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Background Rimegepant, a novel oral calcitonin gene-related peptide receptor antagonist, has been recently approved for the acute migraine treatment. While its efficacy was confirmed in randomized clinical trials, no data is available regarding real-life effectiveness and tolerability. GAINER, a prospective, multicentric study, aimed to evaluate rimegepant effectiveness and tolerability in the real-world setting. Methods Our study involved 16 headache centers across Italy. The main outcomes were: i) 2 h pain freedom, and ii) occurrence of treatment-emergent adverse events after administration. Participants were instructed to treat one migraine attack with rimegepant 75 mg orally disintegrating tablet. Using an ad hoc diary, participants prospectively collected migraine attack features at baseline and every 30 min after rimegepant administration, up to 2 h post dose. A 24 h follow up was also collected. Results We enrolled 103 participants with migraine (74.8% female, mean age 44.4 [42.0 – 46.7] years, 24.3% with chronic migraine of whom 44.0% presented a concomitant diagnosis of medication overuse headache). The number of previously failed preventive classes was 2.7 [2.3 – 3.2]. Participants presented a mean of 9.6 [8.2 – 10.9] monthly migraine days at baseline. At rimegepant intake, 40.8% of patients rated migraine intensity as severe. Pain freedom 2 h post dose was reported in 44.7% (46/103) of individuals. Pain freedom 2 h post dose was not influenced by baseline pain severity ( p  = 0.316), but it was associated with timing of intake ( p  = 0.032) with a higher rate of 2 h pain freedom when rimegepant was taken within 1 h from pain onset. Mild adverse events were reported in 15.5% total attacks (16/103), predominantly fatigue ( n  = 6), gastrointestinal symptoms ( n  = 6), somnolence ( n  = 4), and transient cognitive difficulties ( n  = 3). Tolerability was rated as good-to-excellent in 85.4% cases (88/103). Conclusions Our data confirms rimegepant effectiveness and safety in the acute migraine treatment in a real-world setting in a cohort of participants that includes subjects with episodic or chronic migraine, medication overuse and a high number of prior preventive treatment failures. Trial registration The study was preregistered on clinicaltrial.gov, NCT05903027.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO 2 /FiO 2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.

Background and purpose Although there is extensive evidence about the safety of monoclonal antibodies against calcitonin gene‐related peptide (anti‐CGRP mAbs) in combination with traditional drugs, scarce data are available on the safety of their combination with other mAbs. This study aimed to evaluate the 6‐month effectiveness and tolerability of anti‐CGRP mAbs in combination with other mAbs for different diseases. Methods Patients included in the Italian Headache Registry and treated concomitantly with an anti‐CGRP mAb and another mAb were included. Effectiveness outcomes for migraine included reduction from baseline of monthly headache days (MHDs), Migraine Disability Assessment (MIDAS) score, Headache Impact Test‐6 (HIT‐6) scores, and Patients' Global Impression of Change (PGIC) scale. Adverse events (AEs) were recorded. Results Thirty‐eight patients were included. In 27 patients (71.1%), the anti‐CGRP mAb was added to a previously ongoing mAb. Nine patients (23.7%) discontinued one of the two mAbs before the end of treatment (seven discontinued the anti‐CGRP mAb and two the other mAb). One patient discontinued for AEs. Anti‐CGRP mAbs were discontinued due to ineffectiveness (n = 5, 55.5%) and one each (11.1%) for clinical remission and lost to follow‐up. MHDs significantly decreased from baseline to 3 months (p < 0.0001) and 6 months (p < 0.001), as did the MIDAS and the HIT‐6 scores at 3 and 6 months (p < 0.001). For anti‐CGRP mAbs, 27.4% of patients reported PGIC ≥ 5 at 3 months and 48.3% at 6 months. Mild AEs associated with introduction of a second mAb were detected in six patients (15.8%). Conclusions In this real‐world study, anti‐CGRP mAbs showed safety and effectiveness when administered concomitantly with other mAbs.

