Host upregulation of lipid droplets drives antiviral responses.
When a host cell is infected by a virus, it activates the innate immune response, setting off a cascade of signalling events leading to the production of an antiviral response. This immune response is typically robust and in general works well to clear viral infections, however, viruses have evolved evasion strategies to combat this, and therefore, a better understanding of how this response works in more detail is needed for the development of novel and effective therapeutics. Lipid droplets (LDs) are intracellular organelles and have historically been thought of simply as cellular energy sources, however, have more recently been recognised as critical organelles in signalling events. Importantly, many viruses are known to take over host cellular production of LDs, and it has traditionally been assumed the sole purpose of this is to supply energy for viral life cycle events. However, our recent work positions LDs as important organelles during the first few hours of an antiviral response, showing that they underpin the production of important antiviral cytokines following viral infection. Following infection of cells with either RNA viruses (Zika, Dengue, Influenza A) or a DNA (Herpes Simplex Virus-1) virus, LDs were rapidly upregulated, and this response was also replicated following stimulation with viral mimic agonists. This upregulation of LDs following infection was transient, and interestingly, did not follow the well described homeostatic mechanism of LD upregulation, instead being controlled by EGFR. The cell's ability to mount an effective immune response was greatly diminished when inhibiting EGFR, thus inhibiting LD upregulation during infection, also leading to an increase in viral replication. In this microreview, we extrapolate our recent findings and discuss LDs as an important organelle in the innate immune response.


An acidic region of the 89K murine cytomegalovirus immediate early protein interacts with DNA.
The product of the ie1 gene, the regulatory immediate early protein pp89 of murine cytomegalovirus (MCMV), interacts with core histones, which can mediate the association of pp89 with DNA. We report the capacity of pp89 to interact directly with DNA in the absence of cellular proteins. After separation of proteins by SDS-PAGE, pp89 bound ds- and ssDNA, with a preference for ssDNA. Binding to specific DNA sequences in the MCMV genome was not detected. The DNA-binding region of pp89 was located to amino acids 438 to 534 by analysis of deletion mutants expressed as beta-galactosidase or TrpE fusion proteins. This region is identical to the highly acidic C-terminal region spanning amino acids 424 to 532. The human cytomegalovirus IE1 protein, which contains a similar extended C-terminal acidic region, does not react with DNA under the same experimental conditions.


Parents' Self-Reported Psychological Impacts of COVID-19: Associations With Parental Burnout, Child Behavior, and Income.
The current study investigates associations between parents' perceived coronavirus disease 2019 (COVID-19) psychological impacts and experiences of parental burnout, children's behaviors, and income. Data were collected during an online survey of parents' (N = 1000) pandemic experiences in April 2020. Parents (M = 36.5 years old, SD = 6.0; 82.1% White) with at least one child 12 years or younger reported on measures of mental health, perceived COVID-19 impacts, parental burnout, and perceived increases in children's stress and positive behaviors. Path model analyses revealed that parents who perceived increased psychological impacts from COVID-19 reported higher levels of parental burnout, greater increases in children's stress behaviors, and less positive behavior in children. Additionally, there were significant indirect effects of parental burnout on the link between COVID-19 psychological impacts and children's behaviors. Finally, family income moderated associations between psychological impacts and children's stress behaviors, such that the association was stronger for families with lower income. These results suggest parents' perceptions of how the COVID-19 pandemic has impacted their mental health has implications for parent and child well-being, with stronger associations for low-income families. Given the potential for spillover effects between parents and children, promoting family well-being through practice and policy initiatives is crucial, including providing financial and caregiving relief for parents, and mental and behavioral health support for families.


Multiple switches between GP2015, an etanercept biosimilar, with originator product do not impact efficacy, safety and immunogenicity in patients with chronic plaque-type psoriasis: 30-week results from the phase 3, confirmatory EGALITY study.
EGALITY was a phase III confirmatory efficacy and safety study conducted in patients with plaque-type psoriasis as a part of totality of evidence gathered during the development of GP2015, an etanercept biosimilar. To demonstrate equivalent efficacy and comparable safety and immunogenicity of GP2015 and the etanercept originator product (ETN, Enbrel® ) and evaluate effects of repeated switching between GP2015 and ETN. Results for efficacy, safety and immunogenicity during treatment period (TP) 2 (TP2) are presented pooling the two continued treatment arms (pooled continued) versus the two treatment arms with repeated switches (pooled switched). Patients (n = 531) were randomized 1:1 to self-administer GP2015 or ETN twice-weekly subcutaneously during TP1. Patients with a ≥50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 12 were re-randomized for TP2 to continue the same treatment at once-weekly dosing or to undergo three consecutive treatment switches between GP2015 and ETN until week 30. Patients continued the last-assigned treatment during TP2, until week 52. Mean (standard deviation [SD]) PASI scores at baseline were similar in patients who underwent multiple switches compared to those with continued treatments during TP2. During TP2, PASI 50, PASI 75 and PASI 90 response rates, percent change from baseline in PASI scores and all other efficacy parameters were similar between the pooled switched and pooled continued treatment groups at all time points. The incidence of treatment-emergent adverse events including injection site reactions was comparable between the pooled switched (36.7%) and pooled continued (34.9%) groups. None of the patients in either treatment group were positive for binding anti-drug antibodies in TP2. Treatment efficacy, safety and immunogenicity were similar between the pooled continued and pooled switched treatments during TP2, indicating that there are no effects in the short term on clinical data of multiple switches between GP2015 and ETN.


The dogma of identifying occult bacterial infections in young febrile children: a survey of primary-care physicians.
Management of undifferentiated febrile illness in young children continues to be a controversial issue among primary-care physicians. A self-administered questionnaire was mailed to 600 randomly selected physicians regarding their management of children with high fever and no focus of infection at various ages: 3 weeks, 7 weeks, 4 months and 20 months. Completed questionnaires were returned by 419 (70%) physicians. Nearly 77% of physicians would hospitalize a 3-week old infant with fever and 70% would treat these infants empirically with antibiotics. Sixty-one per cent of physicians would hospitalize a 7-week-old infant with fever and 46% would treat empirically with antibiotics. Approximately 80% and 93% of physicians, respectively, would not hospitalize 4- and 20-month-old infants with high fever and no focus of infection, but 72% and 59%, respectively, would treat such infants with antibiotics. There was considerable variation in the way physicians managed young febrile children with no focus of infection and the clinical approach of some physicians was remarkably different from current knowledge and recommendations.


Physical activity when riding an electric assisted bicycle.
The objectives of the present study were to compare time spent cycling, exercise intensity, and time spent in moderate- (MPA) and vigorous intensity physical activity (VPA) when cycling on an E-bike and a conventional bicycle on two "cycling-to-work" routes with differences in topography, defined as a hilly and a flat route. Eight adults (23-54 years, two women) cycled outdoors on a conventional bicycle and an E-bike, on a flat (8.2 km) and a hilly (7.1 km) route, resulting in 32 journeys. Duration, elevation, and oxygen consumption were recorded using a portable oxygen analyser with GPS. A maximal cardiorespiratory fitness test was performed on a cycle ergometer. Resting metabolic rate was obtained by indirect calorimetry with a canopy hood. The participants spent less time (median (IQR)) cycling on the E-bike compared with the conventional bicycle, on both the hilly (18.8 (4.9) vs. 26.3 (6.4) minutes) and the flat (20.0 (2.9) vs. 23.8 (1.8) minutes) routes. Lower exercise intensity was observed with the E-bike compared with the conventional bicycle, both on the hilly (50 (18) vs. 60 (22) % of maximal oxygen uptake) and the flat (52 (19) vs. 55 (12) % of maximal oxygen uptake) routes. In both cycling modes, most time was spent in MVPA (92-99%). However, fewer minutes were spent in MVPA with the E-bike than the conventional bicycle, for both the hilly (26% lower) and the flat (17% lower) routes. Cycling on the E-bike also resulted in 35 and 15% fewer minutes in vigorous intensity, respectively on the hilly and flat routes. Cycling on the E-bike resulted in lower trip duration and exercise intensity, compared with the conventional bicycle. However, most of the time was spent in MVPA. This suggests that changing the commuting mode from car to E-bike will significantly increase levels of physical activity while commuting.


Exosomes derived from IL-12-anchored renal cancer cells increase induction of specific antitumor response in vitro: a novel vaccine for renal cell carcinoma.
Exosome-based immunotherapy for cancer holds promise, but needs improvements, especially for tumor-derived exosomes. We investigated, whether exosomes derived from IL-12-anchored human renal cancer cells could enhance their immunogenicity and increase induction of specific antitumor response. A mammalian co-expression plasmid of glycolipid-anchored-IL-12 (GPI-IL-12) was constructed by subcloning IL-12A chain gene (P35 subunit) and a fusion gene containing GPI-anchor signal sequence of human placental alkaline phosphatase-1 (hPLAP-1) and IL-12B chain gene (P40 subunit) in pBudCE4.1. Then exosomes were prepared from renal cancer cells modified to express GPI-IL-12. The results showed that exosomes derived from IL-12-anchored renal cancer cells expressed renal cell carcinoma-associated antigen G250 and GPI-IL-12. The incorporation of GPI-IL-12 onto exosomes (exosomes-GPI-IL-12, EXO/IL-12) significantly promotes proliferation of T cells, and subsequently increased the release of IFN-gamma. Notably, stimulation with EXOs/IL-12 could efficiently induce antigen-specific cytotoxic T lymphocytes (CTLs), resulting in more significant cytotoxic effects in vitro. These results suggested that exosomes derived from IL-12-anchored renal cancer cells bore GPI-IL-12 and G250, which have tumor rejection antigen with enhanced immunogenicity and antitumor effects, representing a novel strategy of exosomes-based vaccine for renal cell carcinoma.


