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Objective The study evaluated the association of BMP4tag-SNPs and SNP-SNP interactions involving genes active by BMP4 pathway during craniofacial development in the susceptibility of nonsyndromic orofacial clefts (NSOC) in the Brazilian population.Design Case-control study.Setting Brazilian Oral Cleft Group.Participants The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO).Interventions The genomic DNA was genotyped with allelic discrimination assays for five BMP4tag-SNPs (rs11623717, rs17563, rs2071047, rs2761887 and rs4898820), and analyzed their allelic and genotypic associations using multiple logistic regression. The interactions of these variants with genes involved in the BMP4signaling pathway, including FGFR1, GREM1, NOG, VAX1and the 4p16.2 locus, were explored.Main outcome measures BMP4variants in the NSOC risk.Results Although only nominal pvalues were identified when the whole sample was considered, subgroup analysis including the patients with high African genomic ancestry showed significant associations of rs2761887 with risk for nonsyndromic cleft lip with or without cleft palate (NSCL  ±  P)[(ORhom: 2.16; 95% CI: 1.21–3.85; p=  0.01) and (ORrec: 2.05; 95% CI: 1.21–3.47; p=  0.006)]. Thirteen significant SNP-SNP interactions involving BMP4and the SNPs at FGFR1, GREM1, NOGand VAX1and at locus 4p16.2 for increased risk of NSCL  ±  P were identified.Conclusions Our results demonstrate an increased risk of NSCL  ±  P in Brazilian individuals with enrichment of African ancestry in the presence of the BMP4rs2762887 polymorphism, and reveal relevant genetic contribution of SNP-SNP epistatic interactions involving BMP4variants to NSCL  ±  P risk.

The management of pain following a burn is extremely complex because of the multifactorial nature of burn pain. The main goal of acute pain management is to reduce the patient’s pain, allowing them to maintain function and to prevent the chronification of pain. Opioids are used as first-line treatment in management of burn pain. In this single-center observational study, patients presenting with severe burns were enrolled in our hospital. Pain intensity and anxiety level were evaluated at admission and after 1 h. We evaluated pain treatment using intravenous (IV) morphine. Thirty patients were included in this study. At the time of arrival in hospital, almost all patients reported severe pain and received IV morphine to achieve pain relief. After 1 h, > 65% of patients had no pain. No adverse events were recorded related to morphine administration. The anxiety level improved after pain treatment. Finally, IV morphine used for burn pain management in the emergency setting significantly improves patient outcomes in terms of pain and reduced agitation.

A definitive diagnosis of gastroesophageal reflux disease (GERD) depends on endoscopic and/or pH‐study criteria. However, high resolution manometry (HRM) can identify factors predicting GERD, such as ineffective esophageal motility (IEM), esophago‐gastric junction contractile integral (EGJ‐CI), evaluating esophagogastric junction (EGJ) type and straight leg raise (SLR) maneuver response. We aimed to build and externally validate a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD. A population of 295 consecutive patients undergoing HRM and pH‐study for persistent typical or atypical GERD symptoms was prospectively enrolled to build a model and a nomogram that provides a risk score for AET > 6%. Collected HRM data included IEM, EGJ‐CI, EGJ type and SLR. A supplemental cohort of patients undergoing HRM and pH‐study was also prospectively enrolled in 13 high‐volume esophageal function laboratories across the world in order to validate the model. Discrimination and calibration were used to assess model's accuracy. Gastroesophageal reflux disease was defined as acid exposure time >6%. Out of the analyzed variables, SLR response and EGJ subtype 3 had the highest impact on the score (odd ratio 18.20 and 3.87, respectively). The external validation cohort consisted of 233 patients. In the validation model, the corrected Harrel c‐index was 0.90. The model‐fitting optimism adjusted calibration slope was 0.93 and the integrated calibration index was 0.07, indicating good calibration. A novel HRM score for GERD diagnosis has been created and validated. The MS might be a useful screening tool to stratify the risk and the severity of GERD, allowing a more comprehensive pathophysiologic assessment of the anti‐reflux barrier. ClinicalTrials.gov(Identifier: NCT05851482).

Nitrobindins (Nbs) are all-β-barrel heme proteins present along the evolutionary ladder. They display a highly solvent-exposed ferric heme group with the iron atom being coordinated by the proximal His residue and a water molecule at the distal position. Ferric nitrobindins (Nb(III)) play a role in the conversion of toxic peroxynitrite (ONOO–) to harmless nitrate, with the value of the second-order rate constant being similar to those of most heme proteins. The value of the second-order rate constant of Nbs increases as the pH decreases; this suggests that Nb(III) preferentially reacts with peroxynitrous acid (ONOOH), although ONOO–is more nucleophilic. In this work, we shed light on the molecular basis of the ONOO–and ONOOH reactivity of ferric Mycobacterium tuberculosisNb (Mt-Nb(III)) by dissecting the ligand migration toward the active site, the water molecule release, and the ligand binding process by computer simulations. Classical molecular dynamics simulations were performed by employing a steered molecular dynamics approach and the Jarzynski equality to obtain ligand migration free energy profiles for both ONOO–and ONOOH. Our results indicate that ONOO–and ONOOH migration is almost unhindered, consistent with the exposed metal center of Mt-Nb(III). To further analyze the ligand binding process, we computed potential energy profiles for the displacement of the Fe(III)-coordinated water molecule using a hybrid QM/MM scheme at the DFT level and a nudged elastic band approach. These results indicate that ONOO–exhibits a much larger barrier for ligand displacement than ONOOH, suggesting that water displacement is assisted by protonation of the leaving group by the incoming ONOOH.

