be used differently in health policy-making. Applied research might be more readily useable by a policy system than basic research, but health policy-makers tend to relate more willingly to natural sciences than social sciences. When research is based on the priorities of potential users, and/or is research of proven quality, this increases the possibility that it will be translated into policies. There also appears to be a greater chance of research being used in clinical policies about delivering care to patients, than in national policies on the structures of the health service. • Models of research utilisation in policy-making start with a link to rational or instrumental views of policy-making, and include descriptions of how commissioned research can help to find solutions to problems. Other models relate to an incrementalist view in which policy-making involves a series of small steps over a long period; research findings might gradually cause a shift in perceptions about an issue in a process of ‘enlightenment’. Interactive models of research utilisation stress the way in which policy-makers and researchers might develop links over a long period. Research can also be used symbolically to support decisions already taken. Chapter 3: Examples from Previous Studies • A study of health policy-making in two southern African countries illustrates how policy-making processes can be analysed. It addresses agenda setting, policy formulation and implementation. The methods used included documentary analysis and key informant interviews. • Many previous studies of research utilisation can provide lessons for future assessments. Two broad approaches can be identified. Some studies start with pieces, or programmes, of research and examine their impact. Others consider policy on a particular topic and assess the role of research in the policy-making. There are advantages and drawbacks in each approach, and overlaps between them. • To facilitate comparison, studies of research utilisation are best organised around a conceptual framework. Despite that, the influence of contextual factors in different settings makes it difficult to generalise. • The two methods used most frequently, and usually together, come from the qualitative tradition: documentary analysis and in-depth interviews. Questionnaires, bibliometric analysis, insider knowledge and historical approaches have all been applied. A few recent studies have attempted to score or scale the level of utilisation. • The examples suggest there is a greater level of utilisation and final outcomes in terms of health, health equity, and social and economic gain than is often assumed, whilst still showing much underutilisation. There is considerable variation in the degree of utilisation, both within and between studies. Chapter 4: Key Issues in the Analysis of Research Utilisation in Policy-Making • Increasing attention is focusing on the concept of interfaces between researchers and the users of research. This incorporates the idea that there are likely to be different values and interests between the two communities. • In relation to utilisation, the prioritisation debate revolves around two key aspects: whether priorities are being set that will produce research that policy-makers and others will want to use, and whether priorities are being set that will engage the interests and commitment of the research community. • Interactions across the interface between policy-makers and researchers are important in transferring research to policy-makers. This fits especially well with the interactive model of utilisation. Actions by individual researchers can be useful in generating interaction, but it is desirable to consider the role of the HRS in encouraging or facilitating interactions, networks and mechanisms at a system-wide level. The HRS could provide funding and organisational support for various items including: long-term research centres; research brokerage/translator mechanisms; the creation of official committees of policy-makers and researchers; and mechanisms for review and synthesis of research findings. • There is increased recognition of the significance of policy-makers in their role as the receptors of research. In relation to the perspective of policy-makers there is a spectrum of key questions. These range from whether relevant research is available and effectively being brought to their attention, to whether they are able to absorb it and willing to use it. The HRS has a responsibility, especially in the early parts of the spectrum, but the wider health system also has a responsibility to create appropriate institutional mechanisms and ensure there are staff willing and able to incorporate relevant research. • More attention should be given to the role of incentives, both for researchers to produce utilisable research, and for policy-makers, at the system or individual level, to use it. The assessment of utilisation becomes a key issue if rewards are to focus on relevance as well as research excellence. • An appropriate model for assessing research utilisation in policy-making combines analysis of two issues: the role of receptors and the importance of actions at the interfaces. An emphasis on the role of the receptor is necessary because ultimately it is up to the policy-maker to make the decisions. Any assessment of the success of the HRS in relation to utilisation must accept that the wider political context is beyond the control of the HRS, but consider the activities of the HRS, within its given context, to enhance the utilisation of research by increasing the permeability of the interfaces. Chapter 5: Assessment of Research Utilisation in Health Policy-Making • The reasons for assessing the utilisation of research in policy-making include: advocacy, accountability, and increased understanding. For the World Health Organization there could be a role in conducting such assessments with the aim of providing evidence of the effective use of research resources. This could support advocacy for greater resources to be made available for health research. It is important that the purposes of any assessment are taken into account in planning the methods to be used. • Previous studies demonstrated the difficulties of making generalisations about specific factors associated with high levels of utilisation. To address this in any cross-national WHO initiative involving a series of studies in a range of countries, it would be desirable to structure all the studies around a conceptual framework (such as the interfaces and receptor framework considered here) and base the studies in each country on common themes. These could include policies for the adoption of multi-drug therapy for treating leprosy, and for the equitable access to health services. • Analysis of documents and semi-structured interviews would be appropriate methods in each study assessing the role of research in policy-making on a specific policy theme. Questionnaires could also have a role. These approaches would provide triangulation of methods and data-sources and should also provide material to help identify the relative importance, in relation to the level of utilisation recorded, of the HRS mechanisms described in the previous analysis. The types and sources of research used, and reasons for their use, should also be recorded and attempts made to correlate them with the previous priority setting approaches. It is expected that each study will produce its own narrative or story of what caused utilisation in the particular context, but the data gathered could also be applied to descriptive scales of the level research utilisation. The four scales could cover the consistency of policy with research findings, and the degree of influence of research on agenda setting, policy formulation, and implementation. • The findings from the assessments in each participating country should be collated. For each policy theme or topic the analysis would compare two sets of data: the scales for level of research utilisation in each country, and the contextualised lists of the HRS activities and other mechanisms and networks thought to be important. Although the account here has focused on research impact on policy-making, the evaluations would be stronger as part of a wider analysis covering research utilisation and interactions with practitioners, industry and the public. • Given appropriate and targeted topic and country selection, this approach is likely to meet the purpose of using structured methods to provide examples of effective research utilisation. The approach should contribute towards enhanced understanding of the issues and could provide the basis of an assessment tool which, if used widely in countries, could lead to greater utilisation of health research.Research Policy and Co-operation (RPC) Department of the World Health Organization, Geneva; UK Department of Health’s Policy Research Programme; Alliance for Health Policy and Systems Research from the governments of Norway and Sweden; World Bank and International Development Research Council of Canad

