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We demonstrate evanescent-wave fiber cavity-enhanced spectroscopy in the liquid phase using a near-infrared frequency comb. Exploiting strong fiber-dispersion effects, we show that liquid absorption spectra can be recorded without any external dispersive element. The fiber cavity is used both as sensor and spectrometer. The resonance modes are frequency locked to the comb teeth while the cavity photon lifetime is measured over 155 nm, from 1515 nm to 1670 nm, where absorption bands of liquid polyamines are detected as a proof of concept. Our fiber spectrometer lends itself to in situ, real-time chemical analysis in environmental monitoring, biomedical assays, and micro-opto-fluidic systems. [ABSTRACT FROM AUTHOR]

Background: According to current guidelines, patients with heart valve disease should be followed by Heart Valve Clinics (HVCs). Regular quality analysis is a major prerequisite of an HVC's program, but few data have been reported so far. Methods: We retrospectively collected patients with isolated, native aortic valve stenosis who had been visited in our HVC at least once between 2021 and 2024. For each outpatient visit, symptoms, physical examination, echocardiographic data, complementary tests, and indications were acquired. Also, adverse events (hospitalization, unplanned procedures, and death) were retrieved. Results: A total of 320 patients were included. Mean visits/patient ratio was 1.2. At the first visit, 69.7% already had severe aortic stenosis, and severe symptoms (NYHA ≥ III) were evident in 24.4%. In addition, 26.5%, 59.1%, 12.8%, and 1.6% were in Généreux stage I, II, III, and IV, respectively. Overall, 197 (78.5%) and 54 (21.5%) patients received an indication for transcatheter AVR and surgical AVR, respectively. AVR-free survival was 46%, 23%, and 6% at 6, 12, and 24 months, respectively (mean 8.8 months CI95% 7.7-9.9). Adverse event-free survival was 97.2%, 95.5%, and 85% at 3, 6, and 12 months, respectively. Conclusions: Patients referred to our HVC already had an advanced disease with cardiac damage. Transcatheter AVR was mostly indicated, and it showed excellent short-term results. A low rate of adverse events was seen among patients in follow-up, but the odds of receiving AVR were high and driven by Généreux's stage. Despite these favorable results, further efforts to sensitize earlier patient referral should be made.

Background: In recent years, in case of aortic valve replacement (AVR), a significant increase in the use of bioprostheses has been observed. The Perceval sutureless bioprosthesis has proven to be safe and reliable in the short and mid-term, with limited but promising long-term results. An updated systematic review with the long-term results of patients who underwent a sutureless bioprosthesis implantation with a Perceval biological valve is herewith presented. Methods: Studies published between 2015 and 2024, including the long-term outcomes-with clinical as well as echocardiographic information for up to five years-of patients who underwent a Perceval implantation for AVR were selected from the published literature. The Cochrane GRADE system was used to assess the study quality, and the risk of bias in non-randomized studies (ROBINS-I) tool was used to evaluate studies. Results: Ten studies were selected with an overall number of 5221 patients. The long-term survival ranged from 64.8 to 87.9%, freedom from structural valve degeneration (SVD) from 96.1 to 100%, freedom from significant paravalvular leak from 98.5 to 100%, freedom from prosthetic endocarditis from 90.7 to 99%, and freedom from reintervention from 94 to 100%. The long-term mortality ranged from 6.5 to 27.4%. SVD was observed in 0-4.8% patients. Significant paravalvular leak was observed in 0-3.4% patients, and infective endocarditis was observed in 0-3.4%. A bioprosthesis-related reintervention at long-term follow-up was required for 0-4.3% of patients, and 1.7-7.1% of patients required a late new pacemaker implantation. The transprosthetic mean pressure gradient ranged from 9 to 14.7 mmHg, peak pressure gradient ranged from 17.8 to 26.5 mmHg, and EOA ranged from 1.5 to 1.7 cm 2 . Conclusions: This systematic review shows that there is still a paucity of data about sutureless bioprostheses. Nevertheless, the clinical results from prospective studies or retrospective series are encouraging. Medium- and long-term results seem to support the increasing use of this type of prosthesis.

