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Abstract The Internet of Things (IoT) is revolutionizing the healthcare industry by enhancing personalized patient care. However, the transmission of sensitive health data in IoT systems presents significant security and privacy challenges, further exacerbated by the difficulty of exploiting traditional protection means due to poor battery equipment and limited storage and computational capabilities of IoT devices. The authors analyze techniques applied in the medical context to encrypt sensible data and deal with the unique challenges of resource‐constrained devices. A technique that is facing increasing interest is the Physical Unclonable Function (PUF), where biometrics are implemented on integrated circuits' electric features. PUFs, however, demand special hardware, so in this work, instead of considering the physical device as a source of randomness, an ElectroCardioGram (ECG) can be taken into consideration to make a ‘virtual’ PUF. Such an mechanism leverages individual ECG signals to generate a cryptographic key for encrypting and decrypting data. Due to the poor stability of the ECG signal and the typical noise existing in the measurement process for such a signal, filtering and feature extraction techniques must be adopted. The proposed model considers the adoption of pre‐processing techniques in conjunction with a fuzzy extractor to add stability to the signal. Experiments were performed on a dataset containing ECG records gathered over 6 months, yielding good results in the short term and valuable outcomes in the long term, paving the way for adaptive PUF techniques in this context.

Abstract The Panel on Food Additives and Flavourings (FAF) provides a scientific opinion re‐evaluating the safety of the two food additives argon (E 938) and helium (E 939). Argon (Ar) and helium (He) are two noble gases, highly stable single atoms. Their chemical inertness is well known. Their physicochemical properties have served as a basis for their previous evaluations by SCF and JECFA, which have considered the use of these food additives safe even in the absence of a toxicological evaluation. No business operator or other interested party provided information in response to the call for data published by EFSA to support the re‐evaluation of these two food additives with respect to their identity and specifications, manufacturing process (including the identification and quantification of potential impurities) and how they are applied to food to exert their technological function. One business operator replied to the call for data issued by EFSA reporting use levels of E 938 as a packaging gas in one food category. Based on their physicochemical properties, both gases are considered by the Panel to be of low toxicological concern when used as food additives. No information was available on the potential presence of impurities of toxicological concern resulting from the manufacturing process(es) applied to the production of the food additives E 938 and E 939. The Panel however noted that a minimum purity of 99.0% is required to comply with existing specifications. The Panel concluded that the use of argon (E 938) and helium (E 939) as food additives does not raise a safety concern. The Panel recommended an amendment of the existing EU specifications to introduce the respective CAS numbers.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) provides a scientific opinion on the safety of curdlan as a new food additive used as firming and gelling agent, stabiliser, thickener. Curdlan is a high molecular weight polysaccharide consisting of β‐1,3‐linked glucose units, produced by fermentation from Rhizobium radiobacter biovar 1 strain NTK‐u. The toxicological dataset consisted of sub‐chronic, chronic and carcinogenicity, reproductive and developmental toxicity studies as well as genotoxicity. In vivo data showed that curdlan is not absorbed as such but is extensively metabolised by the gut microbiota into CO2 and other innocuous compounds. Curdlan was not genotoxic and was well‐tolerated with no overt organ‐specific toxicity. Effects observed at very high doses of curdlan, such as decreased growth and increased cecum weight, are common for indigestible bulking compounds and therefore considered physiological responses. In a combined three‐generation reproductive and developmental toxicity study, decreased pup weight was observed during lactation at 7500 mg curdlan/kg body weight (bw) per day, the highest dose tested. The Panel considered the observed effects as treatment‐related and adverse, although likely secondary to nutritional imbalance and identified a conservative no observed adverse effect level (NOAEL) of 2500 mg/kg bw per day. Despite the limitations noted in the dataset, the Panel was able to conclude applying the margin of exposure (MOE) approach. Given that curdlan and its break‐down products are not absorbed and that the identified adverse effect is neither systemic nor local, no adjustment factor was deemed necessary. Thus, an MOE of at least 1 was considered sufficient. The highest exposure estimate was 1441 mg/kg bw per day in toddlers at the 95th percentile of the proposed maximum use level exposure assessment scenario. The Panel concluded that there is no safety concern for the use of curdlan as a food additive at the proposed uses and use levels.

