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In this work, a 3D environment obtained using fibrin scaffold and two cell populations, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), and primary skeletal muscle cells (SkMs), was assembled. Peripheral blood mononuclear cells (PBMCs) fraction obtained after blood filtration with HemaTrate® filter was then added to the 3D culture system to explore their influence on myogenesis. The best cell ratio into a 3D fibrin hydrogel was 1:1 (BM-MSCs plus SkMs:PBMCs) when cultured in a perfusion bioreactor; indeed, excellent viability and myogenic event induction were observed. Myogenic genes were significantly overexpressed when cultured with PBMCs, such as MyoD1 of 118-fold at day 14 and Desmin 6-fold at day 21. Desmin and Myosin Heavy Chain were also detected at protein level by immunostaining along the culture. Moreover, the presence of PBMCs in 3D culture induced a significant downregulation of pro-inflammatory cytokine gene expression, such as IL6. This smart biomimetic environment can be an excellent tool for investigation of cellular crosstalk and PBMC influence on myogenic processes.

In this study, chondrogenic potentials of 3D high-density cultures of Bone Marrow (BM) and Wharton’s Jelly (WJ)-derived mesenchymal stromal cells (MSCs) was investigated by chondrogenesis- and cytokine-related gene expression over a 16-day culture period supplemented with human transforming growth factor (hTGF)-β1 at 10 ng/ml. In BM-MSC 3D models, a marked upregulation of chondrogenesis-related genes, such as SOX9, COL2A1, and ACAN (all p < 0.05) and formation of spherical pellets with structured type II collagen fibers were observed. Similarly, WJ-based high-density culture appeared higher in size and more regular in shape, with a significant overexpression of COL2A1 and ACAN (all p < 0.05) at day 16. Moreover, a similar upregulation trend was documented for IL-6 and IL-10 expression in both BM and WJ 3D systems. In conclusion, MSC-based high-density cultures can be considered a promising in vitro model of cartilage regeneration and tissue engineering. Moreover, our data support the use of WJ-MSCs as a valid alternative for chondrogenic commitment of stem cells in regenerative medicine.

OBJECTIVES: Monoamniotic twin pregnancies are at increased risk of perinatal complications, primarily owing to the risk of cord entanglement. There is no recommendation on whether such pregnancies should be managed in hospital or can be safely managed in an outpatient setting, and the timing of planned delivery is also a subject of debate. The aim of this study was to compare the perinatal outcomes of inpatient vs outpatient fetal surveillance approaches employed among 22 participating study centers, and to calculate the fetal and neonatal death rates according to gestational age, in non-anomalous monoamniotic twins from 26 weeks' gestation. METHODS: The MONOMONO study was a multinational cohort study of consecutive women with monochorionic monoamniotic twin pregnancies, who were referred to 22 university hospitals in Italy, the USA, the UK and Spain, from January 2010 to January 2017. Only non-anomalous uncomplicated monoamniotic twin pregnancies with two live fetuses at 26 + 0 weeks' gestation were included in the study. In 10 of the centers, monoamniotic twins were managed routinely as inpatients, whereas in the other 12 centers they were managed routinely as outpatients. The primary outcome was intrauterine fetal death. We also planned to assess fetal and neonatal death rates according to gestational age per 1-week interval. Outcomes are presented as odds ratio (OR) with 95% CIs. The main outcome was analyzed using both standard logistic regression analysis, in which each fetus was treated as an independent unit, and a generalized mixed-model approach, with each twin pair treated as a cluster unit, considering that the outcome for a twin is not independent of that of its cotwin. RESULTS: 195 consecutive pregnant women with a non-anomalous uncomplicated monoamniotic twin gestation (390 fetuses) were included. Of these, 75 (38.5%) were managed as inpatients and 120 (61.5%) as outpatients. The overall perinatal loss rate was 10.8% (42/390) with a peak fetal death rate of 4.3% (15/348) occurring at 29 weeks' gestation. There was no significant difference in mean gestational age at delivery (31 weeks), birth weight (∼1.6 kg), or emergency delivery rate between the inpatient and outpatient surveillance groups. Based on generalized mixed-model analysis, there was no statistically significant difference in fetal death rates between inpatient management commencing from around 26 weeks compared with outpatient surveillance protocols from 30 weeks (3.3% vs 10.8%; adjusted OR 0.21 (95% CI, 0.04-1.17)). Maternal length of stay in the hospital was 42.1 days in the inpatient group, and 7.4 days in the outpatient group (mean difference 34.70 days (95% CI, 31.36-38.04 days). From 32 + 0 to 36 + 6 weeks, no fetal or neonatal death in either group was recorded. 46 fetuses were delivered after 34 + 0 weeks, and none of them died in utero or within the first 28 days postpartum. CONCLUSION: In uncomplicated monoamniotic twins, inpatient surveillance is associated with similar fetal mortality as outpatient management. After 31 + 6 weeks, and up to 36 + 6 weeks, there were no intrauterine fetal deaths or neonatal deaths. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Phosphatidylcholine (PC) vesicles loaded with Triiodothyronine (T3) were fabricated using different manufacturing methods: thin layer hydration plus sonication (TF-UF), supercritical liposome formation (SC), and microfluidic technology (MF). Vesicles obtained by MF had the lowest mean diameter (88.61 ± 44.48 nm) with a Zeta Potential of -20.1 ± 5.90 mV and loading of 10 mg/g (encapsulation efficiency: 57%). In contrast, SC vesicles showed extremely low encapsulation efficiency (10%) probably due to T3 solubility in ethanol/carbon dioxide mixture; despite TF-UF vesicles exhibiting good size (167.7 ± 90 nm; Zp -8.50 ± 0.60 mV) and loading (10 mg/g), poor mass recovery was obtained (50% loss). MF vesicles had low cytotoxicity, and they were well enough internalized by both HeLa and human tendon stem/progenitor cells (hTSPCs). Their biological activity was also monitored in both 2D and 3D cultures of hTSPCs supplemented with therapeutical concentrations of PC/T3 nano-liposomes. 2D culture showed almost similar constitutive gene expression compared to control culture supplemented with free-T3. On the contrary, when hTPSCs 3D culture was assembled, it showed a more evident homogeneous distribution of FITC labeled vesicles within the high-density structure and a significant upregulation of cell constitutive genes, such as type I Collagen (4.8-fold; p 0.0001) at day 7, compared to the control, suggesting that T3/PC formulation has increased T3 cytosolic concentration, thus improving cells metabolic activity. The study supported MF technology for nano-carriers fabrication and opens perspectives on the activity of PC/T3 nano-vesicles as innovative formulations for TPSCs stimulation in ECM secretion.

