Contextual factors influencing the equitable implementation of precision medicine in routine cancer care in Belgium.

BACKGROUND: Precision medicine represents a paradigm shift in health systems, moving from a one-size-fits-all approach to a more individualized form of care, spanning multiple scientific disciplines including drug discovery, genomics, and health communication. This study aims to explore the contextual factors influencing the equitable implementation of precision medicine in Belgium for incorporating precision medicine into routine cancer care within the Belgian health system. METHODS: As part of a foresight study, our approach evaluates critical factors affecting the implementation of precision oncology. The study scrutinizes contextual, i.e. demographic, economic, societal, technological, environmental, and political/policy-related (DESTEP) factors, identified through a comprehensive literature review and validated by a multidisciplinary group at the Belgian Cancer Center, Sciensano. An expert survey further assesses the importance and likelihood of these factors, illuminating potential barriers and facilitators to implementation. RESULTS: Based on the expert survey, five key elements (rising cancer rates, dedicated healthcare reimbursement budgets, increasing healthcare expenditures, advanced information technology solutions for data transfer, and demand for high-quality data) are expected to influence the equitable implementation of precision medicine in routine cancer care in Belgium in the future. CONCLUSIONS: This work contributes to the knowledge base on precision medicine in Belgium and public health foresight, exploring the implementation challenges and suggesting solutions with an emphasis on the importance of comparative analyses of health systems, evaluation of health technology assessment methods, and the exploration of ethical issues in data privacy and equity.

Red Absorbing Cyclometalated Ir(III) Diimine Photosensitizers Competent for Hydrogen Photocatalysis.

Two new cyclometalated Ir(III) diimine complexes were used as photosensitizers for homogeneous hydrogen evolution reaction (HER). These complexes were characterized by electrochemistry, ultraviolet-visible absorption, time-resolved and steady-state photoluminescence spectroscopy as well as by theoretical methods. The metal-ligand-to-ligand charge transfer character of their lowest excited state was shown to be competent for efficient H2 photoproduction in the presence of [Co(dmgH)2(py)Cl] as the hydrogen evolution catalyst, triethanolamine as the sacrificial electron donor, and HBF4 as the proton source. Under optimized experimental conditions, both complexes displayed HER over a period of more than 90 h, with turnover numbers reaching up to 11,650, 10,600, and 174 molH2 molPS-1 under blue-, green-, and red-light irradiation, respectively. Both complexes showed higher stability and efficiency vs HER than most of the previously described systems of the same kind.

Evaluating methodological approaches to assess the severity of infection with SARS-CoV-2 variants: scoping review and applications on Belgian COVID-19 data.

BACKGROUND: Differences in the genetic material of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants may result in altered virulence characteristics. Assessing the disease severity caused by newly emerging variants is essential to estimate their impact on public health. However, causally inferring the intrinsic severity of infection with variants using observational data is a challenging process on which guidance is still limited. We describe potential limitations and biases that researchers are confronted with and evaluate different methodological approaches to study the severity of infection with SARS-CoV-2 variants. METHODS: We reviewed the literature to identify limitations and potential biases in methods used to study the severity of infection with a particular variant. The impact of different methodological choices is illustrated by using real-world data of Belgian hospitalized COVID-19 patients. RESULTS: We observed different ways of defining coronavirus disease 2019 (COVID-19) disease severity (e.g., admission to the hospital or intensive care unit versus the occurrence of severe complications or death) and exposure to a variant (e.g., linkage of the sequencing or genotyping result with the patient data through a unique identifier versus categorization of patients based on time periods). Different potential selection biases (e.g., overcontrol bias, endogenous selection bias, sample truncation bias) and factors fluctuating over time (e.g., medical expertise and therapeutic strategies, vaccination coverage and natural immunity, pressure on the healthcare system, affected population groups) according to the successive waves of COVID-19, dominated by different variants, were identified. Using data of Belgian hospitalized COVID-19 patients, we were able to document (i) the robustness of the analyses when using different variant exposure ascertainment methods, (ii) indications of the presence of selection bias and (iii) how important confounding variables are fluctuating over time. CONCLUSIONS: When estimating the unbiased marginal effect of SARS-CoV-2 variants on the severity of infection, different strategies can be used and different assumptions can be made, potentially leading to different conclusions. We propose four best practices to identify and reduce potential bias introduced by the study design, the data analysis approach, and the features of the underlying surveillance strategies and data infrastructure.

