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Objectives: To investigate the interobserver agreement among midwives for the interpretation of intrapartum CTG traces, using both the 2015 FIGO guidelines and the physiology-based guidelines., Material and Methods: Retrospective, single-center, observational study conducted at the Maternity Hospital of the University of Parma, Italy, between November 2022 and July 2023. We selected 100 nonconsecutive intrapartum CTG traces from women undergoing operative delivery (cesarean or instrumental vaginal delivery). Participating midwives received the last 60 min of CTG recording prior to the decision for an operative delivery was made. Five midwives with different professional experience classified the CTG tracing according to the 2015 FIGO guidelines and the physiology-based guidelines at the time of the decision for the operative delivery. Each midwife was categorized as senior or junior if her clinical experience was equal or more or less than 5 years. All participating midwives were blinded to the demographic and clinical variables of each case, as well as to the labor and neonatal outcome. The main outcome of the study was the interobserver agreement among the 5 midwives with either guideline. The secondary outcome was the interobserver agreement based on clinical experience. The agreement between the observers was estimated through the Krippendorff's alpha statistics., Results: The interobserver agreement for the interpretation of intrapartum CTG traces according to the 2015 FIGO guideline was in the upper limit of the "unacceptable" classification, with a Krippendorff's alpha of 0.632 (95% CI, 0.545-0.723). The interobserver agreement of the physiology-based CTG guideline was classified as "unacceptable" with a Krippendorff's alpha of 0.359 (95% CI, 0.125-0.582). The interobserver agreement among senior midwives according to the 2015 FIGO guidelines was considered as "tentative acceptable agreement" with a Krippendorff's alpha of 0.724 (95% CI, 0.636-0.805). Among junior midwives, the interobserver agreement according to the latter guideline was classified as "unacceptable" with a Krippendorff's alpha of 0.569 (95% CI, 0.359-0.751). Using the physiology-based guideline, the interobserver agreement of the senior midwives - Krippendorff's alpha 0.493 (95% CI, 0.320-0.623) - and "junior" midwives - Krippendorff's alpha 0.359 (95% CI, 0.100-0.581) - were considered both "unacceptable"., Conclusions: Our study showed that intrapartum CTG interpretation is characterized by an overall unacceptable level of interobserver agreement among midwives, with the 2015 FIGO guidelines showing better agreement compared to physiology-based guidelines. The interpretation of intrapartum CTG by "senior" midwives using the 2015 FIGO guidelines showed the highest, interobserver agreement, indicating a "tentative acceptable agreement".

Segmentation of multiple sclerosis (MS) lesions on brain MRI scans is crucial for diagnosis, disease and treatment monitoring but is a time-consuming task. Despite several automated algorithms have been proposed, there is still no consensus on the most effective method. Here, we applied a consensus-based framework to improve lesion segmentation on T1-weighted and FLAIR scans. The framework is designed to combine publicly available state-of-the-art deep learning models, by running multiple segmentation tasks before merging the outputs of each algorithm. To assess the effectiveness of the approach, we applied it to MRI datasets from two different centers, including a private and a public dataset, with 131 and 30 MS patients respectively, with manually segmented lesion masks available. No further training was performed for any of the included algorithms. Overlap and detection scores were improved, with Dice increasing by 4-8% and precision by 3-4% respectively for the private and public dataset. High agreement was obtained between estimated and true lesion load (ρ = 0.92 and ρ = 0.97) and count (ρ = 0.83 and ρ = 0.94). Overall, this framework ensures accurate and reliable results, exploiting complementary features and overcoming some of the limitations of individual algorithms., (© 2024. The Author(s).)

Biochar is currently garnering interest as an alternative to commercial fertilizer and as a tool to counteract global warming. However, its use is increasingly drawing attention, particularly concerning the fine dust that can be developed during its manufacture, transport, and use. This work aimed to assess the toxicity of fine particulate Biochar (10 ) via in-vitro and in-vivo experiments as a first step for the evaluation of toxicity values. As in-vitro experiments, cell lines showed inhibition of proliferation following the reduction of expression genes involved in cell cycle control, increase in the production of ROS and IL-8, and decrease in intracellular ATP. In-vivo rat exposure induced hyperemia, edema, and inflammatory phenomena with infiltrations of neutrophil granulocytes and macrophages at the alveolar and bronchiolar levels. Both in-vitro and in-vivo studies highlighted how exposure to Biochar particulates leads to an inflammatory condition and oxidative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: This study aimed to investigate Italian dentists' knowledge of and attitudes toward obstructive sleep apnea (OSA) in children., Methods: An anonymous questionnaire was prepared using Google Forms and sent to dentists in Italy through private social platforms. The first part of the questionnaire contained basic demographic data questions, and the second part included items about pediatric OSA., Results: A total of 125 responses were collected within 1 month. The interviews revealed gaps in undergraduate and post-graduate training on OSA, and consequently, low self-evaluation of knowledge and self-confidence in managing young patients with OSA. Dentists showed unfavorable attitudes and poor knowledge of the general findings, risk factors, and consequences of pediatric OSA but demonstrated good knowledge of the beneficial effects of rapid maxillary expansion. Orthodontists showed a more favorable attitude and better recognition of the craniofacial features associated with OSA. In addition, a comparison was made between dentists who had graduated more than 5 years ago and new graduates, and differences were found in undergraduate education, which was better for new graduates, and a small number of questions were better answered by experienced dentists., Conclusion: This study showed a lack of knowledge about pediatric OSA and its management among Italian dentists, revealing the need to update the dentistry curriculum and organize educational interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Arcidiacono, Santagostini, Tagliaferri, Ghezzi, Manfredi and Segù.)

