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ABSTRACT: The objective of this study was to determine the potential effect and interaction of 3-nitrooxypropanol (3-NOP; Bovaer, DSM-Firmenich Nutrition Products Ltd.) and whole cottonseed (WCS) on lactational performance and enteric methane (CH4) emission of dairy cows. A total of 16 multiparous cows, including 8 Holstein Friesian (HF) and 8 Brown Swiss (BS; 224 ± 36 DIM, 26 ± 3.7 kg milk yield, mean ± SD), were used in a split-plot design, where the main plot was the breed of cows. Within each subplot, cows were randomly assigned to a treatment sequence in a replicated 4 × 4 Latin square design with 2 × 2 factorial arrangements of treatments with four 24-d periods. The experimental treatments were as follows: (1) control (basal TMR), (2) 3-NOP (60 mg/kg TMR DM), (3) WCS (5% TMR DM), and (4) 3-NOP + WCS. The treatment diets were balanced for ether extract, crude protein, and NDF contents (4%, 16%, and 43% of TMR DM, respectively). The basal diets were fed twice daily at 0800 and 1800 h. Dry matter intake and milk yield were measured daily, and enteric gas emissions were measured (using the GreenFeed System, C-Lock Inc.) during the last 3 d of each 24-d experimental period when animals were housed in tiestalls. There was no difference in DMI on treatment level, whereas the WCS treatment increased ECM yield and milk fat yield. No interaction of 3-NOP and WCS occurred for any of the enteric gas emission parameters, but 3-NOP decreased CH4 production (g/d), CH4 yield (g/kg DMI), and CH4 intensity (g/kg ECM) by 13%, 14%, and 13%, respectively. Further, an unexpected interaction of breed by 3-NOP was observed for different enteric CH4 emission metrics: HF cows had a greater CH4 mitigation effect compared with BS cows for CH4 production (g/d; 18% vs. 8%), CH4 intensity (g/kg milk yield; 19% vs. 3%), and CH4 intensity (g/kg ECM; 19% vs. 4%). Hydrogen production was increased by 2.85-fold in HF and 1.53-fold in BS cows receiving 3-NOP. Further, a 3-NOP × time interaction occurred for both breeds. In BS cows, 3-NOP tended to reduce CH4 production by 18% at approximately 4 h after morning feeding, but no effect was observed at other time points. In HF cows, the greatest mitigation effect of 3-NOP (29.6%) was observed immediately after morning feeding, and it persisted at around 23% to 26% for 10 h until the second feed provision, and 3 h thereafter, in the evening. In conclusion, supplementing 3-NOP at 60 mg/kg DM to a high-fiber diet resulted in 18% to 19% reduction in enteric CH4 emission in Swiss HF cows. The lower response to 3-NOP by BS cows was unexpected and has not been observed in other studies. These results should be interpreted with caution due to the low number of cows per breed. Finally, supplementing WCS at 5% of DM improved ECM and milk fat yield but did not enhance the CH4 inhibition effect of 3-NOP of dairy cows.

Abstract Introduction Infective endocarditis is a rare but potentially severe disease, associated with significant morbidity and mortality. Our study aims to describe the epidemiology and management aspects of endocarditis in northern Morocco and compare it with international management guidelines. Materials and Methods This is a retrospective study involving all patients hospitalized in the cardiology department of the University Hospital of Tangier for infective endocarditis over a period of 4 years and 7 months, from May 2019 to February 2024. Results Eighty patients were hospitalized for IE during the study period. The average age of the patients was 46 years, with an even sex ratio. IE concerned native valves in 77% of cases, mechanical prostheses in 19% of cases, and on bio prostheses in 4%. The average diagnostic delay was 25 days. Blood cultures were negative in 59% of cases. The predominant infective microorganism was the bacteria Staphylococcus (65.6%). Imaging results showed vegetations in 76.3% of cases, predominantly on the mitral valve (39.3%), followed by the aortic valve (21.3%). The main complications included heart failure (51.2%), peripheral arterial embolisms (22.5%) and splenic infarction (17.5%). Management wise, the most commonly used antibiotic therapy was a combination of ceftriaxone and gentamicin. Clinical and biological improvement was observed in 70% of cases, with a mortality rate of 12.5%. Twelve patients underwent surgery (15%). Urgent surgery was indicated in 66,7% of the operated patients. Conclusion Our study highlights the challenges in managing infective endocarditis in northern Morocco. The prognosis of infective endocarditis can be improved through multidisciplinary management within the implementation of an Endocarditis Team.

Methane (CH4) hydroxylation into methanol (MeOH) by methanotrophic bacteria is an attractive and sustainable approach to producing MeOH. The model strain Methylosinus trichosporium OB3b has been reported to be an efficient hydroxylating biocatalyst. Previous works have shown that regardless of the bioreactor design or operation mode, MeOH concentration reaches a threshold after a few hours, but there are no investigations into the reasons behind this phenomenon. The present work entails monitoring both MeOH and formate concentrations during CH4 hydroxylation, where neither a gaseous substrate nor nutrient shortage was evidenced. Under the assayed reaction conditions, bacterial stress was shown to occur, but methanol was not responsible for this. Formate addition was necessary to start MeOH production. Nuclear magnetic resonance analyses with 13C-formate proved that the formate was instrumental in regenerating NADH; formate was exhausted during the reaction, but increased quantities of formate were unable to prevent MeOH production stop. The formate mass balance showed that the formate-to-methanol yield was around 50%, suggesting a cell regulation phenomenon. Hence, this study presents the possible physiological causes that need to be investigated further. Finally, to the best of our knowledge, this study shows that the reaction can be achieved in the native bacterial culture (i.e., culture medium containing added methanol dehydrogenase inhibitors) by avoiding the centrifugation steps while limiting the hands-on time and water consumption.