Symmetrical erosive peripheral polyarthritis in the Late Archaic Period of Alabama.
Rheumatoid arthritis was first described unambiguously in 1800, but its etiology and historical origins are still obscure. Definite rheumatoid arthritis has not been demonstrated in pre-19th century Old World skeletal remains. Six individuals who lived 3000 to 5000 years ago in northwestern Alabama and present erosive polyarthritis characteristic of rheumatoid arthritis are described. The diagnosis raises the possibility that rheumatoid arthritis can be associated with a New World pathogen or allergen.


Aquabacterium limnoticum sp. nov., isolated from a freshwater spring.
A Gram-negative, facultatively anaerobic, short-rod-shaped, non-motile and non-spore-forming bacterial strain, designated ABP-4(T), was isolated from a freshwater spring in Taiwan and was characterized using the polyphasic taxonomy approach. Growth occurred at 20-40 °C (optimum, 30-37 °C), at pH 7.0-10.0 (optimum, pH 7.0-9.0) and with 0-3% NaCl (optimum, 0%). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ABP-4(T), together with Aquabacterium fontiphilum CS-6(T) (96.4% sequence similarity), Aquabacterium commune B8(T) (96.1%), Aquabacterium citratiphilum B4(T) (95.5%) and Aquabacterium parvum B6(T) (94.7%), formed a deep line within the order Burkholderiales. Strain ABP-4(T) contained summed feature 3 (comprising C(16:1) ω7c and/or C(16:1) ω6c), C(18:1) ω7c and C(16:0) as predominant fatty acids. The major cellular hydroxy fatty acid was C(10:0) 3-OH. The major isoprenoid quinone was Q-8 and the DNA G+C content was 68.6 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, diphosphatidylglycerol and several uncharacterized phospholipids. The DNA-DNA relatedness of strain ABP-4(T) with respect to recognized species of the genus Aquabacterium was less than 70%. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain ABP-4(T) represents a novel species in the genus Aquabacterium, for which the name Aquabacterium limnoticum sp. nov. is proposed. The type strain is ABP-4(T) (=BCRC 80167(T)=KCTC 23306(T)).


Predictors of reintervention after repair of interrupted aortic arch with ventricular septal defect.
Left ventricular outflow tract obstruction after neonatal repair of interrupted aortic arch with ventricular septal defect may warrant reintervention. We sought to identify clinical and preoperative echocardiographic predictors of reintervention for postoperative left ventricular outflow tract obstruction. Retrospective data were collected on neonates with interrupted aortic arch with ventricular septal defect who underwent single-stage repair from 1995 to 2009. Univariate and multivariate analyses were performed to identify predictors of reintervention. Seventy patients underwent repair, with 16 patients requiring reintervention: 8 underwent surgical reintervention, 5 underwent percutaneous reintervention, and 3 underwent both. The median time to reintervention was 1.2 years (range, 0.2 to 7.7). All surgical reoperations involved subaortic resection, and all percutaneous reinterventions included balloon aortic valve dilation. Several preoperative echocardiographic measurements were significant by univariate analysis; however, smaller preoperative aortic root size was an independent predictor (p = 0.02) by multivariate analysis. Patients with an aortic root size less than 6.5 mm were at greater risk for reintervention compared with patients with a root size greater than 6.5 mm (reintervention rate 44% and 12%, respectively; p < 0.001). Postoperative left ventricular outflow tract gradient by echocardiogram before discharge was significantly higher in the reintervention group. Preoperative aortic root size predicts reintervention for postoperative left ventricular outflow tract obstruction after single-stage repair of interrupted aortic arch with ventricular septal defect. Patients with elevated left ventricular outflow tract gradients at discharge are at higher risk of having progressive obstruction and require closer follow-up to ensure early identification and management.


Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis.
Several converging lines of evidence suggest that keratinocyte stem cells including those clonogenic in vitro, are the target cells in skin carcinogenesis. However, the mechanism of their involvement in carcinogenesis continues to be unknown. Recently, we have demonstrated that the number of keratinocyte clonogenic stem cells from mice is a genetically defined and quantitative complex trait. In this study, we analyzed the size of the colonies in BALB/c, C57BL/6, and their (BALB/cxC57BL/6)F1 hybrid mice. We found that the size of the colonies is also genetically regulated and that there are at least two types of clonogenic keratinocytes that form either small or large colonies. Small and large colony numbers were significantly different in BALB/c and C57BL/6 mice. We performed a genome-wide scan of small and large colony number in the two backcrosses [BALB/cx (BALB/cxC57BL/6)F1]; [C57BL/6x (BALB/cxC57BL/6) F1]; and [(BALB/cxC57BL/6)F1x (BALB/cxC57BL/6)F1] intercross mice. We report here that the loci on chromosomes 4 and 9 play a role in the regulation of large and small colony number respectively. We conclude that mouse epidermis has two major types of stem cells generating small and large colonies, and regulated by different genes. Our results suggest that the loci, including one major and several minor loci linked to the subpopulation of keratinocytes forming small colonies were related, if not identical to, the loci linked to susceptibility or resistance to skin tumor promotion and skin tumor development.


Microbial community evolution during simulated managed aquifer recharge in response to different biodegradable dissolved organic carbon (BDOC) concentrations.
This study investigates the evolution of the microbial community in laboratory-scale soil columns simulating the infiltration zone of managed aquifer recharge (MAR) systems and analogous natural aquifer sediment ecosystems. Parallel systems were supplemented with either moderate (1.1 mg/L) or low (0.5 mg/L) biodegradable dissolved organic carbon (BDOC) for a period of six months during which time, spatial (1 cm, 30 cm, 60 cm, 90 cm, and 120 cm) and temporal (monthly) analyses of sediment-associated microbial community structure were analyzed. Total microbial biomass associated with sediments was positively correlated with BDOC concentration where a significant decline in BDOC was observed along the column length. Analysis of 16S rRNA genes indicated dominance by Bacteria with Archaea comprising less than 1 percent of the total community. Proteobacteria was found to be the major phylum in samples from all column depths with contributions from Betaproteobacteria, Alphaproteobacteria and Gammaproteobacteria. Microbial community structure at all the phylum, class and genus levels differed significantly at 1 cm between columns receiving moderate and low BDOC concentrations; in contrast strong similarities were observed both between parallel column systems and across samples from 30 to 120 cm depths. Samples from 1 cm depth of the low BDOC columns exhibited higher microbial diversity (expressed as Shannon Index) than those at 1 cm of moderate BDOC columns, and both increased from 5.4 to 5.9 at 1 cm depth to 6.7-8.3 at 30-120 cm depths. The microbial community structure reached steady state after 3-4 months since the initiation of the experiment, which also resulted in an improved DOC removal during the same time period. This study suggested that BDOC could significantly influence microbial community structure regarding both composition and diversity of artificial MAR systems and analogous natural aquifer sediment ecosystems.


Clearing the Dust-Off Abiotrophia defectiva.
Abiotrophia defectiva (ABI), a nutritional variant Streptococcus (NVS), is an uncommon cause of infective endocarditis (IE) involving both native and prosthetic heart valves. Due to the fastidious nature and special nutritional requirements, contribution of ABI to IE had been underestimated. Here we describe a case of Abiotrophia spp. native valve endocarditis in a 40-year-old female intravenous drug user who did not have any other potential source of infection. Blood cultures grew ABI along with Acinetobacter spp. perhaps from licking the needle before injecting. Transesophageal echocardiogram showed mobile vegetations attached to tricuspid and mitral valves. Susceptibility testing is important due to underlying differences in susceptibility to both penicillin and ceftriaxone between ABI and other genera of NVS, though both antibiotics are recommended alternate empiric first-line therapies along with synergistic gentamicin use in accordance with established guidelines to treat NVS endocarditis. She was successfully treated with intravenous ceftriaxone and gentamicin for 6 weeks with clinical and echocardiographic resolution of IE. This case highlights the importance of modern microbial techniques and equipment for accurate and rapid identification of challenging pathogens.


Swelling of poly(methyl methacrylate) resin at the repair joint.
This study investigated the thickness of a swollen layer between heat-activated and autopolymerized denture base polymer based on poly(methyl methacrylate) and autopolymerized repair acrylic resin. The repair surfaces of polymerized poly(methyl methacrylate) resin specimens (n = 5) were wet with methyl methacrylate liquid for 0, 0.5, 3, 30, or 60 minutes before the mixed repair resin was applied and polymerized to the surface of the specimen. The specimens were wet ground to a thickness of 0.15 mm, and the repair joint was examined using a light microscope. The thickness of the layer of swollen poly(methyl methacrylate) at the repair joint was measured from the micrographs. Both the type of polymer, ie, heat-activated or autopolymerized, and the wetting time of the repair surface with methyl methacrylate had a significant effect on the thickness of the swollen layer (P < .001). Prolonged wetting time of the repair surface of the autopolymerized poly(methyl methacrylate) increased the thickness of the swollen layer (r = .944, P = .000), but had less effect on the thickness of the swollen layer of heat-activated poly(methyl methacrylate) (r = .391, P = .005). This study suggests that methyl methacrylate diffuses more easily into an autopolymerized poly(methyl methacrylate) than into heat-activated poly(methyl methacrylate) during the repair of denture base polymer.


[Heart energetics and adaptation of the organism to temperature].
In working isolated preparations of the rat heart, effects of prolonged adaptation of the organism to cold (1-3 degrees) or warmth (25-27 degrees) as well as 10-minus 6 M noradrenaline administration on the efficiency (E) of the heart mechanical work, were studied. In the cold adaptation E decreases, i.e. the amount of warmth released by the heart through the same amount of work, increases. In the warmth adaptation the heart E increases. The respective changes of the heart warmth production are only revealed in the working heart, as the temperature adaptation has no effect on the O2 consumption by the stopped heart. Contrary to the skeletal muscles, the heart E during the cold adaptation does not decrease under effect of noradrenaline. In the control and, particularly, during the warmth adaptation, the heart E decreases under effect of noradrenaline.