Background: Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, potentially determining the insurgence of sarcopenia. Evidence suggests that motoneuron and neuromuscular junction (NMJ) degeneration contribute to sarcopenia pathogenesis. Seeking for strategies able to slow down sarcopenia insurgence and progression, we investigated whether a 2-year mixed-model training involving aerobic, strength and balance exercises would be effective for improving or preserving motoneuronal health and NMJ stability, together with muscle mass, strength and functionality in an old, sarcopenic population., Methods: Forty-five sarcopenic elderly (34 females; 11 males) with low dual-energy X-ray absorptiometry (DXA) lean mass and Short Physical Performance Battery (SPPB) score <9 were randomly assigned to either a control group [Healthy Aging Lifestyle Education (HALE), n = 21] or an intervention group [MultiComponent Intervention (MCI), n = 24]. MCI trained three times per week for 2 years with a mix of aerobic, strength and balance exercises matched with nutritional advice. Before and after the intervention, ultrasound scans of the vastus lateralis (VL), SPPB and a blood sample were obtained. VL architecture [pennation angle (PA) and fascicle length (Lf)] and cross-sectional area (CSA) were measured. As biomarkers of neuronal health and NMJ stability status, neurofilament light chain (NfL) and C-terminal agrin fragment (CAF) concentrations were measured in serum. Differences in ultrasound parameters, NfL and CAF concentration and physical performance between baseline and follow-up were tested with mixed ANOVA or Wilcoxon test. The relationship between changes in physical performance and NfL or CAF concentration was assessed through correlation analyses., Results: At follow-up, MCI showed preserved VL architecture (PA, Lf) despite a reduced CSA (-8.4%, P < 0.001), accompanied by maintained CAF concentration and ameliorated overall SPPB performance (P = 0.007). Conversely, HALE showed 12.7% decrease in muscle CSA (P < 0.001), together with 5.1% and 5.5% reduction in PA and Lf (P < 0.001 and P = 0.001, respectively), and a 6.2% increase in CAF (P = 0.009) but improved SPPB balance score (P = 0.007). NfL concentration did not change in either group. In the population, negative correlations between changes in CAF concentration and SPPB total score were found (P = 0.047), whereas no correlation between NfL and SPPB variations was observed., Conclusions: The present findings suggest that our 2-year mixed aerobic, strength and balance training seemed effective for preventing the age and sarcopenia-related increases in CAF concentration, preserving NMJ stability as well as muscle structure (PA and Lf) and improving physical performance in sarcopenic older individuals., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on human health is established and interest in them is progressively increasing. Environmental and occupational risk factors affecting human health include chemical agents. Benzene represents a pollutant of concern due to its ubiquity and because it may alter gene expression by epigenetic mechanisms, including miRNA expression changes. This review summarizes recent findings on miRNAs associated with benzene exposure considering in vivo, in vitro and human findings in order to better understand the molecular mechanisms through which benzene induces toxic effects and to evaluate whether selected miRNAs may be used as biomarkers associated with benzene exposure. Original research has been included and the study selection, data extraction and assessments agreed with PRISMA criteria. Both in vitro studies and human results showed a variation in miRNAs' expression after exposure to benzene. In vivo surveys also exhibited this trend, but they cannot be regarded as conclusive because of their small number. However, this review confirms the potential role of miRNAs as "early warning" signals in the biological response induced by exposure to benzene. The importance of identifying miRNAs' expression, which, once validated, might work as sentinel molecules to better understand the extent of the exposure to xenobiotics, is clear. The identification of miRNAs as a molecular signature associated with specific exposure would be advantageous for disease prevention and health promotion in the workplace.

