Child marriage and perinatal health in Ecuador, 2015-2020.
This study sought to estimate the prevalence and distribution of newborns to mothers under age 18 in Ecuador and the association between perinatal indicators and maternal marital status. Newborn records obtained from Ecuador's Instituto Nacional de Estadísticas y Censos (INEC) between 2015 and 2020 were used to assess the joint association between maternal age groups (10-15, 16-17, 18-19, and 20-24 years) and marital status (married, common-law, and single) with low birthweight, preterm birth, and inadequate prenatal care. The prevalence of newborns to mothers under age 18 was 9.3% overall, but declined over the study period, drastically among married mothers. The association between marital status and perinatal indicators depended on maternal age. The more favorable outcomes observed among married mothers aged 20-24 years (compared to their single counterparts) weaken or disappear among mothers under age 18. Mothers in stable unions exhibited outcomes in between those of married and single mothers.


CO2 response of cyclic electron flow around PSI (CEF-PSI) in tobacco leaves--relative electron fluxes through PSI and PSII determine the magnitude of non-photochemical quenching (NPQ) of Chl fluorescence.
We hypothesized that cyclic electron flow around photosystem I (CEF-PSI) participates in the induction of non-photochemical quenching (NPQ) of chlorophyll (Chl) fluorescence when the rate of photosynthetic linear electron flow (LEF) is electron-acceptor limited. To test this hypothesis, the relationships among photosynthesis rate, electron fluxes through both PSI and PSII [Je(PSI) and Je(PSII)] and Chl fluorescence parameters were analyzed simultaneously in intact leaves of tobacco plants at several light intensities and partial pressures of ambient CO2 (Ca). At low light intensities, decreasing Ca lowered the photosynthesis rate, but Je(PSI) and Je(PSII) remained constant. Je(PSI) was larger than Je(PSII), indicating the existence of CEF-PSI. Increasing the light intensity enhanced photosynthesis and both Je(PSI) and Je (PSII). Je(PSI)/Je(PSII) also increased at high light and at high light and low Ca combined, showing a strong, positive relationship with NPQ of Chl fluorescence. These results indicated that CEF-PSI contributed to the dissipation of photon energy in excess of that consumed by photosynthesis by driving NPQ of Chl fluorescence. The main physiological function of CEF-PSI in photosynthesis of higher plants is discussed.


Radioimmunotherapy: a new treatment modality for B-cell non-Hodgkin's lymphoma.
The field of radioimmunotherapy for the treatment of non-Hodgkin's lymphoma (NHL) has advanced significantly over the past decade, and several radioimmunoconjugates are being tested in clinical trials. Two of these antibodies target CD20: yttrium-90 (Y-90)-labeled ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 (I-131)-labeled tositumomab (Bexxar). Other agents target either CD22 (Y-90 epratuzumab) or human leukocyte antigen (HLA)-DR (I-131 Lym-1), respectively. In February 2002, Y-90-labeled ibritumomab tiuxetan became the first radioimmunoconjugate to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer. Tositumomab/I-131 tositumomab was approved in June 2003. Thus, two radioimmunoconjugates have been approved for the treatment of NHL. Both agents, when administered as a single dose, have produced impressive tumor response rates with an acceptable toxicity profile. The main side effect is reversible myelosuppression. Radioimmunotherapy produces overall response rates of approximately 80% in patients with low-grade lymphomas, and 25% to 30% of patients achieve a complete remission. Lower response rates (approximately 40%) have been reported in patients with large-cell lymphomas. This review discusses the clinical trials of radioimmunotherapeutic agents for NHL that demonstrated their safety and efficacy and outlines the current status of these agents.


