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Background High levels of outpatient antibiotic use remain observed in many European countries. Several studies have shown a strong relationship between antibiotic use and bacterial resistance. Aim To assess the long-term effect of a standardised educational seminar on antibiotic prescriptions by GPs. Design and setting Randomised controlled trial of 171 GPs (of 203 initially randomised) in France. Method GPs in the control group (n = 99) received no antibiotic prescription recommendation. Intervention group GPs (n = 72) attended an interactive seminar presenting evidence-based guidelines on antibiotic prescription for respiratory infections. The proportion of prescriptions containing an antibiotic in each group and related costs were compared to the baseline up to 30 months following the intervention. Data were obtained from the National Health Insurance System database. Results In the intervention group, 4-6 months after the intervention, there was a significant decrease in the proportion of prescriptions containing an antibiotic from 15.2 ± 5.4% to 12.3 ± 5.8% (-2.8% [95% CI = -3.8 to -1.9], P<0.001). By contrast, an increase was observed in controls from 15.3 ± 6.0 to 16.4 ± 6.7% (+1.1% [95% CI = +0.4 to +1.8], P<0.01), resulting in a between-group difference of 3.93% ([95% CI = 2.75 to 5.11], P<0.001). The between-group difference was maintained 30 months after intervention (1.99% [95% CI = 0.56 to 3.42], P<0.01). Persistence of the intervention effect over the entire study period was confirmed in a hierarchical multivariate analysis. Conclusion This randomised trial shows that a standardised and interactive educational seminar results in a long-term reduction in antibiotic prescribing and could justify a large-scale implementation of this intervention. [ABSTRACT FROM AUTHOR]

Two-dimensional and van der Waals ferromagnets are ideal platform to study low-dimensional magnetism and proximity effects in van der Waals heterostructures. Their ultimate two-dimensional character also offers the opportunity to easily adjust their magnetic properties using strain or electric fields. Among 2D ferromagnets, the Cr 1 + x Te2 compounds with x = 0–1 are very promising because their magnetic properties depend on the amount of self-intercalated Cr atoms between pure CrTe2 layers and the Curie temperature ( T C ) can reach room temperature for certain compositions. Here, we investigate the evolution of the composition as well as the structural and magnetic properties of thin Cr1.33Te2 (Cr2Te3) films epitaxially grown on graphene upon annealing. We observe a transition above 450 °C from the Cr1.33Te2 phase with perpendicular magnetic anisotropy and a T C of 180 K to a composition close to Cr 1.39 Te2 with in-plane magnetic anisotropy and a T C of 240–250 K. This phase remains stable up to 650 °C above which a pure Cr film starts to form. This work demonstrates the complex interplay between intercalated Cr, lattice parameters, and magnetic properties in Cr 1 + x Te2 compounds. [ABSTRACT FROM AUTHOR]

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Treatment with talazoparib resulted in an improvement or no change from baseline in patient-reported pain and health-related quality of life in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair alterations in the TALAPRO-1 trial. Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory—Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. In the 97 men in the PRO population treated with talazoparib (BRCA1/2 , n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (–1.08 [–1.52, –0.65]) and the BRCA1/2 subset (–1.15 [–1.67, –0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib. [ABSTRACT FROM AUTHOR]

Background: While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors.Methods/design: Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study's primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples.Discussion: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials.Trial Registration: Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018. [ABSTRACT FROM AUTHOR]

The Berry phase of wave functions is a key quantity to understand various low-energy properties of matter, among which electric polarisation, orbital magnetism, as well as topological and ultra-relativistic phenomena. Standard approaches to probe the Berry phase in solids rely on the electron dynamics in response to electromagnetic forces. In graphene, probing the Berry phase - of the massless relativistic electrons requires an external magnetic field. Here, we show that the Berry phase also affects the static response of the electrons to a single atomic scatterer, through wavefront dislocations in the surrounding standing-wave interference. This provides a new experimentalmethod to measure the graphene Berry phase in the absence of any magnetic field and demonstrates that local disorder can be exploited as probe of topological quantummatter in scanning tunnelling microscopy experiments. [ABSTRACT FROM AUTHOR]

Aims Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. Methods Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m 2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated. Results Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2–9.0) in the trebananib arm and 7.2 months (95% CI, 4.8–8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68–1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78–6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7–7.6]; placebo, 3.9 months [95% CI, 2.3–6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%). Conclusions Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified. Trial registration: ClinicalTrials.gov , NCT01281254 [ABSTRACT FROM AUTHOR]

Background. The participation rate in organized breast cancer screening in France is lower than recommended. Non-participants either use opportunistic screening or do not use either screening modality. Objective. To assess any differences in perceptions, attitudes and knowledge related to breast cancer screening between users of opportunistic screening and non-users of any screening mammograms and to identify potential barriers to participation in organized screening. Methods. Six focus groups were conducted in May 2010 with 34 French non-participants in organized screening, 15 who used opportunistic screening (OpS group) and 19 who used no screening (NoS group). The guide used for both groups explored perceptions and attitudes related to health, cancer and screening; perceptions of femininity; and knowledge about breast cancer screening. Thematic content analysis was performed. Results. Perceptions, attitudes and knowledge differed between the two groups. Women in the OpS group perceived a high susceptibility to breast cancer, visited their gynaecologist regularly, were unfamiliar with organized screening modalities and had doubts about its quality. NoS women had very high- or low-perceived susceptibility to breast cancer, knew about screening modalities, had doubts about its usefulness and expressed negative opinions of mammograms. Conclusions. Differences in perceptions and attitudes related to breast cancer screening partially explain why some women choose opportunistic screening or no screening. General practitioners and gynaecologists are in a unique position to provide individually tailored preventative messages to improve participation in organized screening. [ABSTRACT FROM AUTHOR]

Background: To describe French general practioners' (GPs) adaptation strategies to ensure follow-up care of nursing home patients during the first wave of COVID-19 (May 2020) and to identify factors associated with each strategy., Methods: A national cross-sectional study was conducted with online questionnaires in May 2020 among GPs practicing in France (metropolitan and overseas) and usually providing nursing home visits before pandemic. The outcome was defined as the GPs' adaptation strategies for managing nursing home patients and was categorized into four groups: Maintenance of Nursing Home Visits NHV (reference), Stopping NHV, Numeric adaptation (teleconsultations only), Mixed adaptation (NHV and teleconsultations). The probability of adaptation strategies was analyzed by multilevel logistic models in which the GPs represented level 1 and the counties level 2. We applied three random-intercept multilevel logistic models with the county of GP's practice as random effect., Results: This analysis included 2,146 responses by GPs coming from 98 French counties. Overall, 40.4% of GPs maintained NHV, while other strategies were: Stopping visits (24.1%), Numeric adaptation (15.4%), Mixed adaptation (20.1%). Several individual (age, training GP, perceived status of being at high risk of severe COVID, compliance with temporary delegation of the patient's management) and territorial factors (excess mortality rate due to COVID-19, GPs' density, proportion of over-75s, presence of reinforcement measures for nursing home patients) were identified as associated with each strategy., Conclusions: This study highlights a rapid adaptation of general practice to keep supporting nursing home patients. Heterogeneity of adaptation strategies could reflect both the lack of national guidelines and the heterogeneity among GPs' usual practices. Policymakers should take actions at a territorial level (subnational) to strengthen support to nursing home patients considering adaptations to the local context of the pandemic outbreak and perspective of local actors., (© 2024. The Author(s).)

Background: The benefits of comprehensive geriatric assessment (CGA) are well established for hospital care but less so for primary care. Our primary objective was to assess the effect of two multifaceted interventions based on a CGA adapted for primary care on a composite criterion combining all-cause mortality, emergency department visits, unplanned hospital admissions, and institutionalisation., Methods: This open-label, pragmatic, three-arm, cluster-randomised controlled trial involved 39 general practices in France. It included 634 patients aged 70 years or over with chronic health conditions and/or an unplanned hospital admission in the past 3 months, between 05/2016 and 08/2018. Interventions were in arm 1: a systematic nurse-led CGA; arm 2: a GP-led CGA, at the GP's discretion; arm 3: standard care. The primary composite endpoint was assessed at 12 months. The secondary endpoints included: components of the composite endpoint, health-related quality of life (Duke Health Profile), functional status (Katz Activities of Daily Living Index) and medications (number) at 12 months. Pairwise comparisons between the experimental groups and the control were tested. The main analysis was performed on the intention-to-treat (ITT) population, after imputing missing information and adjusting for baseline imbalances by mixed effects regressions., Results: For the primary composite outcome, no statistically significant difference was found between arm 1 and the control (adjusted odds ratio [aOR] = 0.81 [95%CI 0.54-1.21], P = 0.31), whereas arm 2 and the control differed significantly (aOR = 0.60 [0.39-0.93], P = 0.022). A statistically lower risk of unplanned hospital admission in arm 2 vs control (aOR = 0.57 [0.36-0.92], P = 0.020)) was observed, while no statistically significant differences were found for the other components and between arm 1 and the control. None of the other secondary endpoints differed between arms., Conclusions: Our study led in community-dwelling older patients with chronic conditions found no significant effect of a CGA adapted for primary care on mortality, functional independence and quality of life, but suggests that a GP-led CGA may reduce the risk of unplanned hospital admission. Our study demonstrates the feasibility of incorporating CGA into clinical practice and highlights its potential benefits when applied on a case-by-case basis, guided by the GPs who develop the resulting PCP., Trial Registration: NCT02664454., (© 2024. The Author(s).)