In myeloproliferative neoplasm (MPNs), bone marrow fibrosis - mainly driven by the neoplastic megakaryocytic clone - dictates a more severe disease stage with dismal prognosis and higher risk of leukemic evolution. Therefore, accurate patient allocation into different disease categories and timely identification of fibrotic transformation are mandatory for adequate treatment planning. Diagnostic strategy still mainly relies on clinical/laboratory assessment and bone marrow histopathology, which, however, requires an invasive procedure and frequently poses challenges also to expert hemopathologists. Here we tested the diagnostic accuracy of the detection, by flow cytometry, of CCR2 + CD34 + cells to discriminate among MPN subtypes with different degrees of bone marrow fibrosis. We found that the detection of CCR2 on MPN CD34 + cells has a very good diagnostic accuracy for the differential diagnosis between "true" ET and prePMF (AUC 0.892, P <0.0001), and a good diagnostic accuracy for the differential diagnosis between prePMF and overtPMF (AUC 0.817, P =0.0089). Remarkably, in MPN population, the percentage of CCR2-expressing cells parallels the degree of bone marrow fibrosis. In ET/PV patients with a clinical picture suggestive for transition into spent phase, we demonstrated that only patients with confirmed secondary MF showed significantly higher levels of CCR2 + CD34 + cells. Overall, flow cytometric CCR2 + CD34 + cell detection can be envisioned in support of conventional bone marrow histopathology in compelling clinical scenarios, with the great advantage of being extremely rapid. For patients in follow-up, its role can be conceived as an initial patient screening for subsequent bone marrow biopsy when disease evolution is suspected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pozzi, Carubbi, Gobbi, Tagliaferri, Mirandola, Vitale and Masselli.)

During aging, many physiological systems spontaneously change independent of the presence of chronic diseases. The reward system is not an exception and its dysfunction generally includes a reduction in dopamine and glutamate activities and the loss of neurons of the ventral tegmental area (VTA). These impairments are even more pronounced in older persons who have neurodegenerative diseases and/or are affected by cognitive and motoric frailty. All these changes may result in the occurrence of cognitive and motoric frailty and accelerated progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. In particular, the loss of neurons in VTA may determine an acceleration of depressive symptoms and cognitive and motor frailty trajectory, producing an increased risk of disability and mortality. Thus, we hypothesize the existence of a loop between reward system dysfunction, depression, and neurodegenerative diseases in older persons. Longitudinal studies are needed to evaluate the determinant role of the reward system in the onset of motoric-cognitive risk syndrome.

Background: One of the most problematic expression of ageing is frailty, and an approach based on its early identification is mandatory. The Sunfrail-tool (ST), a 9-item questionnaire, is a promising instrument for screening frailty., Aims: To assess the diagnostic accuracy and the construct validity between the ST and a Comprehensive Geriatric Assessment (CGA), composed by six tests representative of the bio-psycho-social model of frailty; To verify the discriminating power of five key-questions of the ST; To investigate the role of the ST in a clinical-pathway of falls' prevention., Methods: In this retrospective study, we enrolled 235 patients from the Frailty-Multimorbidity Lab of the University-Hospital of Parma. The STs' answers were obtained from the patient's clinical information. A patient was considered frail if at least one of the CGAs' tests resulted positive., Results: The ST was associated with the CGA's judgement with an Area Under the Curve of 0.691 (CI 95%: 0.591-0.791). Each CGA's test was associated with the ST total score. The five key-question showed a potential discriminating power in the CGA's tests of the corresponding domains. The fall-related question of the ST was significantly associated with the Short Physical Performance Battery total score (OR: 0.839, CI 95%: 0.766-0.918), a proxy of the risk of falling., Discussion: The results suggest that the ST can capture the complexity of frailty. The ST showed a good discriminating power, and it can guide a second-level assessment to key frailty domains and/or clinical pathways., Conclusions: The ST is a valid and easy-to-use instrument for the screening of frailty., (© 2021. The Author(s).)