Abstract The EFSA Panel on Food Additives and Flavourings was requested to evaluate 14 flavouring substances assigned to the Flavouring Group Evaluation 80 (FGE.80), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Thirteen substances have already been considered in FGE.80 and its revision and in FGE.96 [FL‐no: 10.005, 10.024, 10.025, 10.050, 10.061, 10.069, 10.070, 10.072, 10.169, 13.009, 13.012, 13.161 and 16.055]. The remaining flavouring substance 3a,4,5,7a‐tetrahydro‐3,6‐dimethylbenzofuran‐2(3H)‐one [FL‐no: 10.057] has been cleared with respect to genotoxicity in FGE.217Rev3 and it is considered in this revision 2 of FGE.80. The substance [FL‐no: 10.057] was evaluated through a stepwise approach that integrates information on the structure–activity relationships, intake from current uses, threshold of toxicological concern (TTC) and available data on metabolism and toxicity. The Panel concluded that [FL‐no: 10.057] does not give rise to safety concerns at its levels of dietary intake, when estimated on the basis of the ‘Maximised Survey‐derived Daily Intake’ (MSDI) approach. Besides the safety assessment of the flavouring substance, the specifications for the material of commerce have also been considered and the information provided was complete for [FL‐no: 10.057]. However, for the flavouring substance [FL‐no: 10.057] in the present revision and for eight substances evaluated in previous revisions, the ‘modified Theoretical Added Maximum Daily Intakes’ (mTAMDIs) values are above the TTC for their structural class (III). For four substances previously evaluated in FGE.80Rev1 and in FGE.96, use levels are still needed to calculate the mTAMDI estimates. Therefore, in total for 13 flavouring substances, data on uses and use levels should be provided to finalise their safety evaluations. For [FL‐no: 10.050, 10.069 and 13.161], information on the composition of stereoisomeric mixtures is needed.

Abstract Background Non‐photosensitive trichothiodystrophies (TTDs) are a diverse group of genodermatoses within the subset of conditions known as “sulphur‐deficient brittle hair” syndromes. A part of them has only recently been identified, revealing novel causative genes and very rare phenotypes of these genetic skin disorders. At the same time, the molecular basis of previously published and unresolved cases has been revealed through the introduction of innovative genetic techniques. We have previously described the facial phenotype of patients with the Photosensitive form of TTD during childhood. This study marks the beginning of an effort to expand the analysis to include individuals of the same age who do not have photosensitivity. Methods A total of 26 facial portraits of TTD paediatric patients with Non‐photosensitivity from the literature were analysed using computer‐aided technologies, and their facial features were examined through a detailed clinical review. Results Distinct facial features were identified in both Photosensitive and Non‐photosensitive TTDs. Conclusion The present study has comprehensively elucidated the facial features in TTDs, encompassing the Non‐photosensitive clinical spectrum.

Abstract This study describes the effects on the skeletal phenotype of two pivotal factors, density and water volume, don the hatchery (larval) phase of gilthead seabream (Sparus aurata) larvae previoulsy described for two model species (Danio rerio and Oryzias latipes) and sub‐adult (pre‐ongrowing) gilthead seabream (Sparus aurata). The experimental trial was conducted using single conditions in a pilot study, starting with a total of 615,385 eggs from the same batch. Three densities (LD low density: 25 larvae/L; MD medium density: 125 larvae/L; and HD high density: 250 larvae/L) and two water volumes (500 and 1000 L) were tested from spawning up to 60 days post‐hatching (dph) (average standard length: 1.79 cm; average dry weight: 27.11 mg). On the final samples, morphometric, anatomical, and histological data were collected for data pertinent to meristic counts and skeletal anomalies. The results (analyzed by means of multivariate analyses) indicated that the LD‐reared larvae were significantly longer and heavier than HD‐reared fish. Furthermore, LD‐reared gilthead seabream exhibited a significant reduction in the frequency of individuals with anomalies of jaws, vertebral body shape, and vertebral arches than the MD and HD conditions, which is in agreement with previous experiments carried out on model species and gilthead seabream sub‐adults.