Accessing Photoredox Transformations with an Iron(III) Photosensitizer and Green Light.

Efficient excited-state electron transfer between an iron(III) photosensitizer and organic electron donors was realized with green light irradiation. This advance was enabled by the use of the previously reported iron photosensitizer, [Fe(phtmeimb)2]+ (phtmeimb = {phenyl[tris(3-methyl-imidazolin-2-ylidene)]borate}, that exhibited long-lived and luminescent ligand-to-metal charge-transfer (LMCT) excited states. A benchmark dehalogenation reaction was investigated with yields that exceed 90% and an enhanced stability relative to the prototypical photosensitizer [Ru(bpy)3]2+. The initial catalytic step is electron transfer from an amine to the photoexcited iron sensitizer, which is shown to occur with a large cage-escape yield. For LMCT excited states, this reductive electron transfer is vectorial and may be a general advantage of Fe(III) photosensitizers. In-depth time-resolved spectroscopic methods, including transient absorption characterization from the ultraviolet to the infrared regions, provided a quantitative description of the catalytic mechanism with associated rate constants and yields.

Photo-CIDNP Reveals Different Protonation Sites Depending on the Primary Step of the Photoinduced Electron-/Proton-Transfer Process with Ru(II) Polyazaaromatic Complexes.

The excited-state quenching of [Ru(TAP)2(HAT)]2+ (TAP = 1,4,5,8-tetraazaphenanthrene, HAT= 1,4,5,8,9,12-hexaazatriphenylene) by hydroquinone (H2Q), N-acetyl-tyrosine (N-Ac-Tyr) or guanosine-5'-monophosphate (GMP) was investigated at various pH values. The quenching occurs via electron/proton transfer, as evidenced by transient absorption spectroscopy and confirmed by 1H photochemically induced dynamic nuclear polarization (photo-CIDNP). Reductive quenching also occurs in strongly acidic solution despite a much shorter lifetime of the protonated excited-state complex. Photo-CIDNP revealed a different mechanism at low pH, involving protonation before electron transfer and yielding a distinct protonated monoreduced complex. The experimental photo-CIDNP patterns are consistent with density functional theory calculations. This work highlights the power of 1H photo-CIDNP for characterizing, at the atomic level, transient species involved in electron-transfer processes.

On the coupling of solvent characteristics to the electronic structure of solute molecules.

We present the results of a theoretical investigation focusing on the solvent structure surrounding the -1, 0 and +1 charged species of F, Cl, Br and I halogen atoms and F2, Cl2, Br2 and I2 di-halogen molecules in a methanol solvent and its influence on the electronic structure of the solute molecules. Our results show a large stabilizing effect arising from the solute-solvent interactions. Well-formed first solvation shells are observed for all species, the structure of which is strongly influenced by the charge of the solute species. Detailed analysis reveals that coordination number, CN, solvent orientation, θ, and solute-solvent distance, d, are important structural characteristics which are coupled to changes in the electronic structure of the solute. We propose that the fundamental chemistry of any solute species is generally regulated by these solvent degrees of freedom.

Policy brief Belgian EBCP mirror group Artificial Intelligence in cancer care.

Artificial Intelligence (AI) is already a reality in health systems, bringing benefits to patients, healthcare providers, and other stakeholders in the health care. To further leverage AI in health, Belgium is advised to make policy-level decisions about how to fund, design and undertake actions focussing on data access and inclusion, IT-infrastructure, legal and ethical frameworks, public and professional trust, in addition to education and interpretation. EU initiatives, such as European Health data space (EHDS), the Genomics Data Infrastructure (GDI) and the EU Cancer Imaging Infrastructure (EUCAIM) are building EU data infrastructures. To continue these positive developments, Belgium should continue to invest and support existing European data infrastructures. At the national level, a clear vision and strategy need to be developed and infrastructures need to be harmonized at the European level.

Synthesis of Ru(II) and Os(II) photosensitizers bearing one 9,10-diamino-1,4,5,8-tetraazaphenanthrene scaffold.

