Improving calculation, interpretation and communication of familial colorectal cancer risk: Protocol for a randomized controlled trial

Contains fulltext : 88114.pdf (publisher's version ) (Open Access)BACKGROUND: Individuals with multiple relatives with colorectal cancer (CRC) and/or a relative with early-onset CRC have an increased risk of developing CRC. They are eligible for preventive measures, such as surveillance by regular colonoscopy and/or genetic counselling. Currently, most at-risk individuals do not follow the indicated follow-up policy. In a new guideline on familial and hereditary CRC, clinicians have new tasks in calculating, interpreting, and communicating familial CRC risk. This will lead to better recognition of individuals at an increased familial CRC risk, enabling them to take effective preventive measures. This trial compares two implementation strategies (a common versus an intensive implementation strategy), focussing on clinicians' risk calculation, interpretation, and communication, as well as patients' uptake of the indicated follow-up policy. METHODS: A clustered randomized controlled trial including an effect, process, and cost evaluation will be conducted in eighteen hospitals. Nine hospitals in the control group will receive the common implementation strategy (i.e., dissemination of the guideline). In the intervention group, an intensive implementation strategy will be introduced. Clinicians will receive education and tools for risk calculation, interpretation, and communication. Patients will also receive these tools, in addition to patient decision aids. The effect evaluation includes assessment of the number of patients for whom risk calculation, interpretation, and communication is performed correctly, and the number of patients following the indicated follow-up policy. The actual exposure to the implementation strategies and users' experiences will be assessed in the process evaluation. In a cost evaluation, the costs of the implementation strategies will be determined. DISCUSSION: The results of this study will help determine the most effective method as well as the costs of improving the recognition of individuals at an increased familial CRC risk. It will provide insight into the experiences of both patients and clinicians with these strategies.The knowledge gathered in this study can be used to improve the recognition of familial and hereditary CRC at both the national and international level, and will serve as an example to improve care for patients and their relatives worldwide. Our results may also be useful in improving healthcare in other diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00929097

High-Yield Synthesis of PPh₃-Ligated Decanuclear Tl–Pd Cluster, Pd₉[Tl(acac)](CO)₉(PPh₃)₆: Comparative Analysis of Tl(I)–Pd(0) Bonding Connectivities with Known Tl–Pd Clusters and Resulting Insight Concerning Their Dissimilar Dynamic Solution Behavior

