General practitioners' representation of early-stage CKD is a barrier to adequate management and patient empowerment: a phenomenological study.

BACKGROUND: In high-income countries, chronic kidney disease (CKD) affects over 10% of the population. Identifying these patients early is a priority, especially as new treatments are available to reduce the risk of cardiovascular and renal morbidity. We aimed at understanding the management and care pathway of patients with early-to-moderate CKD defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 (CKD-EPI), by analyzing the experience of general practitioners in a region in France. METHODS: This qualitative semiopragmatic phenomenological study analyzed in-depth interviews held with a purposive sample (age, gender, training, type of practice, rural/urban context) of 24 general practitioners, with triangulation of research until data saturation. RESULTS: From diagnostic, etiological and prognostic viewpoints, the general practitioners enrolled in our study perceived CKD as a complex, poorly-defined clinical entity in asymptomatic and multimorbid patients. They distinguished it from a rare condition they considered as 'mainly renal'. The fact that they did not perceive early-stage CKD as a disease was a hindrance to patient care, which should protect the kidneys with a preventive approach. Indeed, general practitioners perceived CKD patient management as a pathway requiring a personalized, integrative model, common to all chronic diseases, without necessarily involving a nephrologist, at least in the early stages. CONCLUSIONS: This study shows how the general practitioners' representations influence their attitudes and interventions. Clarifying the concept of early-stage CKD by taking factors like age and etiology into account would facilitate personalized management of this heterogeneous, often multimorbid, population. Finally, organizational models to support patient empowerment in an integrative care pathway must be established and validated.

Combined Technique for Internal Carotid Artery Terminus or Middle Cerebral Artery Occlusions in the ASTER2 Trial.

BACKGROUND: The aim of this study was to report the results of a subgroup analysis of the ASTER2 trial (Effect of Thrombectomy With Combined Contact Aspiration and Stent Retriever vs Stent Retriever Alone on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion) comparing the safety and efficacy of the combined technique (CoT) and stent retriever as a first-line approach in internal carotid artery (ICA) terminus±M1-middle cerebral artery (M1-MCA) and isolated M1-MCA occlusions. METHODS: Patients enrolled in the ASTER2 trial with ICA terminus±M1-MCA and isolated M1-MCA occlusions were included in this subgroup analysis. The effect of first-line CoT versus stent retriever according to the occlusion site was assessed on angiographic (first-pass effect, expanded Treatment in Cerebral Infarction score ≥2b50, and expanded Treatment in Cerebral Infarction score ≥2c grades at the end of the first-line strategy and at the end of the procedure) and clinicoradiological outcomes (24-hour National Institutes of Health Stroke Scale, ECASS-III [European Cooperative Acute Stroke Study] grades, and 3-month modified Rankin Scale). RESULTS: Three hundred sixty-two patients were included in the postsubgroup analysis according to the occlusion site: 299 were treated for isolated M1-MCA occlusion (150 with first-line CoT) and 63 were treated for ICA terminus±M1-MCA occlusion (30 with first-line CoT). Expanded Treatment in Cerebral Infarction score ≥2b50 (odds ratio, 11.83 [95% CI, 2.32-60.12]) and expanded Treatment in Cerebral Infarction score ≥2c (odds ratio, 4.09 [95% CI, 1.39-11.94]) were significantly higher in first-line CoT compared with first-line stent retriever in patients with ICA terminus±M1-MCA occlusion but not in patients with isolated M1-MCA. CONCLUSIONS: First-line CoT was associated with higher reperfusion grades in patients with ICA terminus±M1-MCA at the end of the procedure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03290885.

Antithrombotic therapies for neurointerventional surgery: a 2021 French comprehensive national survey.

BACKGROUND: Neurointerventionists lack guidelines for the use of antithrombotic therapies in their clinical practice; consequently, there is likely to be significant heterogeneity in antithrombotic use between centers. Through a nationwide survey, we aimed to obtain an exhaustive cross-sectional overview of antithrombotic use in neurointerventional procedures in France. METHODS: In April 2021, French neurointerventional surgery centers were invited to participate in a nationwide 51-question survey disseminated through an active trainee-led research collaborative network (the JENI-RC). RESULTS: All 40 centers answered the survey. Fifty-one percent of centers reported using ticagrelor and 43% used clopidogrel as premedication before intracranial stenting. For flow diversion treatment, dual antiplatelet therapy was maintained for 3 or 6 months in 39% and 53% of centers, respectively, and aspirin was prescribed for 12 months or more than 12 months in 63% and 26% of centers, respectively. For unruptured aneurysms, the most common heparin bolus dose was 50 IU/kg (59%), and only 35% of centers monitored heparin activity for dose adjustment. Tirofiban was used in 64% of centers to treat thromboembolic complications. Fifteen percent of these comprehensive stroke centers reported using tenecteplase to treat acute ischemic strokes. Cangrelor appeared as an emergent drug in specific indications. CONCLUSION: This nationwide survey highlights the important heterogeneity in clinical practices across centers. There is a pressing need for trials and guidelines to further evaluate and harmonize antithrombotic regimens in the neurointerventional field.