The synthesis of eight Ru(II) and Os(II) photosensitizers bearing a common 9,10-disubstituted-1,4,5,8-tetraazaphenanthrene backbone is reported. With Os(II) photosensitizers, the 9,10-diNH2-1,4,5,8-tetraazaphenanthrene could be directly chelated onto the metal center via the heteroaromatic moiety, whereas similar conditions using Ru(II) resulted in the formation of an o-quinonediimine derivative. Hence, an alternative route, proceeding via the chelation of 9-NH2-10-NO2-1,4,5,8-tetraazaphenanthrene and subsequent ligand reduction of the corresponding photosensitizers was developed. Photosensitizers chelated via the polypyridyl-type moiety exhibited classical photophysical properties whereas the o-quinonediimine chelated Ru(II) analogues exhibited red-shifted absorption (520 nm) and no photoluminescence at room temperature in acetonitrile. The most promising photosensitizers were investigated for excited-state quenching with guanosine-5'-monophosphate in aqueous buffered conditions where reductive excited-state electron transfer was observed by nanosecond transient absorption spectroscopy.

Unlocking the genomic landscape: Results of the Beyond 1 Million Genomes (B1MG) pilot in Belgium towards Genomic Data Infrastructure (GDI).

Genomic medicine has great potential to offer insights into how humans' genetic variation can affect their health, prevention options and treatment responses. The Beyond 1 Million Genomes (B1MG) project was kicked off in 2020 with the aim of building a federated network of genomic data in Europe, in which Belgium took part as a piloting country. B1MG developed a framework to enable all interested countries to self-evaluate the level of maturity of national genomic medicine practices following a common matrix, called Maturity Level Model (MLM), that contained 49 indicators across eight domains: I. Governance and strategy; II. Investment and economic model; III. Ethics, legislation and policy; IV. Public awareness and acceptance; V. Workforce skills and organisation; VI. Clinical organisation, infrastructure and tools; VII. Clinical genomics guidelines and infrastructure; and VIII. Data management, standards and infrastructure. The ongoing Genomic Data Infrastructure (GDI) project aims to capitalise on the experience of B1MG piloting countries and their MLM results. In this paper, we present the qualitative and quantitative outcomes of B1MG MLM assessment in Belgium and discuss their relevance to GDI. The insights gained from this study can be helpful for steering future policy directions and interventions on genomics in Belgium and beyond.

The aqueous Ca2+ system, in comparison with Zn2+, Fe3+, and Al3+: an ab initio molecular dynamics study.

Herein, we report on the structure and dynamics of the aqueous Ca(2+) system studied by using ab initio molecular dynamics (AIMD) simulations. Our detailed study revealed the formation of well-formed hydration shells with characteristics that were significantly different to those of bulk water. To facilitate a robust comparison with state-of-the-art X-ray absorption fine structure (XAFS) data, we employ a 1st principles MD-XAFS procedure and directly compare simulated and experimental XAFS spectra. A comparison of the data for the aqueous Ca(2+) system with those of the recently reported Zn(2+), Fe(3+), and Al(3+) species showed that many of their structural characteristics correlated well with charge density on the cation. Some very important exceptions were found, which indicated a strong sensitivity of the solvent structure towards the cation's valence electronic structure. Average dipole moments for the 2nd shell of all cations were suppressed relative to bulk water.

Rydberg electron capture by neutral Al hydrolysis products.

We predict that electron attachment may be used with ESI-MS techniques to observe neutral Al metal aqua-oxo-hydroxo species and the complex polymerization and precipitation reactions in which they participate. Neutral aqueous metal species have, so far, been invisible to ESI-MS techniques.

Photosensitized Activation of Diazonium Derivatives for C-B Bond Formation.

Aryl diazonium salts are ubiquitous building blocks in chemistry, as they are useful radical precursors in organic synthesis as well as for the functionalization of solid materials. They can be reduced electrochemically or through a photo-induced electron transfer reaction. Here we provide a detailed picture of the ground and excited-state reactivity of a series of 9 rare and earth abundant photosensitizers with 13 aryl diazonium salts, which also included 3 macrocyclic calix[4]arene tetradiazonium salts. Nanosecond transient absorption spectroscopy confirmed the occurrence of excited-state electron transfer and was used to quantify cage-escape yields, i.e. the efficiency with which the formed radicals separate and escape the solvent cage. Cage-escape yields were large; increased when the driving force for photo-induced electron transfer increased and also tracked with the C-N2 + bond cleavage propensity, amongst others. A photo-induced borylation reaction was then investigated with all the photosensitizers and proceeded with yields between 9 and 74%.