BackgroundAbout 10–20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.MethodsWe conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.ResultsPancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.ConclusionDonor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

Statement of the Problem: Salivary gland tumors represent about 3% of the head and neck tumors. Pleomorphic adenoma (PA) is the most common benign salivary gland tumor.Purpose: This study was conducted to investigate and describe some clinical and histopathological aspects of salivary pleomorphic adenomas with special reference to the epithelial and mesenchymal components.Materials and Method: One hundred tissue samples diagnosed as PA were sourced from archival tissue blocks between 2009 and 2019 in this retrospective study. Some clinical and demographic features, including age, sex, tumor size, and tumor location were recorded. This study included only samples taken by excisional biopsy. Then, the samples were histologically classified into three subtypes according to the proportion of epithelial and stromal components. The demographic and clinicopathological variables were statistically analyzed using Chi-square test or Fisher’s exact test, considering a significance level of 5% (p< .05).Results: In the present study, most cases (61%) were found in females, representing a female–male ratio of 1.6:1. The peak incidence was seen in the 4th and 5th decades of life. In 87% of cases, PA occurred in major salivary glands. There was a significant difference between the age of the patient and squamous metaplasia (p= 0.036). There was also a significant difference between the size of tumor and the amount of myxoid stroma (p= 0.021). Extensive myxoid stroma was mostly seen in tumors larger than 3.37cm (p= 0.001). In addition, there was a statistically significant difference between capsular invasion and the development of squamous metaplasia (p= 0.001).Conclusion: In this study, there was a significant correlation between the gland type and capsular features and between the size of tumor and rate of squamous metaplasia. A detailed clinical and histopathological analysis of PAs may provide a better insight to the pathophysiology of the lesion, tumor cell differentiation, and prognostic factors.

Stenotrophomonas maltophilia has been demonstrated herein to reduce CO2 without any cofactor, photon or hydrogen (H2) addition during reaction. S. maltophilia reduces 13CO2 into 13C-labeled formate in batch mode. Two intracellular enzymes are curently being considered for their ability to catalyze the CO2 reduction reaction: a Fe-nitrogenase and a formate dehydrogenase (FeS-FDH). The reaction was intensified by implementing the bacteria in an electrolysis cell continuously fed with CO2. In this configuration, CO2 removal reached up to 25% v/v at 30°C and atmospheric pressure.

Abstract Data on using the 21-gene Recurrence Score (RS) testing on second breast cancer (BC; second primary or local recurrence) are lacking. This cohort study examined patients with first and second BC, who underwent 21-gene testing both times. It included a ‘study-cohort’ (60 N0/N1mi/N1 ER + HER2‒ BC patients with ≥2 RS results >1 year apart) and a ‘general 21-gene-tested BC-cohort’ (2044 previously described N0/N1mi/N1 patients). The median time between the first and second BC was 5.2 (IQR, 3.1–7.1) years; the second BC was ipsilateral in 68%. Patient/tumor characteristics of the first- and second-BC in the ‘study-cohort’ were similar, except for the RS which was higher in the second BC (median [IQR]: 23 [17–30] vs 17 [14–22], p

Statement of the Problem: Enamel organ (EO) is an ectodermal derived structure, which is involved in the different aspects of tooth development. Tooth development shares the same regulatory molecules and genes expressed in other developing organs. Endothelin- 1 (ET-1) and Endothelin A receptor (ETAR), (ET-1/ETAR) axis, are involved in differentiation of embryonic stem cells and organ development.Purpose: The present study aimed to investigate the ET-1 and ETAR expression profiles during the development of human primary tooth EO with the relatively large sample size.Materials and Method: In this experimental study, 33 human fetuses aged from 13 to 23 weeks (3 samples from each fetal age) were collected. The samples were divided into three age groups (

Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.

Background: Tooth development involves reciprocal interactions between the oral epithelium and ectomesenchyme. The inner layer cells of the enamel organ (EO), known as the inner enamel epithelium (IEE), undergo differentiation into preameloblasts and subsequently mature ameloblasts. These ameloblasts play a crucial role in the secretion of enamel matrix proteins, including amelogenin. This experimental study aimed to analyze the expression profile of amelogenin in various histological structures of human primary developing teeth, employing a relatively large sample size. Methods: This experimental study included 33 human fetuses aged between 13 and 23 weeks, with three samples obtained from each gestational age. The samples were categorized into three age groups of ≥13 and

Abstract Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan–Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4–99.2%) vs 97.9% (94.6–99.2%); DRFS, 91.5% (86.6–94.7%) vs 91.2% (86.0–94.6%); BCSM, 0.5% (0.1–3.7%) vs 1.6% (0.5–4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2–8.6%] vs 6.2% [2.0–17.7%] for CT-treated and untreated patients, respectively, p = 0.024).

