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The calibration of Micro-Electro-Mechanical System (MEMS) microphones remains a critical challenge due to their miniaturized geometry and sensitivity to non-uniform acoustic fields. This study presents an advanced calibration methodology that integrates Finite Element Method (FEM) simulations with experimental corrections to improve the accuracy of pressure comparison calibrations using active couplers. A key innovation is the incorporation of asymmetric acoustic field analysis, which systematically quantifies and corrects discrepancies arising from cavity geometry, sensor positioning, and resonance effects peculiar of MEMS microphones. The proposed approach significantly reduces measurement uncertainties, especially in the high-frequency range above 5 kHz, where standard calibration techniques face challenges in taking into account localized pressure variations. Furthermore, the implementation of a measurement set-up, which includes the insert voltage technique, allows for an accurate assessment of the preamplifier gain and minimizes systematic errors. Experimental validation shows that the refined calibration methodology produces highly reliable correction values, ensuring a robust performance over a wide frequency range (20 Hz–20 kHz). These advances establish a rigorous framework for standardizing the calibration of MEMS microphones, strengthening their applicability in acoustic monitoring, sound source localization, and environmental sensing.

The blood–brain barrier (BBB) poses a significant challenge to drug delivery to the brain. A promising approach involves low-frequency, low-intensity pulsed ultrasound (US) waves combined with intravenously injected microbubbles (MB) to temporarily and non-invasively open the BBB. However, current technologies cannot easily integrate this procedure with US imaging. Passive cavitation detection, tracing the harmonic emissions of MB during sonication, has been the preferred method for real-time monitoring of US-mediated BBB opening. We used an ultrasound advanced open platform (ULA-OP) to simultaneously perform US-mediated BBB opening and US imaging with a single linear-array probe. In vitro guinea pig brains were perfused with MB and sonicated with different plane-wave transmission patterns. The most effective US pattern was interleaved with B-mode imaging pulses, enabling the direct assessment of the MB distribution during treatment. The extent of BBB permeabilization was assessed by quantifying FITC-albumin extravasation into the brain via confocal microscopy. US-treated hemispheres displayed BBB permeabilization, while control hemispheres did not. B-mode imaging allowed direct evaluation of MB distribution and interaction with the US beam. Therefore, we achieved effective BBB opening and simultaneous MB imaging using the same diagnostic probe, paving the way for US-guided therapeutic ultrasound application in the clinical context.

The blood–brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system. The combined use of low-intensity pulsed ultrasound waves and intravascular microbubbles (MB) represents a promising solution to this issue, allowing reversible disruption of the barrier. In this study, we evaluate the feasibility of BBB opening through a biocompatible, polyolefin-based plate in an in vitro whole brain model. Twelve in vitro guinea pig brains were employed; brains were insonated using a planar transducer with or without interposing the polyolefin plate during arterial infusion of MB. Circulating MBs were visualized with an ultrasonographic device with a linear probe. BBB permeabilization was assessed by quantifying at confocal microscopy the extravasation of FITC-albumin perfused after each treatment. US-treated brains displayed BBB permeabilization exclusively in the volume under the US beam; no significant differences were observed between brains insonated with or without the polyolefin plate. Control brains not perfused with MB did not show signs of FITC-albumin extravasation. Our preclinical study suggests that polyolefin cranial plate could be implanted as a skull replacement to maintain craniotomic windows and perform post-surgical repeated BBB opening with ultrasound guidance to deliver therapeutic agents to the central nervous system.

Sonodynamic therapy is an emerging approach that uses low-intensity ultrasound to activate a sonosensitizer agent triggering its cytotoxicity for selective cancer cell killing. Several molecules have been proposed as sonosensitizer agents, but most of these, as chlorophyll, are strongly hydrophobic with a low selectivity towards cancer tissues. Nanocarriers can help to deliver more efficiently the sonosensitizer agents in the target tumor site, increasing at the same time their sonodynamic effect, since nanosystems act as cavitation nuclei. Herein, we propose the incorporation of unmodified plant-extracted chlorophyll into nanocarriers with different composition and structure (i.e., liposomes, solid lipid nanoparticles and poly(lactic-co-glycolic acid) nanoparticles) to obtain aqueous formulations of this natural pigment. The nanocarriers have been deeply characterized and then incubated with human prostatic cancer cells (PC-3) and spheroids (DU-145) to assess the influence of the different formulations on the chlorophyll sonodynamic effect. The highest sonodynamic cytotoxicity was obtained with chlorophyll loaded into poly(lactic-co-glycolic acid) nanoparticles, showing promising results for future clinical investigations on sonodynamic therapy.