The real-time monitoring of densely populated areas with high seismic and volcanic risk is of crucial importance for the safety of people and infrastructures. When an earthquake occurs, the Earth surface experiences both translational and rotational motions. The latter are usually not monitored, but their measurement and characterization are essential for a full description of the ground motion. Here we present preliminary observational data of a high-sensitivity rotational sensor based on a 2-km-long fiber-optic Sagnac gyroscope, presently under construction in the middle of the Campi Flegrei Volcanic Area (Pozzuoli, Italy). We have evaluated its performance by analyzing data continuously recorded during an acquisition campaign of five months. The experimental setup was composed of a digital nine-component seismic station equipped with both a rotational sensor and conventional seismic sensors (seismometers, accelerometers, and tiltmeters). During this experiment we detected seismic noise and ground rotations wavefield induced by small to medium local earthquakes ( M D <3). The prototype gyroscope shows a very promising sensitivity in the range of 5×10 -7 -8×10 -9 r a d / s / H z over the frequency bandwidth 5 mHz-50 Hz. Future upgrades and perspectives are discussed.

Background: To assess the equivalence of tranexamic acid (TRAN) versus synthetic oxytocin (OXY) in reducing post-partum blood loss, in full-term patients (37-42 weeks), at low risk of post-partum hemorrhage, with vaginal childbirth., Methods: Phase III, randomized (1:1), open-label, longitudinal, multi-center, prospective clinical trial (Prot. n 63209, ClinicalTrials.gov Identifier: NCT02775773). From January 7, 2020, to June 30, 2023, a total of 256 women were enrolled at two general urban community hospitals in Italy, serving a multi-ethnic patient population with National Health Insurance. The primary outcome was to explore a potential equivalence between the two treatments (OXY and TRAN) in preventing total blood loss. Therefore, we randomized 231 women into two groups: Group A (OXY), 127 women who were administered 10UI intramuscularly within 5 min from childbirth; Group B (TRAN), 104 women to whom 1-g slow intravenous infusion was administered within 5 min from childbirth., Findings: At the time of delivery, mean blood loss for OXY group versus TRAN group was 269.12 mL versus 263.88 mL, respectively, with equivalence between the two groups. Similarly, there was equivalence in total blood loss between the OXY and the TRAN group (397.66 mL versus 405.64 mL, respectively. No statistical differences between Hb levels at admission and discharge in the two groups were reported. No difference was found in terms of additional uterotonic and surgical therapies between the two groups of patients. Neither group showed thrombotic complications at check-up performed after 7 days or after a questionnaire regarding adverse effects, subjected after 40 days., Interpretation: The study shows the equivalence of tranexamic acid versus synthetic oxytocin in post-partum blood loss prophylaxis in term patients at low risk of PPH with vaginal childbirth. The safety profiles of OXY and TRAN were similar., Funding: None., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

Introduction: Obese patients are at risk of complications after cardiac surgery. The aim of this study is to investigate safety and efficacy of a minimally invasive approach via upper sternotomy in this setting., Methods: We retrospectively reviewed 203 obese patients who underwent isolated, elective aortic valve replacement between January 2014 and January 2023 - 106 with minimally invasive aortic valve replacement (MIAVR) and 97 with conventional aortic valve replacement (CAVR). To account for baseline differences, a propensity-matching analysis was performed obtaining two balanced groups of 91 patients each., Results: The 30-day mortality rate was comparable between groups (1.1% MIAVR vs. 0% CAVR, P=0.99). MIAVR patients had faster extubation than CAVR patients (6 ± 2 vs. 9 ± 2 hours, P<0.01). Continuous positive airway pressure therapy was less common in the MIAVR than in the CAVR group (3.3% vs. 13.2%, P=0.03). Other postoperative complications did not differ significantly. Intensive care unit stay (1.8 ± 1.2 vs. 3.2 ± 1.4 days, P<0.01), but not hospital stay (6.7 ± 2.1 vs. 7.2 ± 1.9 days, P=0.09), was shorter for MIAVR than for CAVR patients. Follow-up survival was comparable (logrank P-value = 0.58)., Conclusion: MIAVR via upper sternotomy has been shown to be a safe and effective option for obese patients. Respiratory outcome was promising with shorter mechanical ventilation time and reduced need for post-extubation support. The length of stay in the intensive care unit was reduced. These advantages might be important for the obese patient to whom minimally invasive surgery should not be denied.