Introduction: Chronic low back pain disorders (CLBDs) present a substantial societal burden; however, optimal treatment remains debated. To date, pairwise and network meta-analyses have evaluated individual treatment modes, yet a comparison of a wide range of common treatments is required to evaluate their relative effectiveness. Using network meta-analysis, we aim to evaluate the effectiveness of treatments (acupuncture, education or advice, electrophysical agents, exercise, manual therapies/manipulation, massage, the McKenzie method, pharmacotherapy, psychological therapies, surgery, epidural injections, percutaneous treatments, traction, physical therapy, multidisciplinary pain management, placebo, 'usual care' and/or no treatment) on pain intensity, disability and/or mental health in patients with CLBDs., Methods and Analysis: Six electronic databases and reference lists of 285 prior systematic reviews were searched. Eligible studies will be randomised controlled/clinical trials (including cross-over and cluster designs) that examine individual treatments or treatment combinations in adult patients with CLBDs. Studies must be published in English, German or Chinese as a full-journal publication in a peer-reviewed journal. A narrative approach will be used to synthesise and report qualitative and quantitative data, and, where feasible, network meta-analyses will be performed. Reporting of the review will be informed by Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidance, including the network meta-analysis extension (PRISMA-NMA). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for network meta-analysis will be implemented for assessing the quality of the findings., Ethics and Dissemination: Ethical approval is not required for this systematic review of the published data. Findings will be disseminated via peer-reviewed publication., Prospero Registration Number: PROSPERO registration number CRD42020182039., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The clinical diagnosis of late Fetal Growth Restriction (FGR) involves the integration of Doppler ultrasound data and Fetal Heart Rate (FHR) monitoring through computer assisted computerized cardiotocography (cCTG). The aim of the study was to evaluate the diagnostic power of combined Doppler and cCTG parameters by contrasting late FGR -and healthy controls., Methods: The study was conducted from January 2018 to May 2020. Only pregnant women who had the last Doppler measurement obtained within 1 week before delivery and cCTG performed within 24 h before delivery were included in the study. Two hundred forty-nine pregnant women fulfilling the inclusion criteria were enrolled in the study; 95 were confirmed as late FGR and 154 were included in the control group., Results: Among the extracted cCTG parameters, Delta Index, Short Term Variability (STV), Long Term Variability (LTV), Acceleration and Deceleration Phase Rectified Slope (APRS, DPRS) values were lower in the late FGR participants compared to the control group. In the FGR cohort, Delta, STV, APRS, and DPRS were found different when stratifying by MCA&#95;PI (MCA&#95;PI <5th centile or > 5th centile). STV and DPRS were the only parameters to be found different when stratifying by (UA&#95;PI >95th centile or UA&#95;PI <95th centile). Additionally, we measured the predictive power of cCTG parameters toward the identification of associated Doppler measures using figures of merit extracted from ROC curves. The AUC of ROC curves were accurate for STV (0,70), Delta (0,68), APRS (0,65) and DPRS (0,71) when UA&#95;PI values were > 95th centile while, the accuracy attributable to the prediction of MCA&#95;PI was 0.76, 0.77, 0.73, and 0.76 for STV, Delta, APRS, and DPRS, respectively. An association of UA&#95;PI>95th centile and MCA&#95;PI<5th centile with higher risk for NICU admission, was observed, while CPR < 5th centile resulted not associated with any perinatal outcome. Values of STV, Delta, APRS, DPRS were significantly lower for FGR neonates admitted to NICU, compared with the uncomplicated FGR cohort., Conclusions: The results of this study show the contribution of advanced cCTG parameters and fetal Doppler to the identification of late FGR and the association of those parameters with the risk for NICU admission., Trial Registration: Retrospectively registered., (© 2021. The Author(s).)

Most patients who had COVID-19 are still symptomatic after many months post infection, but the long-term outcomes are not yet well defined. The aim of our prospective/retrospective study was to define the cardiac sequelae of COVID-19 infection. This monocentric cohort study included 160 consecutive patients who had been discharged from the ward or from the outpatient clinic after a diagnosis of COVID-19 and subsequently referred for a follow-up visit. Clinical features' data about the acute phase along with information about the follow-up visit, including ECG and Echocardiographic parameters, were recorded. At an average follow-up of 5 months, echocardiography showed morpho-functional characteristics of both right (RV) and left (LV) ventricles, such as RV dilation, increased pressure in the pulmonary circulation, and bi-ventricular systolic-diastolic dysfunction. When examined using multivariate analysis, independent of age, sex, and co-morbidities, RV and LV changes were significantly associated with chest High-Resolution computed tomography score and hemodynamic Instability (HI), and with C-reactive protein, respectively. Our results suggest that COVID-19 may impact RV and LV differently. Notably, the extent of the pneumonia and HI may affect RV, whereas the inflammatory status may influence LV. A long-term follow-up is warranted to refine and customize the most appropriate therapeutic strategies.

Background: Endocrine-disrupting chemicals (EDCs) are compounds that interfere with aspects of hormonal signaling. Considerable attention has been paid to their biological effects especially in women of childbearing age or during pregnancy as EDCs have been reported to cross the placenta becoming concentrated in the fetus' circulation. Lifestyle habits, daily consumption of packaged foods and use of healthcare/cosmetic products are associated with increased EDCs levels. This cross-sectional research examined the EDCs levels and the lifestyle determinants of EDC exposure in a cohort of reproductive-age women from Northern Italy. Methods: Forty-five women (median age: 36, IQR: 30-38) were evaluated for urinary bisphenol A (BPA) and phthalates levels and also studied for EDCs' major determinants of daily exposure; food frequency/dietary, physical activity, smoking habits and weight status. Results: Although 100% of women seemed to have been exposed to common sources of EDCs, they reported a healthy lifestyle. The multivariable model described a positive and significant association between consumption of sauces/dressings in plastic containers and monoethyl phthalate exposure ( p = 0.037). Conclusions: Since reproductive age encompasses a critical window for future health and functioning of the "mothers-to-be" and their children, future studies on prenatal dietary BPA and phthalate exposure and the role of consumer product choices in reducing such exposure are recommended.