Tissue engineering strategies can be relevant for cartilage repair and regeneration. A collagen matrix was functionalized with the addition of poly-lactic-co-glycolic acid microcarriers (PLGA-MCs) carrying a human Transforming Growth Factor β1 (hTFG-β1) payload, to provide a 3D biomimetic environment with the capacity to direct stem cell commitment towards a chondrogenic phenotype. PLGA-MCs (mean size 3 ± 0.9 μm) were prepared via supercritical emulsion extraction technology and tailored to sustain delivery of payload into the collagen hydrogel for 21 days. PLGA-MCs were coseeded with human Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) in the collagen matrix. Chondrogenic induction was suggested when dynamic perfusion was applied as indicated by transcriptional upregulation of COL2A1 gene (5-fold, p &lt, 0.01) and downregulation of COL1A1 (0.07-fold, 0.05) and COL3A1 (0.11-fold, 0.05) genes, at day 16, as monitored by qRT-PCR. Histological and quantitative-immunofluorescence (qIF) analysis confirmed cell activity by remodeling the synthetic extracellular matrix when cultured in perfused conditions. Static constructs lacked evidence of chondrogenic specific gene overexpression, which was probably due to a reduced mass exchange, as determined by 3D system Finite Element Modelling (FEM) analysis. Proinflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokine gene expression by hBM-MSC was observed only in dynamic culture (TNF and IL-1β 10-fold, p &lt, 0.001, TGF-β1 4-fold, p &lt, 0.01 at Day 16) confirming the cells’ immunomodulatory activity mainly in relation to their commitment and not due to the synthetic environment. This study supports the use of 3D hydrogel scaffolds, equipped for growth factor controlled delivery, as tissue engineered models for the study of in vitro chondrogenic differentiation and opens clinical perspectives for injectable collagen-based advanced therapy systems.

Purpose Infertility is a topic of growing interest, and female infertility is often treated with gonadotropins. Evidence regarding comparative safety and efficacy of different gonadotropin formulations is available from clinical studies, while real-world data are missing. The present study aims to investigate effectiveness and safety of treatment with different gonadotropin formulations in women undergoing medically assisted procreation treatments in Latium, a region in central Italy, through a real-world data approach. Methods A retrospective population-based cohort study in women between the ages of 18 and 45 years who were prescribed with at least one gonadotropin between 2007 and 2019 was conducted. Women were enrolled from the regional drug dispense registry, and data on their clinical history, exposure to therapeutic cycles (based on recombinant “REC” or extractives “EXT” gonadotropin, or combined protocol “CMD” (REC + EXT)), and maternal/infantile outcomes were linked from the regional healthcare administrative databases. Multivariate logistic regression models were applied to estimate the association between exposure and outcomes. Results Overall, 90,292 therapeutic cycles prescribed to 35,899 women were linked to pregnancies. Overall, 15.8% of cycles successfully led to pregnancy. Compared to extractives, recombinant and combined treatments showed a stronger association with conception rate (RRREC adj = 1.06, 95% CI: 1.01–1.12; RRCBD adj = 1.17, 95% CI: 1.11–1.24). Maternal outcomes occurred in less than 5% of deliveries, and no significant differences between treatments were observed (REC vs EXT, pre-eclampsia: RR adj = 1.24, 95% CI: 0.86–1.79, ovarian hyperstimulation syndrome: RR adj = 1.25, 95% CI: 0.59–2.65, gestational diabetes: RR adj = 1.06, 95% CI: 0.84–1.35). Regarding infantile outcomes, similar results were obtained for different gonadotropin formulations (REC vs EXT: low birth weight: RR adj = 0.98, 95% CI: 0.83–1.26, multiple births: RR adj = 1.06, 95% CI: 0.92–1.23, preterm birth: RR adj = 1.03, 95% CI: 0.92–1.26). Conclusions Efficacy and safety profiles of REC proved to be similar to those of EXT. Regarding the efficacy in terms of conception rate and birth rate, protocols using the combined approach performed slightly better. Outcomes related to maternal and infantile safety were generally very rare, and safety features were overlapping between gonadotropin formulations.