Abstract Preventing traffic accidents is of paramount importance for society's well‐being. The topic is particularly relevant for driving automation given the high expectations about automated vehicles and the difficulty in estimating reliable safety figures for those complex systems. Under this premise, the present manuscript investigates how to derive a safety benchmark model for evasive lane‐change maneuvers that can also be applied in microsimulation frameworks. The approach leverages a jerk‐limited bang‐bang kinematic model for lane‐change and validates its minimum time prediction against other kinematic approaches and vehicle dynamical models based on a robust minimum‐time optimal control formulation. It is shown how kinematic modeling does not embrace steering angle constraints (at low‐speed) and misses the inertia effect (at high‐speed) thus introducing discrepancies. However, due to the introduction of a braking model, it can be safely claimed that the low‐speed discrepancy between the kinematic and the dynamic models lies in a region where stopping is still the most efficient reaction. Moreover, a method is shown to compute the effective lateral acceleration for a kinematic model to match the dynamical system's maneuvering. The kinematic lane‐change model can thus constitute a valid performance benchmark provided that conservative assumptions are used when calibrating its maximum lateral acceleration.

Abstract Super‐coarse dust particles (diameters >10 μm) are evidenced to be more abundant in the atmosphere than model estimates and contribute significantly to the dust climate impacts. Since super‐coarse dust accounts for less dust extinction in the visible‐to‐near‐infrared (VIS‐NIR) than in the thermal infrared (TIR) spectral regime, they are suspected to be underestimated by remote sensing instruments operates only in VIS‐NIR, including Aerosol Robotic Networks (AERONET), a widely used data set for dust model validation. In this study, we perform a radiative closure assessment using the AERONET‐retrieved size distribution in comparison with the collocated Atmospheric Infrared Sounder (AIRS) TIR observations with comprehensive uncertainty analysis. The consistently warm bias in the comparisons suggests a potential underestimation of super‐coarse dust in the AERONET retrievals due to the limited VIS‐NIR sensitivity. An extra super‐coarse mode included in the AERONET‐retrieved size distribution helps improve the TIR closure without deteriorating the retrieval accuracy in the VIS‐NIR.

Abstract Background Mesenchymal neoplasms of the uterus encompass a diverse group of tumors, with varying characteristics and origins, collectively accounting for 8% of uterine malignancies. The most common variants include uterine leiomyosarcoma, low‐grade and high‐grade endometrial stromal sarcoma, adenosarcoma, and undifferentiated sarcoma. Clinical presentation is often nonspecific and can lead to delayed diagnosis. Uterine sarcomas are generally aggressive, resulting in poorer prognosis compared to carcinomas. Recent advances in molecular techniques, such as next‐generation sequencing (NGS), have led to the identification of new subtypes of uterine sarcomas, including COL1A1::PDGFB fusion‐associated fibrosarcoma, which has a specific chromosomal translocation t(17;22)(q22;q13). Imatinib, a tyrosine kinase inhibitor (TKI), is an effective treatment for dermatofibrosarcoma protuberans (DFSP), marked by this translocation. Case We present the case of a 42‐year‐old woman diagnosed with COL1A1::PDGFB fusion‐associated uterine fibrosarcoma. The patient underwent total hysterectomy and excision of the tumor, initially misdiagnosed as a low‐grade leiomyosarcoma. Subsequent histological examination, immunohistochemistry, and fluorescence in situ hybridization (FISH) confirmed the diagnosis. After 10 months, disease recurrence was detected, and Imatinib therapy was initiated at a dose of 400 mg daily. An allergic reaction led to a temporary discontinuation, but upon resumption with appropriate medication, a positive radiological response was observed. The patient achieved a complete remission after 2 years and is still on Imatinib treatment. Conclusions COL1A1::PDGFB fusion‐associated uterine fibrosarcoma is an extremely rare mesenchymal neoplasm. In a case we present herein, we treated a patient with imatinib as first‐line medical therapy. The patient is currently in complete remission after 37 months from treatment start. To the best of our knowledge, this represents a unique observation. We also provide a detailed literature review of the published cases so far. Prospective case series are needed to further understand the natural history of these tumors and optimize treatment strategies.