Background: The assessment of muscle mass is a key determinant of the diagnosis of sarcopenia. We introduce for the first time an ultrasound imaging method for diagnosing sarcopenia based on changes in muscle geometric proportions., Methods: Vastus lateralis muscle fascicle length (Lf) and thickness (Tm) were measured at 35% distal femur length by ultrasonography in a population of 279 individuals classified as moderately active elderly (MAE), sedentary elderly (SE) (n = 109), mobility impaired elderly (MIE) (n = 43), and in adult young controls (YC) (n = 60). The ratio of Lf/Tm was calculated to obtain an ultrasound index of the loss of muscle mass associated with sarcopenia (USI). In a subsample of elderly male individuals (n = 76) in which corresponding DXA measurements were available (MAE, n = 52 and SE, n = 24), DXA-derived skeletal muscle index (SMI, appendicular limb mass/height 2 ) was compared with corresponding USI values., Results: For both young and older participants, USI values were found to be independent of sex, height and body mass. USI values were 3.70 ± 0.52 for YC, 4.50 ± 0.72 for the MAE, 5.05 ± 1.11 for the SE and 6.31 ± 1.38 for the MIE, all significantly different between each other (P < 0.0001). Based on the USI Z-scores, with reference to the YC population, the 219 elderly participants were stratified according to their muscle sarcopenic status. Individuals with USI values within a range of 3.70 < USI ≥ 4.23 were classified as non-sarcopenic (prevalence 23.7%), those with USI values within 4.23 < USI ≥ 4.76 were classified as pre-sarcopenic (prevalence 23.7%), those with USI values within 4.76 < USI ≥ 5.29 were classified as moderately sarcopenic (prevalence 15.1%), those with USI values within range 5.29 < USI ≥ 5.82 were classified as sarcopenic (prevalence 27.9%), and those with USI values >5.82 were classified as severely sarcopenic (prevalence 9.6%). The DXA-derived SMI was found to be significantly correlated with USI (r = 0.61, P < 0.0001). Notably, the USI cut-off value for moderate sarcopenia (4.76 a.u.) was found to coincide with the DXA cut-off value of sarcopenia (7.26 kg/m 2 )., Conclusions: We propose a novel, practical, and inexpensive imaging marker of the loss of muscle mass associated with sarcopenia, called the ultrasound sarcopenic index (USI), based on changes in muscle geometric proportions. These changes provide a useful 'signature of sarcopenia' and allow the stratification of individuals according to the presence and severity of muscle sarcopenia. We are convinced that the USI will be a useful clinical tool for confirming the diagnosis of sarcopenia, of which the assessment of muscle mass is a key-component., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Current tests available to diagnose fetal hypoxia in-utero lack sensitivity thus failing to identify many fetuses at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may be used as non-invasive biomarkers for pregnancy complications. With the intent to identify putative markers of fetal growth restriction (FGR) and new therapeutic druggable targets, we examined, in maternal blood samples, the expression of a group of microRNAs, known to be regulated by hypoxia. The expression of microRNAs was evaluated in maternal plasma samples collected from (1) women carrying a preterm FGR fetus (FGR group) or (2) women with an appropriately grown fetus matched at the same gestational age (Control group). To discriminate between early- and late-onset FGR, the study population was divided into two subgroups according to the gestational age at delivery. Four microRNAs were identified as possible candidates for the diagnosis of FGR: miR-16-5p, miR-103-3p, miR-107-3p, and miR-27b-3p. All four selected miRNAs, measured by RT-PCR, resulted upregulated in FGR blood samples before the 32nd week of gestation. By contrast, miRNA103-3p and miRNA107-3p, analyzed between the 32nd and 37th week of gestation, showed lower expression in the FGR group compared to aged matched controls. Our results showed that measurement of miRNAs in maternal blood may form the basis for a future diagnostic test to determine the degree of fetal hypoxia in FGR, thus allowing the start of appropriate therapeutic interventions to alleviate the burden of this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tagliaferri, Cepparulo, Vinciguerra, Campanile, Esposito, Maruotti, Zullo, Annunziato and Pignataro.)

Late intrauterine growth restriction (IUGR) is a fetal pathological condition characterized by chronic hypoxia secondary to placental insufficiency, resulting in an abnormal rate of fetal growth. This pathology has been associated with increased fetal and neonatal morbidity and mortality. In standard clinical practice, late IUGR diagnosis can only be suspected in the third trimester and ultimately confirmed at birth. This study presents a radial basis function support vector machine (RBF-SVM) classification based on quantitative features extracted from fetal heart rate (FHR) signals acquired using routine cardiotocography (CTG) in a population of 160 healthy and 102 late IUGR fetuses. First, the individual performance of each time, frequency, and nonlinear feature was tested. To improve the unsatisfactory results of univariate analysis we firstly adopted a Recursive Feature Elimination approach to select the best subset of FHR-based parameters contributing to the discrimination of healthy vs. late IUGR fetuses. A fine tuning of the RBF-SVM model parameters resulted in a satisfactory classification performance in the training set (accuracy 0.93, sensitivity 0.93, specificity 0.84). Comparable results were obtained when applying the model on a totally independent testing set. This investigation supports the use of a multivariate approach for the in utero identification of late IUGR condition based on quantitative FHR features encompassing different domains. The proposed model allows describing the relationships among features beyond the traditional linear approaches, thus improving the classification performance. This framework has the potential to be proposed as a screening tool for the identification of late IUGR fetuses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pini, Lucchini, Esposito, Tagliaferri, Campanile, Magenes and Signorini.)

