Digital public health (DiPH) provides novel approaches for prevention, potentially leading to long-term health benefits in resource-limited health systems. However, cost-effectiveness of DiPH ...interventions is unclear. This systematized review investigates the use of decision-analytic modelling in health economic evaluations of DiPH primary prevention and health promotion interventions, focusing on intervention's design, methods used, results, and reporting quality.
PubMed, CINAHL, and Web of Science were searched for studies of decision-analytic economic evaluations of digital interventions in primary prevention or health promotion, published up to June 2022. Intervention characteristics and selected items were extracted based on the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Incremental cost-effectiveness ratios (ICERs) were then extracted and price-adjusted to compare the economic evaluation results. Finally, the included studies' reporting quality was assessed by building a score using CHEERS.
The database search (including search update) produced 2,273 hits. After removing duplicates, 1,434 titles and abstracts were screened. Of the 89 studies meeting the full-text search criteria, 14 were ultimately reviewed. The most common targets were physical activity (five studies) and weight loss (four). Digital applications include text messages, web-based inventions, app-based interventions, e-learning devices, and the promotion of smartphone apps. The mean ICER of the 12 studies using quality-adjusted life years (QALYs) is €20,955 per QALY (min. - €3,949; max. €114,211). The mean of reported CHEERS items per study is 81% (min. 59%; max. 91%).
This review only includes primary prevention and health promotion, and thus excludes other DiPH fields (e.g. secondary prevention). It also focuses on decision-analytic models, excluding study-based economic evaluations. Standard methods of economic evaluation could be adapted more to the specifics of DiPH by measuring the effectiveness of more current technologies through alternative methods, incorporating a societal perspective, and more clearly defining comparators. Nevertheless, the review demonstrates using common thresholds that the new field of DiPH shows potential for cost-effective preventive interventions.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We develop a general minimally coupled subspace approach (MCSA) to compute absolute entropies of macromolecules, such as proteins, from computer generated canonical ensembles. Our approach overcomes ...limitations of current estimates such as the quasi-harmonic approximation which neglects non-linear and higher-order correlations as well as multi-minima characteristics of protein energy landscapes. Here, Full Correlation Analysis, adaptive kernel density estimation, and mutual information expansions are combined and high accuracy is demonstrated for a number of test systems ranging from alkanes to a 14 residue peptide. We further computed the configurational entropy for the full 67-residue cofactor of the TATA box binding protein illustrating that MCSA yields improved results also for large macromolecular systems.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many protein-protein docking protocols are based on a shotgun approach, in which thousands of independent random-start trajectories minimize the rigid-body degrees of freedom. Another strategy is ...enumerative sampling as used in ZDOCK. Here, we introduce an alternative strategy, ReplicaDock, using a small number of long trajectories of temperature replica exchange. We compare replica exchange sampling as low-resolution stage of RosettaDock with RosettaDock's original shotgun sampling as well as with ZDOCK. A benchmark of 30 complexes starting from structures of the unbound binding partners shows improved performance for ReplicaDock and ZDOCK when compared to shotgun sampling at equal or less computational expense. ReplicaDock and ZDOCK consistently reach lower energies and generate significantly more near-native conformations than shotgun sampling. Accordingly, they both improve typical metrics of prediction quality of complex structures after refinement. Additionally, the refined ReplicaDock ensembles reach significantly lower interface energies and many previously hidden features of the docking energy landscape become visible when ReplicaDock is applied.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protein dynamics on the atomic level and on the microsecond timescale has recently become accessible from both computation and experiment. To validate molecular dynamics (MD) at the submicrosecond ...timescale against experiment we present microsecond MD simulations in 10 different force-field configurations for two globular proteins, ubiquitin and the gb3 domain of protein G, for which extensive NMR data is available. We find that the reproduction of the measured NMR data strongly depends on the chosen force field and electrostatics treatment. Generally, particle-mesh Ewald outperforms cut-off and reaction-field approaches. A comparison to measured J-couplings across hydrogen bonds suggests that there is room for improvement in the force-field description of hydrogen bonds in most modern force fields. Our results show that with current force fields, simulations beyond hundreds of nanoseconds run an increased risk of undergoing transitions to nonnative conformational states or will persist within states of high free energy for too long, thus skewing the obtained population frequencies. Only for the AMBER99sb force field have such transitions not been observed. Thus, our results have significance for the interpretation of data obtained with long MD simulations, for the selection of force fields for MD studies and for force-field development. We hope that this comprehensive benchmark based on NMR data applied to many popular MD force fields will serve as a useful resource to the MD community. Finally, we find that for gb3, the force-field AMBER99sb reaches comparable accuracy in back-calculated residual dipolar couplings and J-couplings across hydrogen bonds to ensembles obtained by refinement against NMR data.