Kinesin's backsteps under mechanical load

Kinesins move processively toward the plus end of microtubules by hydrolyzing ATP for each step. From an enzymatic perspective, the mechanism of mechanical motion coupled to the nucleotide chemistry is often well explained using a single-loop cyclic reaction. However, several difficulties arise in interpreting kinesin's backstepping within this framework, especially when external forces oppose the motion of kinesin. We review evidence, such as an ATP-independent stall force and a slower cycle time for backsteps, that has emerged to challenge the idea that kinesin backstepping is due to ATP synthesis, i.e., the reverse cycle of kinesin's forward-stepping chemomechanics. Supplementing the conventional single-loop chemomechanics with routes for ATP-hydrolyzing backward steps and nucleotide-free steps, especially under load, gives a better physical interpretation of the experimental data on backsteps.Comment: 5 figures and 2 table

Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material.The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders

Evidence-informed health policy: are we beginning to get there at last

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A Characterization of Scale Invariant Responses in Enzymatic Networks

An ubiquitous property of biological sensory systems is adaptation: a step increase in stimulus triggers an initial change in a biochemical or physiological response, followed by a more gradual relaxation toward a basal, pre-stimulus level. Adaptation helps maintain essential variables within acceptable bounds and allows organisms to readjust themselves to an optimum and non-saturating sensitivity range when faced with a prolonged change in their environment. Recently, it was shown theoretically and experimentally that many adapting systems, both at the organism and single-cell level, enjoy a remarkable additional feature: scale invariance, meaning that the initial, transient behavior remains (approximately) the same even when the background signal level is scaled. In this work, we set out to investigate under what conditions a broadly used model of biochemical enzymatic networks will exhibit scale-invariant behavior. An exhaustive computational study led us to discover a new property of surprising simplicity and generality, uniform linearizations with fast output (ULFO), whose validity we show is both necessary and sufficient for scale invariance of enzymatic networks. Based on this study, we go on to develop a mathematical explanation of how ULFO results in scale invariance. Our work provides a surprisingly consistent, simple, and general framework for understanding this phenomenon, and results in concrete experimental predictions