Objective This study assesses the degree of root curvature in patients with non-syndromic cleft lip and/or palate (NSCL/P).Design Retrospective. Case-control study.Setting Root curvature was assessed in lower premolars and molars in 800 panoramic radiographs: 400 from patients with cleft and 400 from healthy control individuals. Root curvature was classified according to its angulation, as well as its apical, medial, or coronal localization.Results The frequency of mild curvature in the NSCL/P group compared to the control group was higher in premolars especially in the left second premolar in cleft palate (OR: 6.91; 95% CI: 3.23−14.77; P< .0001). The frequency of moderate curvature in molars was significantly higher in the cleft group, with the highest risk in the right first molar in the cleft lip group (OR: 2.74; 95% CI: 1.67−4.52; P< .0001). Inclination was more frequently observed in the apical third of the root in the group with cleft, whereas for the control group, the curvature was more frequent in the medial third. In patients with cleft, the OR of curvature in the apical third was significant in premolars (left lower second premolar: Cleft lip, OR: 1.91; 95% CI: 1.04−3.52; P= .03; right lower second premolar: Cleft lip, OR: 1.91, 95% CI: 1.04−3.50; P= .03, cleft lip and palate, OR: 1.75; 95% CI: 1.12−2.73; P= .01).Conclusion The results of the current study indicate differences in root curvature in patients with non-syndromic cleft lip and/or palate, which should be considered during the dental treatment planning of patients.

Flying ad-hoc networks (FANETs) are a powerful tool for inspecting safety-critical scenarios, including post-disaster areas or military fields, where they ensure prompt area monitoring and fast detection of events of interest. However, wide area deployment of FANETs requires fast and reliable communications among devices and their base station to ensure prompt intervention upon detection of anomalies. Existing long-range communication technologies are inadequate to meet the data rate requirements and delay constraints of safety-critical applications. Previous solutions to enable ad-hoc communications in mobile networks also fall short of exploiting the controllable mobility of FANETs. To face this challenge, we formulate the connected deployment problem, where we require the FANET to dynamically create connected coverage formations to ensure multi-hop low-latency communications while performing the monitoring task. We show that addressing the above problem under the joint requirement of maximizing event coverage is NP-hard. We propose a joint Task Management and Routing Algorithm called TaMaRA, a polynomial-time solution based on a two-phase approximation of the problem. By means of extensive simulations and real field experiments we show that our approach outperforms existing solutions in terms of monitoring accuracy and system responsiveness.

One of the most significant revisions to the ICH E6 GCP Guideline in the last 20 years was issued in November 2016, adopted by the EMA in December 2016 and by the FDA as a Guidance Document in March 2018. The new section on Quality Management requires the implementation of a systematic approach for managing risks throughout the course of a clinical study. The addendum also emphasizes appropriate sponsor oversight. Currently available risk management solutions are fairly elaborate, having been developed for and adopted mainly by larger companies. Small to medium size companies find these solutions too complex and not easily adaptable. In this paper, we present a simple but robust toolkit for clinical study risk management for small to medium sized organizations in order to facilitate compliance. The toolkit consists of customizable templates for the following: Clinical Risk Management SOP; Clinical Risk Management Plan; Vendor Oversight SOP; Vendor Oversight Plan; and Clinical Risk Log. The tools were prepared by the DIA GCP-QA Community members and presented at the 2018 DIA Annual Meeting in Boston.

Abstract: Purpose: To assess the additional value of multiplanar reformations (MPR) in comparison with axial images alone for location of the transition zone in CT of mechanical small-bowel obstruction (SBO). Materials and methods: Sixty-nine consecutive patients with mechanical SBO underwent 16-slice multi detector row CT (MDCT). The gold standard for the precise location of the transition zone was established by two experienced abdominal radiologists, unblinded to clinical and surgical reports, reviewing all CT examinations. On a workstation, two blinded readers independently located the transition zone using first axial slices alone and then 1 month later MPR (axial, coronal, sagittal and oblique views) according to a three-point confidence scale. Diagnostic accuracy and mean confidence score were evaluated for both the transverse and multiplanar data sets. Results: Accuracy of transition zone location for reader 1 and reader 2 was 86% and 84% with axial slices alone, and by using MPR 93% (significant: P = 0.03) and 90% (not significant: P = 0.08), respectively. Mean confidence score was significantly increased for both readers using MPR: 0.3 higher (P = 0.0001) and 0.37 higher (P = 0.0001) respectively. Conclusion: MPR can increase both accuracy and confidence in the location of the transition zone in CT of SBO.

Background: Conventional three-access laparoscopic appendectomy (CLA) is currently the gold standard treatment, however, Single-Port Laparoscopic Appendectomy (SILA) has been proposed as an alternative. The aim of this systematic review/meta-analysis was to evaluate safety and efficacy of SILA compared with conventional approach. Methods: Per PRISMA guidelines, we systematically reviewed randomised controlled trials (RCTs) comparing CLA vs SILA for acute appendicitis. The randomised Mantel–Haenszel method was used for the meta-analysis. Statistical data analysis was performed with the Review Manager software and the risk of bias was assessed with the Cochrane "Risk of Bias" assessment tool. Results: Twenty-one studies (RCTs) were selected (2646 patients). The operative time was significantly longer in the SILA group (MD = 7,32), confirmed in both paediatric (MD = 9,80), (Q= 1,47) and adult subgroups (MD = 5,92), (Q= 55,85). Overall postoperative morbidity was higher in patients who underwent SILA, but the result was not statistically significant. In SILA group were assessed shorter hospital stays, fewer wound infections and higher conversion rate, but the results were not statistically significant. Meta-analysis was not performed about cosmetics of skin scars and postoperative pain because different scales were used in each study. Conclusions: This analysis show that SILA, although associated with fewer postoperative wound infection, has a significantly longer operative time. Furthermore, the risk of postoperative general complications is still present. Further studies will be required to analyse outcomes related to postoperative pain and the cosmetics of the surgical scar.