Protein dynamics are essential for protein function, and yet it has been challenging to access the underlying atomic motions in solution on nanosecond-to-microsecond time scales. We present a ...structural ensemble of ubiquitin, refined against residual dipolar couplings (RDCs), comprising solution dynamics up to microseconds. The ensemble covers the complete structural heterogeneity observed in 46 ubiquitin crystal structures, most of which are complexes with other proteins. Conformational selection, rather than induced-fit motion, thus suffices to explain the molecular recognition dynamics of ubiquitin. Marked correlations are seen between the flexibility of the ensemble and contacts formed in ubiquitin complexes. A large part of the solution dynamics is concentrated in one concerted mode, which accounts for most of ubiquitin's molecular recognition heterogeneity and ensures a low entropic complex formation cost.
Mass spectrometry-based proteomics has greatly benefitted from enormous advances in high resolution instrumentation in recent years. In particular, the combination of a linear ion trap with the ...Orbitrap analyzer has proven to be a popular instrument configuration. Complementing this hybrid trap-trap instrument, as well as the standalone Orbitrap analyzer termed Exactive, we here present coupling of a quadrupole mass filter to an Orbitrap analyzer. This “Q Exactive” instrument features high ion currents because of an S-lens, and fast high-energy collision-induced dissociation peptide fragmentation because of parallel filling and detection modes. The image current from the detector is processed by an “enhanced Fourier Transformation” algorithm, doubling mass spectrometric resolution. Together with almost instantaneous isolation and fragmentation, the instrument achieves overall cycle times of 1 s for a top10 higher energy collisional dissociation method. More than 2500 proteins can be identified in standard 90-min gradients of tryptic digests of mammalian cell lysate— a significant improvement over previous Orbitrap mass spectrometers. Furthermore, the quadrupole Orbitrap analyzer combination enables multiplexed operation at the MS and tandem MS levels. This is demonstrated in a multiplexed single ion monitoring mode, in which the quadrupole rapidly switches among different narrow mass ranges that are analyzed in a single composite MS spectrum. Similarly, the quadrupole allows fragmentation of different precursor masses in rapid succession, followed by joint analysis of the higher energy collisional dissociation fragment ions in the Orbitrap analyzer. High performance in a robust benchtop format together with the ability to perform complex multiplexed scan modes make the Q Exactive an exciting new instrument for the proteomics and general analytical communities.
The high-resolution refinement of docked protein-protein complexes can provide valuable structural and mechanistic insight into protein complex formation complementing experiment. Monte Carlo (MC) ...based approaches are frequently applied to sample putative interaction geometries of proteins including also possible conformational changes of the binding partners. In order to explore efficiency improvements of the MC sampling, several enhanced sampling techniques, including temperature or Hamiltonian replica exchange and well-tempered ensemble approaches, have been combined with the MC method and were evaluated on 20 protein complexes using unbound partner structures. The well-tempered ensemble method combined with a 2-dimensional temperature and Hamiltonian replica exchange scheme (WTE-H-REMC) was identified as the most efficient search strategy. Comparison with prolonged MC searches indicates that the WTE-H-REMC approach requires approximately 5 times fewer MC steps to identify near native docking geometries compared to conventional MC searches.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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