Prolonged Ca2+ and force transients in myosin RLC transgenic mouse fibers expressing malignant and benign FHC mutations.
Clinical studies have revealed that mutations in the ventricular myosin regulatory light chain (RLC) lead to the development of familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular hypertrophy, myofibrillar disarray and sudden cardiac death. While mutations in other contractile proteins have been studied widely by others, there is no report elucidating the mechanism(s) associated with FHC-linked RLC mutations. In this study, we have assessed the functional consequences of two RLC mutations, R58Q and N47K, in transgenic mice. Clinical phenotypes associated with these mutations included inter-ventricular hypertrophy, abnormal ECG findings and the R58Q mutation caused multiple cases of premature sudden cardiac death. Simultaneous measurements of the ATPase and force in transgenic skinned papillary muscle fibers from mutated versus control mice showed an increase in the Ca(2+) sensitivity of ATPase and steady-state force only in R58Q fibers. The calculated energy cost or rate of dissociation of force generating myosin cross-bridges (ATPase/force ratio) plotted as a function of activation state was the same in all groups of fibers. Both mutations caused prolonged [Ca(2+)] transients in electrically stimulated intact papillary muscles; however, the R58Q mutation also resulted in a significantly prolonged force transient. Our results suggest that the phenotypes of FHC observed in patients harboring these RLC mutations correlate with the extent of physiological changes monitored in transgenic fibers. Cardiac hypertrophy observed in patients is most likely caused by the activation of compensatory mechanisms ensuing from higher workloads due to incomplete relaxation as evidenced by prolonged [Ca(2+)] transients for both N47K and R58Q fibers. Furthermore, the poor prognosis of the R58Q patients may be associated with more severe diastolic dysfunction due to the slower off-rate of Ca(2+) from troponin C leading to longer force and [Ca(2+)] transients and increased Ca(2+) sensitivity of ATPase and force.


Psychometric Properties of the Keratoconus Outcomes Research Questionnaire: A Save Sight Keratoconus Registry Study.
The aim of this study was to evaluate the psychometric properties of the Keratoconus Outcomes Research Questionnaire (KORQ) in patients enrolled in the Save Sight Keratoconus Registry. A cross-sectional study was conducted utilizing prospectively collected web-based registry data. The psychometric properties of the KORQ were assessed using both classical test theory and Rasch analysis. Andrich group rating scale variant of the Rasch analysis was conducted using Winsteps software, Version 3.92.1. The KORQ was completed by 189 patients with keratoconus (men, 67.7%; white, 69.8%; median age 29 years; better eye median values: visual acuity, 75 LogMAR letters; Kmax, 51.3 D; K2, 46.5 D; thinnest pachymetry, 485 μm). Cronbach's α for the "Activity Limitation" and "Symptoms" scales were 0.95 and 0.91, respectively, with both scales free from floor or ceiling effects. On Rasch analysis, the category thresholds were ordered and well-spaced for both scales. The Activity Limitation scale had excellent psychometric properties including person separation index (3.6), unidimensionality (variance explained, 65.4%), fit statistics (<1.3 MnSq), and measurement range (3.6 logits). Similarly, the Symptoms scale had satisfactory psychometric properties including person separation index (2.5), unidimensionality (variance explained, 54.3%), fit statistics (<1.30 MnSq except for 1 item), and measurement range (2.0 logits). Both scales were well targeted to the population and free of differential item functioning. The KORQ is a psychometrically robust patient-reported outcome measure for evaluating quality of life parameters in keratoconus. It enables routine collection and monitoring of meaningful patient-reported outcome data in clinical settings, including registries.


Partial nitrification in MBBRs for mainstream deammonification with thin biofilms and alternating feed supply.
A new principle for mainstream nitrogen removal through nitritation followed by anammox was studied in a two-stage moving bed biofilm reactor (MBBR) configuration. The first stage was optimized for nitritation by using thin biofilms and a feed alternating between synthetic mainstream wastewater at 15°C and, for shorter periods, synthetic reject water at 30 °C. The exposure of the biofilm to reject water conditions aimed to improve the growth conditions for ammonia oxidizing bacteria, while inhibiting nitrite oxidizing bacteria. The biofilm thickness was maintained below 200 μm to ensure high exposure of the total biomass to the bulk reactor conditions. Nitritation was successfully achieved in the configuration, with a nitrite accumulation ratio above 75% during the majority of the study, and ammonia removal rates between 0.25 and 0.50 g NH4-N/L,d. The anoxic second stage, optimized for anammox, was fed with the effluent from the nitritation reactor, reaching nitrogen removal rates above 0.20 g TN/L,d.


Prostaglandin analogues for the treatment of glaucoma and ocular hypertension: a systematic review of economic evidence.
We conducted a systematic review of economic studies of prostaglandin analogues for the treatment of glaucoma to assess the scope of current cost-effectiveness evidence and its relevance to decision-makers. The literature search retrieved 102 studies published before July 2005; after additional hand searching of conference proceedings, 13 full-text articles and 13 abstracts met the inclusion criteria. The reviewers extracted the key characteristics of each of the economic evaluations, and all studies received a grade in five categories to summarise the quality of the study: methodology, transparency, sensitivity, relevance and overall score. The current economic literature is predominantly focused on identifying the short-term direct cost of glaucoma treatment, particularly the precise quantification of glaucoma drug costs. Using the European and US treatment guidelines as a benchmark, it is evident that the current body of literature does not satisfy the needs of decision-makers, although certain studies provide some valuable information, which is a step towards reaching this goal. The main methodological issue in the economic models is an absence of a clinically relevant long-term effectiveness measure, or where this measure is produced, there is a lack of transparency and validation of the methods used. More attention needs to be given to modelling the consequences of treatment, and those consequences should include patient compliance, control of intraocular pressure and progression of visual field deficit, since these drive both the costs and the overall outcomes. We recognise that constructing the 'ideal' clinical outcome measure represents a major challenge to researchers. As such, we have outlined a modelling framework that could be used to produce the required level of economic evidence, and ongoing clinical research (such as the Early Manifest Glaucoma Trial) could provide the validated link between intraocular pressure and disease progression, which forms an essential part of such models.


A general dead-time correction method based on live-time stamping. Application to the measurement of short-lived radionuclides.
Dead-time correction formulae are established in the general case of superimposed non-homogeneous Poisson processes. Based on the same principles as conventional live-timed counting, this method exploits the additional information made available using digital signal processing systems, and especially the possibility to store the time stamps of live-time intervals. No approximation needs to be made to obtain those formulae. Estimates of the variances of corrected rates are also presented. This method is applied to the activity measurement of short-lived radionuclides.


Outdoor smoke-free policies at sports clubs across Europe: Current status, recent evidence, and future challenges.
This commentary emphasizes the importance of implementing outdoor smoke-free policies at sports clubs, particularly highlighting their limited adoption across Europe. The primary aim was to assess the progress made in the Netherlands, explore the strategies employed, and outline future challenges. Our methodology involved an examination of national regulations and the voluntary adoption of smoke-free policies at sports clubs throughout Europe. We also assessed the adoption and implementation of these policies using recent evidence, leading to the identification of impending challenges in their implementation across Europe. While only a few European countries currently have national legislation prohibiting outdoor smoking at sports clubs, voluntary initiatives promoting such policies have emerged in various nations. Experiences from the Netherlands have demonstrated the feasibility of implementing outdoor smoke-free policies at sports clubs. To expand these policies across Europe, five key challenges need to be addressed: 1) encouraging smoke-free policies at sports clubs that are less inclined to adopt them, 2) ensuring consistent compliance and enforcement of outdoor smoke-free policies, 3) preventing smoking just outside the sports club, 4) garnering support from various stakeholders to ensure widespread adoption of smoke-free sports clubs, and 5) establishing monitoring and evaluation mechanisms for policy implementation. The Dutch experiences serve as a testimony to the feasibility of outdoor smoke-free policies at sports clubs. By addressing the remaining challenges, we can create healthier sports environments for children and take substantial steps towards realizing a smoke-free Europe.


Automated monitoring of respiratory rate as a novel humane endpoint: A refinement in mouse metastatic lung cancer models.
In oncology research, while xenograft tumor models are easily visualized and humane endpoints can be clearly defined, metastatic tumor models are often based on more subjective clinical observations as endpoints. This study aimed at identifying objective non-invasive criteria for predicting imminent distress and mortality in metastatic lung tumor-bearing mice. BALB/c and C57BL/6 mice were inoculated with CT26 or B16F10 cells, respectively. The mice were housed in Vium smart cages to continuously monitor and stream respiratory rate and locomotion for up to 28 days until scheduled euthanasia or humane endpoint criteria were met. Body weight and body temperature were measured during the study. On days 11, 14, 17 and 28, lungs of subsets of animals were microCT imaged in vivo to assess lung metastasis progression and then euthanized for lung microscopic evaluations. Beginning at day 21, most tumor-bearing animals developed increased respiratory rates followed by decreased locomotion 1-2 days later, compared with the baseline values. Increases in respiratory rate did not correlate to surface tumor nodule counts or lung weight. Body weight measurement did not show significant changes from days 14-28 in either tumor-bearing or control animals. We propose that increases in respiratory rate (1.3-1.5 X) can be used to provide an objective benchmark to signal the need for increased clinical observations or euthanasia. Adoption of this novel humane endpoint criterion would allow investigators time to collect tissue samples prior to spontaneous morbidity or death and significantly reduce the distress of mice in the terminal stages of these metastatic lung tumor models.