Abstract Background Clear-cell renal cell carcinomas (ccRCCs) are malignant tumors with high metastatic potential and resistance to treatments occurs almost constantly. Compared to primary tumors, there are still limited genomic data that has been obtained from metastatic samples. Methods We aimed to characterize metastatic ccRCC by way of whole-genome analyses of metastatic formalin-fixed samples, using OncoScan® technology. We identified a frequent, unexpected pL1575P NOTCH1 mutation which we set out to characterize for translational purposes. We thus implemented patient-derived xenografts from metastatic samples of human ccRCC to explore its clinical significance. Results We showed that pL1575P NOTCH1 mutation was an activating mutation, leading to the expression of NOTCH1-intracellular domain-active fragments in both cancer cells and tumor endothelial cells, suggesting a trans-differentiation of cancer cells into tumor micro-vessels. We demonstrated that this mutation could be used as a predictive biomarker of response to CB-103, a specific NOTCH1-intracellular domain inhibitor. One striking result was the considerable anti-angiogenic effect, coherent with the presence of NOTCH1 mutation in tumor micro-vessels. Conclusions We identified a frequent, unexpected pL1575P_c4724T_C NOTCH1 mutation as a new biomarker for ccRCC metastases, predictive of response to the CB103 NOTCH1-intracellular domain inhibitor.

In the current study we evaluated an afterschool nutrition education programme, called Vetri Cooking Lab (VCL), for promoting healthy and diverse eating habits among at-risk children in the Greater Philadelphia area. To understand potential programme impacts, we conducted a longitudinal analysis of survey data collected before and after participation in VCL. Main study included cooking confidence, cooking knowledge, changes in dietary consumption behaviours, and changes in vegetable preferences. Participants included students in grades 3–11 enrolled in VCL during the 2018–19 school year at VCL sites (n = 60) throughout Philadelphia, PA, and Camden, NJ. Eligible participants completed surveys both before and after participating in the programme. We found that students’ confidence and knowledge increased (P < 0.001) after the cooking intervention. Knowledge and confidence were positively associated (r = 0.55; P < 0.001). Confidence was correlated with consumption behaviour changes (r = 0.18; P = 0.022). Confidence was positively associated with consumption changes in both our adjusted (OR = 1.81; P < 0.001) and unadjusted models (aOR = 1.88; P = 0.013). Compared to Black students, White students were more likely to report consumption changes (aOR = 5.83; P = 0.013). Hispanic/Latino participants and participants who spoke Spanish had nearly three times higher odds of consumption behaviour changes (Hispanic/Latino OR = 2.55; P = 0.007; Spanish OR = 3.04; P = 0.005). Student age and gender were not associated with behaviour changes. Our research demonstrates that programmes integrating practical cooking skills education along with nutrition, food, and cooking education can improve confidence and knowledge about healthy food choices amongst children driving an overall improvement in children’s eating habits.

The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of anti-tumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS). Paradoxically, a significant number of cancer patients do not manifest autoimmune features during the course of their illness, with rare instances of paraneoplastic syndromes. This discrepancy can be attributed to various immune-mediated locks, including regulatory or suppressive immune cells, anergic autoreactive lymphocytes, or induction of effector cells exhaustion due to chronic stimulation. Overcoming these locks holds the risk to induce autoimmune mechanisms during cancer progression, a phenomenon notably observed with anti-immune checkpoint therapies, in contrast to more conventional treatments like chemotherapy or radiotherapy. Therefore, the challenge arises in managing immune-related adverse events (irAEs) induced by immune checkpoint inhibitors treatment, as decoupling them from the anti-tumor activity poses a significant clinical dilemma. This review summarizes recent advances in understanding the link between B-cell driven anti-tumor responses and autoimmune reactions in cancer patients, and discusses the clinical implications of this relationship.

Regeneration of craniofacial bone defects is a key issue in the bone regeneration field. Hence, novel treatment strategies, such as tissue engineering using porous scaffolds, have been developed. An ideal tissue-engineered scaffold for bone tissue regeneration should possess pores to facilitate nutrients transmission and support reparative tissue ingrowth, bioactivity for osteoconduction and osseointegration, and biocompatibility to improve cell attachment, proliferation, and extracellular matrix formation. In the present study, we manufactured chitosan-based hydrogels substituted with alginate with optimized properties by extrusion-based three-dimensional (3D) printing. 3D printing of the scaffolds enables the designing and developing of complex architectures for craniofacial reconstruction using computer-aided design (CAD). Different ratios (2.5, 5, and 10%) of hydroxyapatite were added to the hydrogel, printed, and subsequently lyophilized to augment the physical and biological characteristics of the scaffolds. Hydroxyapatite incorporation into the chitosan-based scaffolds increased the porosity and pore size of the printed scaffolds. In addition, the presence of hydroxyapatite amplified apatite formation and decreased the size of formed apatite crystals. All the scaffold samples showed biocompatible properties and did not have toxicity toward rat bone marrow mesenchymal stem cells. Furthermore, the scaffolds containing 5% w/w hydroxyapatite exhibited significant growth in cell viability compared to the control. Overall, it is concluded that chitosan-based scaffolds adorned with hydroxyapatite are considerable for regenerating craniofacial bone defects.