Free-standing, 2D gold nanosheets (AuNS) offer broad potential applications from computing to biosensing and healthcare. Such applications, however, require improved control of material growth. We recently reported the synthesis of AuNS only ∼0.47 nm (two atoms) thick, which exhibited very high catalytic activity. The synthesis is a one-pot, seedless procedure in which chloroauric acid is reduced by sodium citrate in the presence of methyl orange (MO). In this study, we use spectrophotometric analysis and TEM imaging to probe AuNS formation and optimize the procedure. Previously, we suggested that MO acted as the confining agent, directing two-dimensional growth of the gold. Here, we provide the first reported analysis of the HAuCl4and MO reaction. We show that MO is rapidly oxidized to give 4-diazobenzenesulfonic acid, indicating that a complex interplay between HAuCl4, MO, and other reaction products leads to AuNS formation. Time-resolved studies indicate that synthesis time can be significantly reduced from over 12 to 2–3 h. Decreasing the reaction temperature from 20 to 4 °C improved AuNS yield by 16-fold, and the catalytic activity of the optimized material matches that obtained previously. Our elucidation of AuNS formation mechanisms has opened avenues to further improve and tune the synthesis, enhancing the potential applications of ultrathin AuNS.

Aerial drones are increasingly used to perform monitoring tasks in a large number of applications. Current solutions to trajectory planning rely on perfect knowledge of ongoing events requiring inspection. Nevertheless, in many scenarios the events’ time and position can only be estimated with some uncertainty. Unlike previous work, we consider critical scenarios where a squad of drones is required to autonomously inspect an area of interest under uncertainty of time and location of target events. The main goal of the squad is to ensure maximum coverage of event monitoring with minimum average inspection delay. With no initial knowledge, the drones share their local observations of the environment and apply the Parzen-Rosenblatt approach to manage a dynamic probabilistic map of ongoing events. This map is integrated into a virtual force approach for a joint solution to distributed dynamic trajectory planning and collision avoidance. Through extensive simulations and real-field experiments, we compare our proposal against AC-GAP, a state-of-art solution for UAVs, and Sweep, a sweep-based algorithm for multiple robots. We show that our proposal discovers new events 30-40$\%$% faster than the other algorithms, and outperforms them in terms of percentage of visited events and inspection delay, under a wide variety of scenarios.

Globular folded proteins are powerful building blocks to create biomaterials with mechanical robustness and inherent biological functionality. Here we explore their potential as advanced drug delivery scaffolds, by embedding microbubbles (MBs) within a photo-activated, chemically cross-linked bovine serum albumin (BSA) protein network. Using a combination of circular dichroism (CD), rheology, small angle neutron scattering (SANS) and microscopy we determine the nanoscale and mesoscale structure and mechanics of this novel multi-composite system. Optical and confocal microscopy confirms the presence of MBs within the protein hydrogel, their reduced diffusion and their effective rupture using ultrasound, a requirement for burst drug release. CD confirms that the inclusion of MBs does not impact the proportion of folded proteins within the cross-linked protein network. Rheological characterisation demonstrates that the mechanics of the BSA hydrogels is reduced in the presence of MBs. Furthermore, SANS reveals that embedding MBs in the protein hydrogel network results in a smaller number of clusters that are larger in size (∼16.6% reduction in number of clusters, 17.4% increase in cluster size). Taken together, we show that MBs can be successfully embedded within a folded protein network and ruptured upon application of ultrasound. The fundamental insight into the impact of embedded MBs in protein scaffolds at the nanoscale and mesoscale is important in the development of future platforms for targeted and controlled drug delivery applications.

Hereditary gingival fibromatosis (HGF) is an uncommon genetic condition characterized by slow but progressive fibrous, non‐hemorrhagic, and painless growth of the gingival tissues due to the increased deposition of collagen and other macromolecules of the extracellular matrix. HGF occurs in approximately 1:750,000 individuals and can exhibit dominant or recessive inheritance. To date, five loci(2p21‐p22, 2p22.3‐p23.3, 4q12, 5q13‐q22, and 11p15) and three genes [REST(RE1‐silencing transcription factor), SOS1(Son‐of‐Sevenless‐1), and ZNF862(zinc finger protein 862 gene)] have been associated with HGF. Here, our study aimed to identify genetic variants associated with HGF by applying whole‐exome sequencing (WES) and bioinformatics analyses. Thirteen Brazilian individuals with HGF and nine relatives without HGF from four unrelated families were chosen for our investigation. Blood collected from the patients and their relatives were used for WES. Five Web‐available tools, namely, CADD, PolyPhen, SIFT, Mutation Taster, and Franklin's algorithms, were used to predict protein damage. WES revealed pathogenic variants affecting the known HGF genes REST(c.1491_1492delAG) and SOS1(c.3265_3266insTAAC) in two families. Additionally, potentially pathogenic variants segregating in the other two families were mapped to ALK receptor tyrosine kinase gene (ALK) (c.361C > T) and to collagen type I receptor and thrombospondin receptor gene (CD36) (c.1133G > T). Our findings reinforce the high genetic heterogeneity of HGF, identifying new variants in HGF known genes (RESTand SOS1) and ALKand CD36as new genes that cause HGF.

ObjectiveTo determine how distinct combinations of resistance training prescription (RTx) variables (load, sets and frequency) affect muscle strength and hypertrophy.Data sourcesMEDLINE, Embase, Emcare, SPORTDiscus, CINAHL, and Web of Science were searched until February 2022.Eligibility criteriaRandomised trials that included healthy adults, compared at least 2 predefined conditions (non-exercise control (CTRL) and 12 RTx, differentiated by load, sets and/or weekly frequency), and reported muscle strength and/or hypertrophy were included.AnalysesSystematic review and Bayesian network meta-analysis methodology was used to compare RTxs and CTRL. Surface under the cumulative ranking curve values were used to rank conditions. Confidence was assessed with threshold analysis.ResultsThe strength network included 178 studies (n=5097; women=45%). The hypertrophy network included 119 studies (n=3364; women=47%). All RTxs were superior to CTRL for muscle strength and hypertrophy. Higher-load (>80% of single repetition maximum) prescriptions maximised strength gains, and all prescriptions comparably promoted muscle hypertrophy. While the calculated effects of many prescriptions were similar, higher-load, multiset, thrice-weekly training (standardised mean difference (95% credible interval); 1.60 (1.38 to 1.82) vs CTRL) was the highest-ranked RTx for strength, and higher-load, multiset, twice-weekly training (0.66 (0.47 to 0.85) vs CTRL) was the highest-ranked RTx for hypertrophy. Threshold analysis demonstrated these results were extremely robust.ConclusionAll RTx promoted strength and hypertrophy compared with no exercise. The highest-ranked prescriptions for strength involved higher loads, whereas the highest-ranked prescriptions for hypertrophy included multiple sets.PROSPERO registration numberCRD42021259663 and CRD42021258902.

Lipid-shelled nanobubbles (NBs) are emerging as potential dual diagnostic and therapeutic agents. Similar to their micron-scale counterparts, microbubbles (1–10 μm), they can act as ultrasound contrast agents as well as locally enhance therapeutic uptake. Recently, it has been shown that the reduced size of NBs (<1 μm) promotes increased uptake and accumulation in tumor interstitial space, which can enhance their diagnostic and therapeutic performance. However, accurate characterization of NB size and concentration is challenging and may limit their translation into clinical use. Their submicron nature limits accuracy of conventional microscopy techniques, while common light scattering techniques fail to distinguish between subpopulations present in NB samples (i.e., bubbles and liposomes). Due to the difficulty in the characterization of NBs, relatively little is known about the influence of size on their therapeutic performance. In this study, we describe a novel method of using a commercially available nanoparticle tracking analysis system, to distinguish between NBs and liposomes based on their differing optical properties. We used this technique to characterize three NB populations of varying size, isolated via centrifugation, and subsequently used this to assess their potential for enhancing localized delivery. Confocal fluorescence microscopy and image analysis were used to quantify the ultrasound enhanced uptake of fluorescent dextran into live colorectal cancer cells. Our results showed that the amount of localized uptake did not follow the expected trends, in which larger NB populations out-perform smaller NBs, at matched concentration. To understand this observed behavior, the stability of each NB population was assessed. It was found that dilution of the NB samples from their stock concentration influences their stability, and it is hypothesized that both the total free lipid and interbubble distance play a role in NB lifetime, in agreement with previously proposed theories and models.

The sinoatrial node (SAN) of the heart produces rhythmic action potentials, generated via calcium signaling within and among pacemaker cells. Our previous work has described the SAN as composed of a hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4)-expressing pacemaker cell meshwork, which merges with a network of connexin 43+/F-actin+cells. It is also known that sympathetic and parasympathetic innervation create an autonomic plexus in the SAN that modulates heart rate and rhythm. However, the anatomical details of the interaction of this plexus with the pacemaker cell meshwork have yet to be described.

Purpose: This study assesses the potential impact of the European Income Stabilization Tool (IST – a whole farm income risk management [RM] tool) within a farm cooperative specializing in vineyards and operating in a small area of production. The authors assess the conditions under which IST could improve the well-being of the associated farmers and, at the same time, improve financial sustainability. Financial aspects are of particular relevance since the characteristics of the cooperative cause the management of the tool to become potentially risky. Design/methodology/approach: The analysis relies on a balanced panel dataset to report the production and economic characteristics of individual associated farms. This is the basis for simulating the implementation of the IST as described in the current European regulation. The expected utility approach is then used to assess the potential impact on farmers' well-being under different levels of risk aversion and premiums. The analysis of the IST annual cash flow allows for an accurate assessment of its financial sustainability. Findings: The results suggest that the IST can improve farmers' well-being under plausible levels of risk aversion and premiums, making most farmers willing to support its implementation. Furthermore, the tool could be financially sustainable even if implemented in a specialized and geographically concentrated group of farms. In addition, the results suggest that the use of strategies such as the IST could help cope with negative annual balances by treating the financial sustainability of the fund. Originality/value: The analysis adds to previous research on the IST by accounting for farmers' risk aversion. Furthermore, it is the first analysis that simulates the implementation of this tool in a sector-specific and concentrated group of farms. The results provide useful evidence for those subjects planning to implement the IST in small and specialized farming systems.

Flexible and biocompatible adhesives with sensing capabilities can be integrated onto human body and organ surfaces, characterized by complex geometries, thus having the potential to sense their physiological stimuli offering monitoring and diagnosis of a wide spectrum of diseases. The challenges in this innovative field are the following: (i) the coupling method between the smart adhesive and the soft human substrates, (ii) the bioresorbable behavior of the material, and (iii) the electrical exchange with the substrate. Here, we introduce a multifunctional composite by mixing silk fibroin, featuring piezoelectric properties, with a soluble plant-derived polyphenol (i.e., chestnut tannin) modified with graphene nanoplatelets. This material behaves as a glue on different substrates and gives rise to high elongation at break, conformability, and adhesive performances to gastrointestinal tissues in a rat model and favors the printability viaextrusion-based 3D printing. Exploiting these properties, we designed a bioresorbable 3D printed flexible and self-adhesive piezoelectric device that senses the motility once applied onto a phantom intestine and the hand gesture by signal translation. Experimental results also include the biocompatibility study using gastrointestinal cells. These findings could have applicability in animal model studies, and, thanks to the bioresorbable behavior of the materials, such an adhesive device could be used for monitoring the motility of the gastrointestinal tract and for the diagnosis of motility disorders.

Nanomedicines, while having been approved for cancer therapy, present many challenges such as low stability, rapid clearance, and nonspecificity leading to off-target toxicity. Cubosomes are porous lyotropic liquid crystalline nanoparticles that have shown great premise as drug delivery vehicles; however, their behavior in vivois largely underexplored, hindering clinical translation. Here, we have engineered cubosomes based on the space group Im3mthat are loaded with copper acetylacetonate as a model drug, and their surfaces are functionalized for the first time with Affimer proteins via copper-free click chemistry to actively target overexpressed carcinoembryonic antigens on LS174T colorectal cancer cells. Unlike nontargeted cubosomes, Affimer tagged cubosomes showed preferential accumulation in cancer cells compared to normal cells not only in vitro(2D monolayer cell culture and 3D spheroid models) but also in vivoin colorectal cancer mouse xenografts, while exhibiting low nonspecific absorption and toxicity in other vital organs. Cancerous spheroids had maximum cell death compared to noncancerous cells upon targeted delivery. Xenografts subjected to targeted drug-loaded cubosomes showed a 5–7-fold higher drug accumulation in the tumor tissue compared to the liver, kidneys, and other vital organs, a significant decrease in tumor growth, and an increased survival rate compared to the nontargeted group. This work encompasses the first thorough preclinical investigation of Affimer targeted cubosomes as a cancer therapeutic.

We present the characterization of the CTAB-oleate controlled synthesis of gold nanorods (AuNRs). Concentrations of key compounds in the synthetic system were varied in the presence of oleate, including HCl, borohydride, silver nitrate, and ascorbic acid. The longitudinal surface plasmon resonance peak was sensitive to changes in all concentrations. Reducing the concentration of Ag ions below 66 μM led to slower reaction kinetics and incomplete Au reduction. Variation of the ascorbic acid concentration revealed that oleate is responsible for around 44% of reduction of Au3+to Au+before nucleation in these experiments. Increasing the oleate concentration significantly slows the growth kinetics and leads to much longer synthesis times of above 12 h for reaction completion. These observations will enable the design of better methods of synthesizing of AuNRs using binary surfactants.

Surveys on Serial Transverse Enteroplasty (STEP) published in international literature (1 January 2003– 31 May 2021) were searched. Articles were included from 17 countries: 1/23 comparative and 22/23 cohort studies. STEP was performed on 308 patients: pediatrics, adults, and mixed ages. Pediatric group included 16 studies and the adult 6. Pre-STEP residual small bowell (SB) length for pediatrics and adults ranged from 18 to 26 cm and from 30 to 70 cm, respectively. Post-STEP increased SB length for pediatrics and adults ranged between 42 and 100% and 50% and 176%, respectively. For pediatrics, enteral autonomy was reached in 32.22% of cases, parenteral nutrition (PN) dependence was 36.11%, a repeated STEP procedure (Re-STEP) was needed in 17.22%, and a bowel transplant was performed in 6.11%. In adults, enteral autonomy was achieved in 52.38%, while PN dependence was 37.1%, and no Re-STEP or transplantation were required. For the mixed group, post-STEP bowel length increased from 2 to 50 cm, enteral autonomy was obtained in 43%, PN dependence was 57%, without reported Re-STEP or transplantation. Mortality rates were between 5.55% (pediatric) and 7.14% (adults). Preoperative length with preservation of ileocecal valve represented the main predictive factors to achieve enteral autonomy.