Abstract Objective Sleep impairment is one of the most common comorbidities affecting people with epilepsy (PWE). The bidirectional relation between epilepsy and sleep has been widely established. Several studies investigated subjective sleep quality and daytime vigilance in PWE, highlighting frequent complaints of sleep fragmentation, difficulties in falling asleep, and daytime sleepiness. The present study aimed to evaluate sleep structure in drug‐naive PWE, distributed on the basis of epilepsy type, and compared with controls. Methods This observational study included adult patients newly diagnosed with epilepsy and drug‐naive as well as a control group of healthy subjects. All PWE and controls underwent a dynamic 24‐h EEG with signals for sleep recording to evaluate sleep architecture, structure, continuity, and fragmentation. Results Twenty‐four PWE were included and distributed in two groups based on epilepsy type. Eleven patients were included in the generalized epilepsy group (63.6% male; 34.91 ± 9.80 years) and 13 patients in the focal epilepsy group (53.8% male; 38.69 ± 12.74 years). The control group included 16 subjects (56.3% male; 32.75 ± 12.19 years). Patients with generalized or focal epilepsy had a significantly lower sleep efficiency than controls. Moreover, both patient groups presented the alteration of markers of sleep fragmentation and loss of continuity, with higher indices of sleep stage transitions and arousal. Finally, the two patient groups presented less REM sleep than controls. Significance This study highlighted the alteration of sleep quality, continuity, and stability in both patients with focal or generalized epilepsy compared with controls, also in the absence of ictal events. This sleep impairment resulted in the reduction of REM sleep. Therefore, these findings may be explained by the increase in awakenings and sleep stage shifts, which may be attributed to both sleep networks impairment and neurotransmission dysfunction in PWE, and also possibly triggered by paroxysmal interictal abnormalities.

Programmed cell death‐1 (PD‐1) signaling downregulates the T‐cell response, promoting an exhausted state in tumor‐infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin‐related protein‐1 (Drp1)‐dependent mitochondrial fission plays a crucial role in sustaining T‐cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD‐1 in tumor‐infiltrating T cells. Here, we show that PD‐1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)‐derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD‐1neg counterparts. Also, PD‐1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD‐1 signaling directly prevents mitochondrial fragmentation following T‐cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor‐infiltrating PD‐1pos CD8+ T cells seems to be a mechanism exploited by PD‐1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor‐infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.

Abstract Introduction Young adults with vertical transmission (VT) of human immunodeficiency virus (HIV) represent a fragile population. This study evaluates factors associated with viro‐immunological outcome of these patients. Methods We performed a multicenter study including HIV‐infected subjects with VT ≥ 18 years old from six Italian clinics. Subjects were observed from birth to death, lost to follow‐up, or last visit until December 31, 2019. Condition of “optimal viro‐immunological status” (OS) was defined as the simultaneous presence of HIV ribonucleic acid (RNA) 500 cells/mm3, and CD4+/CD8+ ratio ≥ 1. Results A total of 126 subjects were enrolled. At 18 years of age, 52/126 (44.4%) had HIV‐RNA > 50 copies/mL, 47/126 (38.2%) had CD4+