A model for simulating the active dispersal of juvenile sea turtles with a case study on western Pacific leatherback turtles.
Oceanic currents are known to broadly shape the dispersal of juvenile sea turtles during their pelagic stage. Accordingly, simple passive drift models are widely used to investigate the distribution at sea of various juvenile sea turtle populations. However, evidence is growing that juveniles do not drift purely passively but also display some swimming activity likely directed towards favorable habitats. We therefore present here a novel Sea Turtle Active Movement Model (STAMM) in which juvenile sea turtles actively disperse under the combined effects of oceanic currents and habitat-driven movements. This model applies to all sea turtle species but is calibrated here for leatherback turtles (Dermochelys coriacea). It is first tested in a simulation of the active dispersal of juveniles originating from Jamursba-Medi, a main nesting beach of the western Pacific leatherback population. Dispersal into the North Pacific Ocean is specifically investigated. Simulation results demonstrate that, while oceanic currents broadly shape the dispersal area, modeled habitat-driven movements strongly structure the spatial and temporal distribution of juveniles within this area. In particular, these movements lead juveniles to gather in the North Pacific Transition Zone (NPTZ) and to undertake seasonal north-south migrations. More surprisingly, juveniles in the NPTZ are simulated to swim mostly towards west which considerably slows down their progression towards the American west coast. This increases their residence time, and hence the risk of interactions with fisheries, in the central and eastern part of the North Pacific basin. Simulated habitat-driven movements also strongly reduce the risk of cold-induced mortality. This risk appears to be larger among the juveniles that rapidly circulate into the Kuroshio than among those that first drift into the North Equatorial Counter Current (NECC). This mechanism might induce marked interannual variability in juvenile survival as the strength and position of the NECC are directly linked to El Niño activity.


Ab initio folding of proteins using restraints derived from evolutionary information.
We present our predictions in the ab initio structure prediction category of CASP3. Eleven targets were folded, using a method based on a Monte Carlo search driven by secondary and tertiary restraints derived from multiple sequence alignments. Our results can be qualitatively summarized as follows: The global fold can be considered "correct" for targets 65 and 74, "almost correct" for targets 64, 75, and 77, "half-correct" for target 79, and "wrong" for targets 52, 56, 59, and 63. Target 72 has not yet been solved experimentally. On average, for small helical and alpha/beta proteins (on the order of 110 residues or smaller), the method predicted low resolution structures with a reasonably good prediction of the global topology. Most encouraging is that in some situations, such as with target 75 and, particularly, target 77, the method can predict a substantial portion of a rare or even a novel fold. However, the current method still fails on some beta proteins, proteins over the 110-residue threshold, and sequences in which only a poor multiple sequence alignment can be built. On the other hand, for small proteins, the method gives results of quality at least similar to that of threading, with the advantage of not being restricted to known folds in the protein database. Overall, these results indicate that some progress has been made on the ab initio protein folding problem. Detailed information about our results can be obtained by connecting to http:/(/)www.bioinformatics.danforthcenter.org/+ ++CASP3.


Thermocouple design for measuring temperatures of small insects.
Contact thermocouples often are used to measure surface body temperature changes of insects during cold exposure. However, small temperature changes of minute insects can be difficult to detect, particularly during the measurement of supercooling points. We developed two thermocouple designs, which use 0.51 mm diameter or 0.127 mm diameter copper-constantan wires, to improve our ability to resolve insect exotherms. We tested the designs with adults from three parasitoid species: Tetrastichus planipennisi, Spathius agrili, and S. floridanus. These species are <3 mm long and <0.1 mg. Mean exotherms were greater for fine-gauge thermocouples than thick-gauge thermocouples for the smallest species tested, T. planipennisi. This difference was not apparent for larger species S. agrili and S. floridanus. Thermocouple design did not affect the mean supercooling point for any of the species. The cradle thermocouple design developed with the fine gauge wire was reusable and allowed for easy insect recovery after cold exposure.