Introduction: The primary aim of this study was to ascertain the strength of association between cerebral blood flow assessed in anterior (ACA), middle (MCA), and posterior (PCA) cerebral arteries and the following clinical outcomes: small for gestational age (SGA), induction of labor (IOL) for oligohydramnios and caesarean section (CS) for nonreassuring fetal status (NRFS) during labor. Material and methods: Retrospective analysis of prospectively collected data on consecutive singleton pregnancies from 40 0/7 to 41 6/7 week of gestation. UA, ACA, MCA, PCA pulsatility index (PI) were measured from 40 weeks of gestations. Furthermore, the ratios between cerebral blood flow and UA (CPR, ACA/UA and PCA/UA) were calculated and correlated with the observed outcomes. Results: Two hundred twenty-four singleton pregnancies were included in the study. Mean PI of either ACA (p = .04), MCA (p = .008), and PCA (p = .003) were lower in the SGA compared to non-SGA group; furthermore, mean PCA PI was significantly lower than MCA PI (p = .04). Furthermore, CPR (p = .016), ACA/UA (p = .02), and PCA/UA (p = .003) were significantly lower in the SGA group compared to controls. UA, ACA, MCA, and PCA PI were higher in women undergoing IOL for oligohydramnios compared to controls. Logistic regression analysis showed that CPR and PCA/UA ratio were independently associated with SGA. SGA, ACA PI, and ACA/UA were independently associated with CS for NRFS. Finally, birthweight centile, were independently associated with IOL oligohydramnios. Despite this, the predictive accuracy of Doppler in detecting any of the explored outcome was only poor to moderate. Conclusion: Redistribution of cerebral blood flow at term is significantly associated with SGA, IOL for oligohydramnios and CS for NRFS in labor. However, the predictive accuracy of Doppler at term is only poor to moderate, thus advising against its use in clinical practice as a standalone screening test for adverse perinatal outcome in pregnancies at term. Key Message Redistribution of cerebral blood flow at term is significantly associated with SGA, IOL for oligohydramnios and CS for NRFS in labor.

INTRODUCTION: The aim of this study was to explore the effect of maternal fluorinated steroid therapy on fetuses affected by second-degree immune-mediated congenital atrioventricular block. MATERIAL AND METHODS: Studies reporting the outcome of fetuses with second-degree immune-mediated congenital atrioventricular block diagnosed on prenatal ultrasound and treated with fluorinated steroids compared with those not treated were included. The primary outcome was the overall progression of congenital atrioventricular block to either continuous or intermittent third-degree congenital atrioventricular block at birth. Meta-analyses of proportions using random effect model and meta-analyses using individual data random-effect logistic regression were used. RESULTS: Five studies (71 fetuses) were included. The progression rate to congenital atrioventricular block at birth in fetuses treated with steroids was 52% (95% confidence interval 23-79) and in fetuses not receiving steroid therapy 73% (95% confidence interval 39-94). The overall rate of regression to either first-degree, intermittent first-/second-degree or sinus rhythm in fetuses treated with steroids was 25% (95% confidence interval 12-41) compared with 23% (95% confidence interval 8-44) in those not treated. Stable (constant) second-degree congenital atrioventricular block at birth was present in 11% (95% confidence interval 2-27) of cases in the treated group and in none of the newborns in the untreated group, whereas complete regression to sinus rhythm occurred in 21% (95% confidence interval 6-42) of fetuses receiving steroids vs. 9% (95% confidence interval 0-41) of those untreated. CONCLUSIONS: There is still limited evidence as to the benefit of administered fluorinated steroids in terms of affecting outcome of fetuses with second-degree immune-mediated congenital atrioventricular block.

OBJECTIVE: To evaluate the benefits and harms of discontinuation of oxytocin after the active phase of labor is reached. DATA SOURCES: Electronic databases (ie, MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, ScienceDirect, the Cochrane Library at the CENTRAL Register of Controlled Trials, Scielo) were searched from their inception until April 2017. METHODS OF STUDY SELECTION: We included all randomized controlled trials comparing discontinuation (ie, intervention group) and continuation (ie, control group) of oxytocin infusion after the active phase of labor is reached, either after induction or augmentation of labor. Discontinuation of oxytocin infusion was defined as discontinuing oxytocin infusion when the active phase of labor was achieved. Continuation of oxytocin infusion was defined as continuing oxytocin infusion until delivery. Only trials in singleton gestations with vertex presentation at term were included. The primary outcome was the incidence of cesarean delivery. TABULATION, INTEGRATION, AND RESULTS: Nine randomized controlled trials, including 1,538 singleton gestations, were identified as relevant and included in the meta-analysis. All nine trials included only women undergoing induction of labor. In the discontinuation group, if arrest of labor occurred, usually defined as no cervical dilation in 2 hours or inadequate uterine contractions for 2 hours or more, oxytocin infusion was restarted. Women in the control group had oxytocin continued until delivery usually at the same dose used at the time the active phase was reached. Women who were randomized to have discontinuation of oxytocin infusion after the active phase of labor was reached had a significantly lower risk of cesarean delivery (9.3% compared with 14.7%; relative risk 0.64, 95% CI 0.48-0.87) and of uterine tachysystole (6.2% compared with 13.1%; relative risk 0.53, 95% CI 0.33-0.84) compared with those who were randomized to have continuation of oxytocin infusion until delivery. Discontinuation of oxytocin infusion was associated with an increase in the duration of the active phase of labor (mean difference 27.65 minutes, 95% CI 3.94-51.36). CONCLUSION: In singleton gestations with cephalic presentation at term undergoing induction, discontinuation of oxytocin infusion after the active phase of labor at approximately 5 cm is reached reduces the risk of cesarean delivery and of uterine tachysystole compared with continuous oxytocin infusion. Given this evidence, discontinuation of oxytocin infusion once the active stage of labor is established in women being induced should be considered as an alternative management plan.