Homologous and Heterologous Prime-Boost Vaccination: Impact on Clinical Severity of SARS-CoV-2 Omicron Infection among Hospitalized COVID-19 Patients in Belgium.

We investigated effectiveness of (1) mRNA booster vaccination versus primary vaccination only and (2) heterologous (viral vector-mRNA) versus homologous (mRNA-mRNA) prime-boost vaccination against severe outcomes of BA.1, BA.2, BA.4 or BA.5 Omicron infection (confirmed by whole genome sequencing) among hospitalized COVID-19 patients using observational data from national COVID-19 registries. In addition, it was investigated whether the difference between the heterologous and homologous prime-boost vaccination was homogenous across Omicron sub-lineages. Regression standardization (parametric g-formula) was used to estimate counterfactual risks for severe COVID-19 (combination of severity indicators), intensive care unit (ICU) admission, and in-hospital mortality under exposure to different vaccination schedules. The estimated risk for severe COVID-19 and in-hospital mortality was significantly lower with an mRNA booster vaccination as compared to only a primary vaccination schedule (RR = 0.59 [0.33; 0.85] and RR = 0.47 [0.15; 0.79], respectively). No significance difference was observed in the estimated risk for severe COVID-19, ICU admission and in-hospital mortality with a heterologous compared to a homologous prime-boost vaccination schedule, and this difference was not significantly modified by the Omicron sub-lineage. Our results support evidence that mRNA booster vaccination reduced the risk of severe COVID-19 disease during the Omicron-predominant period.

Ion association in AlCl3 aqueous solutions from constrained first-principles molecular dynamics.

The Car-Parrinello-based molecular dynamics (CPMD) method was used to investigate the ion-pairing behavior between Cl(-) and Al(3+) ions in an aqueous AlCl(3) solution containing 63 water molecules. A series of constrained simulations was carried out at 300 K for up to 16 ps each, with the internuclear separation (r(Al-Cl)) between the Al(3+) ion and one of the Cl(-) ions held constant. The calculated potential of mean force (PMF) of the Al(3+)-Cl(-) ion pair shows a global minimum at r(Al-Cl) = 2.3 Å corresponding to a contact ion pair (CIP). Two local minima assigned to solvent-separated ion pairs (SSIPs) are identified at r(Al-Cl) = 4.4 and 6.0 Å. The positions of the free energy minima coincide with the hydration-shell intervals of the Al(3+) cation, suggesting that the Cl(-) ion is inclined to reside in regions with low concentrations of water molecules, that is, between the first and second hydration shells of Al(3+) and between the second shell and the bulk. A detailed analysis of the solvent structure around the Al(3+) and Cl(-) ions as a function of r(Al-Cl) is presented. The results are compared to structural data from X-ray measurements and unconstrained CPMD simulations of single Al(3+) and Cl(-) ions and AlCl(3) solutions. The dipole moments of the water molecules in the first and second hydration shells of Al(3+) and in the bulk region and those of Cl(-) ions were calculated as a function of r(Al-Cl). Major changes in the electronic structure of the system were found to result from the removal of Cl(-) from the first hydration shell of the Al(3+) cation. Finally, two unconstrained CPMD simulations of aqueous AlCl(3) solutions corresponding to CIP and SSIP configurations were performed (17 ps, 300 K). Only minor structural changes were observed in these systems, confirming their stability.

Cisplatin cytotoxicity: a theoretical study of induced mutations.

We investigate possible mutations in the genetic code induced by cisplatin with an approach combining molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Specifically, the impact of platination on the natural tautomeric equilibrium in guanine-cytosine (GC) base pairs is assessed to disclose the possible role played by non-canonical forms in anti-tumour activity. To obtain valuable predictions, the main interactions present in a real DNA environment, namely hydration and stacking, are simultaneously taken into account. According to our results, the Pt-DNA adduct promotes a single proton transfer reaction in GC in the DNA sequence AG[combining low line]G[combining low line]C. Such rare tautomers might play an important role in the cisplatin biological activity since they meet the stability requirements necessary to promote a permanent mutation.