Abstract Background The 2019 guidelines for cardiovascular risk stratification by the European Society of Cardiology and European Association for the Study of Diabetes (ESC-EASD) suggested screening for silent coronary disease in very high risk patients with severe target organ damage (TOD) (i.e. peripheral occlusive arterial disease or severe nephropathy) or high coronary artery calcium (CAC) score. This study aimed to test the validity of this strategy. Methods In this retrospective study, we included 385 asymptomatic patients with diabetes and no history of coronary disease but with TOD or ≥ 3 risk factors in addition to diabetes. CAC score was measured using computed tomography scan and a stress myocardial scintigraphy was performed to detect silent myocardial ischemia (SMI), with subsequent coronary angiography in those with SMI. Various strategies to select patients to be screened for SMI were tested. Results CAC score was ≥ 100 Agatston units (AU) in 175 patients (45.5%). SMI was present in 39 patients (10.1%) and among the 30 patients who underwent angiography, 15 had coronary stenoses and 12 had a revascularization procedure. The most effective strategy consisted in performing myocardial scintigraphy in the 146 patients with severe TOD and, among the 239 other patients without severe TOD, in those with CAC ≥ 100 AU: this strategy provided 82% sensitivity for SMI diagnosis, and identified all the patients with stenoses. Conclusion The ESC-EASD guidelines suggesting SMI screening in asymptomatic patients with very high risk assessed by severe TOD or high CAC score appears effective and could identify all the patients with stenoses eligible for revascularization.

BackgroundEmergency departments (EDs) manage many patients with suicide risk, but effective interventions for suicidality are challenging to implement in this setting. ReachCare is a technology-facilitated version of an evidence-based intervention for suicidal ED patients. Here, we present findings on the acceptability and quality of ReachCare in the ED, as well as a comparison of these measures across 3 potential delivery modalities ObjectiveOur aim was to test the feasibility of the ReachCare intervention in its entirety through conducting a pilot study with patients presenting with suicidality to the ED. We tested three different ways of receiving the ED-based components of ReachCare: (1) self-administered on the tablet app using a chatbot interface, (2) administered by an in-person clinician, or (3) administered by a telehealth clinician. MethodsIn total, 47 ED patients who screened positive for suicide risk were randomly allocated to receive one of three delivery modalities of ReachCare in the ED: (1) self-administered on the patient-facing tablet app with a chatbot interface, (2) delivered by an in-person clinician, or (3) delivered by a telehealth clinician, with the latter two using a clinician-facing web app. We measured demographic and clinical characteristics, acceptability and appropriateness of the intervention, and quality and completeness of the resulting safety plans. ResultsPatients assigned high ratings for the acceptability (median 4.00/5, IQR 4.00-4.50) and appropriateness (median 4.00/5, IQR 4.00-4.25) of ReachCare’s ED components, and there were no substantial differences across the 3 delivery modalities [H(acceptability)=3.90, P=.14; H(appropriateness)=1.05, P=.59]. The self-administered modality took significantly less time than the 2 clinician modalities (H=27.91, P

Background: The few studies that have examined associations between greenspace and lung function in adulthood have yielded conflicting results and none have examined whether the rate of lung function decline is affected. Objective: We explored the association between residential greenspace and change in lung function over 20 years in 5559 adults from 22 centers in 11 countries participating in the population-based, international European Community Respiratory Health Survey. Methods: Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured by spirometry when participants were approximately 35 (1990–1994), 44 (1999–2003), and 55 (2010–2014) years old. Greenness was assessed as the mean Normalized Difference Vegetation Index (NDVI) in 500 m, 300 m, and 100 m circular buffers around the residential addresses at the time of lung function measurement. Green spaces were defined as the presence of agricultural, natural, or urban green spaces in a circular 300 m buffer. Associations of these greenspace parameters with the rate of lung function change were assessed using adjusted linear mixed effects regression models with random intercepts for subjects nested within centers. Sensitivity analyses considered air pollution exposures. Results: A 0.2-increase (average interquartile range) in NDVI in the 500 m buffer was consistently associated with a faster decline in FVC (−1.25 mL/year [95% confidence interval: −2.18 to −0.33]). These associations were especially pronounced in females and those living in areas with low PM10 levels. We found no consistent associations with FEV1 and the FEV1/FVC ratio. Residing near forests or urban green spaces was associated with a faster decline in FEV1, while agricultural land and forests were related to a greater decline in FVC. Conclusions: More residential greenspace was not associated with better lung function in middle-aged European adults. Instead, we observed slight but consistent declines in lung function parameters. The potentially detrimental association requires verification in future studies.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.