In this study, regenerated silk (RS) obtained from Bombyx Moricocoons is compounded with carboxyl-functionalized carbon nanotubes (f-CNTs) in an aqueous environment for the fabrication of functional bio-adhesives. Molecular interactions between RS and carboxyl groups of CNTs result in structural increase of the β-sheet formation, obtaining a resistant adhesive suitable for a wet biological substrate. Moreover, the functionalization of CNTs promotes their dispersion in RS, thus enabling the production of films with controlled electrical conductivity. The practical utility of such a property is demonstrated through the fabrication of a piezoelectric device implanted in a rat to monitor the breathing in vivo and to be used as a self-powered system. Finally, RS/f-CNTs were used as a printable biomaterial ink to three dimensionally print bilayer hollow tubular structures composed of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and RS. Initial tests carried out by seeding and growing human skin fibroblasts demonstrated that the 3D printed bilayer hollow cylindrical structures offer a suitable surface for the seeded cells to attach and proliferate. In general, the herein proposed RS/f-CNT composite serves as a versatile material for solvent-free dispersion processing and 3D printing, thus paving a new approach to prepare multifunctional materials with potential applications of great interest in sealing biological substrates and implantable devices for regenerative medicine.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute non atherothrombotic coronary syndrome. It predominantly affects female sex. Both diagnosis and therapeutic decision–making are challenging due to its unpredictable course and recurrence rate. We describe a case of a 50y old man with chest pain(CP), referred to our cathlab for primary percutaneous coronary intervention(PCI) through the Emergency Medical Service, with an anterior ST–segment elevation myocardial infarction(STEMI) detected on ECG. A type 2b SCAD starting from the Left Main(LM) involving proximal Left Anterior Descending (LAD) artery and circumflex artery(Cx) was detected. PCI with Drug–Eluting Stent(DES) implantation on LM and proximal LAD was deemed necessary due to ongoing ischemia and LM involvement. IntraVascular UltraSound(IVUS) on LAD and LM showed good stent deployment and confirmed a non–obstructive SCAD of Cx,left untreated. Patient was started with dual antiplatelet therapy and after 5 days in our cardiac intensive care unit(ICU) he was moved to cardiology unit. Few hours later he had recurrence of CP and an Inferior STEMI was detected. A progression of SCAD of the Cx with critical flow limitation in its proximal tract was found at coronary angiography. Then PCI with DES release was performed using a T and Small Protrusion technique on LM–LAD–Cx and cutting–balloon was used to fenestrate intima with a successful drainage of the intramural hematoma (IH) in the distal portion. Our case represents an uncommon presentation of SCAD, as STEMI involving a male patient. In a recent large cohort of SCAD patients only 10% were men. Male SCAD patients are younger, have less frequently prior MI, depression, emotional stress triggers and are less likely to have associated fibromuscular dysplasia. More often they report physical stress triggers and a more subtle clinical presentation. Conservative management remains the mainstay of treatment in the absence of ongoing ischemia, hemodynamic instability, or LM involvement. When PCI is indicated, it is often associated with an unfavorable course (difficult wiring of the lesion, propagation, and potential milking of the IH along the vessel).Cutting balloon technique has been increasingly used in the interventional approach to SCAD. Several questions remain unanswered about appropriate antithrombotic regimen, duration of ICU observation and the opportunity to perform coronary imaging to review the disease prior to a safe discharge.

As the burden of allergic and immunologic disease continues to increase, there is increased demand for a larger Allergy and Immunology (AI) subspecialty workforce. The field must prioritize the expansion of our workforce and the recruitment of exceptional and diverse trainees to ensure the vitality of the specialty. Although the AI fellowship match has traditionally been competitive, recent trends in fellowship applications have demonstrated fewer applicants per fellowship position. This trend has made recruitment a priority on the agenda of the national AI societies.

Aim: Nonsyndromic cleft lip and/or palate (NSCL ± P) is the most common craniofacial birth defect. This study aims to determine demographic characteristics and the epidemiologic profile of NSCL ± P in Bahia, Brazil. Subject and methods: 692 patients of three Cleft Lip and Palate Treatment Centers were interviewed. Results: Cleft lip and palate (CLP) was the most frequent type of oral cleft (52.8%), particularly unilateral (34.8%) and affecting the left side (p&lt; 0.001). Family history of cleft was found in 27.6%, especially between cousins (49.7%; p&lt; 0.001). The Salvador metropolitan area represented 45.2% of the samples, followed by Mid-South (17.7%) and Mid-North Bahia (13.9%). In the South of the state, the risk of developing CL and CLP was statistically significant (p= 0.03; p= 0.006, respectively), and in the region of Vale do São Francisco there was a significant risk of developing CLP (p= 0.01), both in relation to CP. Young age and alcohol use in pregnancy were associated to giving birth to children with CLP (p= 0.02, p= 0.03, respectively). The use of folate and other vitamins diminished the risk of developing CL and CLP if compared to CP (p= 0.009). Conclusion: It is hoped that the results of this research may be useful in planning actions of public service that should take care of affected individuals.

In the last decade's robotic gastrectomy (RG) has increasingly widespread as a valid minimally invasive option for treatment of gastric cancer. In literature, evidence of its routine use is not yet well established. The aims of this study are to report our initial experience and to present possible advantages of our hybrid operative technique for subtotal gastrectomy.

The growing trend in biodegradable and renewable materials has generated a demand for new food packaging applications. This study aimed to produce active cellulose-based papers incorporated with two different essential oil isolated active compounds, eugenol, and linalool, to promote the inhibition of pathogenic bacteria's growth. Cellulose was extracted from eucalyptus sawdust by receiving chemical and mechanical treatment and incorporating the active compounds by microwave. FTIR, SEM, TGA, DSC, and antibacterial activity against E. coli, Salmonella,S. aureus, and L. monocytogenescharacterized active papers prepared by casting. Cellulose–eugenol papers showed chemical interactions by hydrogen bonding, in concern to linalool paper bands, identified by FTIR results. Highlighting that after the active compound's addition, the hydrogen energy bond values decreased from 22.5 to 22.3 kJ mol−1, confirming the cellulose fibers' swelling with the oils, which slightly amorphized the papers. The active compounds changed the paper's morphology, increasing porosity and roughness, as seen in the SEM images. Besides, TGA indicated that the active compounds increased the papers' thermal resistance. The active papers exhibited excellent antimicrobial activity against all the microorganisms; the cellulose–eugenol papers demonstrated a more significant antibacterial effect (24 mm), with a larger inhibition zone than linalool paper (12 mm). These results revealed that cellulose-based papers containing eugenol or linalool have good potential to prepare antimicrobial edible papers or coatings for various types of food packaging applications.