The gut microbiota could influence the pathophysiology of age-related sarcopenia through multiple mechanisms implying modulation of chronic inflammation and anabolic resistance. The aim of this study was to compare the fecal microbiota composition and functionality, assessed by shotgun metagenomics sequencing, between two groups of elderly outpatients, differing only for the presence of primary sarcopenia. Five sarcopenic elderly subjects and twelve non-sarcopenic controls, classified according to lower limb function and bioimpedance-derived skeletal muscle index, provided a stool sample, which was analyzed with shotgun metagenomics approaches, to determine the overall microbiota composition, the representation of bacteria at the species level, and the prediction of bacterial genes involved in functional metabolic pathways. Sarcopenic subjects displayed different fecal microbiota compositions at the species level, with significant depletion of two species known for their metabolic capacity of producing short-chain fatty acids (SCFAs), Faecalibacterium prausnitzii and Roseburia inulinivorans , and of Alistipes shahii . Additionally, their fecal metagenome had different representation of genes belonging to 108 metabolic pathways, namely, depletion of genes involved in SCFA synthesis, carotenoid and isoflavone biotransformation, and amino acid interconversion. These results support the hypothesis of an association between microbiota and sarcopenia, indicating novel possible mediators, whose clinical relevance should be investigated in future studies.

Covid-19 infection is a multisystem disease more frequent in older individuals, especially in those with multiple chronic diseases. This multimorbid and frail population requires attention and a personalized comprehensive assessment in order to avoid the occurrence of adverse outcomes. As other diseases, the COVID-19 presentation in older patients is often atypical with less severe and unspecific symptoms. These subjects both at home and during hospitalization suffer isolation and the lack of support of caregivers. The geriatric care in COVID-19 wards is often missing. The application of additional instruments would be necessary to facilitate and personalize the clinical approach, not only based on diseases but also on functional status. This narrative review starts from diagnostic evaluation, continues with adapted pharmacologic treatment and ends with the recovery phase targeting the nutrition and physical exercise. We developed a check-list of respiratory, gastro-intestinal and other less-specific symptoms, summarized in a table and easily to be filled-up by patients, nurses and general practitioners. As second step, we reported the clinical phases of this disease. Far to be considered just viral infective and respiratory, this disease is also an inflammatory and thrombotic condition with frequent bacterial over-infection. We finally considered timing and selection of treatment, which depend on the disease phase, co-administration of other drugs and require the monitoring of renal, liver and cardiac function. This underlines the role of age not just as a limitation, but also an opportunity to increase the quality and the appropriateness of multidisciplinary and multidimensional intervention in this population.

The presentation of common acute diseases in older age is often referred to as "atypical". Frequently, the symptoms are neither single nor tissue related. In most cases, the onset of symptoms and diseases is the expression of a diminished reserve with a failure of the body system and imbalance of brain function. Delirium is one of the main devastating and prevalent atypical symptoms and could be considered as a geriatric syndrome. It encompasses an array of neuropsychiatric symptoms and represents a disarrangement of the cerebral function in response to one or more stressors. The most recent definition, reported in the DSM-V, depicts delirium as a clear disturbance in attention and awareness. The deficit is to be developed in a relatively short time period (usually hours or days). The attention disorder must be associated with another cognitive impairment in memory, orientation, language, visual-spatial or perception abilities. For the treatment, it is imperative to remove the potential causes of delirium before prescribing drugs. Even a non-pharmacological approach to reducing the precipitating causes should be identified and planned. When we are forced to approach the pharmacological treatment of hyperactive delirium in older persons, we should select highly cost-effective drugs. High attention should be devoted to the correct balance between improvement of psychiatric symptoms and occurrence of side effects. Clinicians should be guided in the correct choice of drugs following cluster symptoms presentation, excluding drugs that could potentially produce complications rather than advantages. In this brief point-of-view, we propose a novel pharmacological flow-chart of treatment in relation to the basic clusters of diseases of an older patient acutely admitted to the hospital and, in particular, we emphasize "What We Should Not Do!", with the intention of avoiding possible side effects of drugs used.

Increased oxidative stress has been implicated as a potential causal factor in the development of several diseases. In the last decade, an extensive literature has been produced on vitamin D, not limited to its well-known function like a steroid hormone on skeletal tissue, but for its potential pleiotropic role in human health. Several researchers have suggested relationships between vitamin D intake and health outcomes such as cancer prevention and increased immunity, or possible role in preventing diabetes, and in inflammation. Little is known about its antioxidant effect. The aim of the present review was to explore major evidence regarding the potential scavenger capacity of vitamin D in high-evidence human studies. Studies considered by the present review suggest that the potential role of vitamin D as an antioxidant could not be confirmed. Current literature showed controversial effects about the ability of cholecalciferol to prevent or ameliorate oxidative stress biomarkers, and there is need of further and high-quality studies testing the antioxidant effect of vitamin D supplementation.