Many-body approach to proton emission and the role of spectroscopic factors

The process of proton emission from nuclei is studied by utilizing the two-potential approach of Gurvitz and Kalbermann in the context of the full many-body problem. A time-dependent approach is used for calculating the decay width. Starting from an initial many-body quasi-stationary state, we employ the Feshbach projection operator approach and reduce the formalism to an effective one-body problem. We show that the decay width can be expressed in terms of a one-body matrix element multiplied by a normalization factor. We demonstrate that the traditional interpretation of this normalization as the square root of a spectroscopic factor is only valid for one particular choice of projection operator. This causes no problem for the calculation of the decay width in a consistent microscopic approach, but it leads to ambiguities in the interpretation of experimental results. In particular, spectroscopic factors extracted from a comparison of the measured decay width with a calculated single-particle width may be affected.Comment: 17 pages, Revte

Secular evolution versus hierarchical merging: galaxy evolution along the Hubble sequence, in the field and rich environments

In the current galaxy formation scenarios, two physical phenomena are invoked to build disk galaxies: hierarchical mergers and more quiescent external gas accretion, coming from intergalactic filaments. Although both are thought to play a role, their relative importance is not known precisely. Here we consider the constraints on these scenarios brought by the observation-deduced star formation history on the one hand, and observed dynamics of galaxies on the other hand: the high frequency of bars and spirals, the high frequency of perturbations such as lopsidedness, warps, or polar rings. All these observations are not easily reproduced in simulations without important gas accretion. N-body simulations taking into account the mass exchange between stars and gas through star formation and feedback, can reproduce the data, only if galaxies double their mass in about 10 Gyr through gas accretion. Warped and polar ring systems are good tracers of this accretion, which occurs from cold gas which has not been virialised in the system's potential. The relative importance of these phenomena are compared between the field and rich clusters. The respective role of mergers and gas accretion vary considerably with environment.Comment: 18 pages, 8 figures, review paper to "Penetrating Bars through Masks of Cosmic Dust: the Hubble Tuning Fork Strikes a New Note", Pilanesberg, ed. D. Block et al., Kluwe

Cold gas accretion in galaxies

Evidence for the accretion of cold gas in galaxies has been rapidly accumulating in the past years. HI observations of galaxies and their environment have brought to light new facts and phenomena which are evidence of ongoing or recent accretion: 1) A large number of galaxies are accompanied by gas-rich dwarfs or are surrounded by HI cloud complexes, tails and filaments. It may be regarded as direct evidence of cold gas accretion in the local universe. It is probably the same kind of phenomenon of material infall as the stellar streams observed in the halos of our galaxy and M31. 2) Considerable amounts of extra-planar HI have been found in nearby spiral galaxies. While a large fraction of this gas is produced by galactic fountains, it is likely that a part of it is of extragalactic origin. 3) Spirals are known to have extended and warped outer layers of HI. It is not clear how these have formed, and how and for how long the warps can be sustained. Gas infall has been proposed as the origin. 4) The majority of galactic disks are lopsided in their morphology as well as in their kinematics. Also here recent accretion has been advocated as a possible cause. In our view, accretion takes place both through the arrival and merging of gas-rich satellites and through gas infall from the intergalactic medium (IGM). The infall may have observable effects on the disk such as bursts of star formation and lopsidedness. We infer a mean ``visible'' accretion rate of cold gas in galaxies of at least 0.2 Msol/yr. In order to reach the accretion rates needed to sustain the observed star formation (~1 Msol/yr), additional infall of large amounts of gas from the IGM seems to be required.Comment: To appear in Astronomy & Astrophysics Reviews. 34 pages. Full-resolution version available at http://www.astron.nl/~oosterlo/accretionRevie

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN.

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of (-1.0_{-1.1}^{+0.9})  eV^{2}. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation