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Using martingale theory, we compute, in very few lines, exact analytical expressions for various first-exit-time statistics associated with one-dimensional biased diffusion. Examples include the distribution for the first-exit time from an interval, moments for the first-exit site, and functionals of the position, which involve memory and time integration. As a key example, we compute analytically the mean area swept by a biased diffusion until it escapes an interval that may be asymmetric and have arbitrary length. The mean area allows us to derive the hitherto unexplored cross-correlation function between the first-exit time and the first-exit site, which vanishes only for exit problems from symmetric intervals. As a colophon, we explore connections of our results with gambling, showing that betting on the time-integrated value of a losing game it is possible to design a strategy that leads to a net average win. [ABSTRACT FROM AUTHOR]

Purpose: The efficacy of the 1-h bundle for emergency department (ED) patients with suspected sepsis, which includes lactate measurement, blood culture, broad-spectrum antibiotics administration, administration of 30 mL/kg crystalloid fluid for hypotension or lactate ≥ 4 mmol/L, remains controversial. Methods: We carried out a pragmatic stepped-wedge cluster-randomized trial in 23 EDs in France and Spain. Adult patients with Sepsis-3 criteria or a quick sequential organ failure assessment (SOFA) score ≥ 2 or a lactate > 2 mmol/L were eligible. The intervention was the implementation of the 1-h sepsis bundle. The primary outcome was in-hospital mortality truncated at 28 days. Secondary outcomes included volume of fluid resuscitation at 24 h, acute heart failure at 24 h, SOFA score at 72 h, intensive care unit (ICU) length of stay, number of days on mechanical ventilation or renal replacement therapy, vasopressor free days, unnecessary antibiotic administration, and mortality at 28 days. 1148 patients were planned to be analysed; the study period ended after 873 patients were included. Results: 872 patients (mean age 66, 42% female) were analyzed: 387 (44.4%) in the intervention group and 485 (55.6%) in the control group. Median SOFA score was 3 [1–5]. Median time to antibiotic administration was 40 min in the intervention group vs 113 min in the control group (difference − 73 [95% confidence interval (CI) − 93 to − 53]). There was a significantly higher rate, volume, and shorter time to fluid resuscitation within 3 h in the intervention group. There were 47 (12.1%) in-hospital deaths in the intervention group compared to 61 (12.6%) in the control group (difference in percentage − 0.4 [95% CI − 5.1 to 4.2], adjusted relative risk (aRR) 0.81 [95% CI 0.48 to 1.39]). There were no differences between groups for other secondary endpoints. Conclusions: Among patients with suspected sepsis in the ED, the implementation of the 1-h sepsis bundle was not associated with significant difference in in-hospital mortality. However, this study may be underpowered to report a statistically significant difference between groups. [ABSTRACT FROM AUTHOR]

Concrete's weak tensile strength renders it susceptible to cracking under prolonged loads, leading to reduced load-bearing capacity and reinforcing bar corrosion. This study investigates the effectiveness of microbial-based self-healing in high-strength concrete, focusing on two bacterial strains: Sporosarcina koreensis and Bacillus. Results demonstrate significant enhancements in micro- and macro-physical properties of high-strength bacterial concrete with Bacillus flexus and S. koreensis, surpassing the control. Bacillus flexus-infused concrete exhibits a remarkable 21.8% increase in compressive strength at 7 days and 11.7% at 56 days. Similarly, S. koreensis-treated concrete shows 12.2% and 7.4% increases at 7 and 56 days, respectively. Enhanced crack healing occurs due to calcite precipitation, confirmed by X-ray diffraction and scanning electron microscopy. Both bacterial strains achieve crack closure within 42 days, with widths of 259.7 µm and 288.7 µm, respectively. Moreover, bacterial concrete from these strains excels in durability against water, acid, and salt exposure, surpassing control concrete. These findings emphasize microbial-based self-healing's potential in high-strength concrete, providing a practical strategy to enhance structural resilience and extend concrete infrastructure lifespan. [ABSTRACT FROM AUTHOR]

The NICO (non-invasive airway management in comatose patients) randomized controlled trial found that withholding intubation in acute poisoned comatose patients with a Glasgow Coma Scale < 9 led to significant clinical improvement in terms of in-hospital death, length of stay in the intensive care unit (ICU), and length of hospital stay compared to routine practice. The trial also conducted an economic evaluation, which showed that withholding intubation was both cost-saving and event-reducing. The study suggests that policymakers should consider utilizing these monetary benefits in critical care. [Extracted from the article]