Enterococcus faecalis is a commensal bacterium of the gastrointestinal tract but also a major nosocomial pathogen. This bacterium uses regulators like BglG/SacY family of transcriptional antiterminators to adapt its metabolism during host colonization. In this report, we investigated the role of the BglG/SacY family antiterminator NagY in the regulation of the nagY-nagE operon in presence of N-acetylglucosamine, with nagE encoding a transporter of this carbohydrate, as well as the expression of the virulence factor HylA. We showed that this last protein is involved in biofilm formation and glycosaminoglycans degradation that are important features in bacterial infection, confirmed in the Galleria mellonella model. In order to elucidate the evolution of these actors, we performed phylogenomic analyses on E. faecalis and Enterococcaceae genomes, identified orthologous sequences of NagY, NagE, and HylA, and we report their taxonomic distribution. The study of the conservation of the upstream region of nagY and hylA genes showed that the molecular mechanism of NagY regulation involves ribonucleic antiterminator sequence overlapping a rho-independent terminator, suggesting a regulation conforming to the canonical model of BglG/SacY family antiterminators. In the perspective of opportunism understanding, we offer new insights into the mechanism of host sensing thanks to the NagY antiterminator and its targets expression.

Abstract Background Oral malignancies have a significant effect on the quality of life among the affected patients. Curcumin is an antioxidant with a low bioavailability in the target tissue. Niosomes are carriers of increasing the therapeutic effects of drugs and reducing their side effects. This study aimed to determine the effective dose of curcumin niosome in the culture and then to compare its prophylactic effect in the form of mouthwash with that of its injectable form on oral cancer in rats. Methods This was an in-vitro and in-vivo study. Firstly, KB oral cancer cells and human umbilical vein endothelial cells (HUVEC) were treated in separate groups with free curcumin, curcumin-loaded niosomes, and the unloaded niosomes at four doses of 4, 8, 16, and 32 μg. The study rats were then divided into the following four groups: 1) no intervention, 2) only carcinogenic substance, 3) carcinogenic substance with curcumin-loaded niosome injection, and 4) carcinogenic substance with a mouthwash containing niosome. Results At the cellular level, a dose of 16 μg after 24 h was selected as an effective dose. In the animal phase, the use of injectable curcumin niosome was observed to significantly prevent the development of severe forms of dysplasia. Conclusions In this in-vitro and in-vivo study, curcumin-loaded niosome was effective in preventing the development of severe forms of dysplasia and the inhibition of the growth of cancer cells.

Abstract Background Due to increased risk of pyelonephritis, patients with intestinal reconstruction of the lower urinary tract (IRLUT) have long been advised against kidney transplantation. The aim of this study was to compare the outcomes of transplantation between patients with IRLUT and patients with normal LUT (NLUT) using propensity score matching method. Methods The study included 23 kidney recipients with IRLUT matched to 46 kidney recipients with NLUT using known allograft survival and pyelonephritis risk factors as covariates. One‐, 5‐, and 10‐year graft survival, pyelonephritis, and surgical complications occurrence and graft function were compared. Results One‐, 5‐, and 10‐year graft survival were 96%, 91%, and 63% in the IRLUT group and 96%, 88%, and 70% in the NLUT group, respectively (p = 0.72). Patients with IRLUT had increased cumulative risk of pyelonephritis at 10 years (70% vs. 19%; log‐rank

Autophagy means self-eating and is the degradation process of cellular proteins and organelles. In cancers, autophagy has a conflicting function. While it acts as a tumor suppressor by inhibiting the accumulation of damaged organelles and proteins, it functions as an oncogene and accelerates tumor progression. The related articles in the limited period of time of 2005 to mid-2020 were reviewed through searching PubMed, Google Scholar, and Scopus database. A total of 100 articles met all the selection criteria. The articles published in the last two decades related to the role of miRNAs in regulating autophagy and metastases were selected. Both miRNAs and autophagy involve in different signaling pathways that are activated in cancers. MicroRNAs and autophagy are critical factors for prediction of prognosis in cancer patients. Significant advancement has been achieved over the last decades. The development in therapeutic strategies has improved the survival rate of cancer patients. Metastasis is a multistep process; therefore, new detection biomarkers and treatment strategies are needed.

The control of non-coding repeated DNA by DNA methylation plays an important role in genomic stability, contributing to health and healthy aging. Mind-body practices can elicit psychophysical wellbeing via epigenetic mechanisms, including DNA methylation. However, in this context the effects of movement meditations have rarely been examined. Consequently, the current study investigates the effects of a specifically structured movement meditation, called the Quadrato Motor Training (QMT) on psychophysical wellbeing and on the methylation level of repeated sequences. An 8-week daily QMT program was administered to healthy women aged 40-60 years and compared with a passive control group matched for gender and age. Psychological well-being was assessed within both groups by using self-reporting scales, including the Meaning in Life Questionnaire [MLQ] and Psychological Wellbeing Scale [PWB]). DNA methylation profiles of repeated sequences (ribosomal DNA, LINE-1 and Alu) were determined in saliva samples by deep-sequencing. In contrast to controls, the QMT group exhibited increased Search for Meaning, decreased Presence of Meaning and increased Positive Relations, suggesting that QMT may lessen the automatic patterns of thinking. In the QMT group, we also found site-specific significant methylation variations in ribosomal DNA and LINE-1 repeats, consistent with increased genome stability. Finally, the correlations found between changes in methylation and psychometric indices (MLQ and PWB) suggest that the observed epigenetic and psychological changes are interrelated. Collectively, the current results indicate that QMT may improve psychophysical health trajectories by influencing the DNA methylation of specific repetitive sequences.