The incidence of anterior cruciate ligament reconstruction (ACLR) surgeries is increasing and graft choice is important for a rapid return to activity, especially in patients older than 30 years. The aim of this study is to compare in term of quality of life and knee stability of patients who undergone ACLR using quadrupled semitendinosus (ST4) graft against patients who undergone ACLR with synthetic ligaments. Thirty-nine patients undergoing ACLR were enrolled in the study and were divided into two groups: ACLR with synthetic ligaments-LARS (group A) and ACLR with quadrupled semitendinosus graft ST4 (group B). They underwent surgery at Policlinico di Bari Orthopedic Unit between January 2017 and January 2020. Group A was composed by nineteen patients (36.16 ± 4.41 mean age-years, 22.47 ± 2.63 mean BMI-kg/m2, 39.37 ± 10.05 mean time evaluation after surgery-months) and group B was composed by twenty patients (34.95 ± 3.59 mean age-years, 21.1 ± 2.88 mean BMI-kg/m2, 36.75 ± 8.69 mean time evaluation after surgery-months). For each patient, the following data were recorded: age; side of injury, BMI, date of surgery, anterior knee laxity with the arthrometer, and Lysholm knee scoring scale. Mean value of anterior tibial translation (ATT) in group A was 3.09 mm ± 0.65 and in group B was 2.66 mm ± 1.61 (pvalue of 0.1139). Mann–-Whitney U test used to compare the Lysholm means values between groups showed a pvalue of 0.9307. LARS has comparable clinical and functional outcomes compared with hamstring autografts at short-term of 3 years follow-up. Level of Evidence: IV.

Abstract The coronavirus disease (COVID‐19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella‐like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID‐19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59‐year‐old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS‐CoV‐2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high‐flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin were continued and the patient received a high‐dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID‐19 disease‐related cutaneous manifestations, where is justified to continue the multidrug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.

Abstract Kienböck disease, also known as lunatomalacia, is a rare condition which can lead to progressive wrist pain and abnormal carpal motion. We present the case of a 30‐year‐old patient with Down syndrome who came to our observation for treatment of stage III C Kienböck disease. In September 2019, the patient reported wrist pain with limitation in movements and initially underwent conservative treatment without benefit. In October 2020, pain symptoms and difficult movements with reduced strength worsened and surgical treatment was proposed, but the patient and his family declined. Thereby the patient underwent conservative treatment with hyperbaric oxygen therapy (HBOT) 60 sessions, 100% oxygen at 2.5 absolute atmospheres (ATA), oxygen total time 60 min, once daily, five times per week. After 6 months, a positive clinical and radiological evolution were observed, with an improvement in the patterns of pain, motion, and strength and an almost complete involution of the process of aseptic necrosis of the semilunar. To the best of our knowledge, this is the first report of stage III C Kienböck's disease in Down's syndrome patient treated with HBOT.

Abstract The ever‐wider spread of distributed generation in distribution systems feeds the increasing demand for voltage regulation in low‐voltage networks. For these distribution grids, characterised by simpler structures than medium voltage systems but with a larger number of buses and feeders, voltage control devices have to guarantee fast and reliable operation, as well as economic and simple implementation. A key issue is ensuring adequate voltage amplitude for the active users, which present both load and generation. Variations of active power injections/absorptions by active users can produce long‐duration variations of the voltage amplitudes that exceed normal operating ranges admitted for the feeders, thus causing distributed generation tripping and poor power quality for the loads. This work is intended as ‘concept proof' to demonstrate the possibility of obtaining a simple, compact, and cheap device that guarantees adequate voltage amplitudes at low‐voltage user's premises. The device consists of a transformer that can vary its winding arrangements using controlled static switches. A summary of the construction aspects is recalled focussing attention on the control logic and operating characteristics. Various laboratory tests on a prototype are reported, under various operating conditions, highlighting the pros and cons of the considered solution and the margins of improvement.