Gene conversion occurs within the mating-type locus of Cryptococcus neoformans during sexual reproduction.
Meiotic recombination of sex chromosomes is thought to be repressed in organisms with heterogametic sex determination (e.g. mammalian X/Y chromosomes), due to extensive divergence and chromosomal rearrangements between the two chromosomes. However, proper segregation of sex chromosomes during meiosis requires crossing-over occurring within the pseudoautosomal regions (PAR). Recent studies reveal that recombination, in the form of gene conversion, is widely distributed within and may have played important roles in the evolution of some chromosomal regions within which recombination was thought to be repressed, such as the centromere cores of maize. Cryptococcus neoformans, a major human pathogenic fungus, has an unusually large mating-type locus (MAT, >100 kb), and the MAT alleles from the two opposite mating-types show extensive nucleotide sequence divergence and chromosomal rearrangements, mirroring characteristics of sex chromosomes. Meiotic recombination was assumed to be repressed within the C. neoformans MAT locus. A previous study identified recombination hot spots flanking the C. neoformans MAT, and these hot spots are associated with high GC content. Here, we investigated a GC-rich intergenic region located within the MAT locus of C. neoformans to establish if this region also exhibits unique recombination behavior during meiosis. Population genetics analysis of natural C. neoformans isolates revealed signals of homogenization spanning this GC-rich intergenic region within different C. neoformans lineages, consistent with a model in which gene conversion of this region during meiosis prevents it from diversifying within each lineage. By analyzing meiotic progeny from laboratory crosses, we found that meiotic recombination (gene conversion) occurs around the GC-rich intergenic region at a frequency equal to or greater than the meiotic recombination frequency observed in other genomic regions. We discuss the implications of these findings with regards to the possible functional and evolutionary importance of gene conversion within the C. neoformans MAT locus and, more generally, in fungi.


Candidate gene analysis of metamorphic timing in ambystomatid salamanders.
Although much is known about the ecological significance of metamorphosis and metamorphic timing, few studies have examined the underlying genetic architecture of these traits, and no study has attempted to associate phenotypic variation to molecular variation in specific genes. Here we report on a candidate gene approach (CGA) to test specific loci for a statistical contribution to variation in metamorphic timing. Three segregating populations (SP1, SP2 and SP3) were constructed utilizing three species of paedomorphic Mexican ambystomatid salamander, including the axolotl, Ambystoma mexicanum. We used these replicated species to test the hypothesis that inheritance of alternate genotypes at two thyroid hormone receptor loci (TRalpha, TRbeta) affects metamorphic timing in ambystomatid salamanders. A significant TRalpha*SP effect indicated that variation in metamorphic timing may be influenced by TRalpha genotype, however, the effect was not a simple one, as both the magnitude and direction of the phenotypic effect depended upon the genetic background. These are the first data to implicate a specific gene in contributing to variation in metamorphic timing. In general, candidate gene approaches can be extended to any number of loci and to any organism where simple genetic crosses can be performed to create segregating populations. The approach is thus of particular value in ecological studies where target genes have been identified but the study organism is not one of the few well-characterized model systems that dominate genetic research.


Inactivation of biofilm bacteria.
The current project was developed to examine inactivation of biofilm bacteria and to characterize the interaction of biocides with pipe surfaces. Unattached bacteria were quite susceptible to the variety of disinfectants tested. Viable bacterial counts were reduced 99% by exposure to 0.08 mg of hypochlorous acid (pH 7.0) per liter (1 to 2 degrees C) for 1 min. For monochloramine, 94 mg/liter was required to kill 99% of the bacteria within 1 min. These results were consistent with those found by other investigators. Biofilm bacteria grown on the surfaces of granular activated carbon particles, metal coupons, or glass microscope slides were 150 to more than 3,000 times more resistant to hypochlorous acid (free chlorine, pH 7.0) than were unattached cells. In contrast, resistance of biofilm bacteria to monochloramine disinfection ranged from 2- to 100-fold more than that of unattached cells. The results suggested that, relative to inactivation of unattached bacteria, monochloramine was better able to penetrate and kill biofilm bacteria than free chlorine. For free chlorine, the data indicated that transport of the disinfectant into the biofilm was a major rate-limiting factor. Because of this phenomenon, increasing the level of free chlorine did not increase disinfection efficiency. Experiments where equal weights of disinfectants were used suggested that the greater penetrating power of monochloramine compensated for its limited disinfection activity. These studies showed that monochloramine was as effective as free chlorine for inactivation of biofilm bacteria. The research provides important insights into strategies for control of biofilm bacteria.