BackgroundMany individuals with suicide risk present to acute care settings such as emergency departments (EDs). However, staffing and time constraints mean that many EDs are not well equipped to deliver evidence-based interventions for patients experiencing suicidality. An existing intervention initiated in the ED for patients with suicide risk (Emergency Department Safety Assessment and Follow-up Evaluation [ED-SAFE]) has been found to be effective but faces trenchant barriers for widespread adoption. ObjectiveOn the basis of the ED-SAFE intervention, we aimed to develop 2 apps for patients with suicide risk: a web app guiding patients through safety planning in the ED (ED app) and a smartphone app providing patients components of the ED-SAFE program on their phones after discharge (patient app). We then tested the usability of these apps with patients presenting to the ED with suicide risk. MethodsUsing a user-centered design framework, we first developed user personas to explore the needs and characteristics of patients who are at risk for suicide using inputs from clinicians (n=3) and suicidologists (n=4). Next, we validated these personas during interviews with individuals with lived experience of suicidality (n=6) and used them to inform our application designs. We field-tested the apps with ED patients presenting with suicide risk (n=14) in 2 iterative cycles to assess their usability and engagement using a mixed methods approach. We also rated the quality and fidelity of the safety plans created. ResultsWe developed 2 interoperable and complementary apps. The first is a web app designed for use on a tablet device during ED admission that guides the patient by creating a safety plan using a chatbot-style interface. The second is a smartphone app for use after discharge and allows the patient to view, edit, and share their completed safety plan; access self-care education, helplines, and behavioral health referrals; and track follow-up appointments with the study clinician. The initial prototype usability testing (n=9) demonstrated satisfactory scores (ED app System Usability Scale [SUS], mean 78.6/100, SD 24.1; User Engagement Scale, mean 3.74/5, SD 0.72; patient app SUS, mean 81.7/100, SD 20.1). After refining the apps based on participant feedback, the second cycle testing (n=5) showed improvement (ED app SUS, mean 90.5/100, SD 9.9; User Engagement Scale, mean 4.07/5, SD 0.36; patient app SUS, mean 97.0/100, SD 1.9). The quality ratings for completed safety plans were satisfactory (Safety Planning Intervention Scoring Algorithm-Brief, mean 27.4, SD 3.4). ConclusionsBy adopting a user-centered approach and creating personas to guide development, we were able to create apps for ED patients with suicide risk and obtain satisfactory usability, engagement, and quality scores. Developing digital health tools based on user-centered design principles that deliver evidence-based intervention components may help overcome trenchant implementation barriers in challenging health care settings.

IntroductionOral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis.Materials and MethodsCells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay.ResultsNormal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p

Abstract Background Epicardial adipose tissue (EAT) is considered a novel diagnostic marker for cardiometabolic disease. This study aimed to evaluate whether EAT volume was associated with stress-induced myocardial ischemia in asymptomatic people living with diabetes—independently of confounding factors—and whether it could predict this condition. Methods We included asymptomatic patients with diabetes and no coronary history, who had undergone both a stress a myocardial scintigraphy to diagnose myocardial ischemia, and a computed tomography to measure their coronary artery calcium (CAC) score. EAT volume was retrospectively measured from computed tomography imaging. Determinants of EAT volume and asymptomatic myocardial ischemia were evaluated. Results The study population comprised 274 individuals, including 153 men. Mean (± standard deviation) age was 62 ± 9 years, and 243, 23 and 8 had type 2, type 1, or another type of diabetes, respectively. Mean body mass index was 30 ± 6 kg/m2, and mean EAT volume 96 ± 36 cm3. Myocardial ischemia was detected in 32 patients (11.7%). EAT volume was positively correlated with age, body mass index and triglyceridemia, but negatively correlated with HbA1c, HDL- and LDL-cholesterol levels. Furthermore, EAT volume was lower in people with retinopathy, but higher in men, in current smokers, in patients with nephropathy, those with a CAC score > 100 Agatston units, and finally in individuals with myocardial ischemia (110 ± 37 cm3 vs 94 ± 37 cm3 in those without myocardial ischemia, p

Background and Objective: Due to the significant importance of the teeth in mastication, speech, and aesthetics, it is necessary to identify all involved genes in the tooth development. Therefore, this study aimed to evaluate the role of endothelin-1 and its A receptor in dental lamina in different stages of tooth development. Materials and Methods: This cross-sectional study included 33 fetal samples that were divided into three groups regarding gestational age. All samples were then stained by immunohistochemistry. Subsequently, the analysis was conducted in SPSS software (version 20) through the two-way ANOVA and Tukeychr('39')s tests to examine the differences between the variables. A p-value less than 0.05 was considered statistically significant. Results: There was a significant difference between the gestational age and the expression level of endothelin-1 in dental lamina (P

ObjectiveThe frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases.MethodsPatients with vasculitis were selected from patients followed for FMF in the French JIR-cohort.ResultsTwenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications.ConclusionThis study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.