Introduction: Physicians frequently use point-of-care ultrasound for intravenous access and bloodwork in the ED. Recently, AIUM and ACEP released recommendations on ultrasound-guided peripheral intravenous lines (USPIVs), but there are no agreed upon standardized policies. We sought to determine whether the use of sterile-covered transducers (SCT) decreases the rate of contamination when compared to uncovered transducers (UCT) after standard low-level disinfection (LLD). Methods: This is a randomized control trial comparing contamination rates of US transducers between SCT and UCT after their use for USPIV by the vascular access team, also known as the "PICC" team, over a 3-month period. A sample of admitted patient with an USPIV order were included and randomized to SCT (experimental) or UCT (control) arms. Transducers were swabbed and inserted into the SystemSURE Plus Adenosine Triphosphate (ATP) Luminometer to calculate Relative Light Units (RLU). We performed a cost analysis of requiring sterile covers for USPIVs. Results: The UCT and SCT arms contained 35 and 38 patients, respectively. The SCT group had a mean of 0.34 compared to the UCT group mean of 2.29. Each sterile cover costs $8.49, and over 3000 USPIVs are placed annually by the "PICC" team. Conclusion: Contamination rates were similar among the UCT and SCT groups after LLD. 254 inpatient USPIVs are performed monthly, not including failed attempts or covers used in the ED where USPIV placement is an essential part of ED workflow. This study suggests that the use of SCT does not significantly affect transducer contamination rates. These findings question burdensome regulatory hospital policies that are not evidence-based. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing has been instrumental in uncovering cellular spatiotemporal context. This task is challenging as cells simultaneously encode multiple, potentially cross-interfering, biological signals. Here we propose scPrisma, a spectral computational method that uses topological priors to decouple, enhance and filter different classes of biological processes in single-cell data, such as periodic and linear signals. We apply scPrisma to the analysis of the cell cycle in HeLa cells, circadian rhythm and spatial zonation in liver lobules, diurnal cycle in Chlamydomonas and circadian rhythm in the suprachiasmatic nucleus in the brain. scPrisma can be used to distinguish mixed cellular populations by specific characteristics such as cell type and uncover regulatory networks and cell–cell interactions specific to predefined biological signals, such as the circadian rhythm. We show scPrisma's flexibility in incorporating prior knowledge, inference of topologically informative genes and generalization to additional diverse templates and systems. scPrisma can be used as a stand-alone workflow for signal analysis and as a prior step for downstream single-cell analysis. scPrisma deconvolutes different biological processes in single-cell RNA-sequencing data. [ABSTRACT FROM AUTHOR]

Breast cancer is the leading malignancy in women worldwide, both in terms of incidence and mortality. Triple-negative breast cancer (TNBC) is the type with the worst clinical outcomes and with fewer therapeutic options than other types of breast cancer. GK-1 is a peptide that in the experimental model of the metastatic 4T1 breast cancer has demonstrated anti-tumor and anti-metastatic properties. Herein, GK-1 (5 mg/kg, i.v.) weekly administrated not only decreases tumor growth and the number of lung macro-metastases but also lung and lymph nodes micro-metastases. Histological analysis reveals that GK-1 reduced 57% of the intra-tumor vascular areas, diminished the leukemoid reaction's progression, and the spleens' weight and length. A significant reduction in VEGF-C, SDF-1, angiopoietin-2, and endothelin-1 angiogenic factors was induced. Moreover, GK-1 prevents T cell exhaustion in the tumor-infiltrating lymphocytes (TILs) decreasing PD-1 expression. It also increased IFN-γ and granzyme-B expression and the cytotoxic activity of CD8+ TILs cells against tumor cells. All these features were found to be associated with a better antitumor response and prognosis. Altogether, these results reinforce the potential of GK-1 to improve the clinical outcome of triple-negative breast cancer immunotherapy. Translation research is ongoing towards its evaluation in humans. [ABSTRACT FROM AUTHOR]

The letter discusses a randomized trial on the effect of the 1-h sepsis bundle in patients with suspected sepsis in the emergency department. The authors report a statistically significant change in medical care after the intervention, but caution against attributing low mortality rates solely to antibiotic administration. They emphasize that the 1-h bundle may be beneficial for sicker patients, but caution against applying it universally to all patients with suspected sepsis. The authors also distinguish between early antibiotics and the 1-h sepsis bundle, warning against conflating the two concepts. [Extracted from the article]

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP. Acquired resistance to osimertinib is driven by PDK1 in preclinical models of non-small cell lung cancer and reveals PDK1 as a potential target for restoring osimertinib sensitivity. [ABSTRACT FROM AUTHOR]

Background: Point-of-care ultrasound (POCUS) has demonstrated excellent sensitivity and specificity for the diagnosis of DVT in the emergency department (ED). Before POCUS became widespread, patients underwent radiology department comprehensive lower extremity venous duplex ultrasounds (RADUS) which may be associated with a prolonged length of stay. Objectives: The goal of this study is to evaluate the impact of POCUS on ED arrival to disposition (ATD) time for patients presenting to the ED with suspected lower extremity DVT. Methods: This is a retrospective chart analysis of ED visits to an urban, university-affiliated community hospital from January 2019 to December 2020. This study compared ATD between patients who underwent POCUS by an emergency medicine physician and RADUS by the radiology department. Results: In total, 1204 patients underwent POCUS, and 1582 patients were evaluated with RADUS. The POCUS mean ATD was 313 ± 16.8 min compared to the RADUS arm average of 323 ± 57.9 min (p = 0.56). Order to disposition time (OTD) was prolonged among the RADUS group relative to POCUS. ATD was significantly reduced in the POCUS subgroup of patients presenting during night shift when RADUS was not available, 326 ± 28.2 min versus 630 ± 109 min (p < 0.05). Conclusion: ED POCUS scans decrease the amount of time between order placement and disposition when compared to RADUS. POCUS significantly decreases length of stay in the ED when RADUS is not available. [ABSTRACT FROM AUTHOR]

