Combined frequency-amplitude nonlinear modulation: theory and applications

In this work we formulate a generalized theoretical model to describe the nonlinear dynamics observed in combined frequency-amplitude modulators whose characteristic parameters exhibit a nonlinear dependence on the input modulating signal. The derived analytical solution may give a satisfactory explanation of recent laboratory observations on magnetic spin-transfer oscillators and fully agrees with results of micromagnetic calculations. Since the theory has been developed independently of the mechanism causing the nonlinearities, it may encompass the description of modulation processes of any physical nature, a promising feature for potential applications in the field of communication systems.Comment: 8 pages, 4 figures, to be published on IEEE Transactions on Magnetic

Management of Hypothyroidism in Internal Medicine: Patient Profile and Effects of an Educational Programme in the Cluster-Randomized FADOI TIAMO Study.

Background and aims: There is still limited knowledge regarding the clinical profile and appropriateness of treatment in patients with hypothyroidism hospitalized in Internal Medicine (IM) Departments in Italy. The aim of this study is to evaluate: 1) the characteristics of patients and possible deviations from national and international clinical practice recommendations (CPRs) in evidence-based guidelines (EBGs); 2) the improvement of patient management by means of a standardized educational programme (EP). Methods: A nationwide multicentre study, comprising two replications of a retrospective survey (phases 1 and 3) with an intervening EP (phase 2) in half of the centres and no EP in the other half, was conducted. The EP was based on outreach visits. Centres were assigned to the two arms of the study, labelled the training group (TG) and control group (CG) respectively, by cluster randomization. Four EBGs and 39 CPRs provided the basis on which 22 treatment management indicators were identified (7 referring to the time of hospital admission, 15 to post-admission). Results: The 21 participating centres recruited 587 hospitalized patients with hypothyroidism, 421 of which were females (71.7%, mean age 74.1 + 14.4 yrs): 318 in phase 1 and 269 in phase 3. The cause of hypothyroidism was unknown in 282 patients (48%). Evaluation at the time of admission identified satisfactory adherence to CPRs (>50%) for 63.6% of the indicators. In the phase 3, TG centres showed significant improvement vs CG in 4 of the 15 post-admission indicators, while 1 out of 15 was significantly worse. Conclusions: The EP based on outreach visits significantly improved some indicators in the management of patients with hypothyroidism, with specific reference to appropriateness of TSH dosage and levothyroxine (LT4) treatment modality. Clinical trial registration: ClinicalTrials.gov, identifier NCT05314790

Light-Scattering Observation Of Surface Acoustic Modes In High-Order Brillouin Zones Of A Si(001) Grating

In Brillouin light-scattering (BLS) measurements of an ion-milled Si(001) surface grating with grating wavelength Lambda(G) =0.35 mu m, we have observed numerous high-order zone-folded surface acoustic modes between the second and third zone boundaries associated with the grating. A surprisingly intense signal from a zone-folded longitudinal resonance was observed in the absence of direct hybridization with the Rayleigh modes. The relative intensities of all of the modes have been calculated by allowing for coupling between modes related by up to two grating reciprocal-lattice vectors, and for a grating profile with nonzero first and second Fourier amplitudes. The Fourier amplitudes inferred from the BLS measurements and calculations agree very well with those obtained from a direct measurement of the grating profile using atomic-force microscopy

Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma

Background: Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma. Methods: The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours. Results: Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis. Conclusion: The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process. Keywords: HER2, gastric cancer, FISH, immunohistochemistr

Monitoring cfDNA in plasma and in other liquid biopsies of advanced EGFR mutated NSCLC patients: A pilot study and a review of the literature

In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC

Optimizing PD-L1 evaluation on cytological samples from advanced non-small-cell lung cancer

Aim: Programmed cell death-ligand 1 (PD-L1) predicts response to immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) patients. Most NSCLCs are diagnosed at an advanced stage and using minimally invasive diagnostic procedures that yield small biopsies or cytological samples. Methods: Cytological smears and paired histological samples from 52 advanced NSCLC patients were tested for PD-L1 expression by immunocyto/histochemistry (ICC/IHC) and for PD-L1 gene status by FISH. Results: PD-L1 was overexpressed in 9/52 (17%) cytological samples and in seven (13.5%) matched biopsies. The concordance between immunocytochemistry and IHC was 92.3% (48/52; p < 0.001). The concordance between PD-L1 gene status on cytology and histology was 69.2% (18/26; p < 0.001). No correlation between IHC and fluorescence in situ hybridization results was found. Conclusion: Our data support the feasibility and reliability of PD-L1 protein and PD-L1 gene assessment on direct cytological smears from NSCLC patients whenever histological sample are inadequate

Real-world Outcomes of Relapsed/Refractory Diffuse Large B-cell Lymphoma Treated With Polatuzumab Vedotin-based Therapy.

After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician's discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1-2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy

Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment

Background Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 x 10(9)/L, platelets <100 x 10(9)/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/)

Exchange of nutrients and oxygen across the sediment-water interface below a Sparus aurata marine fish farm in the north-western Mediterranean Sea

Purpose: This study analyzes the effects of aquaculture activities in open seawater in the north-western coastal waters of the Mediterranean Sea. It is the first of its kind to be based on benthic flux data gathered in situ below fish farms for this particular area. Materials and methods: Samples were collected on four sampling campaigns over a 1-year cycle under a Sparus aurata fish farm facility where benthic fluxes were measured in situ using light and dark benthic chambers. Bottom water and sediment samples were also collected. Data were compared to those for a nearby control station. Results and discussion: Significant differences were found (ANOVA, p < 0. 05) between concentrations of organic matter (OM), total phosphorus and redox potentials in sediments located under the cages and those of the control station. The consumption of dissolved oxygen (DO) by sediment and positive ammonium (NH4 +) fluxes was stimulated by OM content, with correlations of r = -0. 60 (p < 0. 01) and r = 0. 70 (p < 0. 01), respectively. The OM content of sediments was found to be consistently higher under the cages than at the control station, with the highest value (1. 8 ± 0. 7 %) under the cages observed during the early summer; values of DO and NH4 + fluxes were -64 ± 17 and 12. 7 ± 1. 0 mmol m-2 day-1, respectively. PO4 3- fluxes were consistently higher in the fish farm sediments (between 0. 58 and 0. 98 mmol m-2 day-1) than those observed at the control station. Nitrate (NO3 -) fluxes were found to be consistently negative due to denitrification occurring in the sediments and were related to the concentration of NO3 - in bottom waters (r = 0. 92, p < 0. 01). Si fluxes were shown to be associated with water temperature (r = 0. 59, p < 0. 05). Conclusions: The results imply that sediments located below cages accumulate organic matter originating from aquaculture activities, especially during summer months when this activity increases. Sediments undergo biogeochemical changes that mainly affect fluxes of DO, NH4 + and soluble reactive phosphorus, although these do not seem to have a significant impact on the quality of the water column due to the hydrodynamic characteristics of the area. © 2012 Springer-Verlag.We would like to thank the Caja del Mediterraneo for a predoctoral fellowship fund for this research and Antonio Asuncion Acuigroup Maremar manager for the facilities and support in conducting the study. The translation of this paper was funded by the Universidad Politecnica de Valencia, Spain. We are grateful for the valuable comments of the anonymous reviewers on previous versions of the manuscript.Morata Higón, T.; Sospedra, J.; Falco Giaccaglia, SL.; Rodilla Alama, M. (2012). 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