Density functional theory interpretation of the 1H photo-chemically induced dynamic nuclear polarization enhancements characterizing photoreduced polyazaaromatic Ru(II) coordination complexes.

The unprotonated and protonated monoreduced forms of the polyazaaromatic Ru(II) coordination complexes [Ru(tap)(3)](2+) and [Ru(tap)(2)(phen)](2+) (tap = 1,4,5,8-tetraazaphenanthrene ; phen = 1,10-phenanthroline), that is, [Ru(tap)(3)](*+), [Ru(tap)(2)(phen)](*+), [Ru(tap)(2)(tap-H)](*2+), and [Ru(tap)(tap-H)(phen)](*2+), were studied by Density Functional Theory (DFT). The electron spin density of these radical cations, the isotropic Fermi-contact, and the anisotropic dipolar contributions to the hyperfine coupling constants of the H nuclei were calculated in vacuo and using a continuum model for water solvation. For [Ru(tap)(2)(phen)](*+), as well as for its protonated form, the DFT results show that the unpaired electron is not localized on the phen ligand. For both [Ru(tap)(3)](*+) and [Ru(tap)(2)(phen)](*+), they reveal high electron spin density in the vicinity of tap H-2 and tap H-7 (the H atoms in the ortho position of the tap non-chelating N atoms). These results are in full agreement with recent steady-state (1)H photo-Chemically Induced Dynamic Nuclear Polarization (photo-CIDNP) measurements. The DFT calculations performed for the protonated species also predict major (1)H photo-CIDNP enhancements at these positions. Interestingly, they indicate significantly different polarization for tap H-9,10, suggesting that the occurrence of a photoinduced electron transfer with protonation of the reduced species might be detected by high-precision photo-CIDNP experiments.

Structure and dynamics of the hydration shells of the Zn(2+) ion from ab initio molecular dynamics and combined ab initio and classical molecular dynamics simulations.

Results of ab initio molecular dynamics (AIMD) simulations (density functional theory+PBE96) of the dynamics of waters in the hydration shells surrounding the Zn(2+) ion (T approximately 300 K, rho approximately 1 gm/cm(3)) are compared to simulations using a combined quantum and classical molecular dynamics [AIMD/molecular mechanical (MM)] approach. Both classes of simulations were performed with 64 solvating water molecules ( approximately 15 ps) and used the same methods in the electronic structure calculation (plane-wave basis set, time steps, effective mass, etc.). In the AIMD/MM calculation, only six waters of hydration were included in the quantum mechanical (QM) region. The remaining 58 waters were treated with a published flexible water-water interaction potential. No reparametrization of the water-water potential was attempted. Additional AIMD/MM simulations were performed with 256 water molecules. The hydration structures predicted from the AIMD and AIMD/MM simulations are found to agree in detail with each other and with the structural results from x-ray data despite the very limited QM region in the AIMD/MM simulation. To further evaluate the agreement of these parameter-free simulations, predicted extended x-ray absorption fine structure (EXAFS) spectra were compared directly to the recently obtained EXAFS data and they agree in remarkable detail with the experimental observations. The first hydration shell contains six water molecules in a highly symmetric octahedral structure is (maximally located at 2.13-2.15 A versus 2.072 A EXAFS experiment). The widths of the peak of the simulated EXAFS spectra agree well with the data (8.4 A(2) versus 8.9 A(2) in experiment). Analysis of the H-bond structure of the hydration region shows that the second hydration shell is trigonally bound to the first shell water with a high degree of agreement between the AIMD and AIMD/MM calculations. Beyond the second shell, the bonding pattern returns to the tetrahedral structure of bulk water. The AIMD/MM results emphasize the importance of a quantum description of the first hydration shell to correctly describe the hydration region. In these calculations the full d(10) electronic structure of the valence shell of the Zn(2+) ion is retained. The simulations show substantial and complex charge relocation on both the Zn(2+) ion and the first hydration shell. The dipole moment of the waters in the first hydration shell is 3.4 D (3.3 D AIMD/MM) versus 2.73 D bulk. Little polarization is found for the waters in the second hydration shell (2.8 D). No exchanges were seen between the first and the second hydrations shells; however, many water transfers between the second hydration shell and the bulk were observed. For 64 waters, the AIMD and AIMD/MM simulations give nearly identical results for exchange dynamics. However, in the larger particle simulations (256 waters) there is a significant reduction in the second shell to bulk exchanges.