Background: The purpose of our study was to compare the knee implant SIGMA to the ATTUNE knee implant in a cruciate-retaining (CR) fixed-bearing (FB) total knee replacement (TKR) surgery, with no patellar resurfacing. Methods: We examined 40 patients (19 SIGMA; 21 ATTUNE) who underwent a TKR FB CR surgery, without patellar resurfacing, due to osteoarthritis, between August 2013 and July 2017. All surgeries were performed by a single surgeon. We performed a cross-sectional analytical study based on preoperative patient data and data collected in follow-up sessions. All patients were asked to fill a quality-of-life (QOL) questionnaire, SF-36 translated to the Hebrew language. All patients were clinically evaluated using the Knee Society Score (KSS) and the Knee Function Score (KFS). Results: Patients from the SIGMA cohort reported fewer postoperative physical function limitations in the SF-36 (p = 0.01) and the KFS (p = 0.04). Patients who underwent surgery using the SIGMA implant reported increased vitality when compared to the ATTUNE (p = 0.02). No significant differences were found between the groups in other measures of quality of life, ranges of motion, valgus, and postoperative knee stability. The average follow-up period was significantly longer for the SIGMA (p < 0.00001). Conclusion: Significant differences were found in postoperative physical function and vitality scores between SIGMA and ATTUNE knee implants. SIGMA cohort presented superior results. Presumably, these findings are due to the differences in follow-up times. [ABSTRACT FROM AUTHOR]

Background: Monitoring proteinuria in patients with kidney disease is of crucial importance given its implications for long-term disease progression and clinical management. Leveraging digital health technology to provide a clinical grade urinalysis result from home holds the potential to greatly enhance the clinical experience and workflows for patients, caregivers, and providers. The goal of this study was to evaluate the acceptability and feasibility of a home-based urinalysis kit using a smartphone application. Methods: This is a prospective cohort study of children and young adults (5–21 years of age) at a single pediatric center. The study received ethical board approval. Families performed a home urine test using the Healthy.io smartphone app. The app was compared with standard of care of either home dipstick monitoring or urinalysis performed in clinic or a local laboratory. Patient satisfaction was compared between the new app and current practice. Results: A total of 103 children, 63 (61%) male and median age 10.9 years (inter-quartile range 7.8–14.2), were enrolled. Primary diagnosis included 47 (46%) glomerular disease, 48 (47%) non-glomerular kidney disease, and 8 (8%) kidney transplant recipients. One hundred and one (98%) patients reported being satisfied with the smartphone app compared to 41 (40%) patients who were satisfied with the current practice for urine protein monitoring (p < 0.0001). Positive themes identified included ease of use, convenience, and immediacy and accuracy of results. Conclusions: The Healthy.io home urine testing app received very high rates of satisfaction among patients and caregivers compared to current practice and holds great potential to enhance patient-centered care. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Effect of the 1-h bundle on mortality in patients with suspected sepsis in the emergency department: a stepped wedge cluster randomized clinical trial." The correction addresses an error in the second author's name, which was incorrectly given as "Marta Cancella De Abreu" instead of "Marta Cancella de Abreu." The authors apologize for the mistake, and the original article has been corrected. The document also includes the names of all the authors involved in the study. [Extracted from the article]

Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E−09), rs2285521 in GGA2 (P = 4.43E−08), and rs198459 in MYRF (P = 1.60E−06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E−08, P = 6.21E−08, and P = 7.93E−04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E−05, P = 2.70E−04, and P = 2.90E−05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration. [ABSTRACT FROM AUTHOR]

The Alpine goat (Capra aegagrus hircus) is parasitized by the barber pole worm (Haemonchus contortus). Hematological parameters from transcript and metagenome analysis in the host are reflective of infestation. We explored comparisons between blood samples of control, infected, infected zoledronic acid-treated, and infected antibody (anti-γδ T cells) treated wethers under controlled conditions. Seven days post-inoculation (dpi), we identified 7,627 transcripts associated with the different treatment types. Microbiome measurements at 7 dpi revealed fewer raw read counts across all treatments and a less diverse microbial flora than at 21 dpi. This study identifies treatment specific transcripts and an increase in microflora abundance and diversity as wethers age. Further, F/B ratio reflect health, based on depression or elevation above thresholds defined by the baseline of non-infected controls. Forty Alpine wethers were studied where blood samples were collected from five goats in four treatment groups on 7 dpi and 21 dpi. Transcript and microbiome profiles were obtained using the Partek Flow (St. Louis, Missouri, USA) software suites pipelines. Inflammation comparisons were based on the Firmicutes/Bacteriodetes ratios that are calculated as well as the reduction of microbial diversity. [ABSTRACT FROM AUTHOR]