Portable optical spectrometers are crucial devices for bio-chemical sensing and spectroscopic applications whereby robust, compact and cost-effective set-ups are desirable. However, existing miniaturized instruments typically struggle to achieve broad wavelength operation and high spectral resolution at the same time. Here, an all-fiber optical spectrometer based on two cascaded Bragg gratings is devised and demonstrated, showing a record resolution and a wavelength span-to-resolution ratio larger than that of most miniature broadband spectrometers reported to date. Thanks to a synchronous control of the grating lengths and to a unique combination of their reflection features, spectral analysis of incoherent light within 1 pm is achieved. On the other hand, fast and reproducible wavelength tuning over several nanometers on a millisecond-timescale is ensured by mechanical stretching of the internal fiber, limited only by the actuator's dynamic range. A striking evidence of the spectrometer capabilities is provided with Doppler-limited spectroscopy of gas absorption bands performed with a near-infrared LED source. The observed spectra exhibit lineshapes comparable with those obtained by laser-based set-ups and the retrieved gas-line parameters are in agreement with existing spectroscopic databases. The spectrometer lends itself to applications in high-resolution interrogation of multiple fiber-optic sensors as well as broadband imaging with supercontinuum light.

Objective: The aim of this study is to assess whether the touch of osteopathic manipulative treatment (OMT) can affect the endogenous production of oxytocin in full-term pregnant women and the assessment of well-being following the treatment., Patients and Methods: In this study have been enrolled 57 pregnant women at full-term pregnancy (37th-41st week) for evaluation of the concentration of salivary oxytocin 2 minutes before and 2 minutes after a single session of OMT by an osteopath lasting for 30 minutes. Pre-OMT and post-OMT saliva samples were collected with the use of Salivette® salivary swabs. 7 salivary swabs were excluded from the analysis. 50 samples were analyzed with an appropriate ELISA kit., Results: The mean OT salivary concentration pre-OMT was 89.98±16.39, and post-OMT was 100.60±19.13 tends to increase with p=0.0000051. In multivariate analysis, two subgroups show interesting data in the mean difference in OT salivary concentration post-OMT: women with painful contractions (p=0.06) and women under 35 years (p=0.09)., Conclusions: The results of this study demonstrate that the effectiveness of OMT-increasing endogenous oxytocin is statistically significant in full-term pregnant women. The sensation of well-being found in most women indicates that there has been a predominantly central rather than peripheral oxytocin release after OMT.

Objective: The use of episiotomy during operative vaginal birth (OVB) is rather debated among operators and in literature. It is also important to evaluate the indications for which episiotomy is performed. In fact, the consequences of an episiotomy can be invalidating for patients with long-lasting results. The aim of this study is the evaluation of the role of episiotomy during OVB with the vacuum extractor and its correlation with Obstetric Anal Sphincter Injuries (OASIs). Methods: On of 9165 vaginal births, a total of 498 OVB (5.4%) were enrolled in a longitudinal prospective observational study. The incidence of OASIs was evaluated in our population after OVB performed with the vacuum extractor, during which the execution of episiotomy was performed indicated by clinician in charge. Results: OASIs occurred in 4% of the patients ( n  = 20). Episiotomy was performed in 39% of them ( n  = 181). OASIs incidence was 6% ( n  = 17) in the No Episiotomy and 1.8% ( n  = 3) in Episiotomy group ( p <.001). Performance of episiotomy during OVB determined a protective effect against OASIs ( p  = 0.025 in full cohort and p  = 0.013 in the primiparous group). An expulsive phase under one hour was an almost significant protective factor ( p  = 0.052). Conclusions: The use of episiotomy during OVB was associated with much lower OASIs rates in nulliparous women with a vacuum extraction; OR 0.23 (CI 95% 0.07-0.81) p  = 0.037 in nulliparous women and the number necessary to treat was 18 among nulliparous women to prevent 1 OASIs. A further risk factor that emerged from the analysis is a prolonged expulsive period, whereas fundal pressure does not seem to have a statistically significant influence.

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.

Background: In patients undergoing mitral valve surgery, restrictive suture annuloplasty (De Vega) for less-than-severe functional tricuspid regurgitation has been proven to be safe and effective. The aim of this study is to determine whether the adjunct of the plication of the posterior tricuspid leaflet with the same running suture (bicuspidized De Vega or "De Kay") is equally safe and effective., Methods: Single center, retrospective study on patients submitted to suture repair of the tricuspid valve during mitral valve surgery, with either conventional or De Kay, between January 2014 and December 2020. Comparison was based on degree of residual tricuspid valve regurgitation and right ventricular assessment at discharge., Results: Over the course of the study period, 255 patients undergoing mitral valve surgery had a dilated (>40 mm or >20 mm/m 2 ) tricuspid valve annulus, with less-than-severe tricuspid regurgitation. Conventional De Vega was employed in 166 patients (65.1%) and De Kay in the remaining 89 (34.9%). At discharge the adjunct of postero-septal commissure plication has similar outcomes to the classic De Vega repair. It seems to preserve right ventricular function., Conclusions: De Kay repair guarantees the same tricuspidal regurgitation reduction as compared with conventional De Vega early after surgery.