Fractional charges are one of the wonders of the fractional quantum Hall effect. Such objects are also anticipated in two-dimensional hexagonal lattices under time reversal symmetry-emerging as bound states of a rotating bond texture called a Kekulé vortex. However, the physical mechanisms inducing such topological defects remain elusive, preventing experimental realization. Here, we report the observation of Kekulé vortices in the local density of states of graphene under time reversal symmetry. The vortices result from intervalley scattering on chemisorbed hydrogen adatoms. We uncover that their 2π winding is reminiscent of the Berry phase π of the massless Dirac electrons. We can also induce a Kekulé pattern without vortices by creating point scatterers such as divacancies, which break different point symmetries. Our local-probe study thus confirms point defects as versatile building blocks for Kekulé engineering of graphene's electronic structure., (© 2024. The Author(s).)

2D materials, such as transition metal dichalcogenides, are ideal platforms for spin-to-charge conversion (SCC) as they possess strong spin-orbit coupling (SOC), reduced dimensionality and crystal symmetries as well as tuneable band structure, compared to metallic structures. Moreover, SCC can be tuned with the number of layers, electric field, or strain. Here, SCC in epitaxially grown 2D PtSe 2 by THz spintronic emission is studied since its 1T crystal symmetry and strong SOC favor SCC. High quality of as-grown PtSe 2 layers is demonstrated, followed by in situ ferromagnet deposition by sputtering that leaves the PtSe 2 unaffected, resulting in well-defined clean interfaces as evidenced with extensive characterization. Through this atomic growth control and using THz spintronic emission, the unique thickness-dependent electronic structure of PtSe 2 allows the control of SCC. Indeed, the transition from the inverse Rashba-Edelstein effect (IREE) in 1-3 monolayers (ML) to the inverse spin Hall effect (ISHE) in multilayers (>3 ML) of PtSe 2 enabling the extraction of the perpendicular spin diffusion length and relative strength of IREE and ISHE is demonstrated. This band structure flexibility makes PtSe 2 an ideal candidate to explore the underlying mechanisms and engineering of the SCC as well as for the development of tuneable THz spintronic emitters., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

The study of moiré engineering started with the advent of van der Waals heterostructures, in which stacking 2D layers with different lattice constants leads to a moiré pattern controlling their electronic properties. The field entered a new era when it was found that adjusting the twist between two graphene layers led to strongly-correlated-electron physics and topological effects associated with atomic relaxation. A twist is now routinely used to adjust the properties of 2D materials. This study investigates a new type of moiré superlattice in bilayer graphene when one layer is biaxially strained with respect to the other-so-called biaxial heterostrain. Scanning tunneling microscopy measurements uncover spiraling electronic states associated with a novel symmetry-breaking atomic reconstruction at small biaxial heterostrain. Atomistic calculations using experimental parameters as inputs reveal that a giant atomic swirl forms around regions of aligned stacking to reduce the mechanical energy of the bilayer. Tight-binding calculations performed on the relaxed structure show that the observed electronic states decorate spiraling domain wall solitons as required by topology. This study establishes biaxial heterostrain as an important parameter to be harnessed for the next step of moiré engineering in van der Waals multilayers., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs., Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors., Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023., Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions)., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population., Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred., Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