In patients visiting the emergency department (ED), a potential association between electrolytes disturbance and coronavirus disease 2019 (COVID-19) has not been well studied. We aim to describe electrolyte disturbance and explore risk factors for COVID-19 infection in patients visiting the ED. We carried out a case–control study in three hospitals in France, including adult ED inpatients (≥ 18 years old). A total of 594 ED case patients in whom infection with COVID-19 was confirmed, were matched to 594 non-COVID-19 ED patients (controls) from the same period, according to sex and age. Hyponatremia was defined by a sodium of less than 135 mmol/L (reference range 135–145 mmol/L), hypokalemia by a potassium of less than 3.5 mmol/L (reference range 3.5–5.0 mmol/L), and hypochloremia by a chloride of less than 95 mmol/L (reference range 98–108 mmol/L). Among both case patients and controls, the median (IQR) age was 65 years (IQR 51–76), and 44% were women. Hyponatremia was more common among case patients than among controls, as was hypokalemia and hypochloremia. Based on the results of the multivariate logistic regression, hyponatremia, and hypokalemia were associated with COVID-19 among case patients overall, with an adjusted odds ratio of 1.89 [95% CI 1.24–2.89] for hyponatremia and 1.76 [95% CI 1.20–2.60] for hypokalemia. Hyponatremia and hypokalemia are independently associated with COVID-19 infection in adults visiting the ED, and could act as surrogate biomarkers for the emergency physician in suspected COVID-19 patients. [ABSTRACT FROM AUTHOR]

Unrefined non-centrifugal sugars in Southeast Asia emanate from various plant sources including sugarcane, palm, and coconut. To assess food and flavor characteristic differences of these unrefined sugars, seven cane, three palm, and two coconut sugars were evaluated in term of their physicochemical, antioxidant, and volatile flavor properties. Results indicated that unrefined sugars from cane had significantly higher ICUMSA color value than palm and coconut sugars, yet they possessed comparable total soluble solid levels. Cane sugars also presented superior phenolic and flavonoid contents and antioxidant activities, particularly in Thai and Japanese products. Each sugar had distinct volatile flavor composition, comprising acids, Maillard reaction products (furanone, pyrazine, furan, and pyrrole), aldehydes, alcohols, and sulfurs. All traditionally made unrefined sugars had significantly greater Maillard reaction products and less acetic acid than in industrially manufactured cane sugars. Then, propanoic acid and [R-(R*,R*)]-2,3-butanediol were solely major volatiles in palm sugars from Thailand. Additionally, mass spectrometry-based electronic-nose (e-nose) profiling detection provided specific ion masses from various volatile components as potential chemical markers in monitoring aroma characteristic of unrefined sugars and differentiated these sugars into nine statistical clusters based on their materials and origins, wherein palm sugars from Thailand and Indonesia, as well as cane sugars from Thailand and Japan, had comparable volatile profiles. [ABSTRACT FROM AUTHOR]

Restricted food intake, either from lack of food sources or endogenous fasting, during reproductive periods is a widespread phenomenon across the animal kingdom. Considering previous studies show the canonical upstream regulator of reproduction in vertebrates, the hypothalamic Gonadotropin-releasing hormone (Gnrh), is inhibited in some fasting animals, we sought to understand the neuroendocrine control of reproduction in fasted states. Here, we explore the roles of the midbrain neuropeptide, Gnrh2, in inducing reproduction via its pituitary prevalence, gonadotropin synthesis, gametogenesis, and reproductive outputs in the zebrafish model undergoing different feeding regimes. We discovered a fasting-induced four-fold increase in length and abundance of Gnrh2 neuronal projections to the pituitary and in close proximity to gonadotropes, whereas the hypothalamic Gnrh3 neurons are reduced by six-fold in length. Subsequently, we analyzed the functional roles of Gnrh2 by comparing reproductive parameters of a Gnrh2-depleted model, gnrh2−/−, to wild-type zebrafish undergoing different feeding conditions. We found that Gnrh2 depletion in fasted states compromises spawning success, with associated decreases in gonadotropin production, oogenesis, fecundity, and male courting behavior. Gnrh2 neurons do not compensate in other circumstances by which Gnrh3 is depleted, such as in gnrh3−/− zebrafish, implying that Gnrh2 acts to induce reproduction specifically in fasted zebrafish. [ABSTRACT FROM AUTHOR]