Background: The increasing use of biological substitutes for surgical aortic valve replacement (AVR), has led to the development of new bioprostheses with improved hemodynamics and expected durability., Methods: In this observational retrospective two-center cohort study, two innovative bioprostheses, INSPIRIS Resilia and AVALUS were analyzed. We analyzed early and 2.4-year follow-up results in terms of safety, clinical outcome and hemodynamic performance., Results: From November 2017 to February 2021, 148 patients underwent AVR with INSPIRIS Resilia (N.=74) or AVALUS (N.=74) bioprosthesis. The 30-day and mid-term mortality was comparable (1% vs. 3%, P=0.1 and 7% vs. 4%, P=0.4, respectively). Valve-related mortality was observed in one AVALUS patient. Three (4%) patients of the AVALUS group developed prosthetic endocarditis and two of them died after reoperation. No other cases of prosthetic endocarditis were observed. No cases of structural valve degeneration or significant paravalvular leak were detected at follow-up. Median follow-up peak pressure gradient was 21 vs. 23 mmHg (P=0.4) and the mean pressure gradient was 12 vs. 13 mmHg (P=0.9) for Inspiris and AVALUS, respectively. The effective orifice area (EOA) and indexed EOA were 1.5 cm 2 vs. 1.4 cm 2 (P=0.4) and 0.8 vs. 0.7 cm 2 /m 2 (P=0.5), respectively. Indexed left ventricular mass regression was -33 vs. -52 g/m 2 for the Inspiris and AVALUS groups, respectively, (R 2 -adjusted =0.14; P<0.01)., Conclusions: INSPIRIS Resilia and AVALUS bioprostheses were reliable with comparable results in safety, clinical outcome and hemodynamic performance. After statistical adjustment, AVALUS was associated with better left ventricular mass reduction. Long-term follow-up would provide definitive comparative results.

The placenta is a crucial interface between the fetus and the maternal environment. It allows for nutrient absorption, thermal regulation, waste elimination, and gas exchange through the mother's blood supply. Furthermore, the placenta determines important adjustments and epigenetic modifications that can change the phenotypic expression of the individual even long after birth. Polyethylene glycol (PEG) is a polyether compound derived from petroleum with many applications, from medicine to industrial manufacturing. In this study, for the first time, an integration of ultra-high-performance liquid chromatography (UHPLC) coupled with mass spectrometry (MS) was used to detect suites of PEG compounds in human placenta samples, collected from 12 placentas, originating from physiological pregnancy. In 10 placentas, we identified fragments of PEG in both chorioamniotic membranes and placental cotyledons, for a total of 36 samples.

Microplastics (MPs) are defined as plastic particles smaller than 5 mm. They have been found almost everywhere they have been searched for and recent discoveries have also demonstrated their presence in human placenta, blood, meconium, and breastmilk, but their location and toxicity to humans have not been reported to date. The aim of this study was twofold: 1. To locate MPs within the intra/extracellular compartment in human placenta. 2. To understand whether their presence and location are associated with possible structural changes of cell organelles. Using variable pressure scanning electron microscopy and transmission electron microscopy, MPs have been localized in ten human placentas. In this study, we demonstrated for the first time the presence and localization in the cellular compartment of fragments compatible with MPs in the human placenta and we hypothesized a possible correlation between their presence and important ultrastructural alterations of some intracytoplasmic organelles (mitochondria and endoplasmic reticulum). These alterations have never been reported in normal healthy term pregnancies until today. They could be the result of a prolonged attempt to remove and destroy the plastic particles inside the placental tissue. The presence of virtually indestructible particles in term human placenta could contribute to the activation of pathological traits, such as oxidative stress, apoptosis, and inflammation, characteristic of metabolic disorders underlying obesity, diabetes, and metabolic syndrome and partially accounting for the recent epidemic of non-communicable diseases.