Background and Aims This study evaluates the distribution and prognostic role of transcranial color‐coded Doppler (TCCD) spectral patterns following a successful endovascular thrombectomy (EVT). Methods This multicenter prospective study included patients with internal carotid or middle cerebral artery (MCA) occlusion treated in the early time window (< 6 h) with a successful EVT (mTICI ≥ 2b), without symptomatic hemorrhagic transformation within 24 h. TCCDs were performed 24–48 h and 7 days from EVT. TCCD flow was graded by Consensus on Grading Intracranial Flow Obstruction (COGIF) score (1: no flow; 2–3: low flow; 4a: normal; 4b: residual stenosis; 4c: hyperperfusion). MCA flow velocities were compared between sides and time points. Outcomes were clinical improvement (decrease of 8 points/30% on day 7 NIHSS vs. baseline) and three‐month mRS. Results 188 ischemic stroke patients were included (48% female, median age 77). The median NIHSS was 16 at admission and 3 at day 7. Day 1 TCCD showed slightly higher velocities in the treated MCA compared to the contralateral MCA, without significant differences between day 1 and day 7. Despite mTICI ≥ 2b, 13/187 (7%) patients showed a partial recanalization or residual stenosis at 24 h. Clinical improvement was lacking in 27 patients (14.4%). COGIF scores 3 and 4b at day 1 were significantly associated with lack of improvement at day 7 (aOR 0.03, 95% CI 0.01–0.16, p < 0.001) and worse mRS score at 3 months (mRS ordinal shift analysis, aOR 7.78, 95% CI 2.16–28.54, p = 0.002). Conclusions Day 1 post‐EVT TCCD COGIF score, but no flow velocities alone, are associated with clinical outcomes.

The COVIVAX study assessed the association between COVID-19 vaccination and the risk of common neurological disorders in a multicenter case-control design. Vaccination exposure was compared between individuals with a first diagnosis of a neurological disorder (cases) and age- and sex-matched controls. A total of 624 participants were enrolled, and after random 1:1 matching 265 cases and 265 matched controls (total 530 participants) were included in the analyses. The most frequent neurological diagnosis in cases were stroke (60.4%), multiple sclerosis (11.3%) and seizures (6.4%). The proportion of vaccinated participants was 72.1% among cases and 79.6% among controls. A protective role of vaccination on the risk of developing a new neurological disorder was detected in the unadjusted analysis (OR 0.50; 95% CI 0.29–0.86; p  = 0.0114). After adjustment for confounders, the number of vaccination doses received was associated with a reduced risk of developing new neurological disorders for participants aged over 60 years ( p  = 0.0472; OR 0.14, 95% CI 0.03–0.68), with pre-existing comorbidities ( p  = 0.0122; OR 0.04, 95% CI 0.01–0.99) and for stroke ( p  = 0.0232; OR 0.04, 95% CI 0.02–0.97). The COVIVAX study provided no warning sign regarding an increase in the risk of developing new neurological disorders following COVID-19 vaccination of any type or doses. A potentially protective effect of multiple doses of COVID-19 vaccines against the risk of stroke in people aged over 60 needs to be confirmed by further studies.

Background: Lasmiditan, an oral 5-HT1F receptor agonist, has been recently approved for acute migraine treatment. While its efficacy was confirmed in randomized clinical trials, scarce data is available regarding effectiveness and tolerability in the real-world setting. Objectives: To evaluate lasmiditan effectiveness and tolerability in the real-world setting in 16 Italian headache centers. Design: LasmiDitan as Acute migRaine Treatment (DART) study is a prospective, multicentric, observational study. Methods: We enrolled 58 participants with migraine (84.5% females, age 49.0 (45.2–52.9) years, 24.1% with chronic migraine) reporting 9.4 (7.4–11.3) monthly migraine days. Participants were instructed to treat their migraine attacks with oral lasmiditan 50 or 100 mg. Using an ad hoc electronic diary, participants prospectively collected migraine attack features at baseline and every 30 min after lasmiditan administration, up to 2 h post-dose. The primary outcome was 2-h pain freedom for the first-treated attack after lasmiditan intake. We also collected the occurrence of treatment-emergent adverse events (AE) after administration. Results: Overall, participants treated 100 attacks, of which 58 first-treated attacks. Regarding first-treated attacks, 44.8% of subjects rated migraine intensity as severe at lasmiditan intake. Pain freedom 2-h post-dosing was reported in 32.8% (19/58) of individuals and was associated with baseline pain intensity, being higher in subjects treating a mild/moderate attack (p = 0.044). Conversely, it was not influenced by timing of intake (p = 0.375), dosage (p = 0.727), or previous triptan failure (p = 0.351). Regarding all-treated attacks, pain freedom 2-h post-dosing was 37.0% (37/100). At least one AE was reported by 53.4% of participants (31/58), predominantly asthenia, dizziness, somnolence, anxiety or agitation, and paresthesia. Tolerability was rated as good-to-excellent by 51.8% of subjects. Conclusion: Our study supports clinical effectiveness of oral lasmiditan 50 and 100 mg for the treatment of acute migraine attacks. Lasmiditan effectiveness was not associated with the previous triptan failure and may therefore represent a valuable therapeutic option in subjects who did not benefit from, or have contraindications to, triptans. Trail registration: The study was preregistered on clinicaltrial.gov, NCT05903040 (https://clinicaltrials.gov/study/NCT05903040?cond=migraine&intr=lasmiditan&rank=5).