According to the 2018 European Union Ageing Report, the demographic profile of the European population is projected to be older. Aging cannot be considered a homogeneous process, and only in certain cases is "successful", with maintained functional ability, which is determined by intrinsic capacity, the environment, and their interaction. When intrinsic capacity is lost, elders with chronic diseases develop frailty, a condition with high-risk of disability. Old-age dependency-ratio is projected to increase from 29.6% to 51.2% in the EU in 2070: thus, the need of new approaches targeting the prevention of disability. Numerous studies are conducted in the European Innovation Partnership on Active and Healthy Ageing and addressing identification, treatment, coordination and integration of care in frail older subjects. SUNFRAIL is aimed at developing a model, good practices and tools to improve the identification, prevention and care of frailty and management of multimorbidity. SPRINTT is testing the effectiveness of a multi-component treatment able to treat frailty and sarcopenia. VIGOUR, a project aimed at strengthening integrated-care in different contexts of European Countries, verifies enablers and obstacles encountered in the real world by these good practices. Through the creation of Parma-Lab and Frailty-Team in the Academic-Hospital of Parma combined with the contribution of Parma Health-Trust in the "Community Health-Centers", the Projects were translated into Health Services Arena. This response bridging European Studies and clinical practice, aims to early detecting and caring 75-year older citizens with frailty and multimorbidity, living in the community, not institutionalized and at risk of hospitalization and mobility ADL-disability.

Objective: This study used a new method called Acceleration (or Deceleration) Phase-Rectified Slope, APRS (or DPRS) to analyze computerized Cardiotocographic (cCTG) traces in intrauterine growth restriction (IUGR), in order to calculate acceleration- and deceleration-related fluctuations of the fetal heart rate, and to enhance the prediction of neonatal outcome., Method: Cardiotocograms from a population of 59 healthy and 61 IUGR fetuses from the 30th gestation week matched for gestational age were included. APRS and DPRS analysis was compared to the standard linear and nonlinear cCTG parameters. Statistical analysis was performed through the t-test, ANOVA test, Pearson correlation test and receiver operator characteristic (ROC) curves (p < 0, 05)., Results: APRS and DPRS showed high performance to discriminate between Healthy and IUGR fetuses, according to gestational week. A linear correlation with the fetal pH at birth was found in IUGR. The area under the ROC curve was 0.865 for APRS and 0.900 for DPRS before the 34th gestation week., Conclusions: APRS and DPRS could be useful in the identification and management of IUGR fetuses and in the prediction of the neonatal outcome, especially before the 34th week of gestation.

The aim of this study was to evaluate the impact of vibroacoustic stimulation (VAS) on computerized cardiotocography short-term variability (STV) and approximate entropy (ApEn) in both low- and high-risk pregnancies. VAS was performed on 121 high- and 95 low-risk pregnancies after 10 minutes of continuous quiet, while their FHR parameters were monitored and recorded by cCTG analysis. Fetal heart rate was recorded using a computer-assisted equipment. Baseline FHR, accelerations, decelerations, STV, long-term irregularity (LTI), ApEn, and fetal movements (FMs) were calculated for defined observational periods before VAS and after 10 minutes. Data were also investigated in relationship with the perinatal outcome. In each group of patients, FHR after VAS remained almost unmodified. Fetal movements significantly increased after VAS in both groups. Results show that only in the high-risk pregnancies, the increase of STV and the decrease of ApEn after VAS were significantly associated with favorable perinatal outcomes.

Polybrominated diphenyl ethers (PBDEs) are an important class of flame retardants, widely used in a variety of consumer products. In the past several years, PBDEs have become widespread environmental pollutants, and have been detected in water, soil, air, animals and human tissues. Exposure occurs in particular through the diet and the indoor environment. Infants and toddlers have the highest body burden, due to exposure via maternal milk and through house dust. Tetra-, penta- and hexa-BDEs are the congeners most commonly found in humans. Recent concerns on possible adverse health effects of PBDEs are focusing on their potential endocrine disrupting effects and on developmental neurotoxicity.

Intracellular reduction of hexavalent chromium [Cr(VI)] is associated with the production of reactive oxygen species (ROS) and subsequent oxidative damage to different intracellular molecules like DNA, proteins and lipids is believed to contribute to the process of carcinogenesis. Aim of this study was to develop a model to establish a relationship between intracellular and macromolecule-bound chromium and some biomarkers of oxidative stress in two in vitro cell lines. Human lung adenocarcinoma (A549) and human bronchial epithelial (BEAS2B) cells were exposed for 3, 8 and 24 hours to relatively low doses (0.5--1--2 microM) of Cr(VI), i.e., to concentrations similar to what measured and reported by some authors in unexposed subjects and chromate workers. The results show that the differential cytotoxicity of Cr(VI) on the A549 and BEAS2B cell lines may be related both to their different polymorphism of Glutathione S-transferases genes and probably to their unlike permeability to Cr(VI). The glutathione decrease and the induction of HO-1 observed only in BEAS2B cells after Cr(VI) exposure strengthen the idea that glutathione S-transferases activity may accelerate the reduction of Cr(VI) to Cr(III) with the concomitant induction of oxidative stress. In conclusion, the determination of intracellular Cr in cellular models can be considered an important step in comparing in vitro and in vivo models on the basis of target doses and a promising approach to study the effects of pneumotoxic compounds.