Elevated plasma concentrations of the ketone body β-hydroxybutyrate (BHB), an endogenous agonist of the hydroxycarboxylic acid receptor 2 (HCA2), is associated with an increased incidence of inflammatory diseases during lactation in dairy cows. In the early stages of this pathology, an increase in neutrophil recruitment is observed; however, the role of BHB remains elusive. This study characterized the effect of BHB and synthetic agonists of the HCA2 receptor on bovine neutrophil chemotaxis and the signaling pathways involved in this process. We demonstrated that treatment with BHB concentrations between 1.2 and 10 mM and two full selective agonists of the HCA2 receptor, MK-1903 and nicotinic acid, increased bovine neutrophil chemotaxis. We also observed that BHB and HCA2 agonists induced calcium release and phosphorylation of AKT, ERK 1/2 and AMPKα. To evaluate the role of these pathways in bovine neutrophil chemotaxis, we used the pharmacological inhibitors BAPTA-AM, pertussis toxin, U73122, LY294002, U0126 and compound C. Our results suggest that these pathways are required for HCA2 agonist-induced bovine neutrophil chemotaxis in non-physiological condition. Concentrations around 1.4 mM of BHB after calving may exert a chemoattractant effect that is key during the onset of the inflammatory process associated with metabolic disorders in dairy cows. [ABSTRACT FROM AUTHOR]

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. [ABSTRACT FROM AUTHOR]

The exposure of concrete to gamma radiation gives rise to a set of physical and chemical processes over multiple length scales, from molecular to bulk. The literature includes a number of bulk-scale studies which report the radiogenic heating of concrete and the loss of water (unbound, physically-bound, and/or chemically-bound) due to irradiation. This paper mechanistically quantifies observations by these studies, and presents a continuum framework to model the effects of gamma photons on concrete. A basis is presented for comparing otherwise disparate results in the literature for radiolysis rates. The Stefan–Boltzmann Law, adapted to include a gamma heat source term, reasonably describes radiogenic heating in concrete specimens. In multiple studies, the primary mechanism for dehydration is the loss of liquid water in the pore network of the cement product, rather than of water which is physically or chemically bound in a solid state. [ABSTRACT FROM AUTHOR]

A potential therapeutic strategy for diabetes is the transplantation of induced-insulin secreting cells. Based on the common embryonic origin of liver and pancreas, we studied the potential of adult human liver stem-like cells (HLSC) to generate in vitro insulin-producing 3D spheroid structures (HLSC-ILS). HLSC-ILS were generated by a one-step protocol based on charge dependent aggregation of HLSC induced by protamine. 3D aggregation promoted the spontaneous differentiation into cells expressing insulin and several key markers of pancreatic β cells. HLSC-ILS showed endocrine granules similar to those seen in human β cells. In static and dynamic in vitro conditions, such structures produced C-peptide after stimulation with high glucose. HLSC-ILS significantly reduced hyperglycemia and restored a normo-glycemic profile when implanted in streptozotocin-diabetic SCID mice. Diabetic mice expressed human C-peptide and very low or undetectable levels of murine C-peptide. Hyperglycemia and a diabetic profile were restored after HLSC-ISL explant. The gene expression profile of in vitro generated HLSC-ILS showed a differentiation from HLSC profile and an endocrine commitment with the enhanced expression of several markers of β cell differentiation. The comparative analysis of gene expression profiles after 2 and 4 weeks of in vivo implantation showed a further β-cell differentiation, with a genetic profile still immature but closer to that of human islets. In conclusion, protamine-induced spheroid aggregation of HLSC triggers a spontaneous differentiation to an endocrine phenotype. Although the in vitro differentiated HLSC-ILS were immature, they responded to high glucose with insulin secretion and in vivo reversed hyperglycemia in diabetic SCID mice. [ABSTRACT FROM AUTHOR]

Distinguishing the taste and aroma of different sugar syrups is important in determining their utility in the food and beverage industries and for their marketing to consumers. Herein, thick sugar syrups were prepared from the squeezed stalk juices of two important sugar crops: sweet sorghum and sugarcane. The sugar syrups were distinguished in terms of composition, taste characteristics, volatile profile, and antioxidant activity. Sweet sorghum syrup contained lower sucrose and total sugar, but retained greater amounts of minerals and organic acids than sugarcane syrup. Correspondingly, sweet sorghum syrup exhibited lower sweetness and higher saltiness and bitterness than sugarcane syrup. Sweet sorghum syrup exhibited a more complex volatile aroma composition, the major components of which were acetaldehyde, 2-methylpropanal, 3-methylbutanal, and 2-methylbutanal, followed by intermediate amounts of ketones, alcohols, and pyrazines. Additionally, sweet sorghum syrup exhibited a higher total phenolic content and superior antioxidant capabilities in oxygen radical absorbance capacity and 1,1-diphenyl-2-picrylhydrazine radical-scavenging activity assays than sugarcane syrup. The results of the present study demonstrate the suitability of sweet sorghum and sugarcane syrups as sweeteners and food ingredients for consumer and industrial applications. [ABSTRACT FROM AUTHOR]