Objectives: To describe and compare the initial clinical characteristics of a cohort of patients with suspected COVID-19 managed by general practitioners (GPs); to assess whether 3-month persistent symptoms were more frequent among confirmed cases than among no-COVID cases; and to identify factors predictive of persistent symptoms and adverse outcomes among confirmed cases., Design and Setting: A comparative, prospective, multicentre cohort study in primary care in the Paris region of France., Participants: 521 patients aged ≥18 with suspected COVID-19 were enrolled between March and May 2020., Outcome Measures: Initial symptoms, COVID-19 status, persistent symptoms 3 months after inclusion and a composite criterion for potentially COVID-19-related events (hospitalisation, death, emergency department visits). The final COVID-19 status ('confirmed', 'no-COVID' and 'uncertain' cases) was determined by the GP after the receipt of the laboratory test results., Results: 516 patients were analysed; 166 (32.2%) were classified into the 'confirmed COVID' group, 180 (34.9%) into the 'no-COVID' group and 170 (32.9%) in the 'uncertain COVID' group. Confirmed cases were more likely to have persistent symptoms than no-COVID cases (p=0.09); initial fever/feeling feverish and anosmia were independently associated with persistent symptoms. At 3 months, we observed 16 (9.8%) COVID-19-related hospital admissions, 3 (1.8%) intensive care unit admissions, 13 (37.1%) referrals to an emergency department and no death. Age >70 and/or at least one comorbidity (OR 6.53; 95% CI 1.13-37.84; p=0.036), abnormalities in a lung examination (15.39; 95% CI 1.61-146.77; p=0.057) and two or more systemic symptoms (38.61; 95% CI 2.30-647.40; p=0.011) were associated with the composite criterion., Conclusions: Although most patients with COVID-19 in primary care had mild disease with a benign course, almost one in six had persistent symptoms at 3 months. These symptoms were more frequent in the 'confirmed COVID' group. Our findings need to be confirmed in a prospective study with longer follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Visual aids (VAs) seem effective to improve doctor-patient communication. The objective was to describe how VAs are used in consultation and what French general practitioners (GPs) expect of them., Methods: Cross-sectional study using a self-administered questionnaire among French GPs in 2019. Descriptive and multinominal logistic regression analyses were performed., Results: Of the 376 respondents, 70% used VAs at least weekly and 34% daily; 94% considered VAs useful/very useful; 77% felt they did not use VAs enough. Sketches were the most used VAs and considered the most useful. Younger age was significantly associated with a higher rate of use of simple digital images. VAs were mainly used to describe anatomy and facilitate patient comprehension. Main reasons for not using VAs more often were time spent searching, lack of habit and poor quality of available VAs. Many GPs requested a database of good quality VAs., Conclusions: GPs use VAs regularly in consultations but would like to use them more often. Informing GPs of the usefulness of VAs, training them to draw adapted sketches and creating a good quality databank are some possible strategies to increase the use of VAs., Innovation: This study described in detail the use of VAs as tool for doctor-patient communication., Competing Interests: None. The authors have no conflicts of interest to disclose., (© 2023 The Authors.)

The moiré of twisted graphene bilayers can generate flat bands in which charge carriers do not possess enough kinetic energy to escape Coulomb interactions with each other, leading to the formation of novel strongly correlated electronic states. This exceptionally rich physics relies on the precise arrangement between the layers. Here, we survey published scanning tunneling microscope measurements to prove that near the magic-angle, native heterostrain, the relative deformations between the layers, dominates twist in determining the flat bands as opposed to the common belief. This is demonstrated at full filling where electronic correlations have a weak effect and where we also show that tip-induced strain can have a strong influence. In the opposite situation of zero doping, we find that electronic correlation further renormalizes the flat bands in a way that strongly depends on experimental details.

Aim: To evaluate the pCR rate and toxicity of the addition of weekly carboplatin (Cp) to paclitaxel (wP) and dose-dense (dd) epirubicin/cyclophosphamide (EC) in an open-label phase II study in TNBC patients., Methods: Patients were included if they had stage II and III TNBC and received wP (80 mg/m 2 /week) concurrent with weekly Cp (AUC = 2) for 12 weeks, followed by bi-weekly epirubicin (90 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) plus granulocyte colony-stimulating factor (G-CSF) for four cycles, followed by surgery. The primary endpoint was the rate of pCR [(ypT0/isypN0)]. Secondary endpoints included safety and drug delivery., Results: Sixty-three eligible patients were included. Median age was 51 years (range 29-74); 88.9% had stage II disease, 46% were clinically node positive, and 77.8% had grade 3 tumors. Fifty-four percent achieved a pCR. Twelve percent missed two or more doses of wP, whereas at least two cycles of EC were missed in 9.5%. The rate of tolerance without delays or dose reductions is very low (16%). Sixty-two percent had G3/4 neutropenia. Febrile neutropenia occurred in 18 patients of which more than eighty percent occurred during EC despite primary prophylaxis with G-CSF. Thrombocytopenia grade 3/4 was noticed in 11 pts. Three patients developed grade 3 peripheral neuropathy., Conclusion: The addition of weekly carboplatin to neoadjuvant paclitaxel and dd EC leads to a pCR rate comparable to prior studies (54%). However, hematological toxicity and febrile neutropenia rate was unexpectedly high. Future investigations could focus on reversing the sequence, which may lead to better hematological tolerability.