Comparison of pulse-dose and high-dose corticosteroids with no corticosteroid treatment for COVID-19 pneumonia in the intensive care unit.
Corticosteroid dosing in the range of 0.5-2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID-19 pneumonia based on positive results of randomized trials and a meta-analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID-19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID-19 pneumonia, we compared patients treated with 0.5-2 mg/kg/day in methylprednisolone equivalents (high-dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse-dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU-free days at Day 28, and complications potentially attributable to corticosteroids. Pulse-dose corticosteroid therapy was associated with a significant increase in ICU-free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05-2.02; p = 0.03) and compared with high-dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high-dose corticosteroids-but not of pulse-dose corticosteroids-significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12-0.77; p = 0.01). High-dose corticosteroids reduced mortality compared to pulse-dose corticosteroids (p = 0.04). Pulse-dose corticosteroids-but not high-dose corticosteroids-significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27-9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse-dose group when compared to the high-dose group (p = 0.05 for the comparison). In this single-center study, pulse-dose corticosteroid therapy for COVID-19 pneumonia in the ICU was associated with an increase in ICU-free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high-dose corticosteroids on mortality was favorable.


Lysine‑specific demethylase 2 contributes to the proliferation of small cell lung cancer by regulating the expression of TFPI‑2.
The present study aimed to investigate the effect of lysine‑specific demethylase 2 (LSD2) in small cell lung cancer (SCLC) and explore its underlying regulatory mechanism. Cell growth was tested by MTT assay and mRNA and protein expression was determined by quantitative polymerase chain reaction (q‑PCR) and western blot analysis, respectively. Chromatin immunoprecipitation (ChIP) was used to investigate the degree of H3K4me2 enrichment in the promoter region of tissue factor pathway inhibitor‑2 (TFPI‑2). SCLC tissues and cell lines presented significantly higher expression of LSD2 and DNA methyltransferase 3B (DNMT3B) and lower expression of TFPI‑2 compared with the controls. In H1417 cells LSD2 overexpression increased the mRNA and protein expression of DNMT3B, while inhibiting the mRNA and protein expression of TFPI‑2. Following transfection with short interfering (si) RNA‑DNMT3B, the expression of TFPI‑2 increased in H1417 cells. The results of ChIP demonstrated that compared with the controls, H3K4me1 enrichment in the TFPI‑2 promoter region was to a lower degree in the H1417 cells with LSD2 overexpression and a higher degree in the H1417 cells with LSD2 silencing. MTT assays revealed that LSD2 overexpression significantly promoted the growth of H69, DMS‑114 and H1417 cells, which was contradictory to the effect on LSD2 silencing. Compared with the LSD2 overexpression cells, SCLC cells with simultaneous overexpression of LSD2 and TFPI‑2 demonstrated a decreased proliferation. These results suggest that LSD2 achieves a promoting effect on SCLC by indirectly regulating TFPI‑2 expression through the mediation of DNMT3B expression or through the regulation of the demethylation of H3K4me1 in the promoter region of the TFPI‑2 gene.