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Objective The aim of this systematic review and meta-analysis was to quantify the efficacy of cervical cerclage in preventing preterm birth (PTB) in asymptomatic singleton pregnancies with a short mid-trimester cervical length (CL) on transvaginal sonography (TVS) and without prior spontaneous PTB. Methods Electronic databases were searched from inception of each database until February 2017. No language restrictions were applied. All randomized controlled trials (RCTs) of asymptomatic singleton pregnancies without prior spontaneous PTB, found to have short CL

OBJECTIVE: To evaluate benefits and harms of food intake during labor. DATA SOURCES: Electronic databases such as MEDLINE and ClinicalTrials.gov were searched from their inception until October 2016. METHODS OF STUDY SELECTION: We included randomized trials comparing a policy of less-restrictive food intake with a policy of more restrictive food intake during labor. The primary outcome was the mean duration of labor. Meta-analysis was performed using the random-effects model of DerSimonian and Laird to produce summary treatment effects in terms of either a relative risk or a mean difference with 95% confidence interval (CI). TABULATION, INTEGRATION, AND RESULTS: Ten trials, including 3,982 laboring women, were included. All the studies involved laboring singletons considered at low risk because they had no obstetric or medical complications that would increase the likelihood of cesarean delivery. In three studies, women were allowed to select from a low-residue diet throughout the course of labor. One study had honey date syrup as the allowed food intake. Five studies had carbohydrate drinks as food intake in labor. The last one was the only trial that allowed unrestrictive food intake. In the included studies, all women in the intervention group were allowed the assigned food intake until delivery, whereas women in a control group were allowed only ice chips, water, or sips of water until delivery. A policy of less-restrictive food intake was associated with a significantly shorter duration of labor (mean difference -16 minutes, 95% CI -25 to -7). No other benefits or harms in obstetric or neonatal outcome were noticed. Regurgitation during general anesthesia and Mendelson syndrome did not occur in either group. CONCLUSION: Women with low-risk singleton pregnancies who were allowed to eat more freely during labor had a shorter duration of labor. A policy of less-restrictive food intake during labor did not influence other obstetric or neonatal outcomes nor did it increase the incidence of vomiting. Operative delivery rates were similar.

Background Gonadotropins (Gonas) are hormones that play a central role in the follicular growth of women but also useful in male infertility. Gonas used for infertility treatment in women are available as urinary extracts or recombinants. In 2015, the first biosimilar of follitropin alfa was authorised. Objectives We aimed to evaluate use patterns, temporal and spatial variations of Gonas biosimilar formulations in an central Italian region. Methods From administrative healthcare databases of Lazio region, we extracted prescriptions that have occurred over the years 2015-2019. Gona's use was grouped as treatment with urinary (u) and recombinant (r). Special focus was made on biosimilar r-Gona. Use patterns were investigated with respect to characteristics of the patients treated, time trends, differences among local health units and type of prescribing physician. Results For the study period, we retrieved 136,333 Gona dispensations for 22,325 patients. The 10,927 r-Gona biosimilar dispensations (8.01% of all claims, of which 99.43% Bemfola®, and 0.57% Ovaleap®), were mostly referred to women, aged 18-45 years, (87.11% of all patients). Median age was 37 years for women, 38 for men. Since its authorisation, biosimilar r-Gona steadily gained market from 2015 (0,4% of claims) to 2017 (22,7%) followed by a decrease in 2019 (4,3%). Biosimilars claims are more frequent in treating men (10,8%) than women (6,1%). Most biosimilar prescriptions were issued by general practitioners (86.4%), followed by specialists (10.2%) and others. Biosimilar use patterns varied between different local health units (IQR 3.2%-8,5%). Conclusions In clinical pratice, r-Gona biosimilar dispensation, 8,8% of Gonas. are mostly prescribed from general practitioners and are proportionately more targeted at men than women. Further investigation is needed. Key messages More and more men and women are using artificial insemination techniques; it is important to monitor fertility drug use patterns. In times of savings for the economic system,the use of the biosimilar drugs is of increasing interest.

Background Gonadotropins (Gona) are commonly used for infertility treatment in women. They are available as urinary purified extracts (u-Gona) and recombinants (r-Gona). Objectives:We investigated if socio-demographic characteristics of treated women, year of dispensation and type of prescriber may play a role in the choice of a treatment with respect to the other. Methods From administrative healthcare databases, we collected claims of Gona for women, aged 18-45, enrolled in the health care system in the year preceding the first prescription (years 2009-2018). Treatment cycles were defined as a 21-day mobile time window. We identified three groups: u-Gona, r-Gona and treatment with both formulations (m-Gona). To identify determinants, we linked women with the socio-economic position (SEP), a composite deprivation index, based on the 2011 Italian Census data,categorized in 4 levels (high, medium-high, medium-low, low). We associated prescriptions with the type of prescriber, distinguishing between specialists and general practitioners. Results We retrieved 38,598 Gona treatment cycles prescribed to 23,412 women and distributed between formulations as follows: r-Gona 47.4%, u-Gona 26.3% and m-Gona 26.3%. The median age was 38 years for r-Gona and u-Gona, 39 for m-Gona. Comparing the type of prescriber, specialists were more likely to prescribe u-Gona instead of r-Gona (OR: 2.14; 95%CI: 2.02-2.27) than general practitioners. No relation was found between SEP and Gona formulations, except for patients with the highest level who were more likely to be prescribed with r-Gona instead of u-Gona (OR: 1.12; 95%CI: 1.03-1.21). Time trends showed that treatment choices changed over time. Conclusions In the Lazio region, the choice of gonadotropin formulations varied over time and was found to be related to the prescriber and partly to socio-economic position. An analysis of outcomes related to different treatments is under way. Key messages More and more women are using artificial insemination techniques; it is important to monitor fertility drug use patterns and determinants of the choice of a treatment. The use of fertility drugs is a multifactorial phenomenon and a matter of public health interest.