Fetomaternal hemorrhage (FMH) was reported more than 60 years ago for the first time defined by the transfer or transfusion of fetal blood into the maternal circulation before or during delivery. The transfused volume is usually very small but when this value exceeds, it may be clinically significant. Antenatal diagnosis of severe FMH is difficult and it can be suspected in case of reduction of fetal movements, abnormal cardiotocography and ultrasound. FMH is associated to different adverse outcomes and admission to neonatal intensive care. The low incidence of FMH limits the studies, thus being able to rely only on diagnosis and retrospective studies. We present case series of FMH and analyze the steps with the purpose of defining a flow-chart for early diagnosis and management of FMH.

Objective: Previous studies reported a poor outcome in patients with coronavirus 2019 (COVID-19) undergoing cardiac surgery. Complications most frequently described were respiratory failure, renal failure, and thromboembolic events. In their recent experience, the authors observed a very high incidence of bleeding complications. The purpose of the study was to investigate a possible significant correlation between perioperative COVID-19 infection and hemorrhagic complications compared to non-COVID-19 patients., Design: Single-center, observational, retrospective, matched case-control (1:2) study involving patients who underwent open-heart cardiac surgery from February 2020 and March 2021 with positive perioperative diagnosis of COVID-19 infection, matched with patients without COVID-19 infection., Setting: Cardiac surgery unit and intensive care unit of a university tertiary center in a metropolitan area., Participants: In the study period, 773 patients underwent cardiac surgery on cardiopulmonary bypass (CPB). Among them, 23 consecutive patients had perioperative diagnosis of COVID-19 infection (study group). These patients were compared with 46 corresponding controls (control group) that matched for age, sex, body mass index, and Society of Thoracic Surgeons score., Interventions: Open-heart cardiac surgery on CPB., Measurements and Main Results: In the study group, 2 patients (9%) died in the intensive care unit from severe respiratory failure, shock, and multiple organ failure. In the study group, patients showed a significantly higher incidence of bleeding complications (48% v 2%, p = 0.0001) and cases of surgical reexploration for bleeding (35% v 2%, p = 0.0001), a higher incidence of severe postoperative thrombocytopenia (39% v 6%, p = 0.0007), and a higher need of blood components transfusions (74% v 30%, p = 0.0006). Chest tubes blood loss and surgical hemostasis time were markedly prolonged (p = 0.02 and p = 0.003, respectively)., Conclusions: A worrisome increased risk of early and late bleeding complications in COVID-19 patients was observed, and it should be considered when assessing the operative risk. CPB-related inflammatory reaction could exacerbate the deleterious effect of COVID-19 on the coagulation system and likely deviate it toward a hemorrhagic pattern., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The widespread use of plastics determines the inevitable human exposure to its by-products, including microplastics (MPs), which enter the human organism mainly by ingestion, inhalation, and dermal contact. Once internalised, MPs may pass across cell membranes and translocate to different body sites, triggering specific cellular mechanisms. Hence, the potential health impairment caused by the internalisation and accumulation of MPs is of prime concern, as confirmed by numerous studies reporting evident toxic effects in various animal models, marine organisms, and human cell lines. In this pilot single-centre observational prospective study, human breastmilk samples collected from N. 34 women were analysed by Raman Microspectroscopy, and, for the first time, MP contamination was found in 26 out of 34 samples. The detected microparticles were classified according to their shape, colour, dimensions, and chemical composition. The most abundant MPs were composed of polyethylene, polyvinyl chloride, and polypropylene, with sizes ranging from 2 to 12 µm. MP data were statistically analysed in relation to specific patients' data (age, use of personal care products containing plastic compounds, and consumption of fish/shellfish, beverages, and food in plastic packaging), but no significant relationship was found, suggesting that the ubiquitous MP presence makes human exposure inevitable.

There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients., (© 2022 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Since operative vaginal delivery may be risky for women and might cause neonatal complications, the aim of this study is to assess appropriateness of the procedure. This is a prospective, longitudinal, multicenter, observational study and it was conducted in three Italian Obstetric Units (Pisa, Massa Carrara and Prato). All term pregnant women, either nulliparous and multiparous, with singleton pregnancy and a cephalic fetus, with spontaneous or induced labour, requiring vacuum-assisted delivery were enrolled. Indications to operative vaginal delivery were grouped as alterations of fetal cardiotocography (CTG) patterns, delay/arrest of second stage of labour or elective shortening of second stage of labour. A board consisting of five among authors evaluated appropriateness of the procedure., Results: Overall, 466 women undergoing operative vaginal deliveries were included. Cardiotocography, classified as ACOG category 2 or 3 was the indication for vacuum assisted delivery in 253 patients (54.29%). Among these, 66 women (26.1%) had an operative vaginal delivery which was then considered to be inappropriate, while in 114 cases (45.1%) CTG traces resulted to be unreadable., Conclusion: Decision making process, which leads clinicians to go for operative vaginal delivery, is often influenced by shortness of time and complexity of the situation. Therefore, clinicians tend to intervene performing vacuum delivery without adopting critical analysis and without adequately considering the clinical situation. Operative vaginal delivery might be a risky procedure and should be performed only when clinically indicated and after adequate critical analysis., (© 2022. The Author(s).)