Compliance of e-cigarette refill liquids with regulations on labelling, packaging and technical design characteristics in nine European member states.
To evaluate electronic cigarette (e-cigarette) product compliance with European regulations (Tobacco Products Directive (TPD), Implementing Decisions), with a focus on labelling/packaging practices and technical design/safety features. Before the implementation of the TPD, in early 2016, we randomly selected e-cigarette refill liquids from the five top-selling companies in France, Poland, Germany, Netherlands, UK, Spain, Romania, Hungary and Greece. Identical products were purchased after the implementation of the TPD (early 2018) and assessment of compliance was performed on self-matched samples (n=107) using a prospective cohort design. Compliance with the Classification, Labelling and Packaging (CLP) regulations was also evaluated. Following the implementation of the TPD, improvements were noted with regards to the existence of text-only warnings (32.7% pre vs 86.0% post, p<0.001), child-resistant fastenings (93.3% pre vs 100.0% post, p=0.016), tamper-proof vials (58.9% pre vs 86.9%, post p<0.001) and maximum refill volume ≤10 mL in vials (86.9% pre vs 94.4% post, p=0.008). Lower compliance was noted with regards to the inclusion of a leaflet (26.2% pre vs 53.3% post, p<0.001), refilling instructions (28.0% pre vs 51.4% post, p<0.001) and health warnings on the box, vial or leaflet (32.7% pre vs 86.0%, p<0.001). Overall, 86.0% of products had a warning label in the post-TPD phase in comparison to 32.7% of products before the implementation of the TPD (p<0.001). Compliance with the CLP regulations, also increased in the post TPD follow-up phase. This is the first study to evaluate the level of implementation of the e-cigarette regulations in nine EU member states. Our results indicate that refill liquids had substantial but not full compliance in most of the characteristics evaluated. Further effort is needed to ensure complete compliance.


Mutation analysis of BRAF exon 15 and KRAS codons 12 and 13 in Moroccan patients with colorectal cancer.
The RAS/RAF/MEK/MAP kinase cascade transduces signals from the cell surface to the nucleus in order to control cellular responses including proliferation, differentiation and survival. We investigated the occurrence of BRAF exon 15 and KRAS codon 12 and 13 mutations in Moroccan patients with colorectal cancer. Sixty-two samples from patients with sporadic colorectal adenocarcinomas were studied for BRAF exon 15 and KRAS codon 12 and 13 mutations. DNA from paraffin-embedded tissue specimens was analyzed by a combination of polymerase chain reaction-high resolution melting and direct sequencing. Of the analyzed specimens, 29% exhibited KRAS codon 12 or 13 mutations and only 1.6% carried a BRAF codon 600 mutation. KRAS mutations were more often observed in women (35.5%) than in men (22.6%). Patients in the age range between 41 and 60 years were more likely to be carriers of this mutation. No KRAS mutations were detected in patients aged >60 years. Despite the limited study sample, our data suggest that KRAS mutations arise more frequently than BRAF mutations in Moroccan patients with colorectal carcinomas. The KRAS mutation status must be assessed in a large cohort of Moroccan patients to confirm these findings and to determine whether this mutation in combination with extrinsic, environmental or microenvironmental factors might be involved in the high frequency of colorectal cancer in middle-aged Moroccans.


Validation of the 3D reconstructed human skin Comet assay, an animal-free alternative for following-up positive results from standard in vitro genotoxicity assays.
As part of the safety assessment process, all industrial sectors employ genotoxicity test batteries, starting with well-established in vitro assays. However, these batteries have limited predictive capacity for the in vivo situation, which may result in unnecessary follow-up in vivo testing or the loss of promising substances where animal tests are prohibited or not desired. To address this, a project involving regulators, academia and industry was established to develop and validate in vitro human skin-based genotoxicity assays for topically exposed substances, such as cosmetics ingredients. Here, we describe the validation of the 3D reconstructed skin (RS) Comet assay. In this multicenter study, chemicals were applied topically three times to the skin over 48 h. Isolated keratinocytes and fibroblasts were transferred to slides before electrophoresis and the resulting comet formation was recorded as % tail DNA. Before decoding, results of the validation exercise for 32 substances were evaluated by an independent statistician. There was a high predictive capacity of this assay when compared to in vivo outcomes, with a sensitivity of 77 (80)%, a specificity of 88 (97)% and an overall accuracy of 83 (92)%. The numbers reflect the calls of the performing laboratories in the coded phase, whereas those in parenthesis reflect calls according to the agreed evaluation criteria. Intra- and inter-laboratory reproducibility was also very good, with a concordance of 93 and 88%, respectively. These results generated with the Phenion® Full-Thickness skin model demonstrate its suitability for this assay, with reproducibly low background DNA damage and sufficient metabolic capacity to activate pro-mutagens. The validation outcome supports the use of the RS Comet assay to follow up positive results from standard in vitro genotoxicity assays when the expected route of exposure is dermal. Based on the available data, the assay was accepted recently into the OECD test guideline development program.