Infection and resulting bone defects caused by Staphylococcus aureus is one of the major issues in orthopaedic surgeries. Vancomycin hydrochloride (VaH) is largely used to manage these events. Here, a human derived bone paste supplemented with biopolymer microcarriers for VaH sustained delivery to merge osteoinductive and antimicrobial actions is described. In detail, different emulsion formulations were tested to fabricate micro-carriers of poly-lactic-co-glycolic acid (PLGA) and hydroxyapatite (HA) by a proprietary technology (named Supercritical Emulsion Extraction). These carriers (mean size 827 ± 68 μm; loading 47 mgVaH/gPLGA) were assembled with human demineralized bone matrix (DBM) to obtain an antimicrobial bone paste system (250 mg/0.5 cm3 w/v, carrier/DBM). Release profiles in PBS indicated a daily drug average release of about 4 µg/mL over two weeks. This concentration was close to the minimum inhibitory concentration and able to effectively inhibit the S. aureus growth in our experimental sets. Carriers cytotoxicity tests showed absence of adverse effects on cell viability at the concentrations used for paste assembly. This approach points toward the potential of the DBM-carrier-antibiotic system in hampering the bacterial growth with accurately controlled antibiotic release and opens perspectives on functional bone paste with PLGA carriers for the controlled release of bioactive molecules.

We have previously shown that αB-crystallin (CRYAB), a small heat shock protein (sHsp) that prevents irreversible aggregation of unfolded protein by an ATP-independent chaperone activity, plays a pivotal role in the biogenesis of multipass transmembrane proteins (TMPs) assisting their folding from the cytosolic side of the endoplasmic reticulum (ER) (D'Agostino et al., 2013). Here we present evidence, based on phosphomimetic substitutions, that the three phosphorytable serine residues at position 19, 45 and 59 of CRYAB play a different regulatory role in this novel chaperone activity: S19 and S45 have a strong inhibitory effect, either alone or in combination, while S59 has not and counteracts the inhibition caused by single phosphomimetic substitutions at S19 and S45. Interestingly, all phosphomimetic substitutions determine the formation of smaller oligomeric complexes containing CRYAB, indicating that the inhibitory effect seen for S19 and S45 cannot be ascribed to the reduction of oligomerization frequently associated to a decreased chaperone activity. These results indicate that phosphorylation finely regulates the chaperone activity of CRYAB with multipass TMPs and suggest a pivotal role for S59 in this process., Highlights • CRYAB chaperone activity toward ATP7B-H1069Q and Fz4-FEVR. • Phosphomimetic S19D and S45D inhibit CRYAB chaperone activity. • Phosphomimetic S59D protects CRYAB chaperone activity. • Pseudo-phosphorylation decreases CRYAB oligomerization.

We developed a (three-dimensional) 3D scaffold, we named HY-FIB, incorporating a force-transmission band of braided hyaluronate embedded in a cell localizing fibrin hydrogel and poly-lactic-co-glycolic acid (PLGA) nanocarriers as transient components for growth factor controlled delivery. The tenogenic supporting capacity of HY-FIB on human-Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) was explored under static conditions and under bioreactor-induced cyclic strain conditions. HY-FIB elasticity enabled to deliver a mean shear stress of 0.09 Pa for 4 h/day. Tendon and cytokine marker expression by hBM-MSCs were studied. Results: hBM-MSCs embedded in HY-FIB and subjected to mechanical stimulation, resulted in a typical tenogenic phenotype, as indicated by type 1 Collagen fiber immunofluorescence. RT-qPCR showed an increase of type 1 Collagen, scleraxis, and decorin gene expression (3-fold, 1600-fold, and 3-fold, respectively, at day 11) in dynamic conditions. Cells also showed pro-inflammatory (IL-6, TNF, IL-12A, IL-1&beta, ) and anti-inflammatory (IL-10, TGF-&beta, 1) cytokine gene expressions, with a significant increase of anti-inflammatory cytokines in dynamic conditions (IL-10 and TGF-&beta, 1 300-fold and 4-fold, respectively, at day 11). Mechanical signaling, conveyed by HY-FIB to hBM-MSCs, promoted tenogenic gene markers expression and a pro-repair cytokine balance. The results provide strong evidence in support of the HY-FIB system and its interaction with cells and its potential for use as a predictive in vitro model.

Background Cesarean delivery could be complicated by postpartum hemorrhage (PPH), the first cause of maternal death. Objectives To evaluate the efficacy of uterine massage in preventing postpartum hemorrhage at cesarean delivery. Data sources Electronic databases from their inception until October 2017. Study eligibility criteria, participants, and interventions We included all RCTs comparing uterine massage alone or as part of the active management of labor before or after delivery of the placenta, or both, with non-massage in the setting of cesarean delivery. Data collection and analysis The primary outcome was PPH, defined as blood loss >1000 mL. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of mean difference (MD) or relative risk (RR) with 95% confidence interval (CI). Results Only 3 RCTs comparing uterine massage vs no uterine massage were found. The quality of these 3 trials in general was very low with high or unclear risk of bias. All of them included only women in the setting of spontaneous vaginal delivery and none of them included cesarean delivery, and therefore the meta-analysis was not feasible. Conclusions There is not enough evidence to determine if uterine massage prevents postpartum hemorrhage at cesarean delivery.