Influence of autoimmune biomarkers on interstitial lung diseases: A tertiary referral center based case-control study.
The benefit of routinely measuring autoimmune biomarkers to evaluate patients with interstitial lung disease (ILD) remains debated outside specific contexts such as connective tissue disease (CTD). This study aimed at evaluating the influence of biomarkers on outcome on patients with ILD in a case-control study at a tertiary referral center. We hypothesized that patients with positive autoimmune biomarkers have increased odds of developing ILD even in the absence of CTD. We reviewed the medical records of 3573 patients seen at the ILD clinic in Mayo Clinic Rochester between September 2001 and September 2006. We assessed their clinical course through June 25, 2013. We included patients with patterns of ILD most often associated with CTD (n = 1256) while excluding patients with other known causes of ILD. Controls (n = 2317) included cases seen at the ILD clinic without evidence of ILD. We identified 930 (26%) cases of ILD alone, 124 (3%) CTD alone, 326 (9%) ILD combined with CTD, and 2193 (61%) with no ILD or CTD. Positive antinuclear antibodies (ANA), rheumatoid factor and aldolase were associated with ILD. After adjustment for age, gender, race, smoking history and CTD, ANA remained an independent risk factor for ILD (OR 1.70, 95% CI 1.33-2.17). Among patients with ILD, the presence of CTD but not biomarker alone was associated with a better survival. In this study, the presence of positive biomarkers was associated with increased odds of ILD, even in the absence of overt CTD, but was not associated with a better outcome.


Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder.
Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.


Epidemiology and outcomes of people with dementia, delirium, and unspecified cognitive impairment in the general hospital: prospective cohort study of 10,014 admissions.
Cognitive impairment of various kinds is common in older people admitted to hospital, but previous research has usually focused on single conditions in highly-selected groups and has rarely examined associations with outcomes. This study examined prevalence and outcomes of cognitive impairment in a large unselected cohort of people aged 65+ with an emergency medical admission. Between January 1, 2012, and June 30, 2013, admissions to a single general hospital acute medical unit aged 65+ underwent a structured specialist nurse assessment (n = 10,014). We defined 'cognitive spectrum disorder' (CSD) as any combination of delirium, known dementia, or Abbreviated Mental Test (AMT) score < 8/10. Routine data for length of stay (LOS), mortality, and readmission were linked to examine associations with outcomes. A CSD was present in 38.5% of all patients admitted aged over 65, and in more than half of those aged over 85. Overall, 16.7% of older people admitted had delirium alone, 7.9% delirium superimposed on known dementia, 9.4% known dementia alone, and 4.5% unspecified cognitive impairment (AMT score < 8/10, no delirium, no known dementia). Of those with known dementia, 45.8% had delirium superimposed. Outcomes were worse in those with CSD compared to those without - LOS 25.0 vs. 11.8 days, 30-day mortality 13.6% vs. 9.0%, 1-year mortality 40.0% vs. 26.0%, 1-year death or readmission 62.4% vs. 51.5% (all P < 0.01). There was relatively little difference by CSD type, although people with delirium superimposed on dementia had the longest LOS, and people with dementia the worst mortality at 1 year. CSD is common in older inpatients and associated with considerably worse outcomes, with little variation between different types of CSD. Healthcare systems should systematically identify and develop care pathways for older people with CSD admitted as medical emergencies, and avoid only focusing on condition-specific pathways such as those for dementia or delirium alone.


Mechanisms and pathways of Toxoplasma gondii transepithelial migration.
Toxoplasma gondii is a ubiquitous parasite and a prevalent food-borne parasitic pathogen. Infection of the host occurs principally through oral consumption of contaminated food and water with the gastrointestinal tract being the primary route for entry into the host. To promote infection, T. gondii has evolved highly specialized strategies for rapid traversal of the single cell thick intestinal epithelial barrier. Parasite transmigration via the paracellular pathway between adjacent cells enables parasite dissemination to secondary sites of infection where chronic infection of muscle and brain tissue is established. It has recently been proposed that parasite interactions with the integral tight junction (TJ) protein occludin influences parasite transmigration of the intestinal epithelium. We review here the emerging mechanisms of T. gondii transmigration of the small intestinal epithelium alongside the developing role played in modulating the wider TJ-associated proteome to rewire host cell regulatory systems for the benefit of the parasite.


[Formation of L-asparagine and L-glutamine deamidases by bacterial cultures].
Among studied 40 bacterial cultures, 17 strains catalysed hydroxylaminolysis of I.-asparagine and L-glutamine, and among these cultures seven strains belonged to the Pseudomonas genus. Extracts of the cells of Ps. boreopolis 526 (MGU), Ps. aurantiaca IBFM B-14, and Ps. septica IBFM B-40 had the maximum deamidase activity during the stage of decelerated growth. The activity of L-asparaginase 2 was practically the same upon various ways of disintegration of the cells of Ps. aurantiaca IBFM B-14: ballistic technique, ultrasound, extrusion form the solid state. Production of beta-aspartylhydroxamic acid by L-asparaginase 2 depended on the concentration of hydroxylamine and protein in the reaction mixture and on the duration of the reaction.


Hemimandibular Elongation: Is the Corrected Occlusion Maintained Long-Term? Does the Mandible Continue to Grow?
The purpose of this study was to assess for the maintenance of a corrected occlusion and ongoing mandibular growth in a group of patients younger than 26 years with hemimandibular elongation (HME) who underwent bimaxillary orthognathic reconstruction. We conducted a retrospective cohort study of HME patients operated on by a single surgeon at 1 institution between 1999 and 2013. At a minimum, all patients underwent Le Fort I and bilateral sagittal ramus osteotomies. Study exclusions included patients aged 26 years or older; those with clefts, craniofacial disorders, or tumors; and those with a history of temporomandibular joint or orthognathic surgery. The study variables included age, gender, side of condylar hyperactivity, premolar extractions, extent of mandibular deformity and malocclusion, planned surgical change, and longitudinal follow-up. The outcome variables studied were the achievement and maintenance of a corrected occlusion and the occurrence of continued mandibular growth after surgery. We compared the occlusion at intervals including the following: before surgery (T1), 5 weeks postoperatively (T2), and either 6 to 24 months after surgery (T3) or more than 2 years after surgery (T4). Anterior occlusion assessment included evaluation of overjet, overbite, and dental midline position. Posterior occlusion assessment included the Angle classification, first molar vertical position, and first molar transverse position. If the corrected anterior occlusion remained stable and no posterior open bite occurred, then no clinically significant condylar hyperactivity and/or ongoing mandibular growth was judged to have occurred. Seventy-six consecutive patients met the inclusion criteria. Age at operation averaged 18 years (range, 14.5 to 25 years), and the study included 44 female patients (58%). T3 patients (10 of 76, 13%) had documentation of occlusion at a mean of 19 months after surgery. T4 patients (66 of 76, 87%) had documentation of occlusion at a mean of 5 years 8 months after surgery. Only 1 of the 76 study patients (1%) was judged to have clinically significant ongoing mandibular growth after reconstruction. For all other patients, a corrected anterior occlusion was maintained long-term, and a posterior open bite did not develop in any. In 7 of the 76 patients (9%), there was a recurrent posterior crossbite by 1 year after completion of orthodontics but without the need for retreatment. An association was confirmed between mandibular setback and long-term posterior malocclusion even with simultaneous maxillary advancement (P = .05). In HME, a favorable occlusion can be reliably achieved and maintained long-term in most cases using standard bimaxillary orthognathic technique. The need for mandibular setback, even in the presence of simultaneous maxillary advancement, proved to be a factor in the recurrence of long-term posterior malocclusion, although the risk remains low. The results clarify that in patients with HME, by use of the described techniques and timing for surgery, there is no need for an ablative open joint procedure to arrest condylar growth.


Are Invasive Species Stressful? The Glucocorticoid Profile of Native Lizards Exposed to Invasive Fire Ants Depends on the Context.
Invasive species represent a substantial threat to native species worldwide. Research on the impacts of invasive species on wild living vertebrates has focused primarily on population-level effects. The sublethal, individual-level effects of invaders may be equally important but are poorly understood. We investigated the effects of invasive fire ants (Solenopsis invicta) on the physiological stress response of a native lizard (Sceloporus undulatus) within two experimental contexts: directly exposing lizards to a fire ant attack and housing lizards with fire ants in seminatural field enclosures. Lizards directly exposed to brief attack by fire ants had elevated concentrations of the stress hormone corticosterone (CORT), suggesting that these encounters can be physiologically stressful. However, lizards exposed for longer periods to fire ants in field enclosures had lower concentrations of CORT. This may indicate that the combined effects of confinement and fire ant exposure have pushed lizards into allostatic overload. However, lizards from fire ant enclosures appeared to have intact negative feedback controls of the stress response, evidenced by functioning adrenocorticotropic hormone responsiveness and lack of suppression of innate immunity (plasma bactericidal capacity). We review previous studies examining the stress response of wild vertebrates to various anthropogenic stressors and discuss how these-in combination with our results-underscore the importance of considering context (the length, frequency, magnitude, and types of threat) when assessing these impacts.


A novel anti-aldolase C antibody specifically interacts with residues 85-102 of the protein.
Aldolase C is a brain-specific glycolytic isozyme whose complete repertoire of functions are obscure. This lack of knowledge can be addressed using molecular tools that discriminate the protein from the homologous, ubiquitous paralog aldolase A. The anti-aldolase C antibodies currently available are polyclonal and not highly specific. We obtained the novel monoclonal antibody 9F against human aldolase C, characterized its isoform specificity and tested its performance. First, we investigated the specificity of 9F for aldolase C. Then, using bioinformatic tools coupled to molecular cloning and chemical synthesis approaches, we produced truncated human aldolase C fragments, and assessed 9F binding to these fragments by western blot and ELISA assays. This strategy revealed that residues 85-102 harbor the epitope-containing region recognized by 9F. The efficiency of 9F was demonstrated also for immunoprecipitation assays. Finally, surface plasmon resonance revealed that the protein has a high affinity toward the epitope-containing peptide. Taken together, our findings show that epitope recognition is sequence-driven and is independent of the three-dimensional structure. In conclusion, given its specific molecular interaction, 9F is a novel and powerful tool to investigate aldolase C's functions in the brain.