ICU nurses' experiences in providing terminal care.
At least 1 in 5 Americans die while using intensive care service-a number that is expected to increase as society ages. Many of these deaths involve withholding or withdrawing life-sustaining therapies. In these situations, the role of intensive care nurses shifts from providing aggressive care to end-of-life care. While hospice and palliative care nurses typically receive specialized support to cope with death and dying, intensive care nurses usually do not receive this support. Understanding the experiences of intensive care nurses in providing care at the end of life is an important first step to improving terminal care in the intensive care unit (ICU). This phenomenological research study explores the experiences of intensive care nurses who provide terminal care in the ICU. The sample consisted of 18 registered nurses delivering terminal care in an ICU that participated in individual interviews and focus groups. Colaizzi's steps for data analysis were used to identify themes within the context of nursing. Three major themes consisted of (1) barriers to optimal care, (2) internal conflict, and (3) coping. Providing terminal care creates significant personal and professional struggles among ICU nurses.


Long-term Outcomes of Multiple Arterial Coronary Artery Bypass Grafting: A Population-Based Study of Patients in British Columbia, Canada.
Although the long-term survival advantage of multiple arterial grafting (MAG) vs the standard use of left internal thoracic artery (LITA) supplemented by saphenous vein grafts (LITA+SVG) has been demonstrated in several observational studies, to our knowledge its safety and other long-term clinical benefits in a large, population-based cohort are unknown. To compare the safety and long-term outcomes of MAG vs LITA+SVG among overall and selected subgroups of patients. In this population-based observational study, we included 20 076 adult patients with triple-vessel or left-main disease who underwent primary isolated coronary artery bypass grafting (MAG, n = 5580; LITA+SVG, n = 14 496) in the province of British Columbia, Canada, from January 2000 to December 2014, with follow-up to December 2015. We performed propensity-score analyses by weighting and matching and multivariable Cox regression to minimize treatment selection bias. Multiple arterial grafting or LITA+SVG. Mortality, repeated revascularization, myocardial infarction, heart failure, and stroke. Of 5580 participants who underwent MAG, 586 (11%) were women and the mean (SD) age was 60 (8.7) years. Of 14 496 participants who underwent LITA+SVG, 2803 (19%) were women and the mean (SD) age was 68 (8.9) years. The median (interquartile range) follow-up time was 9.1 (5.1-12.6) years and 8.1 (4.5-11.7) years for the groups receiving MAG and LITA+SVG, respectively. Compared with LITA+SVG, MAG was associated with reduced mortality rates (hazard ratio [HR], 0.79; 95% CI, 0.72-0.87) and repeated revascularization rates (HR, 0.74; 95% CI, 0.66-0.84) in 15-year follow-up and reduced incidences of myocardial infarction (HR, 0.63; 95% CI, 0.47-0.85) and heart failure (HR, 0.79; 95% CI, 0.64-0.98) in 7-year follow-up. The long-term benefits were coherent by all 3 statistical methods and persisted among patient subgroups with diabetes, obesity, moderately impaired ejection fraction, chronic obstructive pulmonary disease, peripheral vascular disease, or renal disease. Multiple arterial grafting was not associated with increased morbidity or mortality rates at 30 days overall or within patient subgroups. Compared with LITA+SVG, MAG is associated with reduced mortality, repeated revascularization, myocardial infarction, and heart failure among patients with multivessel disease who are undergoing coronary artery bypass grafting without increased mortality or other adverse events at 30 days. The long-term benefits consistently observed across multiple outcomes and subgroups support the consideration of MAG for a broader spectrum of patients who are undergoing coronary artery bypass grafting in routine practice.