The new Tl­(I)–Pd(0) cluster Pd₉[μ_3/3-Tl­(acac)]­(μ₂-CO)₆(μ₃-CO)₃(PPh₃)₆ (<b>1</b>) was prepared in high yields (over 90%), both by reaction of Pd₁₀(CO)₁₂(PPh₃)₆ (<b>4</b>), PPh₃, and TlPF₆ in THF in the presence of acetylacetone (Hacac) and base (NEt₃) and by direct reaction of Pd₁₀(CO)₁₂(PPh₃)₆ with PPh₃ and Tl­(acac). The composition and molecular structure of <b>1</b> were unambiguously established from 100 K CCD X-ray diffractometry studies of two solvated crystals, <b>1</b>·1.5Hacac·0.5THF (<b>1A</b>) and <b>1</b>·0.3THF (<b>1B</b>), which showed essentially identical geometries for the entire Pd₉Tl­(CO)₉P₆ fragment of pseudo-<i>C</i>_3<i>v</i> symmetry; its composition is in agreement with X-ray Tl/Pd field-emission microanalysis with a scanning electron microscope for crystals of <b>1B</b>. This cluster can be viewed as a markedl<i></i>y deformed Pd₆ octahedron (oct) with the three Pd­(oct) atoms of one of its eight triangular faces connected both by three edge-bridging wingtip (wt) Pd­(μ₂-CO)₂PPh₃ fragments and by a symmetrical capping Tl­(I). Three triply bridging carbonyl ligands asymmetrically cap the lower alternate 3-fold-related triangular faces of the Pd₆ octahedron, and the three other PPh₃ ligands are each coordinated to Pd atoms in the geometrically opposite staggered Pd­(oct)₃ face. The 6s²5d¹⁰ Tl­(I) is also equivalently attached to both chelating O atoms of a bidentate acetylacetonate (acac) monoanion. Although the <i>C</i>₂ axis of the pseudo-<i>C</i>_2<i>v</i> planar Tl­(acac) fragment is approximately parallel to the pseudo-<i>C</i>₃ axis of the TlPd₉ core, the orientation of the Tl­(acac) plane relative to the octahedral-based Pd₉ geometry is considerably different for each of the three independent nondisordered molecules of <b>1</b> in <b>1A</b> and <b>1B</b>; these different planar Tl­(acac) orientations may be mainly attributed to anisotropic crystal-packing effects. Coordination of the Tl­(I) atom to the three Pd­(oct) atoms of the Pd₉ core presumably occurs via its so-called “inert” 6s² electron pair with resulting three short Tl–Pd­(oct) connectivities of mean distance 2.83 Å; these connectivities together with three longer Tl–Pd­(wt) ones of mean distance 3.15 Å give rise to a (crown-like)­Pd₆ sextuple (μ_3/3-Tl) coordination mode. Of particular stereochemical interest is a comparison of solution behavior of <b>1</b> with that for the known structurally related analogue, Pd₉[μ₃-TlCo­(CO)₃L]­(μ₂-CO)₆(μ₃-CO)₃L₆ (<b>2</b>) (with L = PEt₃ instead of PPh₃). In <b>2</b> the Tl­(I) is alternatively attached to a trigonal-bipyramidal Co­(CO)₃L monoanion and primarily coordinated to the three inner Pd­(oct) atoms of a similar PR₃/CO-ligated octahedron; corresponding Tl–Pd­(oct) and Tl–Pd­(wt) mean distances for two independent molecules in <b>2</b> are 2.77 and 3.31 Å, respectively. Variable-temperature ³¹P­{¹H} NMR solution data of <b>1</b> indicate the occurrence of presumed fast wobbling-like motion of the [μ_3/3-Tl­(acac)] entity about the pseudo-<i>C</i>₃ axis of the Pd₉(μ₂-CO)₆(μ₃-CO)₃P₆ fragment <i>without Pd–Tl detachment</i> (i.e., the entire cluster of <b>1</b> remains intact). In direct contrast, corresponding temperature-dependent ³¹P and ¹³C NMR data of <b>2</b> instead are consistent with <i>rapid, reversible dissociation/association of the entire</i> [μ₃-TlCo­(CO)₃L] ligand from the analogous Pd₉(μ₂-CO)₆(μ₃-CO)₃P₆ fragment of <b>2</b>. This highly dissimilar dynamic solution behavior that points to a stronger Tl­(I) attachment to the Pd₉ core in <b>1</b> than that in <b>2</b> may be attributed from the above crystallographic evidence to greater involvement of the outer three wingtip Pd­(wt) atoms in bonding connectivities to the Tl­(I) in <b>1</b> compared to predominant bonding connectivities of only the three inner Pd­(oct) atoms to the Tl­(I) in <b>2</b>. ¹H NMR solution spectra of <b>1</b> also suggest significant covalent character in the bidentate Tl–O­(acac) bonding in <b>1</b> based upon the observation of H­(acac)–Tl coupling; this premise is consistent with its Tl–O distances of 2.35 Å (av) being ca. 0.2 Å shorter than those of 2.52 Å (av) found in crystalline Tl­(acac), which with no observed H–Tl NMR coupling in solution implies ionicity of its bidentate Tl–O bonding. Both <b>1</b> and <b>2</b> conform to an 86 CVE count expected for an octahedral metal polyhedron based upon the Tl­(I) and each wingtip Pd­(μ₂-CO)₂L fragment contributing 2 and 4 CVEs, respectively