Urinary adiponectin is an independent predictor of progression to end-stage renal disease in patients with type 1 diabetes and diabetic nephropathy.
We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabetic nephropathy (DN) as well as for the principal determinants of uADP concentrations. uADP was measured in 2,090 patients with type 1 diabetes followed for a median of 5.8 (4.4-6.9) years and in 111 subjects without diabetes. Progression was defined as a change in albuminuria (albumin excretion rate [AER]) to a higher stage or development of end-stage renal disease (ESRD). Various Cox regression and competing risk models were used to evaluate the predictive value of uADP for DN progression. The added predictive benefit to AER or estimated glomerular filtration rate (eGFR) was estimated by the area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and other statistical indexes. The determinants of uADP were investigated by multiple regression analyses. uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P < 0.001) and was an even better predictor than AER (P = 0.04) or as good as eGFR (P = 0.79). Furthermore, uADP added a significant benefit when used together with AER (NRI 0.794, P = 0.03; IDI 0.115, P < 0.0001) or eGFR (NRI 0.637, P < 0.001; IDI 0.087, P < 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. uADP is a strong independent predictor of DN progression from macroalbuminuria to ESRD and adds a significant predictive benefit to current biomarkers in patients with type 1 diabetes.


Knowledge translation strategies for enhancing nurses' evidence-informed decision making: a scoping review.
Nurses are increasingly expected to engage in evidence-informed decision making (EIDM); the use of research evidence with information about patient preferences, clinical context and resources, and their clinical expertise in decision making. Strategies for enhancing EIDM have been synthesized in high-quality systematic reviews, yet most relate to physicians or mixed disciplines. Existing reviews, specific to nursing, have not captured a broad range of strategies for promoting the knowledge and skills for EIDM, patient outcomes as a result of EIDM, or contextual information for why these strategies "work." To conduct a scoping review to identify and map the literature related to strategies implemented among nurses in tertiary care for promoting EIDM knowledge, skills, and behaviours, as well as patient outcomes and contextual implementation details. A search strategy was developed and executed to identify relevant research evidence. Participants included registered nurses, clinical nurse specialists, nurse practitioners, and advanced practice nurses. Strategies were those enhancing nurses' EIDM knowledge, skills, or behaviours, as well as patient outcomes. Relevant studies included systematic reviews, randomized controlled trials, cluster randomized controlled trials, non-randomized trials (including controlled before and after studies), cluster non-randomized trials, interrupted time series designs, prospective cohort studies, mixed-method studies, and qualitative studies. Two reviewers performed study selection and data extraction using standardized forms. Disagreements were resolved through discussion or third party adjudication. Using a narrative synthesis, the body of research was mapped by design, clinical areas, strategies, and provider and patient outcomes to determine areas appropriate for a systematic review. There are a sufficiently high number of studies to conduct a more focused systematic review by care settings, study design, implementation strategies, or outcomes. A focused review could assist in determining which strategies can be recommended for enhancing EIDM knowledge, skills, and behaviours among nurses in tertiary care.


Extension of Mitogenome Enrichment Based on Single Long-Range PCR: mtDNAs and Putative Mitochondrial-Derived Peptides of Five Rodent Hibernators.
Enriching mitochondrial DNA (mtDNA) for sequencing entire mitochondrial genomes (mitogenomes) can be achieved by single long-range PCR. This avoids interference from the omnipresent nuclear mtDNA sequences (NUMTs). The approach is currently restricted to the use of samples collected from humans and ray-finned fishes. Here, we extended the use of single long-range PCR by introducing back-to-back oligonucleotides that target a sequence of extraordinary homology across vertebrates. The assay was applied to five hibernating rodents, namely alpine marmot, Arctic and European ground squirrels, and common and garden dormice, four of which have not been fully sequenced before. Analysis of the novel mitogenomes focussed on the prediction of mitochondrial-derived peptides (MDPs) providing another level of information encoded by mtDNA. The comparison of MOTS-c, SHLP4 and SHLP6 sequences across vertebrate species identified segments of high homology that argue for future experimentation. In addition, we evaluated four candidate polymorphisms replacing an amino acid in mitochondrially encoded subunits of the oxidative phosphorylation (OXPHOS) system that were reported in relation to cold-adaptation. No obvious pattern was found for the diverse sets of mammalian species that either apply daily or multiday torpor or otherwise cope with cold. In summary, our single long-range PCR assay applying a pair of back-to-back primers that target a consensus sequence motif of Vertebrata has potential to amplify (intact) mitochondrial rings present in templates from a taxonomically diverse range of vertebrates. It could be promising for studying novel mitogenomes, mitotypes of a population and mitochondrial heteroplasmy in a sensitive, straightforward and flexible manner.


Selective detection of fluorophore layers in turbid media: the role of fiber-optic probe design.
Experimental verification of the ability to alter the sensitivity to fluorophore layers in turbid media by varying illumination-collection geometry is presented. Fiber-optic probes and two-layer, fluorophore-doped, turbid phantoms are used to elucidate the roles of spot size, illumination-collection fiber separation, and probe-sample spacing. Variations in single- and multiple-fiber probe design parameters produce significant changes in the relative sensitivity to sample layers in a manner that agrees with prior computational studies.


Microbes participated in macrophyte leaf litters decomposition in freshwater habitat.
Knowledge of aquatic microbes involved in macrophyte leaf litter decomposition is still scarce in freshwater lakes. In situ experiments (150 days) were conducted to study the decomposition processes of macrophyte leaf litters: Zizania latifolia (Zl), Hydrilla verticillata (Hv) and Nymphoides peltata (Np). The decomposition of Np leaf litter was fastest, whereas Zl was slowest. The alpha diversity of both bacterial and fungal communities significantly increased, and their community structures showed significant variations over time. For bacteria, the relative abundance of Gammaproteobacteria decreased, whereas that of Firmicutes, Betaproteobacteria, Deltaproteobacteria and Alphaproteobacteria increased. The dominant fungal phylum Cryptomycota increased significantly in all of the three macrophytes. Both bacteria and fungi were significantly correlated with the dynamics of total phosphorous in the water and the carbon content of the leaf litters. The dynamics of nitrogen content, phosphorous content and N/P ratio of the leaf litters have more influences on fungal communities than on bacteria. In addition, cellulase and xylanase activities were significantly correlated with bacterial and fungal communities, respectively, thereby reflecting the niches differentiation and cooperation between bacteria and fungi on litter decomposition. This work contributes to the understanding of microbially involved carbon and nutrient cycling in macrophyte-dominated freshwater ecosystems.


Poor thiamin and riboflavin status is common among women of childbearing age in rural and urban Cambodia.
Thiamin deficiency in infancy is the underlying cause of beriberi, which can be fatal without rapid treatment. Reports of thiamin deficiency are common in Cambodia; however, population representative data are unavailable. Because B-complex vitamin deficiencies commonly occur in combination, riboflavin was also investigated. We determined the biomarker status of thiamin and riboflavin in women of childbearing age in rural and urban Cambodia. We measured thiamin (erythrocyte thiamin diphosphate; TDP) and riboflavin (erythrocyte glutathione reductase activity coefficient; EGRac) status in a representative sample of Cambodian women (aged 20-45 y) in urban Phnom Penh (n = 146) and rural Prey Veng (n = 156), Cambodia, and, for comparison purposes, in a convenience sample of women in urban Vancouver, British Columbia, Canada (n = 49). Thiamin insufficiency (TDP ≤ 90 nmol/L) was common among both urban (39%) and rural (59%) Cambodian women (P < 0.001), whereas <20% of Vancouver women were thiamin insufficient (P < 0.001). The prevalence of suboptimal and deficient riboflavin status (EGRac ≥ 1.3) was 89%, 92%, and 70% among women in Phnom Penh, Prey Veng, and Vancouver, respectively (P < 0.001). Suboptimal status of both thiamin and riboflavin were common in Cambodian women, with substantially higher rates among women living in rural Prey Veng than in urban Phnom Penh. Strategies may be needed to improve the thiamin and riboflavin status of women in Cambodia. The unexpected finding of high riboflavin inadequacy status in Vancouver women warrants further investigation.


Uterine peristalsis and fertility: current knowledge and future perspectives: a review and meta-analysis.
Although uterine contractions in the non-pregnant uterus have been studied extensively, the knowledge gained has not been used in general fertility treatment work-up. In this review paper, we provide an overview of the current knowledge on uterine peristalsis (UP), based on the available literature. This literature shows that UP influences pregnancy chances in both natural and artificial cycles. Although the physiological background of these contractions is not completely clear, we know that several factors can be of influence, like uterine pathologies and hormones. Several options to alter pregnancy outcome by interfering with uterine contractions have been studied. Our meta-analysis on therapeutic options shows positive results of progesterone at time of embryo transfer in IVF cycles or prostaglandins at time of intrauterine insemination, although the quality of evidence is low. These therapies are probably most beneficial in selected groups of patients with abnormal contraction patterns. The introduction of an objective and user-friendly UP measuring tool suitable for use in daily practice would make it possible to identify and monitor these patients. We suggest that future research should focus on the physiology of initiation of UP and on the development of an effective standard measuring tool.


A taxonomy of 3D occlusion management for visualization.
While an important factor in depth perception, the occlusion effect in 3D environments also has a detrimental impact on tasks involving discovery, access, and spatial relation of objects in a 3D visualization. A number of interactive techniques have been developed in recent years to directly or indirectly deal with this problem using a wide range of different approaches. In this paper, we build on previous work on mapping out the problem space of 3D occlusion by defining a taxonomy of the design space of occlusion management techniques in an effort to formalize a common terminology and theoretical framework for this class of interactions. We classify a total of 50 different techniques for occlusion management using our taxonomy and then go on to analyze the results, deriving a set of five orthogonal design patterns for effective reduction of 3D occlusion. We also discuss the "gaps" in the design space, areas of the taxonomy not yet populated with existing techniques, and use these to suggest future research directions into occlusion management.