Whispering-gallery-mode (WGM) microresonators are amongst the most promising optical sensors for detecting bio-chemical targets. A number of laser interrogation methods have been proposed and demonstrated over the last decade, based on scattering and absorption losses or resonance splitting and shift, harnessing the high-quality factor and ultra-small volume of WGMs. Actually, regardless of the sensitivity enhancement, their practical sensing operation may be hampered by the complexity of coupling devices as well as the signalprocessing required to extract the WGM response. Here, we use a silica microsphere immersed in an aqueous environment and efficiently excite optical WGMs with a free-space visible laser, thus collecting the relevant information from the transmitted and back-scattered light without any optical coupler, fiber, or waveguide. We show that a 640-nm diode laser, actively frequency-locked on resonance, provides real-time, fast sensing of dielectric nanoparticles approaching the surface with direct analog readout. Thanks to our illumination scheme, the sensor can be kept in water and operate for days without degradation or loss of sensitivity. Diverse noise contributions are carefully considered and quantified in our system, showing a minimum detectable particle size below 1 nm essentially limited by the residual laser microcavity jitter. Further analysis reveals that the inherent laserfrequency instability in the short, -mid-term operation regime sets an ultimate bound of 0.3 nm. Based on this work, we envisage the possibility to extend our method in view of developing new viable approaches for detection of nanoplastics in natural water without resorting to complex chemical laboratory methods.

We provide here an overview of passive optical micro-cavities made of droplets in the liquid phase. We focus on resonators that are naturally created and suspended under gravity thanks to interfacial forces, illustrating simple ways to excite whispering-gallery modes in various slow-evaporation liquids using free-space optics. Similar to solid resonators, frequency locking of near-infrared and visible lasers to resonant modes is performed exploiting either phase-sensitive detection of the leakage cavity field or multiple interference between whispering-gallery modes in the scattered light. As opposed to conventional micro-cavity sensors, each droplet acts simultaneously as the sensor and the sample, whereby the internal light can detect dissolved compounds and particles. Optical quality factors up to 107–108 are observed in liquid-polymer droplets through photon lifetime measurements. First attempts in using single water droplets are also reported. These achievements point out their huge potential for direct spectroscopy and bio-chemical sensing in liquid environments. Finally, the first experiments of cavity optomechanics with surface acoustic waves in nanolitre droplets are presented. The possibility to perform studies of viscous-elastic properties points to a new paradigm: a droplet device as an opto-fluid-mechanics laboratory on table-top scale under controlled environmental conditions.

Whispering-gallery mode microresonators have gained wide popularity as experimental platforms for different applications, ranging from biosensing to nonlinear optics. Typically, the resonant modes of dielectric microresonators are stimulated via evanescent wave coupling, facilitated using tapered optical fibers or coupling prisms. However, this method poses serious shortcomings due to fabrication and access-related limitations, which could be elegantly overcome by implementing a free-space coupling approach; although additional alignment procedures are needed in this case. To address this issue, we have developed a new algorithm to excite the microresonator automatically. Here, we show the working mechanism and the preliminary results of our experimental method applied to a home-made silica microsphere, using a visible laser beam with a spatial light modulator and a software control.

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.