AbstractThis short communication aimed to develop a fast and straightforward method for the simultaneous discrimination in buffaloes of the alleles CSN1S1A/B and CSN3X1/X2 using a single protocol. DNA was isolated from 219 individual blood samples. A duplex artificially created restriction site (ACRS-PCR) was accomplished using two pairs of primers generating 86 bp (CSN1S1) and 160 bp (CSN3). Amplicons were contemporary digested by MboI and HinfI for the identification of genotypes.The double simultaneous amplification and digestion proved to be effective for allele identification. The method resulted particularly quick due to the small PCR amplicons and fast digest enzymes that allowed both a rapid amplification (about 1 h and 40 min) and digestion in 10 min. Population analysis indicated that minor allele frequencies were CSN1S1A (0.425) and CSN3X2 (0.306). Linkage disequilibrium (LD) showed r2=0.46, and haplotype analysis revealed all four possible combinations with higher frequency for the CSN1S1B-CSN3X1 (0.553). Considering the tremendous economic impact of the CSN1S1–CSN3variants on the dairy production in buffalo, this method, applicable immediately after the birth from any DNA source, may speed up the selection of sires and dams’ lines with more favourable genotypes.HighlightsCSN1S1–CSN3composite genotype influences dairy performances.Duplex ACRS-PCR identifies the CSN1S1–CSN3composite genotype in a single protocol.The duplex ACRS-PCR method may speed up the selection of lines with more favourable genotypes.

Forest fragmentation is the main cause of biodiversity loss in the Anthropocene and it is triggering a top-down cascade effect that may influence leaf litter decomposition. However, the link between biodiversity loss and changes in ecosystem processes is not fully understood. We conducted an experiment to evaluate whether the exclusion of vertebrates affects the decomposition rates of different litter types (grass, a pioneer species and a mix of litters from a well preserved secondary forest). To answer this question, we placed litter bags inside artificial exclusion plots that were built in two types of vegetation coverage (abandoned pastureland and preserved forest) in the Atlantic forest of southeast Brazil. Our hypothesis is that vertebrate exclusion will change decomposition rates of different litter types due to the top-down cascade effect on soil invertebrates. We found out that vertebrate exclusion did not affect decomposition rates, possibly due to the overlap of ecological functions in the soil fauna responsible for the decomposition process. Furthermore, grass litter was decomposed faster (k value), possibly due to its initial nutrient content and hence litter quality which plays a significant role on decomposition rates.

Background: Long chain omega-3 polyunsaturated fatty acids (ω-3PUFA) supplementation in animal models of diet-induced obesity has consistently shown to improve insulin sensitivity. The same is not always reported in human studies with insulin resistant (IR) subjects with obesity. Objective: We studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in IR subjects with obesity. Methods: Thirteen subjects (BMI = 39.3 ± 1.6 kg/m2) underwent 80 mU/m2·min euglycemic-hyperinsulinemic clamp with subcutaneous (Sc) AT biopsy before and after 3 months of ω-3PUFA (DHA and EPA, 4 g/daily) supplementation. Cytoadipokine plasma profiles were assessed before and after ω-3PUFA. AT-specific inflammatory gene expression was evaluated on Sc fat biopsies. Microarray analysis was performed on the fat biopsies collected during the program. Results: Palmitic and stearic acid plasma levels were significantly reduced (P&lt; 0.05) after ω-3PUFA. Gene expression of pro-inflammatory markers and adipokines were improved after ω-3PUFA (P&lt; 0.05). Systemic inflammation was decreased after ω-3PUFA, as shown by cytokine assessment (P&lt; 0.05). These changes were associated with a 25% increase in insulin-stimulated glucose disposal (4.7 ± 0.6 mg/kg ffm•min vs. 5.9 ± 0.9 mg/kg ffm•min) despite no change in body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with Apolipoprotein E (APOE) being one of the most upregulated genes. Conclusion: High dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT, and systemic inflammation. These findings are associated with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as among the most differentially regulated gene after ω-3PUFA supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.

Purpose: Adopting a Mediterranean-like dietary pattern may help in preventing several chronic diseases. We assessed the eating behaviour and compliance with the Mediterranean diet pyramid recommendations in Italy. Methods: This is a cross-sectional study conducted in subjects aged ≥ 20 years. A 14-question survey based on the updated Mediterranean diet pyramid was launched online from April 2015 to November 2016. At test completion, a personalized pyramid displaying the possible deficiencies and/or excesses was generated, that could be the basis to plan diet and lifestyle modifications. Results: Overall, 27,540 subjects completed the survey: the proportion of females (75.6%), younger subjects (20.7%) and people with a University degree (33.1%) resembled those of the Italian population of Internet users rather than of the general population. 37.8% of participants declared a sedentary lifestyle, including 29.6% of those aged 20–29 years. A lower-than-recommended intake of all food categories included in the Mediterranean diet pyramid, along with excess of sweets, red and processed meats, emerged, that may affect health in the long term. Low adherence to recommendations was observed especially among females and older people. Notably, a discrepancy surfaced between the responders’ perceived and actual behaviour toward the regular consumption of fruits and vegetables (81.8% vs 22.7–32.8%, respectively). Conclusions: The nutritional habits and lifestyle of Italian participants are poorly adherent to the Mediterranean diet recommendations. The personalized pyramid tool may help in raising the awareness of individuals and their families on where to intervene, possibly with the support of healthcare professionals, to improve their behaviour. Level of evidence: Level V, cross-sectional descriptive study.