Solid-state fermentation of soybean residues for bioflocculant production in a pilot-scale bioreactor system.
An innovative approach using soybean residues for the production of bioflocculants through solid-state fermentation was carried out in 4.5 L near-to-adiabatic bioreactors at pilot-scale level. An added inoculum of the strain Bacillus subtilis UPMB13 was tested in comparison with control reactors without any inoculation after the thermophilic phase of the fermentation. The flocculating performances of the extracted bioflocculants were tested on kaolin suspensions, and crude bioflocculants were obtained from 20 g of fermented substrate through ethanol precipitation. The production of bioflocculants was observed to be higher during the death phase of microbial growth. The bioflocculants were observed to be granular in nature and consisted of hydroxyl, carboxyl and methoxyl groups that aid in their flocculating performance. The results show the vast potential of the idea of using wastes to produce bioactive materials that can replace the current dependence on chemicals, for future prospect in water treatment applications.


Precision of the doubly labeled water method in a large-scale application: evaluation of a streamlined-dosing protocol in the Observing Protein and Energy Nutrition (OPEN) study.
To evaluate whether the doubly labeled water (DLW) method is precise under conditions required for a large-scale evaluation of dietary intake instruments. Energy expenditure was measured in 484 subjects (main study). Subjects received one of five different weight DLW dose bottles prepared in advance of the study. A repeat energy expenditure measure was obtained in a subset of 24 subjects (substudy). DLW measures of energy expenditure were performed over a 2-week interval with urine collection at the beginning and end. Free-living environment with three clinic visits in the Maryland suburban area of Washington, DC. A total of 484 subjects (261 men and 223 women) aged 40-69 y, 24 of whom (13 men and 11 women) participated in a substudy in which DLW was administered a second time. The coefficient of variation of the DLW energy expenditure measurement was 5.1%. This included a 2.9% analytical and a 4.2% physiologic variation. Based on observed initial isotopic enrichment, the preweighed dosages were optimal in 70% of the main study subjects, and 9% received a dose that was less than optimal. Only six subjects (1%) were excluded because the final isotopic enrichment was too low to conduct precise measurement. Use of preweighed DLW dosages did not compromise the precision of the DLW method. The DLW method is a reliable measure of energy expenditure for large-scale evaluations of dietary intake instruments.


Multiple functions of Notch signaling in self-renewing organs and cancer.
In recent years a substantial body of evidence has accumulated to support the notion that signaling pathways known to be important during embryonic development play important roles in regulating self-renewing tissues. Moreover, the same pathways are often deregulated during tumorigenesis due to mutations of key elements of these pathways. The Notch signaling cascade meets all of the above-mentioned criteria. We discuss here the pleiotropic roles of the Notch signaling pathway in three different self-renewing organs (intestine, hematopoietic system and skin) and how its deregulation is involved in tumorigenesis.


In vitro activity of alkylating agents on human tumors as measured by a short-term antimetabolic assay.
The activity of some alkylating agents widely used in clinical practice was studied by an in vitro antimetabolic assay, which evaluates the interference of drugs on the incorporation of 3H-thymidine and 3H-uridine in short-term cultures of human tumors. The effect of CCNU, chlorambucil, cisplatin, melphalan, prednimustine, procarbazine and the pro-active derivatives of cyclophosphamide and ifosfamide, 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide, was tested on non-Hodgkin lymphomas, germ cell testicular tumors, breast and ovarian cancers. Similar effects were generally produced by the drugs on both DNA and RNA precursor incorporation, and the in vitro response rates were similar to those clinically obtained for the same tumor types by using the same drugs in monochemotherapy. The effects of different alkylating agents on the individual tumors were not significantly associated, except for the analogues 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide, for which a significant agreement rate was observed. No evidence of acquired resistance to 4-hydroperoxycyclophosphamide and cisplatin after clinical treatment with the same drug was found in samples from ovarian cancer and non-Hodgkin lymphoma, but there was a definite trend in germ cell testicular tumors to lower sensitivity to cisplatin in previously treated patients.


The link between form and meaning in British sign language: effects of iconicity for phonological decisions.
Signed languages exploit the visual/gestural modality to create iconic expression across a wide range of basic conceptual structures in which the phonetic resources of the language are built up into an analogue of a mental image (Taub, 2001). Previously, we demonstrated a processing advantage when iconic properties of signs were made salient in a corresponding picture during a picture and sign matching task (Thompson, Vinson, & Vigliocco, 2009). The current study investigates the extent of iconicity effects with a phonological decision task (does the sign involve straight or curved fingers?) in which the meaning of the sign is irrelevant. The results show that iconicity is a significant predictor of response latencies and accuracy, with more iconic signs leading to slower responses and more errors. We conclude that meaning is activated automatically for highly iconic properties of a sign, and this leads to interference in making form-based decisions. Thus, the current study extends previous work by demonstrating that iconicity effects permeate the entire language system, arising automatically even when access to meaning is not needed.


Uncommon Arrangement of Self-resistance Allows Biosynthesis of de novo Purine Biosynthesis Inhibitor that Acts as an Immunosuppressor.
(-)-FR901483 (1) isolated from the fungus Cladobotryum sp. No.11231 achieves immunosuppression via nucleic acid biosynthesis inhibition rather than IL-2 production inhibition as accomplished by FK506 and cyclosporin A. Recently, we identified the frz gene cluster for the biosynthesis of 1. It contains frzK, a gene homologous to phosphoribosyl pyrophosphate amidotransferase (PPAT)that catalyzes the initial step of de novo purine biosynthesis. We speculated that frzK encodes a PPAT that escapes inhibition by 1 and functions as a self-resistance enzyme (SRE) for the producing host. Nevertheless, details remained elusive. Here, we report the biochemical and structural analyses of FrzK and its Escherichia coli counterpart, PurF. Recombinantly produced FrzK exhibited PPAT activity, albeit weaker than PurF, but evaded strong inhibition by 1. These results confirmed that the target of 1 is PPAT, and FrzK acts as an SRE by maintaining the de novo purine biosynthetic capability in the presence of 1. To understand how FrzK evades inhibition by 1, we determined the crystal structure of PurF in the complex with 1 and constructed a homology model of FrzK. Sequence and structural analyses of various PPATs identified that many residues unique to FrzK occur near the Flexible Loop that remains disordered when inactive but becomes ordered and covers up the active site upon activation by substrate binding. Kinetic characterizations of mutants of the unique residues revealed that the resistance of FrzK against 1 may be conferred by structurally predisposing the Flexible Loop to the active, closed conformation even in the presence of 1.


Evaluation of synergistic antioxidant potential of complex mixtures using oxygen radical absorbance capacity (ORAC) and electron paramagnetic resonance (EPR).
Previous research has demonstrated that certain combinations of compounds result in a decrease in toxic or pro-oxidative effects, previously noted when compounds were administered singly. Thus, there is a need to study many complex interactions further. Two in vitro techniques [electron paramagnetic resonance (EPR) and oxygen radical absorbance capacity (ORAC) assays] were used in this study to assess pro- and antioxidant capacity and synergistic potential of various compounds. Rutin, p-coumaric acid, abscisic acid, ascorbic acid, and a sugar solution were evaluated individually at various concentrations and in all 26 possible combinations at concentrations found in certain foods (honey or papaya), both before and after simulated digestion. EPR results indicated sugar-containing combinations provided significantly higher antioxidant capacity; those combinations containing sugars and ascorbic acid demonstrated synergistic potential. The ORAC assay suggested additive effects, with some combinations having synergistic potential, although fewer combinations were significantly synergistic after digestion. Finally, ascorbic acid, caffeic acid, quercetin, and urate were evaluated at serum-achievable levels. EPR analysis did not demonstrate additive or synergistic potential, although ORAC analysis did, principally in combinations containing ascorbic acid.


Intraventricular haemorrhage and periventricular leucomalacia: ultrasound and autopsy correlation.
The brains of 30 infants who died after at least one real time ultrasound scan were examined after fixation. The ultrasound diagnosis of either periventricular haemorrhage or periventricular leucomalacia was compared with the macroscopic and histological appearances. Each hemisphere was considered separately for both periventricular haemorrhage and periventricular leucomalacia. The accuracy of ultrasound diagnosis for periventricular haemorrhage was 88%, with sensitivity of 91% and specificity of 85%. The accuracy for periventricular leucomalacia was 90%, with sensitivity of 85% and specificity of 93%. Ultrasound was shown to diagnose the entire range of periventricular leucomalacia lesions. Three hemispheres showed the appearance of prolonged flare, and this correlated with extensive spongiosis and microcalcification of the periventricular white matter, although no macroscopic lesion was seen.


Analysis of evidence within the AUA's clinical practice guidelines.
Surgical subspecialty societies release clinical practice guidelines (CPGs) to provide topic-specific recommendations to healthcare providers. We hypothesize that there may be significant differences in statement strength and evidence quality both within the American Urological Association (AUA) guidelines and compared to those published by the American Academy of Orthopedic Surgeons (AAOS) and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). CPGs issued through 2017 were extracted from the AUAnet.org. Statements were characterized by evidence basis, strength, and evidence quality. CPGs were compared among urologic subspecialties and to those from the AAOS and AAO-HNS. Analysis used Fisher's exact tests and Student's t-tests with significance p < 0.05. A total of 25 AUA CPGs (672 statements) were reviewed and 34.6% were non-evidence based with the highest proportions in pediatrics (47.5%) and sexual medicine (46.5%). The AUA has published over twice as many statements as the AAOS and quadruple that of the AAO-HNS. A smaller proportion of the AUA statements were evidence-based (65.4%) compared to the AAOS (80.5%, p < 0.001) and AAO-HNS (99.8%, p < 0.001), and fewer used "high" quality evidence (AUA 7.2% versus AAOS 21.2%, p < 0.001; versus AAO-HNS 16.1%, p < 0.001). The AUA has published broad CPGs that far exceed those from the AAOS and AAO-HNS. The AUA has utilized extensive resources to provide guidance to help standardize care among urologists. The AAOS and AAO-HNS may not provide guidelines when evidence is limited. With the continued increase of high quality clinical trials, the AUA will be able to continue improving its robust set of evidence-based CPGs.