Retinopathy of prematurity screening criteria in Iran: new screening guidelines.
To test the applicability of existing retinopathy of prematurity (ROP) guidelines on Iranian patients and to develop novel ROP screening criteria in Iran. Both eyes of 1932 infants born ≤37 weeks of gestation and/or weighting ≤3000 g were included in this prospective cohort study that was conducted across nine neonatal intensive care units and a tertiary eye hospital ROP clinic. The patients were examined for ROP and the need for treatment (type 1 ROP or worse). All the patients were screened 4 weeks after birth or at 31 weeks of postmenstrual age, whichever was later. The patients were followed until retinal vascularisation was completed or the patients reached 50 weeks of gestational age (GA) without prethreshold ROP. A receiver operating characteristic curve was used to determine the best screening criteria for ROP. Screening criteria from other countries were applied to our patient data to determine their ability to appropriately detect ROP. Patients with ROP requiring treatment. The mean GA±SD and birth weight (BW)±SD of the screened patients were 32±2.7 weeks and 1713±516 g, respectively. Using criteria of GA≤32 weeks or BW ≤2000 yielded sensitivity and specificity of 100% and 26.7%, respectively, for treatment requiring ROP regardless of clinical comorbidities. Using screening recommendations of American Academy of Pediatrics would miss 25.4% of ROP and 8.4%ROP requiring treatment in our cohort. Other countries screening recommendations would result in a significant amount of missed cases of treatment requiring ROP when applied to Iran. As a result, we have proposed new guidelines for premature babies in Iran.


Multiple-window parallel adaptive boundary finding in computer vision.
The problem considered in this paper is the estimation of highly variable object boundaries in noisy images. Boundaries may be those of a tank in an IR image, a spinal canal in a CAT scan, a cloud in a visible light image, etc. Or they may be internal to an object such as the boundary between a spherical surface and a cylindrical surface in a manufactured object. The focus of the paper is on parallel multiple-window boundary estimation algorithms. Here the image field is parti-tioned into an array of rectangular windows, and boundary finders are run simultaneously within the windows. The boundary segments found within the windows are then seamed together to obtain meaningful global boundaries. The entire procedure is treated within a maximum likelihood estimation framework that we have developed for boundary finding. Although our multiple-window estimation approach can be used with a number of local boundary finding algorithms, we concen-trate on one which is based on dynamic programming and will produce the true maximum likelihood boundary. Some theoretical considera-tions for boundary model design and boundary-finding runtime are covered. Included is the use of a low computational cost F-test for test-ing whether a window contains a boundary, and an analytical treatment which shows that use of coarse pixels with a chi-square test or an F-test improves the probability of correctly recognizing whether a boundary is present in a window.


Cerclage Wiring Through a Mini-Open Approach to Assist Reduction of Subtrochanteric Fractures Treated With Cephalomedullary Fixation: Surgical Technique.
Despite advances in the management of subtrochanteric fractures, in particular with the use of cephalomedullary nails, outcomes remain worse than other fractures of the proximal femur. Because an anatomic reduction is needed to offer the best results, several methods of reduction, using clamps and wires have been described. Reduction of fractures in elderly patients is especially complicated because of poor bone quality, comorbidities, and unfavorable fracture patterns. We describe a new technique of reduction and cerclage wiring through a mini-open approach for isolated subtrochanteric, as well as intertrochanteric fractures with extension into the subtrochanteric area, and report our results in a series of patients.