Bifurcation geometry remodelling of vessels in de novo and growing intracranial aneurysms: a multicenter study.

BACKGROUND: Geometrical parameters, including arterial bifurcation angle, tortuosity, and arterial diameters, have been associated with the pathophysiology of intracranial aneurysm (IA) formation. The aim of this study was to investigate whether these parameters were present before or if they resulted from IA formation and growth. METHODS: Patients from nine academic centers were retrospectively identified if they presented with a de novo IA or a significant IA growth on subsequent imaging. For each patient, geometrical parameters were extracted using a semi-automated algorithm and compared between bifurcations with IA formation or growth (aneurysmal group), and their contralateral side without IA (control group). These parameters were compared at two different times using univariable models, multivariable models, and a sensitivity analysis with paired comparison. RESULTS: 46 patients were included with 21 de novo IAs (46%) and 25 significant IA growths (54%). The initial angle was not different between the aneurysmal and control groups (129.7±42.1 vs 119.8±34.3; p=0.264) but was significantly wider at the final stage (140.4±40.9 vs 121.5±34.1; p=0.032), with a more important widening of the aneurysmal angle (10.8±15.8 vs 1.78±7.38; p=0.001). Variations in other parameters were not significant. These results were confirmed by paired comparisons. CONCLUSION: Our study suggests that wider bifurcation angles that have long been deemed causal factors for IA formation or growth may be secondary to IA formation at pathologic bifurcation sites. This finding has implications for our understanding of IA formation pathophysiology.

Benefit of mechanical thrombectomy in acute ischemic stroke related to calcified cerebral embolus.

PURPOSE: Mechanical thrombectomies (MT) in patients with large vessel occlusion (LVO) related to calcified cerebral embolus (CCE) have been reported, through small case series, being associated with low reperfusion rate and worse outcome, compared to regular MT. The purpose of the MASC (Mechanical Thrombectomy in Acute Ischemic Stroke Related to Calcified Cerebral Embolus) study was to evaluate the incidence of CCEs treated by MT and the effectiveness of MT in this indication. METHODS: The MASC study is a retrospective multicentric (n = 37) national study gathering the cases of adult patients who underwent MT for acute ischemic stroke with LVO related to a CCE in France from January 2015 to November 2019. Reperfusion rate (mTICI ≥ 2B), complication rate and 90-day mRS were systematically collected. We then conducted a systematic review by searching for articles in PubMed, Cochrane Library, Embase and Google Scholar from January 2015 to March 2020. A meta-analysis was performed to estimate clinical outcome at 90 days, reperfusion rate and complications. RESULTS: We gathered data from 35 patients. Reperfusion was obtained in 57% of the cases. Good clinical outcome was observed in 28% of the patients. The meta-analysis retrieved 136 patients. Reperfusion and good clinical outcome were obtained in 50% and 29% of the cases, respectively. CONCLUSION: The MASC study found worse angiographic and clinical outcomes compared to regular thrombectomies. Individual patient-based meta-analysis including the MASC findings shows a 50% reperfusion rate and a 29% of good clinical outcome.

From genotypes to phenotypes: expression levels of genes encompassing adaptive SNPs in black spruce.

KEY MESSAGE: Measuring transcript levels for adaptive genes revealed polymorphisms having cis -effect upon gene expression levels related to phenotype variation in a black spruce natural population. Trees growing in temperate and boreal regions must acclimate to changes in climatic factors such as low winter temperatures to survive to seasonal variations. Common garden studies have shown that genetic variation in quantitative traits helps species to survive and adapt to environmental changes and local conditions. Twenty-four genes carrying SNPs were previously associated with genetic adaptation in black spruce (Picea mariana [Mill.] BSP). The objectives of this study were to investigate the potential role of these genes in regulation of winter acclimation and adaptation by studying their patterns of expression as a function of the physiological stage during the annual growth cycle, tissue type, and their SNP genotypic class. Considerable variability in gene expression was observed between different vegetative tissues or organs, and between physiological stages. The genes were expressed predominantly in tissues that could be linked more directly to winter acclimation and adaptation. The expression levels of several of the genes were significantly related to variation in tree height growth or budset timing and expression level variation related to SNP genotypic classes was observed in four of the genes. An interaction between genotypic classes and physiological stages was also observed for some genes, indicating genotypes with different reaction norms in terms of gene expression.