Abstract Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT–CHILD (NCT02562235), a multicenter, single‐arm, 24‐week, open‐label, Phase 3 study. Patients aged 6–17 years in World Health Organization functional class (WHO‐FC) I–III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5–2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty‐four patients (mean age 12.8 years), 18 of whom were in WHO‐FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study‐drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6‐minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT‐proBNP was –66 ± 585 pg/ml (n = 14). There was no change in WHO‐FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

Breast cancer (BC) is a heterogeneous disease in which the tumor microenvironment (TME) seems to impact the clinical outcome. Here, we investigated whether a combination of gene expression signatures relating to both the structural and immune TME aspects can help predict prognosis in women with high‐grade BC (HGBC). Thus, we focused on a combined molecular biomarker variable that involved extracellular matrix (ECM)‐associated gene expression (ECM3 signature) and interferon (IFN)‐associated metagene (IFN metagene) expression. In 97 chemo‐naive HGBCs from the METABRIC dataset, the dichotomous ECM3/IFN (dECIF) variable identified a group of high‐risk patients (ECM3+/IFN− vs other; hazard ratio = 3.2, 95% confidence interval: 1.5–6.7). Notably, ECM3+/IFN− tumors showed low tumor‐infiltrating lymphocytes, high levels of CD33‐positive cells, absence of PD‐1 expression, or low expression of PD‐L1, as suggested by immune profiles and immune‐histochemical analysis on an independent cohort of 131 HGBCs. To make our results transferable to clinical use, we refined the dECIF biomarker using reduced ECM3 and IFN signatures; notably, the prognostic value of this reduced dECIF was comparable to that of the original dECIF. After validation in a new BC cohort, reduced dECIF was translated into a robust qPCR classifier for real‐world clinical use.

Abstract The role of immunosuppressive therapy (IT) in paediatric autoimmune/immune‐mediated myocarditis remains poorly defined. To explore its role, we present a series of three consecutive paediatric patients with biopsy‐proven, virus negative, autoimmune/immune‐mediated myocarditis, with distinct clinical and pathological features, who have been successfully treated with IT, a 14‐year‐old boy with Loeffler's fibroblastic parietal endomyocarditis, a 6‐year‐old child with celiac disease with chronic active lymphocytic myocarditis, and a 13‐year‐old boy with long‐standing heart failure and active lymphocytic myocarditis. Patients started IT and entered follow‐up between July 2017 and September 2019; the first patient completed IT. IT was associated with a substantial and sustained recovery of cardiac function in our patients, regardless of their heterogeneous clinical and pathological features. Combination IT was well tolerated and enabled tapering and weaning off steroids.

Acquired resistance to platinum (Pt)‐based therapies is an urgent unmet need in the management of epithelial ovarian cancer (EOC) patients. Here, we characterized by an unbiased proteomics method three isogenic EOC models of acquired Pt resistance (TOV‐112D, OVSAHO, and MDAH‐2774). Using this approach, we identified several differentially expressed proteins in Pt‐resistant (Pt‐res) compared to parental cells and the chaperone HSP90 as a central hub of these protein networks. Accordingly, up‐regulation of HSP90 was observed in all Pt‐res cells and heat‐shock protein 90 alpha isoform knockout resensitizes Pt‐res cells to cisplatin (CDDP) treatment. Moreover, pharmacological HSP90 inhibition using two different inhibitors [17‐(allylamino)‐17‐demethoxygeldanamycin (17AAG) and ganetespib] synergizes with CDDP in killing Pt‐res cells in all tested models. Mechanistically, genetic or pharmacological HSP90 inhibition plus CDDP ‐induced apoptosis and increased DNA damage, particularly in Pt‐res cells. Importantly, the antitumor activities of HSP90 inhibitors (HSP90i) were confirmed both ex vivo in primary cultures derived from Pt‐res EOC patients ascites and in vivo in a xenograft model. Collectively, our data suggest an innovative antitumor strategy, based on Pt compounds plus HSP90i, to rechallenge Pt‐res EOC patients that might warrant further clinical evaluation.