Purpose: Previous studies have demonstrated handwriting changes in patients with overt hyperthyroidism due to Graves’ disease. The aim of the present study was to investigate handwriting features in patients affected by overt autoimmune hypothyroidism. Methods: Thirty subjects – 24 females and 6 males, mean and median age of 50.15?±?16.8 years and 52.5 years, respectively – with overt hypothyroidism (OH) related to Hashimoto’s thyroiditis (Group 1), and 30 age- and sex-matched euthyroid individuals (Group 2) were recruited to write a “standard text”. Group 1patients repeated the text once the euthyroid state was reached on L-T4 substitution therapy. Group 2subjects wrote the text again 1 to 4 weeks thereafter. The letters underwent a detailed analysis by a handwriting expert, through inspection, a stereoscopic microscope and a magnifying glass. Furthermore, the time that both Groups took to go through with the text was clocked. Results: None of the handwriting variables differed significantly within each Group and between the two Groups. Hypothyroid patients took significantly more time to go through with the text compared to the time taken once they became euthyroid (3.29?±?1.66 vs 2.63?±?1.55 minutes, respectively) and the time taken by the control group (p?&lt;?0.01). Of note, three Group 1patients missed to copy some words or even whole sentences on the paper while they were overtly hypothyroid. Conclusions: The present study demonstrates that handwriting speed is able to disclose the impact of thyroid hormone deficiency on the central nervous system's functions. In particular, the longer time taken to go through with the text and the sentences missed by some hypothyroid patients, are the counterpart of psychomotor slowdown, impaired attention and memory loss peculiar to OH.

Supplemental Digital Content is available in the text.

Functionally significant coronary lesions identification is necessary for appropriate revascularization. This review aims to provide an overview of the available options for coronary stenosis physiologic evaluation with a focus on the latest developments in the field.

Splenic artery aneurysms (SAAs) are the most frequent visceral aneurysms, with a life-threatening risk in case of rupture. Our systematic review investigated the features of minimally invasive surgical approaches in vascular surgery for SAAs: robotic surgery and laparoscopy.

AbstractThe paper analyzes how the betas of real estate investment trusts (REITs) evolved over the period January 1997 to December 2014 using a hybrid betamodel, which shrinks rolling window estimates toward firm-specifics based on prior economic theory. Then, we compare the hybrid beta estimates to those obtained with the most common models used in practice, the CAPM and the Three-Factor model developed by Fama and French, to determine which is the most reliable tool to estimate risk factors for REITs as a particular type of industry. The results indicate that the hybrid beta model is superior to the the CAPM and Three-Factor models in estimating betas for the research sample of Equity REITs we observed over the considered period. This conclusion is based on a non-parametric test comparing the R2from the regressions of each model. Moreover, the annual evolution of the risk loadings obtained using the hybrid beta model seems to be more reasonable given both the specific characteristics of REITs and the impact of the world financial crises that occurred in 2008.

This study sought to identify subcellular Ca2+signals within and among cells comprising the sinoatrial node (SAN) tissue.

Because of their size (1–10 μm), microbubble-based drug delivery agents suffer from confinement to the vasculature, limiting tumor penetration and potentially reducing the drug efficacy. Nanobubbles (NBs) have emerged as promising candidates for ultrasound-triggered drug delivery because of their small size, allowing drug delivery complexes to take advantage of the enhanced permeability and retention effect. In this study, we describe a simple method for production of nested-nanobubbles (Nested-NBs) by encapsulation of NBs (∼100 nm) within drug-loaded liposomes. This method combines the efficient and well-established drug-loading capabilities of liposomes while utilizing NBs as an acoustic trigger for drug release. Encapsulation was characterized using transmission electron microscopy with an encapsulation efficiency of 22 ± 2%. Nested-NBs demonstrated echogenicity using diagnostic B-mode imaging, and acoustic emissions were monitored during high-intensity focused ultrasound (HIFU) in addition to monitoring of model drug release. Results showed that although the encapsulated NBs were destroyed by pulsed HIFU [peak negative pressure (PNP) 1.54–4.83 MPa], signified by loss of echogenicity and detection of inertial cavitation, no model drug release was observed. Changing modality to continuous wave (CW) HIFU produced release across a range of PNPs (2.01–3.90 MPa), likely because of a synergistic effect of mechanical and increased thermal stimuli. Because of this, we predict that our NBs contain a mixed population of both gaseous and liquid core particles, which upon CW HIFU undergo rapid phase conversion, triggering liposomal drug release. This hypothesis was investigated using previously described models to predict the existence of droplets and their phase change potential and the ability of this phase change to induce liposomal drug release.

Aggressive periodontitis (AgP), currently periodontitis grade C, presents early onset, rapid progression, and a poorly established genetic association. Thus, this study aimed to identify genetic variants associated with AgP via whole exome sequencing (WES) through a familial screening approach. WES was performed in two nuclear families, including a proband and a parent affected by AgP and an unaffected parent and sibling. Common variants among affected individuals, excluding those common to healthy people, from each family, composed the data set associated with AgP. In silico analysis evaluated the impact of each variant on protein structure and protein‐protein interactions. Moreover, identified deleterious variants were validated in a populational analysis (n= 96). The missense single nucleotide variations (SNVs) rs142548867 in EEFSEC(c.668C>T), rs574301770 in ZNF136(c.466C>G), and rs72821893 in KRT25(c.800G>A) and the frameshift indels rs37146475 in GPRC6A(c.2323‐2324insT) and c.1366_1372insGGAGCAG in ELNwere identified in AgP and have a predicted functional impact on proteins. In silico analysis indicated that the indel in GPRC6Agenerates a loss of the C‐terminal tail of the Gprca protein. Furthermore, this SNV was significantly associated with AgP in a population‐based investigation. Novel frameshift variation in GPRC6A(c.2323‐2324insT) was identified as a potential genetic alteration associated with AgP occurrence.