By stabilizing the evaporation dynamics of a microliter fluorocarbon droplet, we demonstrate a fast-scan optofluidic Fourier transform (FT) spectrometer on the tip of an optical fiber operating in the 1000-2000 nm window with a resolution of 3.5 cm -1 (i.e., <1 nm at 1560 nm). Compared with other FT near-infrared (NIR) small-scale spectrometers reported in the literature, the fluorocarbon droplet spectrometer shows the largest wavelength span and span/resolution ratio, allowing spectral analysis of broadband or narrowband radiation to be easily performed. Our results open the way for the practical application of droplet spectrometers as advanced optofluidic NIR analyzers with small size and low cost that are capable of operating in harsh environments, even in the absence of electrical power sources.

A droplet optical resonator is a unique environment to investigate light-matter interaction and optomechanics in liquids. Here, we report on light pressure effects derived from whispering gallery modes excited in a liquid-polymer droplet micro-resonator by free-space laser scattering. From the nonlinear resonance spectrum observed in the visible, we provide evidence of photon pressure exerted at the liquid-air boundary and quantify it with a coherent physical model. Our findings pave the way to studies on micro-rheology and nonlinear optofluidics, where droplets serve as miniature liquid laboratories.

Antihuman leukocyte antigen (HLA) antibodies restrict the access to cardiac allografts. Desensitization therapy is a major challenge in patients with cardiogenic shock waiting for urgent heart transplantation (HT). We retrospectively reviewed six patients (mean age of 37.5 years [16-70]) who underwent plasmapheresis (PP) under extracorporeal membrane oxygenation (ECMO) before transplant between January 2017 and September 2018. The average duration of follow-up was 25 months [20-32]. Mean fluorescence intensity (MFI) of HLA-specific antibodies was reported as follows: score 4 for MFI < 1000, score 6 for 1000 < MFI < 3000 and score 8 for MFI > 3000. The mean duration of ECMO support was 29 days [1-74] and 6.8 [1-29] PP sessions were performed per patient before transplant. The mean number of HLA-specific antibodies before HT was 9.6 for score 6 [4-13] and 5.8 for score 8 [1-12]. Four patients had major complications after transplantation (2 hemorrhagic shocks, 5 infectious events). Mean MFI reduction rate was 94% [79-100] for Class I and 44.2% for Class II [0-83]. Hospital survival was 100%, and early antibody-mediated rejection was diagnosed in one patient at 7 days after HT. Plasmapheresis under ECMO support was associated with favorable early outcomes in highly sensitized candidates for urgent heart transplantation., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Small-scale Fourier transform spectrometers are rapidly revolutionizing infrared spectro-chemical analysis, enabling on-site and remote sensing applications that were hardly imaginable just few years ago. While most devices reported to date rely on advanced photonic integration technologies, here we demonstrate a miniaturization strategy which harnesses unforced mechanisms, such as the evaporation of a liquid droplet on a partially reflective substrate. Based on this principle, we describe a self-operating optofluidic spectrometer and the analysis method to retrieve consistent spectral information in spite of the intrinsically non-reproducible droplet formation and evaporation dynamics. We experimentally realize the device on the tip of an optical fiber and demonstrate quantitative measurements of gas absorption with a 2.6 nm resolution, in a 100 s acquisition time, over the 250 nm span allowed by our setup's components. A direct comparison with a commercial optical analyzer clearly points out that a simple evaporating droplet can be an efficient small-scale, inexpensive spectrometer, competitive with the most advanced integrated photonic devices.

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.