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

Ultrasound contrast agents (UCAs) allow to assess brain perfusion via contrast-enhanced ultrasound (CEUS) imaging and to perform ultrasound-based therapies such as blood brain barrier opening. Currently, the heterogeneous distribution of the UCAs within physiological and pathological structures is neglected to dynamically fine-tune the treatment schemes. Since microbubbles are pure intravascular agents, we hypothesize that their distribution can be correlated with Dynamic-Susceptibility-Contrast (DSC) MRI. Pre-operative DSC-MRI and intra-operative CEUS imaging were performed in 31 patients undergoing elective brain tumor resection. At qualitative comparison, CEUS and DSC-MRI showed superimposable anatomical structures and lesion perfusion features in all cases. Quantitative analysis revealed no correlation between CEUS and DSC for MTT, moderate correlation for TTP, and negative correlation for nAUC with DSC-CBV. Our results indicate that DSC-MRI perfusion patterns demonstrate both qualitative and quantitative correlation with CEUS and can be used as a non-invasive biomarker for MBs’ distribution in the human brain.

The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2–3 years of letrozole in postmenopausal patients with breast cancer who have already received 2–3 years of tamoxifen. This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I–III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2–3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635. Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5–13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57–66) in the control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI 0·65–0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed. In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer. Novartis and the Italian Ministry of Health. For the Italian translation of the abstract see Supplementary Materials section.

Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed. Healthy adults aged 18-60 and > 60 years (n = 313 and n = 173, respectively) were randomized (1:1) to receive two primary and one booster injection of 7.5 microg or 15 microg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 microg and 15 microg doses were comparable. The rates for seroprotection (HI>40; SRH>25 mm(2); MN > or = 40) after the primary vaccination ranged 72-87%. Six months after primary vaccination with the 7.5 microg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 microg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations. Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs. (ClinicalTrials.gov) NCT00311480.

Purpose To compare the interpretive performance of synthetic mammography (SM), reconstructed from digital breast tomosynthesis (DBT), and full-field digital mammography (FFDM) in a diagnostic setting, covering different conditions of breast density and mammographic signs. Methods A retrospective analysis was conducted on 231 patients, who underwent FFDM and DBT (from which SM images were reconstructed) between September 2014–September 2015. The study included 250 suspicious breast lesions, all biopsy proven: 148 (59.2%) malignant and 13 (5.2%) high-risk lesions were confirmed by surgery, 89 (35.6%) benign lesions had radiological follow-up. Two breast radiologists, blinded to histology, independently reviewed all cases. Readings were performed with SM alone, then with FFDM, collecting data on: probability of malignancy for each finding, lesion conspicuity, mammographic features and dimensions of detected lesions. Results Agreement between readers was good for BI-RADS classification (Cohen’s k-coefficient = 0.93 ± 0.02) and for lesion dimension (Wilcoxon’s p  = 0.76). Visibility scores assigned to SM and FFDM for each lesion were similar for non-dense and dense breasts, however, there were significant differences ( p  = 0.0009) in distribution of mammographic features subgroups. SM and FFDM had similar sensitivities in non-dense (respectively 94 vs. 91%) and dense breasts (88 vs. 80%) and for all mammographic signs (93 vs. 87% for asymmetric densities, 96 vs. 75% for distortion, 92 vs. 85% for microcalcifications, and both 94% for masses). Based on all data, there was a significant difference in sensitivity for SM (92%) vs. FFDM (87%), p  = 0.02, whereas the two modalities yielded similar results for specificity (SM: 60%, FFDM: 62%, p  = 0.21). Conclusions SM alone showed similar interpretive performance to FFDM, confirming its potential role as an alternative to FFDM in women having tomosynthesis, with the added advantage of halving the patient’s dose exposure.

Guillain–Barré syndrome (GBS) is an autoimmune neurological disorder often preceded by viral illnesses or, more rarely, vaccinations. We report on a unique combination of postcoronavirus disease 2019 (COVID-19) vaccine GBS that occurred months after a parainfectious COVID-19–related GBS. Shortly after manifesting COVID-19 symptoms, a 57-year-old man developed diplopia, right-side facial weakness, and gait instability that, together with electrophysiology and cerebrospinal fluid examinations, led to a diagnosis of post-COVID-19 GBS. The involvement of cranial nerves and IgM seropositivity for ganglioside GD1b were noteworthy. COVID-19 pneumonia, flaccid tetraparesis, and autonomic dysfunction prompted his admission to ICU. He recovered after therapy with intravenous immunoglobulins (IVIg). Six months later, GBS recurred shortly after the first dose of the Pfizer/BioNTech vaccine. Again, the GBS diagnosis was confirmed by cerebrospinal fluid and electrophysiology studies. IgM seropositivity extended to multiple gangliosides, namely for GM3/4, GD1a/b, and GT1b IgM. An IVIg course prompted complete recovery. This case adds to other previously reported observations suggesting a possible causal link between SARS-CoV-2 and GBS. Molecular mimicry and anti-idiotype antibodies might be the underlying mechanisms. Future COVID-19 vaccinations/revaccinations in patients with previous para-/post-COVID-19 GBS deserve a reappraisal, especially if they are seropositive for ganglioside antibodies.