Synthesis of the tricyclic core of vinigrol via an intramolecular Diels-Alder reaction.

[reaction: see text] Herein, we present a successful synthesis of the tricyclic core of vinigrol (1). Our approach takes advantage of a highly regioselective intramolecular Diels-Alder reaction of the diene 11 to construct two rings of the tricyclic vinigrol skeleton 12.

PET imaging of apoptosis with (64)Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V.

PURPOSE: In vivo detection of apoptosis is a diagnostic tool with potential clinical applications in cardiology and oncology. Radiolabeled annexin-V (anxV) is an ideal probe for in vivo apoptosis detection owing to its strong affinity for phosphatidylserine (PS), the molecular flag on the surface of apoptotic cells. Most clinical studies performed to visualize apoptosis have used (99m)Tc-anxV; however, its poor distribution profile often compromises image quality. In this study, tumor apoptosis after therapy was visualized by positron emission tomography (PET) using (64)Cu-labeled streptavidin (SAv), following pre-targeting of apoptotic cells with biotinylated anxV. METHODS: Apoptosis was induced in tumor-bearing mice by photodynamic therapy (PDT) using phthalocyanine dyes as photosensitizers, and red light. After PDT, mice were injected i.v. with biotinylated anxV, followed 2 h later by an avidin chase, and after another 2 h with (64)Cu-DOTA-biotin-SAv. PET images were subsequently recorded up to 13 h after PDT. RESULTS: PET images delineated apoptosis in treated tumors as early as 30 min after (64)Cu-DOTA-biotin-SAv administration, with tumor-to-background ratios reaching a maximum at 3 h post-injection, i.e., 7 h post-PDT. Omitting the administration of biotinylated anxV or the avidin chase failed to provide a clear PET image, confirming that all three steps are essential for adequate visualization of apoptosis. Furthermore, differences in action mechanisms between photosensitizers that target tumor cells directly or via initial vascular stasis were clearly recognized through differences in tracer uptake patterns detecting early or delayed apoptosis. CONCLUSION: This study demonstrates the efficacy of a three-step (64)Cu pretargeting procedure for PET imaging of apoptosis. Our data also confirm the usefulness of small animal PET to evaluate cancer treatment protocols.

Synthesis and biological activities of nucleoside-estradiol conjugates.

Nucleosides were coupled to estradiol via a 17alpha-ethynyl spacer group using Pd(II) as a catalyst. The conjugates were evaluated in vitro for estrogen receptor (ER) binding affinity and cytotoxicity against cell lines with and without ER. The highest receptor binding affinities (RBA approximately 3) were observed with conjugates coupled via a relative long spacer group, while none of the conjugates exhibited cytotoxicity against either cell lines.

Impact on estrogen receptor binding and target tissue uptake of [18F]fluorine substitution at the 16alpha-position of fulvestrant (faslodex; ICI 182,780).

Fulvestrant (Faslodex; ICI 182,780) is a pure estrogen receptor (ER) antagonist recently approved for the treatment of hormone-sensitive breast cancer in post-menopausal women with disease progression following antiestrogen therapy. Fulvestrant strongly binds to the ER and its mode of action consists of inhibition of ER dimerization leading to a down regulation of ER protein cellular levels. With the aim to develop a probe for positron emission tomography (PET) imaging capable of predicting the potential therapeutic efficacy of selective ER modulators (SERM), we prepared three new 16alpha-[18F]fluoro-fulvestrant derivatives. These new radiopharmaceuticals were evaluated for their binding affinity to the human ERalpha and for their target tissue uptake in immature female rats. Substitution of one of the side-chain F-atoms of fulvestrant for 18F would have led to a product of low specific activity; instead we selected the 16alpha-position for 18F-labeling, which at least in the case of estradiol (ES) is well tolerated by the ER. Radiochemical synthesis proceeds by stereoselective introduction of the [18F]fluoride at the 16-18F-position of fulvestrant via opening of an intermediate O-cyclic sulfate followed by hydrolysis of the protecting methoxymethyl (MOM) ether and sulfate groups. Three analogs with different oxidation states of the side chain sulfur, i.e. sulfide, sulfone or sulfoxide (fulvestrant) were prepared. Introduction of the 16(18)F-fluorine led to a dramatic decrease of the apparent binding affinity for ER, as reported by Wakeling et al. (Cancer Res. 1991;51:3867-73). Likewise, in vivo ER-mediated uterus uptake values in immature female rats were disappointing. Overall, our findings suggest that these new PET radiopharmaceuticals are not suitable as tracers to predict ER(+) breast cancer response to hormonal therapy with selective ER modulators.