Droplets are very simple physical systems, whereby surface tension shapes liquids into ideal opto-mechanical devices. This has recently enabled low-viscosity liquid samples to serve as miniature acoustic resonators harnessing optical generation of bulk vibrations, capillaries, or surface waves. Uniquely, a simple room-temperature pendant droplet can be activated as a hypersound-laser emitter when illuminated by a free-space, low-power visible laser thanks to stimulated Brillouin scattering of optical and acoustic whispering-gallery modes. Here, we demonstrate continuous operation of a liquid polymer opto-mechanical resonator and characterize its quality factor and long-term frequency stability. Our results point to the feasibility of all-liquid micro-mechanical oscillators working in the 50-100 MHz range. The stimulated generation of high-quality surface waves on nanoliter droplets gives momentum to new optical schemes for characterization of material viscous-elastic properties, laboratory investigation of atmospheric phenomena, and mass sensing for direct analysis of biological fluids based on ultrasound-hypersound coherent generation and detection.

Liquid droplets are ubiquitous in nature wherein surface tension shapes them into perfect spheres with atomic-scale smooth surfaces. Here, we use stable droplets that cohost equatorial acoustical and optical resonances phase matched to enable the exchange of energy and momentum between sound and light. Relying on free-space laser excitation of multiple whispering-gallery modes, we harness a triple-resonant forward Brillouin scattering to stimulate optomechanical surface waves. Nonlinear amplification of droplet vibrations in the 60-70 MHz range is realized with spectral narrowing beyond the limit of material loss, thereby activating the droplet as hypersound-laser emitter.

Chimerogenesis involving cytochromes P450 is a successful approach to generate catalytically self-sufficient enzymes. However, the connection between the different functional modules should allow a certain degree of flexibility in order to obtain functional and catalytically efficient proteins. We previously applied the molecular Lego approach to develop a chimeric P450 3A4 enzyme linked to the reductase domain of P450 BM3 (BMR). Three constructs were designed with the connecting loop containing no glycine, 3 glycine or 5 glycine residues and showed a different catalytic activity and coupling efficiency. Here we investigate how the linker affects the ability of P450 3A4 to bind substrates and inhibitors. We measure the electron transfer rates and the catalytic properties of the enzyme also in the presence of ketoconazole as inhibitor. The data show that the construct 3A4-5GLY-BMR with the longest loop better retains the binding ability and cooperativity for testosterone, compared to P450 3A4. In both 3A4-3GLY-BMR and 3A4-5GLY-BMR, the substrate induces an increase in the first electron transfer rate and a shorter lag phase related to a domain rearrangements, when compared to the construct without Gly. These data are consistent with docking results and secondary structure predictions showing a propensity to form helical structures in the loop of the 3A4-BMR and 3A4-3GLY-BMR. All three chimeras retain the ability to bind the inhibitor ketoconazole and show an IC 50 comparable with those reported for the wild type protein. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen biosynthesis and metabolism. For instance, CYP1B1 catalyzes the hydroxylation of E2 leading to the production of 4-hydroxyestradiol that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in different tumors including breast cancer. In this scenario, it is worth mentioning that CYP1B1 expression is triggered by estrogens through the estrogen receptor (ER)α in breast cancer cells. In the present study, we evaluated whether the G protein estrogen receptor namely GPER may provide an alternate route toward the expression and function of CYP1B1 in ER-negative breast cancer cells, in main players of the tumor microenvironment as cancer associated fibroblasts (CAFs) that were obtained from breast cancer patients, in CAFs derived from a cutaneous metastasis of an invasive mammary ductal carcinoma and in breast tumor xenografts. Our results show that GPER along with the EGFR/ERK/c-Fos transduction pathway can lead to CYP1B1 regulation through the involvement of a half-ERE sequence located within the CYP1B1 promoter region. As a biological counterpart, we found that both GPER and CYP1B1 mediate growth effects in vitro and in vivo . Altogether, our data suggest that estrogens in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1 regulation. Estrogen-CYP1B1 landscape via GPER should be taken into account in setting novel pharmacological approaches targeting breast cancer development., Competing Interests: CONFLICTS OF INTEREST The authors have no financial or commercial conflicts of interest to declare