Mental health and wellbeing are increasingly threatened in the current post-pandemic times, with stress, especially in students, reaching preoccupying levels. In addition, while many educational programs are unidimensional (i.e., lacking integration between physical, emotional and cognitive elements), there are ways to promote physical, social and mental health in children and adolescents. In this opinion paper, we will discuss the importance of an integrative approach for health development and examine relevant factors, such as awareness and emotional intelligence. We will highlight evidence ranging from behavioral to electrophysiological, structural and molecular, and report several recent studies supporting the effectiveness of a holistic approach in supporting wellbeing and creativity in children and adults, and detailing a specific paradigm named the Quadrato Motor Training (QMT). QMT is a specifically structured movement meditation, involving cognitive, motor and affective components. Finally, we will support a holistic view on education, integrating motion, emotion and cognition to develop a person-centered, or in this case student-centered, approach to wellbeing and health.

PurposeMolecular profiling is crucial in naïve non-small cell lung cancer (NSCLC). While tissue-based analysis is challenged by turnaround time and scarcity of tissue, there is increasing demand for liquid biopsy. We aimed to analyze the use of upfront liquid biopsy as a molecular profiling approach.MethodsThis retrospective multicenter, non-interventional study compared findings and turnaround times of liquid vs. standard-of-care (SOC) tissue-biopsy molecular profiling. The study included naïve advanced NSCLC patients with available liquid biopsy (Guardant360 CDx).ResultsA total of 42 consecutive patients (60% men; median age, 69.5 [39–87] years; 86% stage IV NSCLC) were identified between September 2017 and December 2020. Liquid-biopsy analysis provided results for all 42 patients, whereas the tissue-based analysis failed in 5 (12%) patients due to insufficient tumor samples. In 17 patients, 18 actionable driver mutations were identified. Eleven mutations were detected by both approaches (i.e., concordance of 61%), 4 only by liquid biopsy and 3 only by tissue biopsy. The median time from the molecular request to receiving the molecular solid report on the last biomarker was 21 (range: 5–66) days, whereas the median time from blood draw to the liquid-biopsy results was 10.5 (7–19) days. The median time between the availability of liquid-biopsy findings and that of the last biomarker was 5 days. Treatment changes following the liquid-biopsy results were observed in 3 (7%) patients.ConclusionPerforming liquid-biopsy upfront is feasible and accurate and allows a shorter time for treatment in NSCLC, especially when tumor tissue is scarce.

In the current hypothesis paper, we propose a novel examination of consciousness and self-awareness through the neuro-phenomenological theoretical model known as the Sphere Model of Consciousness (SMC). Our aim is to create a practical instrument to address several methodological issues in consciousness research. We present a preliminary attempt to validate the SMC via a simplified electrophysiological topographic map of the Self. This map depicts the gradual shift from faster to slower frequency bands that appears to mirror the dynamic between the various SMC states of Self. In order to explore our hypothesis that the SMC’s different states of Self correspond to specific frequency bands, we present a mini-review of studies examining the electrophysiological activity that occurs within the different states of Self and in the context of specific meditation types. The theoretical argument presented here is that the SMC’s hierarchical organization of three states of the Self mirrors the hierarchical organization of Focused Attention, Open Monitoring, and Non-Dual meditation types. This is followed by testable predictions and potential applications of the SMC and the hypotheses derived from it. To our knowledge, this is the first integrated electrophysiological account that combines types of Self and meditation practices. We suggest this electro-topographic framework of the Selves enables easier, clearer conceptualization of the connections between meditation types as well as increased understanding of wakefulness states and altered states of consciousness.

Abstract Background Interstitial lung disease is a common complication of systemic sclerosis (SSc-ILD), and it remains difficult to accurately predict its course. Progressing ILD could be more metabolically active, suggesting that the 18F-FDG tracer could be a tool in the managing of SSc-ILD. Methods In our center, SSc patients and controls (non-Hodgkin lymphoma cured after first-line regimen) who had received a PET/CT were screened retrospectively. The FDG uptake (visual intensity, pattern, SUVmax) was systematically recorded in > 30 regions of interest (ROIs) linked to SSc in a blind reviewing by 2 independent nuclear medicine physicians using a standardized form. Results Among the 545 SSc patients followed up in our center, 36, including 22 SSc-ILDs, had a PET/CT, whose indication was cancer screening in most cases. The mean ± SD age was 57.9 ± 13.0 years with 20/36 females. Fourteen patients had a disease duration of less than 2 years. A third had anti-centromere antibodies and 27.8% had anti-topoisomerase antibodies. Pulmonary FDG uptakes were higher in SSc patients than in controls (n = 89), especially in those with ILD compared with those without ILD. Pulmonary FDG uptakes were positively correlated with the ILD severity (fibrosis extent, %FVC, and %DLCO). No significant difference was found in the FDG uptakes from extrathoracic ROIs. Progressing SSc-ILDs within the 2 years after PET/CT (n = 9) had significant higher pulmonary FDG uptakes at baseline than stable SSc-ILDs (n = 13). Conclusion PET/CT could be a useful tool in the assessment of the severity and the prediction of pulmonary function outcome of SSc-ILD.