Angiogenesis has a critical role in the pathophysiology of multiple myeloma (MM); however, the molecular mechanisms underlying this process are not completely elucidated. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) has been recently implicated in solid tumors as a repressor of angiogenesis. In this study, we found that ING4 expression in MM cells was correlated with the expression of the proangiogenic molecules interleukin-8 (IL-8) and osteopontin (OPN). Moreover, we demonstrate that ING4 suppression in MM cells up-regulated IL-8 and OPN, increasing the hypoxia inducible factor-1alpha (HIF-1alpha) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1alpha by siRNA suppressed IL-8 and OPN production by MM cells under hypoxia. A direct interaction between ING4 and the HIF prolyl hydroxylase 2 (HPH-2) was also demonstrated. Finally, we show that ING4 suppression in MM cells significantly increased vessel formation in vitro, blunted by blocking IL-8 or OPN. These in vitro observations were confirmed in vivo by finding that MM patients with high IL-8 production and microvascular density (MVD) have significantly lower ING4 levels compared with those with low IL-8 and MVD. Our data indicate that ING4 exerts an inhibitory effect on the production of proangiogenic molecules and consequently on MM-induced angiogenesis.

Osteoblast impairment occurs within multiple myeloma cell infiltration into the bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is involved in osteoblast formation through the stabilization of dephosphorylated beta-catenin and its nuclear translocation. The effects of multiple myeloma cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear. In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. However, although multiple myeloma cells or multiple myeloma bone marrow plasma affected expression of genes in the canonical Wnt signaling and inhibited beta-catenin stabilization in murine osteoprogenitor cells, they failed to block the canonical Wnt pathway in human mesenchymal or osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor cells did not blunt the inhibitory effect of multiple myeloma cells on osteoblast formation. Consequently, despite the higher Wnt antagonist bone marrow levels in osteolytic multiple myeloma patients compared with nonosteolytic ones, beta-catenin immunostaining was not significantly different. Our results support the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients but show that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.

The proteasome inhibitor bortezomib may increase osteoblast-related markers in multiple myeloma (MM) patients; however, its potential osteoblastic stimulatory effect is not known. In this study, we show that bortezomib significantly induced a stimulatory effect on osteoblast markers in human mesenchymal cells without affecting the number of osteoblast progenitors in bone marrow cultures or the viability of mature osteoblasts. Consistently we found that bortezomib significantly increased the transcription factor Runx2/Cbfa1 activity in human osteoblast progenitors and osteoblasts without affecting nuclear and cytoplasmatic active beta-catenin levels. Consequently a stimulatory effect of bortezomib on bone nodule formation was also demonstrated in osteoblast progenitors. These in vitro observations were confirmed in vivo by the finding of a significant increase in the number of osteoblastic cells x mm(2) of bone tissue and in the number of Runx2/Cbfa1-positive osteoblastic cells that was observed in MM patients who responded to bortezomib. Our in vitro and in vivo observations support the hypothesis that a direct stimulatory effect on bone formation process could occur during bortezomib treatment.

Background and Objectives: The chemokine receptor CXCR3, involved in chemotaxis, is expressed on normal and malignant B cells and plasma cells. Recent data suggest that CXCR3-binding chemokines may also regulate proliferation and survival in endothelial cells through the interaction with two distinct isoforms of CXCR3 (CXCR3-A and CXCR3-B)., Design and Methods: We evaluated the potential expression of CXCR3 isoforms in myeloma cells, also investigating whether CXCR3 expression is affected by cell cycle and apoptosis. Furthermore, we assessed the effect of CXCR3 activation on myeloma cell proliferation and survival., Results: We found that CXCR3 is widely expressed on human myeloma cell lines and freshly purified myeloma cells. The presence of both CXCR3 isoforms, CXCR3-A and CXCR3-B, was observed in myeloma cells with different ratios of expression. Interestingly, we found that CXCR3 expression in myeloma cell was cell cycle dependent and that myeloma growth factors inhibited CXCR3 expression in myeloma cells. On the other hand, we found that FAS (CD95)-mediated apoptosis up-regulated CXCR3 expression. A similar behavior was observed for the CXCR3-binding chemokines. Finally we found that the activation of CXCR3 on myeloma cells by CXCL10/IP-10 partially blunted FAS-mediated apoptosis in myeloma cells that express CXCR3-A and that high concentrations of CXCL10/IP-10 inhibit myeloma cell proliferation. INTERPRETATION AND CONCLUSIONS Our data indicate that myeloma cells express the CXCR3 system with patterns correlated to cell cycle and apoptosis and that CXCR3 activation may affect myeloma cell survival and proliferation.