Objective Little is known about treatments provided by advanced life support (ALS) ambulance teams to patients with acute heart failure (AHF) during the prehospital phase, and their influence on short-term outcome. We evaluated the effect of prehospital care in consecutive patients diagnosed with AHF in Spanish emergency departments (EDs). Methods We selected patients from the EAHFE registry arriving at the ED by ALS ambulances with available follow-up data. We recorded specific prehospital ALS treatments (supplemental oxygen, diuretics, nitroglycerin, non-invasive ventilation) and patients were grouped according to whether they received low- (LIPHT; 0/1 treatments) or high-intensity prehospital therapy (HIPHT; > 1 treatment) for AHF. We also recorded 46 covariates. The primary endpoint was all-cause 7-day mortality, and secondary endpoints were prolonged hospitalisation (> 10 days) and in-hospital and 30-day mortality. Unadjusted and adjusted odds ratios were calculated to compare the groups. Results We included 1493 patients [mean age 80.7 (10) years; women 54.8%]. Prehospital treatment included supplemental oxygen in 71.2%, diuretics in 27.9%, nitroglycerin in 13.5%, and non-invasive ventilation in 5.3%. The LIPHT group included 1041 patients (70.0%) with an unadjusted OR for 7-day mortality of 1.770 (95% CI 1.115-2.811; p = 0.016), and 1.939 (95% CI 1.114-3.287, p = 0.014) after adjustment for 16 discordant covariables. The adjusted ORs for all secondary endpoints were always > 1 in the LIPHT group, but none reached statistical significance. Conclusions Patients finally diagnosed with AHF at then ED that have received LIPHT by the ALS ambulance teams have a poorer short-term outcome, especially during the first 7 days. [ABSTRACT FROM AUTHOR]

Burnout is common in emergency physicians. This syndrome may negatively affect patient care and alter work productivity. We seek to assess whether burnout of emergency physicians impacts waiting times in the emergency department. Prospective study in an academic ED. All patients who visited the main ED for a 4-month period in 2016 were included. Target waiting times are assigned by triage nurse to patients on arrival depending on their severity. The primary endpoint was an exceeded target waiting time for ED patients. All emergency physicians were surveyed by a psychologist to assess their level of burnout using the Maslach Burnout Inventory. We defined the level of burnout of the day in the ED as the mean burnout level of the physicians working that day (8:30 to the 8:30 the next day). A logistic regression model was performed to assess whether burnout level of the day was independently associated with prolonged waiting times, along with previously reported predictors. Target waiting time was exceeded in 7524 patients (59%). Twenty-six emergency physicians were surveyed. Median burnout score was 35 [Interquartile (24-49)]. A burnout level of the day higher than 35 was independently associated with an exceeded target waiting time (adjusted odds ratio 1.54, 95% confidence interval 1.39-1.70), together with previously reported predictors (i.e., day of the week, time of the day, trauma, age and daily census). Burnout of emergency physicians was independently associated with a prolonged waiting time for patients visiting the ED. [ABSTRACT FROM AUTHOR]

Eight non-centrifugal cane brown sugars were compositionally differentiated by their sugar, amino acid, mineral, phenolic, and volatile aroma components. Their taste and aroma profiles were generated using two electronic sensing techniques, namely, a potentiometric electronic tongue (e-tongue) and a mass spectrometry (MS)-based electronic nose (e-nose). The nutritional and phenolic contents varied in brown sugars and influenced relative taste values for sweetness, umami, astringency, and bitterness. Various composition-taste correlations, including both contributive and negative associations, were discovered, whereas minerals and phenolics had a positive effect on astringency and bitterness. Brown sugars were also composed of different formations of volatile aroma components, predominantly acetaldehyde, ethanol, acetic acid, butanoic acid, 2,5-dimethyl pyrazine, and 2,6-dimethyl pyrazine. Hyphenated MS-based e-nose sensing differentiated brown sugars in more detail and generated important discriminant chemical markers for those aroma compounds in the multivariate PCA statistical model, viz., m/z 42 and 43 (acetaldehyde), 46 (ethanol), 55 and 73 (butanoic acid), 60 (acetic acid), and 94, 108, and 122 (pyrazines). [ABSTRACT FROM AUTHOR]

Arginine vasotocin is a hormone produced in the hypothalamus of teleost fish that has been shown to regulate gonad development and sexual behavior. To study the role of arginine vasotocin in the gonadal cycle of the hermaphrodite gilthead seabream, Sparus aurata, we cloned the seabream arginine vasotocin ( avt) complementary DNA (cDNA). We investigated the expression of brain avt throughout the gonad cycle using real-time quantitative PCR and compared its expression levels to the expression levels of two key gonadal steroidogenic enzymes, cyp19a1a and cyp11b2. In July, when the process of sex reversal is thought to begin, avt expression was elevated over the previous 2 months. Avt in the brain remained at or above the level of July until November then peaked again in December. There was no difference between males and females in the expression levels of brain avt throughout the year. However, only in ambisexual fish was the expression of the cyp19a1a gonadal aromatase correlated to the expression of avt in the brain. Cyp11b2 did not show any correlation to brain avt expression. We also found that females had more intense body coloration than males and that this intensity peaked prior to spawning. Avt expression and female coloration were positively correlated. The fact that brain avt expression was lowest during gonad quiescence, together with the observation of a correlation between brain avt with gonadal cyp19a1a and body coloration during that time suggests that avt may play a role during the process of sex reversal and spawning of the gilthead seabream. [ABSTRACT FROM AUTHOR]