The meniscus is a fibrocartilaginous structure included in the knee joint. The meniscus surface appears as a smooth glossy-white tissue, with specialized cells, a complex extracellular matrix and specific regions of vascularization and innervation. Annually, the estimated incidence of meniscus lesions is 66 per 100,000 inhabitants. Meniscectomy is widely undertaken; meniscal suturing and meniscal allograft transplantation could be alternative options. Fibrocartilage tissue engineering can be also proposed for meniscus regeneration, even though the regenerative medicine field is still not completely explored and to date has led to few FDA-approved therapies. Indeed, considerable research has been performed in the field of grafts fabrication and cell manipulation. Even if these bioengineered scaffolds can be molded to fit the patient's anatomy, strategies are still being developed to improve graft integration with the host vasculature and nervous system and to stimulate the body natural healing response. Some approaches for cartilage and meniscus tissue engineering recently proposed are discussed in this chapter.

Controlled delivery of human growth factors is still a challenge in tissue engineering protocols, and poly-lactic acid and poly-lactic-co-glycolic acid carriers have been recently proposed for this purpose. Here, the microencapsulation of two human growth factors, namely Growth Differentiation Factor −5 (hGDF-5) and Transforming Growth Factor β1 (hTGF-β1) was tested, by processing different emulsions with Supercritical Emulsion Extraction (SEE) technology. Polymer molecular weight, co-polymer ratio and surfactant amount in aqueous phases as well as phases mixing rate were varied to fabricate carriers with suitable size and loadings. Carriers with different mean sizes from 0.4 ± 0.09 μm up to 3 ± 0.9 μm were obtained by SEE technology when processing emulsions with different formulations; carriers were loaded with 3 μg/g and 7 μg/g for hGDF-5 and hTGF-β1 with controlled growth factor release over 25 days. Carriers displayed extremely low cytotoxicity when evaluated in Chinese Hamster Ovary cells (CHO-K1). Further, they also exhibited reduced cytotoxicity with respect to carriers obtained by conventional evaporation techniques, and low reactivity on human peripheral blood mononuclear cells (hPBMCs), suggesting their safety and potential use in tissue engineering protocols.

OBJECTIVE: To examine whether chewing gum hastens the return of gastrointestinal function after a cesarean delivery. METHODS: All randomized controlled trials comparing the use of chewing gum in the immediate postoperative recovery period (i.e. intervention group) with a control group were included in the meta-analysis. The primary outcome was the time to first flatus in hours. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of mean difference (MD) or relative risk (RR) with 95% confidence interval (CI). RESULTS: Seventeen trials, including 3041 women, were analyzed. Trials were of moderate to low quality with different inclusion criteria. In most of the included trials chewing gum was given right after delivery, three times a day for 30 min each and until the first flatus. Women who were randomized to the chewing gum group had a significantly lower mean time to first flatus (MD - 6.49 h, 95%CI -8.65 to -4.33), to first bowel sounds (MD - 8.48 h, 95%CI -9.04 to -7.92), less duration of stay (MD - 0.39 days, 95%CI -0.78 to -0.18), lower time to first feces (MD - 9.57 h, 95% CI -10.28 to 8.87) and to the first feeling of hunger (MD - 2.89 h, 95%CI -4.93 to -0.85), less number of episodes of nausea or vomiting (RR 0.33, 95%CI 0.12 to 0.87), less incidence of ileus (RR 0.39, 95%CI 0.19 to 0.80) and significantly higher satisfaction. CONCLUSIONS: Gum chewing starting right after cesarean delivery three times a day for about 30 min until the first flatus is associated with early recovery of bowel motility. As this is a simple, generally inexpensive intervention, providers should consider implementing cesarean postoperative care with gum chewing.

Tissue engineering strategies have relied on engineered 3-dimensional (3D) scaffolds to provide architectural templates that can mimic the native cell environment. Among the several technologies proposed for the fabrication of 3D scaffold, that can be attractive for stem cell cultivation and differentiation, moulding or bioplotting of hydrogels allow the stratification of layers loaded with cells and with specific additives to obtain a predefined microstructural organization. Particularly with bioplotting technology, living cells, named bio-ink, and additives, such as biopolymer microdevices/nanodevices for the controlled delivery of growth factors or biosignals, can be organized spatially into a predesigned 3D pattern by automated fabrication with computer-aided digital files. The technologies for biopolymer microcarrier/nanocarrier fabrication can be strategic to provide a controlled spatiotemporal delivery of specific biosignals within a microenvironment that can better or faster address the stem cells loaded within it. In this review, some examples of growth factor-controlled delivery by biopolymer microdevices/nanodevices embedded within 3D hydrogel scaffolds will be described, to achieve a bioengineered 3D interactive microenvironment for stem cell differentiation. Conventional and recently proposed technologies for biopolymer microcapsule fabrication for controlled delivery over several days will also be illustrated and critically discussed.