The use of Doxorubicin (Dox), a frontline drug for many cancers, is often complicated by dose-limiting cardiotoxicity in approximately 20% of patients. The G-protein estrogen receptor GPER/GPR30 mediates estrogen action as the cardioprotection under certain stressful conditions. For instance, GPER activation by the selective agonist G-1 reduced myocardial inflammation, improved immunosuppression, triggered pro-survival signaling cascades, improved myocardial mechanical performance, and reduced infarct size after ischemia/reperfusion (I/R) injury. Hence, we evaluated whether ligand-activated GPER may exert cardioprotection in male rats chronically treated with Dox. 1 week of G-1 (50 μg/kg/day) intraperitoneal administration mitigated Dox (3 mg/kg/day) adverse effects, as revealed by reduced TNF-α, IL-1β, LDH, and ROS levels. Western blotting analysis of cardiac homogenates indicated that G-1 prevents the increase in p-c-jun, BAX, CTGF, iNOS, and COX2 expression induced by Dox. Moreover, the activation of GPER rescued the inhibitory action elicited by Dox on the expression of BCL2, pERK, and pAKT. TUNEL assay indicated that GPER activation may also attenuate the cardiomyocyte apoptosis upon Dox exposure. Using ex vivo Langendorff perfused heart technique, we also found an increased systolic recovery and a reduction of both infarct size and LDH levels in rats treated with G-1 in combination with Dox respect to animals treated with Dox alone. Accordingly, the beneficial effects induced by G-1 were abrogated in the presence of the GPER selective antagonist G15. These data suggest that GPER activation mitigates Dox-induced cardiotoxicity, thus proposing GPER as a novel pharmacological target to limit the detrimental cardiac effects of Dox treatment. J. Cell. Physiol. 232: 1640-1649, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The β 2 -adrenergic receptor (β 2 AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β 2 AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β 2 AR internalization. Unexpectedly, β-arr1 and β-arr2 and receptor internalization were dispensable for ERK activation. Instead, β 2 AR signaled through Gα s and Gβγ subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for β 2 AR signaling through β-arrestin-independent pathways in key physiological functions and under pathological conditions., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Human liver cytochrome P450 3A4 is the main enzyme involved in drug metabolism. This makes it an attractive target for biocatalytic applications, such as the synthesis of pharmaceuticals and drug metabolites. However, its poor solubility, stability and low coupling have limited its application in the biotechnological context. We previously demonstrated that the solubility of P450 3A4 can be increased by creating fusion proteins between the reductase from Bacillus megaterium BM3 (BMR) and the N-terminally modified P450 3A4 (3A4-BMR). In this work, we aim at increasing stability and coupling efficiency by varying the length of the loop connecting the two domains to allow higher inter-domain flexibility, optimizing the interaction between the domains. Starting from the construct 3A4-BMR containing the short linker Pro-Ser-Arg, two constructs were generated by introducing a 3 and 5 glycine hinge (3A4-3GLY-BMR and 3A4-5GLY-BMR). The three fusion proteins show the typical absorbance at 450 nm of the reduced heme-CO adduct as well as the correct incorporation of the FAD and FMN cofactors. Each of the three chimeric proteins were more stable than P450 3A4 alone. Moreover, the 3A4-BMR-3-GLY enzyme showed the highest NADPH oxidation rate in line with the most positive reduction potential. On the other hand, the 3A4-BMR-5-GLY fusion protein showed a V max increased by 2-fold as well as a higher coupling efficiency when compared to 3A4-BMR in the hydroxylation of the marker substrate testosterone. This protein also showed the highest rate value of cytochrome c reduction when this external electron acceptor is used to intercept electrons from BMR to P450. The data suggest that the flexibility and the interaction between domains in the chimeric proteins is a key parameter to improve turnover and coupling efficiency. These findings provide important guidelines in engineering catalytically self-sufficient human P450 for applications in biocatalysis.

Liquid droplet whispering-gallery-mode microresonators open a new research frontier for sensing, optomechanics and photonic devices. At visible wavelengths, where most liquids are transparent, a major contribution to a droplet optical quality factor is expected theoretically from thermal surface distortions and capillary waves. Here, we investigate experimentally these predictions using transient cavity ring-down spectroscopy. With our scheme, the optical out-coupling and intrinsic loss are measured independently while any perturbation induced by thermal, acoustic and laser-frequency noise is avoided thanks to the ultra-short light-cavity interaction time. The measurements reveal a photon lifetime at least ten times longer than the thermal limit and indicate that capillary fluctuations activate surface scattering effects responsible for light coupling. This suggests that droplet microresonators are an ideal optical platform for ultra-sensitive spectroscopy of highly transparent liquid compounds in nano-liter volumes., Competing Interests: The authors declare no competing financial interests.

Insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGF-I promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategies., Competing Interests: The authors declare no conflict of interest.

G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.

Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1β and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of pro-inflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stroma-cancer interactions.