Van der Waals heterojunctions composed of graphene and transition metal dichalcogenides have gain much attention because of the possibility to control and tailor band structure, promising applications in two-dimensional optoelectronics and electronics. In this report, we characterized the van der Waals heterojunction MoSe 2 /few-layer graphene with a high-quality interface using cutting-edge surface techniques scaling from atomic to microscopic range. These surface analyses gave us a complete picture of the atomic structure and electronic properties of the heterojunction. In particular, we found two important results: the commensurability between the MoSe 2 and few-layer graphene lattices and a band-gap opening in the few-layer graphene. The band gap is as large as 250 meV, and we ascribed it to an interface charge transfer that results in an electronic depletion in the few-layer graphene. This conclusion is well supported by electron spectroscopy data and density functional theory calculations. The commensurability between the MoSe 2 and graphene lattices as well as the band-gap opening clearly show that the interlayer interaction goes beyond the simple van der Waals interaction. Hence, stacking two-dimensional materials in van der Waals heterojunctions enables us to tailor the atomic and electronic properties of individual layers. It also permits the introduction of a band gap in few-layer graphene by interface charge transfer.

Reminders have been used in various settings, but failed to produce convincing evidence of benefits on patient adherence to colorectal cancer (CRC) screening. The aim of this study was to assess the effectiveness of sending general practitioners (GPs) printed reminders about CRC screening. We conducted a cluster-randomized controlled trial involving 144 GPs in the Val-de-Marne district (France), who provided care for any reason to 20 778 patients eligible for CRC screening between June 2010 and November 2011. Data were collected from the main statutory health-insurance programme and local cancer screening agency. GPs were randomly assigned in a 1 : 1 proportion to the intervention or the control group. Every 4 months, intervention-group GPs received a computer-generated printed list of patients who had not performed scheduled faecal occult blood test (FOBT) screening. The primary outcome was patient adherence to FOBT screening or exclusion from CRC screening for medical reasons. The screening adherence rate was 31.2% [95% confidence interval (CI) 30.3-32.1] in the control group and 32.9% (95% CI 32.0-33.8) in the intervention group [crude relative risk, 1.05 (95% CI 1.01-1.09), P<0.01]. This rate was not significantly different between groups by multilevel modelling accounting for clustering and confounding variables [adjusted relative risk, 1.07 (95% CI 0.95-1.20), P=0.27]. Computer-generated printed reminders sent to GPs did not significantly improve patient adherence to organized CRC screening by the FOBT.

A quantitative method for the simultaneous determination of docetaxel (Taxotere), paclitaxel (Taxol), 6alpha-hydroxypaclitaxel, and p-3'-hydroxypaclitaxel in human plasma and oral fluid is developed and validated. Oral fluid (this term is now preferred to saliva) was sampled with a Salivette collection device. The procedure used a simple liquid/liquid extraction with methyl tert-butyl ether followed by LC-ESI-MS/MS. Gradient elution was applied and provided increased robustness to ion suppression by the drug formulation vehicle (polysorbate 80 and Cremophor EL). Adduct ion formation with sodium and potassium was noticed and controlled by mobile-phase optimization. The protonated analytes generated in the positive ion mode were monitored through multiple reaction monitoring. Calibration was performed by internal standardization with cephalomannine, and regression curves were constructed ranging between 2 and 1000 ng/mL in plasma and 0.125 and 62.5 ng/mL in oral fluid, using a weighing factor of 1/x2. The regression curves were quadratic for paclitaxel and docetaxel and linear for the paclitaxel metabolites. Accuracy varied from 91.3 to 103.6%, and imprecision did not exceed 12.7% for all analytes in plasma and oral fluid. In conclusion, a sensitive and robust method was obtained, which fulfilled all validation criteria.