Picture sharing through social networks has become a prominent phenomenon, producing a large amount of data that law enforcers may be entitled to use, under the proper legal framework, as a source of information for investigating a crime. In this work, the authors exploit digital camera ‘fingerprinting’ based on noise residuals (sensor pattern noise or SPN) to achieve a novel forensic task, named picture-to-identity linking. It consists of finding social network accounts that possibly belong to the author of a certain photo (e.g. showing illegal content). The rationale is that the author of the offending photo has likely used the same camera for taking other (legal) pictures, and posted them in a social network account. The authors extend a previous work on the topic by coupling SPN with visual image similarity, a useful cue when pictures have been taken in the same environment (e.g. a room). The authors also improve the framework by allowing for multiple-image queries, and thoroughly evaluate the performance on two corpora of images from social network accounts, including the impact of image modifications. Reported results show a robust improvement with respect to the previous work, and prove the usefulness of picture-to-identity as an aid for digital forensic investigations.

To assess the efficacy of vaginal cleansing before cesarean delivery in reducing postoperative endometritis.MEDLINE, Ovid, EMBASE, Scopus, Clinicaltrials.gov, and Cochrane Library were searched from their inception to January 2017.Selection criteria included all randomized controlled trials comparing vaginal cleansing (ie, intervention group) with a control group (ie, either placebo or no intervention) in women undergoing cesarean delivery. Any method of vaginal cleansing with any type of antiseptic solution was included. The primary outcome was the incidence of endometritis. Meta-analysis was performed using the random-effects model of DerSimonian and Laird to produce summary treatment effects in terms of relative risk (RR) with 95% CI.Sixteen trials (4,837 women) on vaginal cleansing immediately before cesarean delivery were identified as relevant and included in the review. In most of the included studies, 10% povidone-iodine was used as an intervention. The most common way to perform the vaginal cleansing was the use of a sponge stick for approximately 30 seconds. Women who received vaginal cleansing before cesarean delivery had a significantly lower incidence of endometritis (4.5% compared with 8.8%; RR 0.52, 95% CI 0.37-0.72; 15 studies, 4,726 participants) and of postoperative fever (9.4% compared with 14.9%; RR 0.65, 95% CI 0.50-0.86; 11 studies, 4,098 participants) compared with the control group. In the planned subgroup analyses, the reduction in the incidence of endometritis with vaginal cleansing was limited to women in labor before cesarean delivery (8.1% compared with 13.8%; RR 0.52, 95% CI 0.28-0.97; four studies, 440 participants) or those with ruptured membranes (4.3% compared with 20.1%; RR 0.23, 95% CI 0.10-0.52; three studies, 272 participants).Vaginal cleansing immediately before cesarean delivery in women in labor and in women with ruptured membranes reduces the risk of postoperative endometritis. Because it is generally inexpensive and a simple intervention, we recommend preoperative vaginal preparation before cesarean delivery in these women with sponge stick preparation of povidone-iodine 10% for at least 30 seconds. More data are needed to assess whether this intervention may be also useful for cesarean deliveries performed in women not in labor and for those without ruptured membranes.PROSPERO International prospective register of systematic reviews, https://www.crd.york.ac.uk/PROSPERO/, CRD42017054843.

Sir,We thank Dr Illingworth and Dr Duffy for their interest in our work [1]. We agree that it is disappointing that chewing gum, an inexpensive and safe intervention, has not been adopted more broa...

Le Autrici riflettono sul ruolo che hanno i vari tipi di memoria, implicita, sensoriale, esplicita ed episodica nella formazione dell'Inconscio e nello sviluppo della mente infantile. In particolare evidenziano i principali contributi scientifici di Adriano Giannotti sugli stadi iniziali dello sviluppo infantile normale e patologico e sul ruolo che hanno la madre e la relazione della coppia genitoriale in senso lato come processo trasformativo anche delle memorie corporee indicibili nelle memorie verbali. Le Autrici condividono con Adriano Giannotti l'idea che una visione piů complessa della memoria e dell'inconscio richieda un approccio integrato tra il punto di vista delle neuroscienze e quello psicoanalitico. Il trattamento psicoanalitico del bambino, dell'adolescente e dell'adulto ha permesso ad Adriano Giannotti, come alle Autrici, di studiare il come prendono forma i ricordi nei piccoli pazienti con disturbi psicosomatici, il gioco dialettico tra percezione, rappresentazione e memoria, tra comunicazione inconscia e comunicazione dell'inconscio rimosso e di come la cornice analitica facilita l'acquisizione di uno spazio mentale, dove la creazione di un linguaggio comune č tesa a una co-costruzione del ricordo.

– A systematic investigation of the cognitive functions of 22 patients affected with motor neuron disease (MND) compared to 36 controls matched for age and education was performed. The MND group showed cognitive performances slightly but significantly lower than the control group; 6 MND patients, however, had decidedly pathological values. Cognitive impairment was stereotyped and global, with sparing of memory. There was no significant difference between patients with isolated involvement of the lower motor neuron and those with associated pyramidal involvement. Our neuropsychological findings are in agreement with previous clinical, neuroradiological and pathological reports indicating extra-motor cerebral involvement in MND.

Counterfeiting of mass-market products is becoming a phenomenon more and more widespread. Traditionally counterfeiting has been fought using both covert and overt security features applied to products packaging, or with track-and-trace technologies. However the possibility to verify authenticity is usually not available to final consumers with the possible exception of luxury goods. In this short paper we describe our proposal for a simple authentication system based on the use of public-key cryptography combined with a ID-barcode and an online product id verification system implemented on a smartphone app and available to consumers.