Abstract Background The SwiftScan solution (General Electric Healthcare) combines a new low-energy high-resolution sensitivity collimator and a tomographic step-and-shoot continuous (SSC) mode acquisition. The purpose of this study is to determine whether SSC mode can be used in clinical practice with shorter examination times, while preserving image quality and ensuring accurate semi-quantification. Twenty bone scan and 10 lung scan studies were randomly selected over a period of 2 months. Three sets of image datasets were produced: step-and-shoot (SS) acquisition, simulated 25% count reduction using the Poisson resampling method (SimSS), and SimSS continuous acquisition (SimSSC), where SimSS was summed with counts acquired during detector head rotation. Visual assessment (5-point Likert scale, 2 readers) and semi-quantitative evaluation (50 focal uptake from 10 bone studies), assessed by SUVmean, coefficient of variation (COV), and contrast-to-noise ratio (CNR), were performed using t test and Bland-Altman analysis. Results Intra-reader agreement was substantial for reader 1 (k = 0.71) and for reader 2 (k = 0.61). Inter-reader agreement was substantial for SS set (k = 0.93) and moderate for SimSSC (k = 0.52). Bland-Altman analysis showed a good interchangeability of SS and SimSSC SUV values. The mean CNR between SS and SimSSC was not significantly different: 42.9 ± 43.7 [23.7–62.1] vs. 43.1 ± 46 [22.9–63.3] (p = 0.46), respectively. COV values, assessing noise level, did not deviate significantly between SS and SimSSC: 0.20 ± 0.08 [0.18–0.23] vs. 0.21 ± 0.08, [0.18–0.23] (p = 0.15), respectively, whereas a significant difference was demonstrated between SS and SimSS: 0.20 ± 0.08 [0.18–0.23] vs. 0.23 ± 0.09 [0.20–0.25] (p < 0.0001), respectively. Conclusions SSC mode acquisition decreases examination time by approximately 25% in bone and lung SPECT/CT studies compared to SS mode (~ 2 min per single-bed SPECT), without compromising image quality and signal quantification. This SPECT sensitivity improvement also offers the prospect of more comfortable exams, with less motion artifacts, especially in painful or dyspneic patients.

Background: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and has a poor prognosis. The breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes are the key tumor suppressor genes responding in the cases of DNA damage. They repair double-strand DNA breaks to maintain gene stability. Mutations in BRCA1 and BRCA2 lead to genetic instability and develop different cancers, mainly familial breast and ovarian cancers. This study aimed to investigate the expression profiles of BRCA1 and BRCA2 genes in OSCC through the use of immunohistochemistry (IHC) technique. Method: In this retrospective study, a total of 60 samples (20 samples of each grade) were collected from the archive of pathology department of Taleghani educational hospital, Tehran, Iran, from 2000-2017. IHC staining was performed for all tissue samples. Results: BRCA1 immunoreactivity was positive in the cytoplasm and nuclear of 56 and 24 samples, respectively. None of the cancer cells showed nuclear BRCA2 expression; however, BRCA2 cytoplasmic staining existed in 17 cases. Chi-square test showed statistically significant differences between BRCA1 staining (P=0.001) and histological grade, and between BRCA2 expression (P=0.001) and histological grade in the research groups. Conclusion: Altered subcellular localization of BRCA1/2 and immunostaining of the cancer cells at the invasive front may indicate the critical role of BRCA1/2 in the development of OSCC. Early detection of BRCA mutation carriers by IHC has a significant impact on successful treatment.

ObjectiveNovel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology.MethodsSerum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined. Cluster findings were revalidated during a follow-up visit, and compared to those obtained in a group of 47 COPD patients included in the Melbourne Longitudinal COPD Cohort.ResultsUnsupervised clustering identified two clusters within COPD subjects at inclusion. Cluster 1 showed elevated levels of factors contributing to tissue injury, whereas Cluster 2 had higher expression of proteins associated with enhanced immunity and host defense, cell fate, remodeling and repair and altered metabolism/mitochondrial functions. Patients in Cluster 2 had a lower incidence of exacerbations, unscheduled medical visits and prevalence of emphysema and diabetes. These protein expression patterns were conserved during a follow-up second visit, and substanciated, by a large part, in a limited series of COPD patients. Further analyses identified a signature of 15 proteins that accurately differentiated the two COPD clusters at the 2 visits.ConclusionsThis study provides insights into COPD heterogeneity and suggests that overexpression of factors involved in lung immunity/host defense, cell fate/repair/ remodelling and mitochondrial/metabolic activities contribute to better clinical outcomes. Hence, high throughput proteomic assay offers a powerful tool for identifying COPD endotypes and facilitating targeted therapies.

Background: Cleft lip (CL) and cleft palate (CP) are among the most common birth defects in the craniofacial region affected by various environmental and genetic factors. The prevalence of these abnormalities varies in races and countries. Therefore, it is a necessity to design a website to register newborns with CL ± CP in Iran. This study aimed to design a website to record the characteristics of children with CL ± CP. Materials and Methods: First, a website was designed to register the characteristics of children with CL ± CP. To evaluate the accuracy of the website, the characteristics of all children (n = 31) with CL ± CP were recorded and analyzed. Results: Due to the capability of the website to print and create reports in Excel format, the data of registered patients were analyzed. Conclusion: As CL ± CP are very common defects around the world including Iran, it is necessary to design a website to record all information about these children in Iran. Hope this website helps the public health authorities to improve program effectiveness to treat these children.