Abstract Aging is often associated with a decline in physical function that eventually leads to loss of autonomy in activities of daily living (ADL). Walking is a very common ADL, important for main determinants of quality of life in older age, and it requires the integration of many physiological systems. Gait speed has been described as the ‘sixth vital sign’ because it is a core indicator of health and function in aging and disease. We reviewed original studies up to June 2020 that assessed frailty in both longitudinal and cross‐sectional observational studies, paying particular attention to how gait is measured in older population and how the gait parameter adopted may influence the estimated frailty models and the health‐related outcomes of the various studies (i.e. clinical, cognitive, physical, and nutritional outcomes). Eighty‐five studies met the search strategy and were included in the present systematic review. According to the frailty tools, more than 60% of the studies used the physical phenotype model proposed by Fried and colleagues, while one‐third referred to multi‐domain indexes or models and only 5% referred to other single‐domain frailty models (social or cognitive). The great heterogeneity observed in gait measurements and protocols limited the possibility to directly compare the results of the studies and it could represent an important issue causing variability in the different outcome measures in both clinical‐and population‐based settings. Gait appeared to be an indicator of health and function also in frail older adults, and different gait parameters appeared to predict adverse health‐related outcomes in clinical, cognitive, and physical domains and, to a lesser extent, in nutritional domain. Gait has the potential to elucidate the common basic mechanisms of cognitive and motor decline. Advances in technology may extend the validity of gait in different clinical settings also in frail older adults, and technology‐based assessment should be encouraged. Combining various gait parameters may enhance frailty prediction and classification of different frailty phenotypes.

Abstract In this study we aim to show the application of ultrasound evaluation of the fetal heart in the ovine species, as well as its limitations in the field. Ten Dorper sheep, without any sedation, were evaluated starting from the second month of pregnancy through transabdominal ultrasound with an ultrasound device equipped with a convex transducer. Images of the fetal heart were obtained through maternal abdominal ultrasound by identifying the position of the fetus and conducting the following measurements: length and diameter of the heart, dimensions of the right and left ventricles and dimensions of the right and left atria. The measurements could only be conducted with acceptable precision starting from the third month of pregnancy. There was a significant difference only for left ventricle diameter, which was larger in the fifth month of pregnancy. The echocardiographic evaluation of the fetus enables monitoring the heart development identifying early fetal viability, assessing inadequate events that could put the pregnancy at risk, especially for production animals. For the experimental design of research employing production animals, it is important to consider, among other factors, the limitations of the evaluation on the field, such as restraining the animals, the stress caused by handling and environmental conditions, temperature, luminosity, facilities available and the qualifications of the team.

Advancement in the fields of electrification, automation, and digitalisation and emerging social trends are fuelling the transformation of road transport resulting in the introduction of various innovative mobility solutions. Yet the reaction of people to many of the new solutions is still vastly unknown. This creates an unprecedented quandary for transport planners who are requested to design future transport systems and create the related investment plans without fully validated models to base the assessment upon. As some evidence on citizens’ behaviour concerning new mobility solutions starts to be progressively made available, first attempts to update the existing models begin to emerge. Nevertheless, a lot more is needed as some of the transpiring mobility solutions have not yet reached the market, making the corresponding behaviour changes imponderable. In this context, the main purpose of this paper is to provide a review on how travel behaviour changes linked to the deployment of new mobility solutions have been considered in travel demand models. The new mobility solutions studied include carsharing, dynamic ridesharing, micromobility sharing services, and personal and shared autonomous vehicles. An overview and comparison of relevant studies implementing activity or trip-based demand models and other methodologies are presented. The analysis shows that the results of the different studies heavily depend on the extent to which behavioural changes are considered. The results of the review thus point to the need for holistic demand models that carefully mimic the urban reality with everything it has to offer and account for the importance of individual traits in the decision-making processes. Such models need an in-depth understanding of the microscopic mechanisms leading to the travel behaviour shifts linked to the most innovative mobility solutions. To achieve this level of detail, mobility living labs and their real-life experiments and experience with citizens, which are flourishing in Europe, are suggested to play a crucial role in the years to come.