Genetic Diversity of Trichomonas Vaginalis Clinical Isolates According to Restriction Fragment Length Polymorphism Analysis of the 60-kDa Proteinase Gene.
Trichomonas vaginalis is a highly prevalent parasitic that causes the sexually transmitted disease trichomoniasis with some serious health complications. More understanding about genetic features of the parasite can be helpful in the study of the pathogenesis, epidemiology of the infection and drug susceptibility. For this end, we conducted analysis of a fragment (23 kDa) of the p60 of T. vaginalis gene. The restriction fragment length polymorphism (RFLP) methods was used. RFLP analysis showed the difference between T. vaginalis isolates from symptomatic and asymptomatic patients, suggesting a relation between the genetic identity of the isolates and their clinical manifestations.


3-D image reconstruction of reconstituted smooth muscle thin filaments containing calponin: visualization of interactions between F-actin and calponin.
Calponin is a putative thin filament regulatory protein of smooth muscle that inhibits actomyosin ATPase in vitro. We have used electron microscopy and three-dimensional reconstruction to elucidate the structural organization of calponin on actin and actin-tropomyosin filaments. Calponin density was clearly delineated in the reconstructions and found to occur peripherally along the long-pitch actin-helix. The main calponin mass was located over sub-domain 2 of actin, and connected axially adjacent actin monomers by binding to the "upper" and "lower" edges of sub-domains 1 of each actin. When the reconstructions were fitted to the atomic model of F-actin, calponin appeared to contact actin near the N terminus and at residues 349 to 352 close to the C terminus of sub-domain 1 on one monomer. It also touched residues 92 to 95 of sub-domain 1 on the axially neighboring actin and continued up the side of this monomer as far as residues 43 to 48 of sub-domain 2. These positions are consensus binding sites for a number of actin-associated proteins and are also near to sites of weak myosin interaction. Calponin did not appear to block strong myosin binding sites on actin. In contrast to the calponin mass which appeared monomeric in reconstructions, tropomyosin formed a continuous strand of added density along F-actin. When added to tropomyosin-containing filaments, calponin caused a shift of tropomyosin away from sub-domain 1 towards sub-domain 3 of actin, exposing strong myosin-binding sites that were previously covered by tropomyosin. This structural effect is unlike that of troponin and therefore inhibition of actomyosin ATPase by calponin and troponin cannot be strictly analogous. The location of calponin would allow it to directly compete or interact with a number of actin-binding proteins.


Incorporating Quality into Data Envelopment Analysis of Nursing Home Performance: A Case Study.
When using data envelopment analysis (DEA) as a benchmarking technique for nursing homes, it is essential to include measures of the quality of care. We survey applications where quality has been incorporated into DEA models and consider the concerns that arise when the results show that quality measures have been effectively ignored. Three modeling techniques are identified that address these concerns. Each of these techniques requires some input from management as to the proper emphasis to be placed on the quality aspect of performance. We report the results of a case study in which we apply these techniques to a DEA model of nursing home performance. We examine in depth not only the resulting efficiency scores, but also the benchmark sets and the weights given to the input and output measures. We find that two of the techniques are effective in insuring that DEA results discriminate between high and low quality performance.


Asphaltene Adsorption from Toluene onto Silica through Thin Water Layers.
Asphaltenes in crude oil play a pivotal role in reservoir oil production because they control rock-surface wettability. Upon crude oil invasion into a brine-filled reservoir trap, rock adherence of sticky asphaltene agglomerates formed at the crude oil/brine interface can change the initially water-wet porous medium into mixed-oil wetting. If thick, stable water films coat the rock surfaces, however, asphaltenic-oil adhesion is thought to be prevented. We investigate whether water films influence the uptake of asphaltenes in crude oil onto silica surfaces. Water films of known thickness are formed at a silica surface in a quartz crystal microbalance with dissipation and contacted by toluene-solubilized asphaltene. We confirm that thick water films prevent asphaltene molecular contact with the silica surface blocking asphaltene adhesion. The thicker the water film, the smaller is the amount of asphaltene deposited. Film thickness necessary for complete blockage onto silica is greater than about 500 nm, well beyond the range of molecular-chain contact. Water films of thickness less than 500 nm, sandwiched between toluene and solid silica, apparently rupture into thick water pockets and interposed molecularly thin water layers that permit asphaltene adherence.


Milk production change following clinical mastitis and reproductive performance compared among J5 vaccinated and control dairy cattle.
Naturally occurring cases of bovine clinical mastitis (CM) were studied among J5 vaccinates and controls on 3 commercial dairy farms. Milk production change and reproductive performance following CM were compared between the 2 groups. Among 306 controls and 251 vaccinates, there were 221 new cases of CM affecting 120 cows; 437 lactations never had a case of CM. Environmental pathogens made up 90% (159/176) of etiologic agents isolated. Change in daily milk production following CM was associated with J5 vaccination, days in milk (DIM) at onset of CM, and herd effect as well as each 2-way interaction between the 3 factors. The adjusted daily milk for 21 d following CM was 7.6 kg greater among J5 vaccinates than controls; however, this protective effect of vaccination waned with increasing DIM at onset of CM. A mixed linear model with autoregressive order 1 [AR(1)] correlation structure estimated the daily milk production of any cow (whether or not she had CM) on a given DIM. Cows with CM caused by nonagalactiae streptococci, Staphylococcus aureus, Escherichia coli, or Klebsiella lost significant daily milk production for the entire lactation relative to nonmastitic cows. Another mixed linear model for only coliform CM cases (E. coli, Klebsiella, and Enterobacter) within the first 50 DIM showed milk loss for 21 d following coliform CM to be significantly less for J5 vaccinates than for controls, by 6 to 15 kg per day. Cows were significantly less likely to become pregnant if they had CM caused by E. coli (42% pregnant) or Streptococcus spp. (38% pregnant), whereas 78% (342/437) of cows with no mastitis conceived. Days open (number of days from calving until pregnancy) averaged 131 d for cows with no CM and 162 d for cows that had at least one case of CM. Days until conception, days until last breeding, days open, times bred, and percentage of cows pregnant by 200 DIM were not changed with J5 vaccination. Nonetheless, an important benefit of the use of J5 bacterin appears to be reduction of the loss of daily milk production following CM, whether all cases or only those caused by coliform bacteria were considered.


What physical activity surveillance needs: validity of a single-item questionnaire.
Self-report instruments to assess physical activity are still the most feasible option in many population-wide surveys, and often need to be very short owing to resource constraints. The aim of this study was to test the criterion validity of a single-item physical activity measure using accelerometers and to compare its measurement properties by gender, age group (including older adults) and language region. A validation study was carried out within the second follow-up of a large Swiss cohort study (Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, SAPALDIA, n=208) and included an additional convenient sample (n=110). Participants wore an accelerometer over eight consecutive days and then completed the single-item measure. Spearman's rank-order correlations were used to assess the criterion validity. Physical activity levels were higher in men, younger individuals and those from the German-speaking part of Switzerland. Correlation coefficients for the number of days with at least 30 min of moderate-to-vigorous physical activity according to the single item and different accelerometer activity outcomes ranged from 0.40 to 0.54. Correlations were higher for women, younger individuals and participants from the French-speaking and the Italian-speaking parts. The single-item physical activity measure performed at least as well as other physical activity questionnaires. The differences in criterion validity between sub groups indicate that factors such as gender and age should be taken into account when developing physical activity questionnaires and in future validation studies.


Lymphoscintigraphic Findings That Predict Favorable Outcome after Lymphaticovenous Anastomosis.
Radionuclide lymphoscintigraphy is an imaging technique used to radiologically evaluate the lymphatic system which can be utilized to evaluate signs of lymphatic obstruction that could be indication for lymphaticovenous anastomosis (LVA) operations. Our objective was to investigate and identify the radiographic signs in lymphoscinigraphy that predict favorable outcome after LVA. We retrospectively reviewed the medical charts of 80 patients with upper or lower-limb lymphedema who underwent initial lymphoscintigraphy before LVA during the 2011 to 2014 study period to evaluate statistical association between lymphoscintigraphic findings and the clinical result after LVA. Following LVA, clinical improvement was observed in 50 patients (48 female and 2 male) with no clinical improvement evident in the remaining 1 male and 29 females. Dilated lymph vessels and dermal backflow were identified as the abnormal finding in lymphoscintigraphy that were significantly correlated with improved clinical result after LVA. Our conclusion is that radionuclide lymphoscintigraphy prior to LVA is helpful in identifying patients for whom LVA is of benefit. Based on our findings, presence of dilated lymph vessels and presence of dermal backflow are significantly correlated with improved clinical result after LVA.


[Fluctuations of cell cycle duration].
The problems whether the cell cycle is a deterministic or probabilistic process is widely discussed in current literature [1, 3, 7]. Present work deals with fluctuations of the cell cycle in terms of the mathematical model of membrane regulation of cell division. The presence of white noise in the parameters describing the influxes of lipids and antioxidants into the membrane is studied by the methods of Markovian processes, as well as by direct computer simulation. The equation for the distribution function of cell generation times is obtained and the increase of dispersion and the mean cell cycle time during the change of the system parameters which can be related to the density of cell culture is calculated. The theoretical distributions qualitatively agree with experimental data.