Given a set of signals, a classical construction of an optimal truncatable basis for optimally representing the signals, is the principal component analysis (PCA for short) approach. When the information about the signals one would like to represent is a more general property, like smoothness, a different basis should be considered. One example is the Fourier basis which is optimal for representation smooth functions sampled on regular grid. It is derived as the eigenfunctions of the circulant Laplacian operator. In this paper, based on the optimality of the eigenfunctions of the Laplace-Beltrami operator (LBO for short), the construction of PCA for geometric structures is regularized. By assuming smoothness of a given data, one could exploit the intrinsic geometric structure to regularize the construction of a basis by which the observed data is represented. The LBO can be decomposed to provide a representation space optimized for both internal structure and external observations. The proposed model takes the best from both the intrinsic and the extrinsic structures of the data and provides an optimal smooth representation of shapes and forms. [ABSTRACT FROM AUTHOR]

Non-centrifugal cane sugar (NCS) is globally consumed and has various health benefits. It is mostly produced in hardened block form, which is less convenient than in granulated form for food applications. In terms of the traditional processing of NCS, preparation of granulated products is difficult due to the impurities found in the cane juice extracted from the whole stalk. Therefore, the aim of this study was to characterize and determine the physico-chemical properties, wax composition (policosanols and long-chain aldehydes), volatile aroma profiles, and antioxidant activity of traditional NCS in granular form made from four different cane cultivars of Thailand. The total soluble solid, pH, color, and mineral content varied among the sugarcane cultivars, whereas there was no significant difference in the total sugar, phenolic and flavonoid content. The total policosanol, a cholesterol-lowering nutraceutical wax component, and long-chain aldehyde contents were similar in the NCS products amongst three cultivars, and ranged from 2.63 to 3.69 mg/100 g. The granulated NCS products, in which acetaldehyde and dimethyl sulfide were the main volatile compounds, gave less aroma components than traditional NCS. The use of different sugarcane cultivars thus influenced the quality attributes of granulated non-centrifugal sugar products. [ABSTRACT FROM AUTHOR]

The blends of two crosslinked polystyrene- b-polyisoprene (PS- b-PI) copolymers with homopolystyrene were investigated for their dynamic mechanical properties. Elastomeric block copolymer nanofibers utilized as filler were prepared by employing the phase separation property of a polystyrene- b-polyisoprene copolymer, which was then exposed to a crosslinking agent (SCl) for cold vulcanization. The crosslinking density and morphology of nanofillers resulted in three elastomeric block copolymer nanofillers: fully cross-linked nanofiber (FCF), fully crosslinked multi-junctioned nanofiber (FCM), and partially crosslinked multi-junctioned sample (PCM). Uncrosslinked PS-PI block copolymer (UBC) was also studied as a comparison. Crosslinking density was calculated by measuring the change in intensity of the double bond peaks using FTIR spectroscopy. Thermo-mechanical properties and morphology of the blends were characterized by dynamic mechanical analysis (DMA) and scanning electron microscope (SEM). DMA results show that modulus increases with increasing filler loading in the terminal region for both PS/FCM and PS/FCF systems and the increasing rate is related to crosslinking density. [ABSTRACT FROM AUTHOR]

Purpose: Corneal neovascularisation (CNV), with consequent loss of transparency, is due to an imbalance of proangiogenic factors. Cell-surface nucleolin (NCL) has been associated with neo-angiogenesis. There are studies identifying NCL translocation from nucleus to the cell surface, which is essential for endothelial cell proliferation. To find the possible role of NCL in the generation of corneal neovessels, the aim of this study is to characterise the NCL presence and cell-localisation in non-injured corneas, as well as to describe the changes in NCL cell and tissue localisation in CNV, and to analyse the effect of bevacizumab on NCL cellular and tissular distribution. Methods: Suture-induced CNV was performed in mice. The corneal tissues were obtained and the histological and co-immunofluorescence assays were performed using different proteins, such as CD31, cadherin and isolectin B. To determine the possible role of VEGF in NCL presence and localisation in our CNV model, bevacizumab was concomitantly used. Results: Nucleolin was principally observed in the nucleus of the basal epithelial cells of normal corneas. Interestingly, angiogenesis-induced changes were observed in the localisation of NCL, not only in tissue but also at the cellular level where NCL was extranuclear in epithelial cells, stromal cells and neovessels. In contrast, these changes were reverted when bevacizumab was used. Besides, NCL was able to stain only aberrant corneal neovessels in comparison with retinal vessels. Conclusions: NCL mobilisation outside the nucleus during angiogenesis could have a possible role as a proangiogenic molecule in the corneal tissue. [ABSTRACT FROM AUTHOR]