Tuning the excited-state deactivation pathways of dinuclear ruthenium(ii) 2,2'-bipyridine complexes through bridging ligand design.

A detailed photophysical investigation of two dinuclear ruthenium(ii) complexes is reported. The two metallic centers were coordinated to a bis-2,2'-bipyridine bridging ligand, connected either through the para (Lp, Dp) or the meta position (Lm, Dm). The results obtained herein were compared to the prototypical [Ru(bpy)3]2+ parent compound. The formation of dinuclear complexes was accompanied by the expected increase in molar absorption coefficients, i.e. 12 000 M-1 cm-1, 17 000 M-1 cm-1, and 22 000 M-1 cm-1 at the lowest energy MLCTmax transition for [Ru(bpy)3]2+, Dm and Dp respectively. The Lp bridging ligand resulted in a ruthenium(ii) dinuclear complex that absorbed more visible light, and had a longer-lived and more delocalized excited-state compared to a complex with the Lm bridging ligand. Variable temperature measurements provided valuable information about activation energies to the uppermost 3MLCT state and the metal-centered (3MC) state, often accompanied by irreversible ligand-loss chemistry. At 298 K, 48% of [Ru(bpy)3]2+* excited-state underwent deactivation through the 3MC state, whereas this deactivation pathway remained practically unpopulated (<0.5%) in both dinuclear complexes.

Ab initio study of the electron transfer in an ionized stacked complex of guanines.

The charge transfer process in an ionized stacking of two consecutive guanines (G(5')G(3'))(+) has been studied by means of state-averaged CASSCF/MRCI and RASSCF/RASPT2 calculations. The ground and two first excited states of the radical cation have been characterized, and the topology of the corresponding potential energy surfaces (PESs) has been studied as a function of all intermolecular geometrical parameters. The results demonstrate that the charge transfer process in (G(5')G(3'))(+) is governed by the avoiding crossing between the ground and first excited states of the complex. Relative translation motions of both guanines in their molecular planes are shown to lead to the charge migration between G(5') and G(3'). Five stationary points (three minima and two saddle points) have been characterized along the reaction path describing the passage of the positive charge from G(5') to G(3'). The global minimum on the PES is found to correspond to the charge configuration G(5')(+)G(3'). The existence of an intermediate minimum along the reaction path has been established, characterizing a structure where the positive charge is equally distributed between the two guanines. The calculated energy profile allowed us to determine the height of the potential energy barrier (7.33 kcal/mol) and to evaluate the electronic coupling at a geometry close to the avoiding crossing (3.6 kcal/mol). Test calculations showed that the topology of the ground state PES of the complex GG(+) is qualitatively conserved upon optimization of the intramolecular geometrical parameters of the stationary points.

Understanding the within-host dynamics of influenza A virus: from theory to clinical implications.

Mathematical models have provided important insights into acute viral dynamics within individual patients. In this paper, we study the simplest target cell-limited models to investigate the within-host dynamics of influenza A virus infection in humans. Despite the biological simplicity of the models, we show how these can be used to understand the severity of the infection and the key attributes of possible immunotherapy and antiviral drugs for the treatment of infection at different times post infection. Through an analytic approach, we derive and estimate simple summary biological quantities that can provide novel insights into the infection dynamics and the definition of clinical endpoints. We focus on nine quantities, including the area under the viral load curve, peak viral load, the time to peak viral load and the level of cell death due to infection. Using Markov chain Monte Carlo methods, we fitted the models to data collected from 12 untreated volunteers who participated in two clinical studies that tested the antiviral drugs oseltamivir and zanamivir. Based on the results, we also discuss various difficulties in deriving precise estimates of the parameters, even in the very simple models considered, when experimental data are limited to viral load measures and/or there is a limited number of viral load measurements post infection.