Probing the effects of the ester functional group, alkyl side chain length and anions on the bulk nanostructure of ionic liquids: a computational study.
The effects of ester addition on nanostructural properties of biodegradable ILs composed of 1-alkoxycarbonyl-3-alkyl-imidazolium cations ([C1COOCnC1im](+), n = 1, 2, 4) combined with [Br](-), [NO3](-), [BF4](-), [PF6](-), [TfO](-), and [Tf2N](-) were explored by using the molecular dynamics (MD) simulations and quantum theory of atoms in molecules (QTAIM) analysis at 400 K. Various thermodynamic properties of these ILs were extensively computed in our earlier work (Ind. Eng. Chem. Res., 2015, 54, 11678-11700). Nano-scale segregation analysis demonstrates the formation of a small spherical island-like hydrocarbon within the continuous ionic domain for ILs with short alkyl side chain ([C1COOC1C1im]), and a sponge-like nanostructure for the compound with long alkyl side chain ([C1COOC4C1im]). Ester-functionalized ILs with ethyl side chain ([C1COOC2C1im]) are the turning point between two different morphologies. Non-polar channels were observed for [C1COOC4C1im] ILs composed of smaller anions such as [Br] and [NO3], whereas clustering organization was found for the other anions. Formation of the spherical micelle-like nanostructure was seen for lengthened cations. Finally, the incorporation of an ester group into the alkyl side chain of the cation leads to stronger segregation between charged and uncharged networks, which consequently increased the possibility of self-assembly and micelle formation.


Coronary artery embolism from infectious endocarditis treated with catheter thrombectomy using a GuideLiner catheter.
A 27-year-old male with history of IV drug use and recurrent endocarditis necessitating bioprosthetic mitral and tricuspid valve replacements presented with 2 weeks of fevers and chest pain. ECG revealed inferior ST-elevation myocardial infarction and he was taken urgently to the cardiac catheterization laboratory. Coronary angiography revealed thrombotic occlusion of the distal right coronary artery (RCA) with no angiographic evidence of atherosclerotic disease. Aspiration thrombectomy was performed followed by rheolytic thrombectomy. Despite multiple attempts at thrombectomy, significant residual organized thrombus persisted in the distal RCA. Therefore, further thrombectomy was performed by placing a GuideLiner catheter (Vascular Solutions, Minneapolis, MN) deep within the right coronary artery near the bifurcation into the posterior descending and posterior left ventricular arteries. After repeat aspiration, there was significant improvement with thrombolysis in myocardial infarction 3 flow. Intravascular ultrasound of the RCA revealed a normal-appearing vessel without evidence of atherosclerotic disease and mild residual thrombus. The decision was made to not pursue stent placement, given the concern for a likely embolic source. Following the procedure, the patient's chest pain resolved and his ST-segments normalized.


Myc-dependent dedifferentiation of Gata6+ epidermal cells resembles reversal of terminal differentiation.
Dedifferentiation is the process by which terminally differentiated cells acquire the properties of stem cells. During mouse skin wound healing, the differentiated Gata6-lineage positive cells of the sebaceous duct are able to dedifferentiate. Here we have integrated lineage tracing and single-cell mRNA sequencing to uncover the underlying mechanism. Gata6-lineage positive and negative epidermal stem cells in wounds are transcriptionally indistinguishable. Furthermore, in contrast to reprogramming of induced pluripotent stem cells, the same genes are expressed in the epidermal dedifferentiation and differentiation trajectories, indicating that dedifferentiation does not involve adoption of a new cell state. We demonstrate that dedifferentiation is not only induced by wounding, but also by retinoic acid treatment or mechanical expansion of the epidermis. In all three cases, dedifferentiation is dependent on the master transcription factor c-Myc. Mechanotransduction and actin-cytoskeleton remodelling are key features of dedifferentiation. Our study elucidates the molecular basis of epidermal dedifferentiation, which may be generally applicable to adult tissues.


The ISNT Rule: How Often Does It Apply to Disc Photographs and Retinal Nerve Fiber Layer Measurements in the Normal Population?
To determine what percentage of normal eyes follow the ISNT rule, and whether ISNT rule variants may be more generalizable to the normal population. Cross-sectional study. Setting: Institutional setting. Total of 110 normal subjects. Neuroretinal rim assessments from disc photographs and retinal nerve fiber layer (RNFL) thickness measurements from spectral-domain optical coherence tomography. The percentages of subjects that obeyed the ISNT rule and its variants. The ISNT rule is only valid for 37.0% of disc photograph rim assessments and 43.8% of RNFL measurements. Deviation of the nasal sector from the expected ISNT pattern was a major cause for the ISNT rule not being obeyed for both rim and RNFL assessments. Specifically, 10.9% of subjects had wider nasal rims than the inferior rims, 29.4% had wider nasal rims than the superior rims, 14.7% had narrower nasal rims than the temporal rims, and 42.9% had thinner nasal RNFLs compared to the temporal quadrant. Exclusion of the nasal quadrant from the ISNT rule significantly increased the validity of ISNT variant rules, with 70.9% and 76.4% of disc photographs following the IST rule and the IS rule, respectively. Similarly, for RNFL thickness, 70.9% and 71.8% of patients followed the IST and IS rule, respectively. The ISNT rule is only valid for about a third of disc photographs and less than half of RNFL measurements in normal patients. ISNT rule variants, such as the IST and IS rule, may be considered, as they are valid in more than 70% of patients.


Discretely tunable comb spacing of a frequency comb by multilevel phase modulation of a periodic pulse train.
We experimentally demonstrate tunable comb spacing of an original 10-GHz periodic frequency comb by spectral Talbot effect over an unprecedented range of even and odd comb spacing division factors, from 2 to 9. The implementation has been achieved by periodic electro-optic (EO) temporal phase modulation of the original comb (conventional mode-locked optical pulse train) with multilevel modulation functions, produced by an arbitrary waveform generator (AWG). These comb spacing division processes have been observed through the use of a high-resolution (20-MHz) optical spectrum analyzer. Comb spacing tuning is achieved without essentially affecting the spectral bandwidth and total energy of the original comb signal. Our results also confirm that the spectral Talbot method does not require carrier-envelope phase stabilization in the input frequency comb. Numerical studies on the impact of deviations in the applied phase modulation functions confirm the robustness of the technique, in agreement with the experimental results.


Recovery from COVID-19 Pneumonia in a Patient with Acute Severe Colitis.
The coronavirus disease 2019 (COVID-19) pandemic has increased concern regarding SARS-CoV-2 infection in inflammatory bowel disease (IBD) patients, especially those on immunosuppressive therapies or with active disease. There are limited reports describing the clinical features of COVID-19 in an IBD population, and the impact of immunosuppression on the severity of the infection remains unclear. A 33-year-old female patient with a long history of ulcerative colitis, poorly controlled, was admitted with COVID-19 a few days after being discharged from the hospital for treatment of acute severe ulcerative colitis. High-risk factors for COVID-19 complications, i.e., high-dose steroids (40 mg prednisone) and severe active disease, were present at admission. Despite the development of extensive pulmonary involvement, the patient had a favorable outcome. Management of IBD patients during the COVID-19 pandemic has been challenging. Measures to minimize the potential risk of SARS-CoV-2 infection, including strict social distancing and self-isolation, in the IBD population have been recommended, especially for high-risk patients. Although steroid tapering and persistence of biologics are advised by professional groups, the best treatment strategy for IBD patients presenting a flare during the outbreak has yet to be defined.


RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.


Knockdown of REGγ inhibits the proliferation and migration and promotes the apoptosis of multiple myeloma cells by downregulating NF-κB signal pathway.
This study aimed to evaluate the effects of REGγ knockdown on the proliferation, apoptosis and migration of multiple myeloma (MM) cells, and reveal the potential regulatory mechanisms. The expression of REGγ on myeloma cells of 28 MM patients was detected by Western blot. shRNA-REGγ-1 and shRNA-REGγ-2 were constructed to downregulate REGγ in RPMI-8226 cells. The proliferation, apoptosis and migration of transfected cells were analyzed by Cell Counting Kit 8 (CCK8), flow cytometry and transwell chamber, respectively. The expression of phosphorylated p65 (p-p65), p65, NF-kappa-B inhibitor ε (IkBε), matrix metalloproteinase 2 (MMP2), B-cell lymphoma xL (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) in transfected cells was detected by Western blot. Using cycloheximide (CHX), the half-life period of IkBε was detected by Western blot. The expression of REGγ was positive in myeloma cells. The proliferation and migration of RPMI-8226 cells were significantly inhibited by shRNA-REGγ-1/shRNA-REGγ-2, while the apoptosis rates were significantly increased (p < 0.05). The expression of p-p65 and IkBε was significantly reduced in RPMI-8226 cells transfected with shRNA-REGγ-1/shRNA-REGγ-2. The degradation of IkBε was significantly lower in RPMI-8226 cells transfected with shRNA-REGγ-1 than the control (longer half-life period). Besides, the expression of MMP2, Bcl-xL and XIAP in RPMI-8226 cells was significantly inhibited by shRNA-REGγ-1/shRNA-REGγ-2. Knockdown of REGγ may inhibit the proliferation and migration, and promote the apoptosis of RPMI-8226 cells possibly by downregulating NF-κB signal pathway.


Estimation of runoff and sediment yield in the Redrock Creek watershed using AnnAGNPS and GIS.
Sediment has been identified as a significant threat to water quality and channel clogging that in turn may lead to river flooding. With the increasing awareness of the impairment from sediment to water bodies in a watershed, identifying the locations of the major sediment sources and reducing the sediment through management practices will be important for an effective watershed management. The annualized agricultural non-point source pollution(AnnAGNPS) model and newly developed GIS interface for it were applied in a small agricultural watershed, Redrock Creek watershed, Kansas, in this pilot study for exploring the effectiveness of using this model as a management tool. The calibrated model appropriately simulated monthly runoff and sediment yield through the practices in this study and potentially suggested the ways of sediment reduction through evaluating the changes of land use and field operation in the model for the purpose of watershed management.


Aromatase in the brain: not just for reproduction anymore.
Aromatase, the enzyme that synthesises oestrogens from androgen precursors, is expressed in the brain, where it has been classically associated with the regulation of neuroendocrine events and behaviours linked with reproduction. Recent findings, however, have revealed new unexpected roles for brain aromatase, indicating that the enzyme regulates synaptic activity, synaptic plasticity, neurogenesis and the response of neural tissue to injury, and may contribute to control nonreproductive behaviours, mood and cognition. Therefore, the function of brain aromatase is not restricted to the regulation of reproduction as previously thought.