Multidimensional scaling (MDS) is a family of methods that embed a given set of points into a simple, usually flat, domain. The points are assumed to be sampled from some metric space, and the mapping attempts to preserve the distances between each pair of points in the set. Distances in the target space can be computed analytically in this setting. Generalized MDS is an extension that allows mapping one metric space into another, that is, MDS into target spaces in which distances are evaluated numerically rather than analytically. Here, we propose an efficient approach for computing such mappings between surfaces based on their natural spectral decomposition, where the surfaces are treated as sampled metric-spaces. The resulting spectral-GMDS procedure enables efficient embedding by incorporating smoothness of the metric structure into the problem, thereby substantially reducing the complexity involved in its solution while practically overcoming its non-convex nature. The method is compared to existing techniques that compute dense correspondence between shapes. Numerical experiments of the proposed method demonstrate its efficiency and accuracy compared to state-of-the-art approaches especially when isometry invariance is a dominant property. [ABSTRACT FROM AUTHOR]

Amniotic membrane, the inner layer of the placenta, has biological properties (e.g. promotes epithelization, reduces fibrosis, secretes antimicrobial products and inhibits immune responses) which make it a useful option for several ophthalmologic procedures, especially those involving the ocular surface. Its use in eye surgery has been reported by other authors. To our knowledge, there is a lack of descriptive studies on surgical indications using amniotic membrane in Mexican population. Here we describe the eight years Amniotic Membrane Bank experience in Mexico, including a detailed protocol of the donors selection, tissue harvesting, preparation, storage and distribution of amniotic membrane since its establishment in 2007. Moreover, we describe the Ophthalmological indications of amniotic membrane transplantation of the total of 1686 amniotic membranes fragments used during eight years. The five most common indications for amniotic membrane transplantation were pterygium (46 %), corneal ulcers (12.6 %), conjunctival surface repair (11.1 %), neoplasms (7.4 %), and persistent epithelial defects (7.3 %). In addition, we compared the indications of amniotic membrane use in two different types of Institutions: general hospitals and ophthalmologic reference hospitals. We found interesting differences between the indications and use rates between these institutions, although pterygium was the most frequent pathology that amniotic membrane fragments were used in both institutions, there was up to a five-fold increase in the use of amniotic membrane for correction of persistent epithelial defects in reference hospitals which could be explained due to the more complex and severe ophthalmological pathologies admitted in reference hospitals. In conclusion, Amniotic Membrane is used in a numerous ocular pathologies and especially on pterygium in our Mexican population. [ABSTRACT FROM AUTHOR]

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis. [ABSTRACT FROM AUTHOR]

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Objective: To determine the safety and efficacy of topical 0.03 % tacrolimus ointment treatment for subepithelial corneal infiltrates (SEIs). Methods: This prospective non-controlled interventional case series included patients with SEIs who had been previously treated with topical corticosteroids with either no improvement or the medication being withdrawn due to associated intraocular pressure (IOP) elevation. The patients were treated with 0.03 % tacrolimus ointment twice daily for 22 weeks (including a 1-month washout). The objective data were best-corrected Snellen visual acuity (BCVA), IOP, and full ocular examination results, including SEI severity and the Schirmer test. The subjective data were the patients' responses to a questionnaire at all follow-up visits. Results: The patients consisted of five males (45 %) and six females (55 %) (mean age 50 ± 11 years) who were followed up for an average of 22 weeks. The mean BCVA (logarithm of the minimum angle of resolution [logMAR]) before and after treatment was 0.34 ± 0.09 and 0.08 ± 0.04 respectively ( p = 0.042). All the patients evidenced significant objective clinical improvement, and none had a severe degree of SEI at the end of the treatment. The patients reported considerable reduction in the severity of their symptoms (foreign body sensation, glare, etc.). Three patients were excluded due to side-effects (one had severe dizziness and discomfort), and their data were excluded from the study. Conclusion: Topical tacrolimus 0.03 % is a safe and effective alternative treatment in patients with SEIs who do not respond to other treatment modalities or have untoward side-effects from topical steroids. [ABSTRACT FROM AUTHOR]

The presence and conservation of GnRH2 across vertebrate species suggest important biological roles. However, the function of GnRH2 remains unclear. A good research model for GnRH2 functional studies is still lacking largely due to the absence of GnRH2 in the widely used mouse model. Hence, we used the zebrafish, for which powerful genetic tools are available, and developed a transgenic (Tg) line expressing enhanced green fluorescence protein (eGFP). The high sensitivity of eGFP, which can diffuse throughout the neuron, enables us to document the complete projectome of GnRH2 neurons at different developmental stages. Fine projection structures were observed without sacrificing the fish. Crossed with the GnRH3:tdTomato Tg line, the GnRH2:eGFP Tg line provides us with an opportunity to visualize the entire GnRH system simultaneously in one organism. This work will provide a framework to understand the function of the highly-conserved GnRH2 system. [ABSTRACT FROM AUTHOR]