To evaluate the long-term outcome of children following admission to a paediatric intensive care unit. Prospective, long-term follow-up study. Sixteen-bed multi-disciplinary paediatric intensive care unit in a free-standing, university, tertiary, teaching hospital. All children consecutively admitted to the paediatric intensive care unit from 1st January, 1995, to 31st December, 1995. Outcome was evaluated, by telephone interview, at a median of 3.5 years (range 2.3–6 years) after admission to the intensive care unit using a modification of the Glasgow Outcome Score (GOS) to assess functional outcome and the Health State Utility Index (Mark 1) to assess quality of life. Of the children admitted to the intensive care unit, 83.8% were alive at the time of follow-up. While 10.3% of the survivors had an unfavourable outcome and were likely to live dependent on care, 89.7% had a favourable outcome and were likely to lead an independent existence. Although 16.4% had an unfavourable quality of life, 83.6% of the children survived with a favourable quality of life. At the time of follow-up, 16.2% of the children were dead: 49% died in the intensive care unit, 5% died in hospital and 46% died after discharge from hospital. The majority of children admitted to a paediatric intensive care unit survive with an excellent functional outcome and quality of life. Long-term outcome assessment provides a basis for observing trends in outcome over time within the same institution.

The breaker depth index, γb, is commonly used to determine the wave height to water depth ratio where the wave will break (Horikawa, 1988). In the present study, γb has been calculated using a fully nonlinear Boussinesq Type Equations (BTE) wave model with implemented BCI (Breaking Celerity Index). The BCI is a phase-resolving type breaking criterion for calculating the incipient wave breaking conditions (D’Alessandro and Tomasicchio, 2008). The model suitability in predicting γb has been verified against physical data from an experimental investigation conducted with incident regular waves propagating along uniform 1:20 and 1:50 slope beaches (G.V. dos Reis, 1992), and estimates of γb from five existing empirical formulae (Battjes, 1974; Ostendorf and Madsen, 1979; Singamsetti and Wind, 1980; Smith and Kraus, 1990; Goda, 2010). The comparisons showed that BCI presents a better agreement with the physical data with respect to the other investigated formulae in determining the value of γb, independently from the breaker type. In addition, the verification of the BCI in determining γb has been extended to the observed data from a large-scale laboratory experiment on wave hydrodynamics performed over a fixed-bed barred beach (Tomasicchio and Sancho, 2002).

The concept of Smart Home where appliances, sensors, actuators, displays and computing resources are connected and interact to support the life of the citizen is being increasingly researched. In this context, the Wi-Fi communication technology has grown to become the de-facto standard for data communications in Smart Home environments, with cordless telephony being dominated by the DECT protocol. Even though both technologies incorporate sets of security features aimed at securing the confidentiality and integrity of the communications, the nature and the design of both radio-frequency protocols make them vulnerable, up to a certain extent, to privacy leakages through traffic analysis attacks. In this paper we explore the information leakage vulnerabilities inherent to these technologies and their potential impact on citizens’ privacy in the context of the Smart Home. We demonstrate how the websites visited by a smart device can be inferred by applying machine learning and pattern matching techniques to eavesdropped encrypted traffic. Keywords—Privacy, Wireless communications, Machine learning

Smartphones are becoming more and more widespread and powerful and their use is becoming common in applications such as transport, healthcare, security, and surveillance. In this paper we describe the preliminary results of our experience in using an Android smartphone as a tool which can be used in emergency situations to validate the identity of people through the use of two functionalities provided by the most recent generations of smartphones: NFC and face recognition.

Objectives: To provide pharmacists in community practice a framework for using national health observances as opportunities to promote patients' health through education and screenings, to discuss obstacles pharmacists may encounter when developing services within their pharmacies, and to outline examples of activities pharmacists can perform for specific health observances. Data Sources: Articles published between January 1970 and April 2002 were identified through MEDLINE using the search terms wellness, disease prevention, health promotion, Healthy People 2010, treatment of high cholesterol, treatment of high blood pressure, and levels of participation. Additional articles were identified from Web sites and reports from the federal Office of Disease Prevention and Health Promotion (ODPHP), American Heart Association, American Diabetes Association, National Osteoporosis Foundation, National Cancer Institute, American Cancer Society, National Heart, Lung, and Blood Institute, Consumer Product Safety Commission, and Centers for Disease Control and Prevention. Data Synthesis: Healthy People 2010 is a federal program with the goal of increasing the quality and years of healthy life and eliminating health disparities among populations. ODPHP publishes a list of national health observances each year. Community pharmacists can use these month- and week-long observances as opportunities to work toward achieving Healthy People 2010 goals by advocating, facilitating, and/or providing education and screenings to their patients. This article presents advice for pharmacists who want to develop pharmacy-based health promotion activities at various levels of resources and commitment. Specific suggestions include tips on preparing for and implementing education and screening programs and overcoming potential obstacles. Conclusion: As the most accessible health care professionals, pharmacists are in a unique position to help the nation achieve the goals of Healthy People 2010 through their involvement in the promotion of wellness.

Contactless smart cards are used to securely store data and to authorize the execution of sensitive operations. Their contactless interface represents a mixed blessing, allowing fast operations but also such devices to potential attacks. Relay attacks are among the most powerful attacks applicable against contactless smart cards, allowing a contactless reader to interact with a physically far away card establishing a communication channel between them. In this paper we prove that it is possible to conduct such an attack on a geographical scale, basically without any constraints on the reader and card positions and reaching a relay distance of several kilometers, probably the first example in the literature for contactless smart cards, using cheap and off-the-shelf hardware and software tools.