The interplay between neuroinflammatory pathways and Parkinson's disease.
Parkinson's disease, a progressive neurodegenerative disorder predominantly affecting elderly, is marked by the gradual degeneration of the nigrostriatal dopaminergic pathway, culminating in neuronal loss within the substantia nigra pars compacta (SNpc) and dopamine depletion. At the molecular level, neuronal loss in the SNpc has been attributed to factors including neuroinflammation, impaired protein homeostasis, as well as mitochondrial dysfunction and the resulting oxidative stress. This review focuses on the interplay between neuroinflammatory pathways and Parkinson's disease, drawing insights from current literature.


The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to hepatic inflammation to cirrhosis. We sought to identify common genetic variants contributing to NAFLD, using CT measured fatty liver (FL), and alanine aminotransferase levels (ALT), as a biochemical marker of hepatic inflammation. We employed a correlated meta-analysis (CMA) to test whether combining FL and ALT genomewide association (GWA) results, using ∼2.5 million imputed SNPs, could enhance ability to detect variants influencing both traits. Variants of the ERLIN1-CHUK-CWF19L1 gene cluster were associated with concomitant variation of FL and ALT. Nine variants (rs2862954, rs1408579, rs10883451, rs11597086, rs11591741, rs17729876, rs17668255, rs17668357, rs12784396) displayed genomewide significant associations at loci concomitantly influencing FL and ALT (2.47 × 10(-9) ≤ CMA-p ≤ 4.29 × 10(-10)) as compared with the suggestive significance of marginal tests (4.11 × 10(-5) ≤ GWA-p ≤ 2.34 × 10(-6)). For example, the missense variant in ERLIN1-rs2862954 was genomewide significant (CMA-p = 4.88 × 10(-10)) for the combination of FL and ALT, while the respective univariate associations were suggestive (FL:p = 5.74 × 10(-6), ALT:p = 3.71 × 10(-6)). Further we investigated whether the concomitant associations were driven mainly by ALT levels. When we adjusted FL by ALT, the correlated associations diminished but did not vanish (CMA-p ≤ 3.3 × 10(-7)). Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of FL accumulation (measured by CT) to hepatic inflammation (ALT levels), and the association enhances when accounting for the correlations between their scans. CMA approach enhanced the ability to identify novel variants of the ERLIN1-CHUK-CWF19L1 influencing both simple steatosis and hepatic steatosis with inflammation, which suggest that this gene cluster may regulate the susceptibility of NAFLD in a wide spectrum of disease.


Obesity Pharmacotherapy is Effective in the Veterans Affairs Patient Population: A Local and Virtual Cohort Study.
Obesity is a major public health challenge, and the US military veteran population is disproportionately affected. Using deidentified records from a local weight management clinic and a national clinical data repository, obesity pharmacotherapy use and effectiveness for weight loss and obesity comorbidities in this vulnerable population were assessed. During the initial year of the local clinic, 43 records with monthly follow-up of MOVE! lifestyle intervention augmented by obesity pharmacotherapy were found. Nationally, more than 2 million records of prescribed obesity pharmacotherapy compared with metformin as control were identified. Records with detailed documentation of weight trends from 1 year before to 1 year after the prescription date for further analysis were selected for review. The most commonly prescribed medications in the local clinic were metformin, liraglutide, and combination phentermine/topiramate. On average, weight loss of -4.0 ± 2.1 kg over the initial 6-month intervention was observed. In the national cohort, 577,491 records with an obesity or control metformin prescription and adequate weight documentation were identified. The most effective pharmacotherapy in the national cohort was phentermine/topiramate (-0.0931 ± 0.0198 kg/wk difference), followed by liraglutide, lorcaserin, and orlistat. Obesity pharmacotherapy is effective in achieving clinically meaningful weight loss in veterans as part of an integrated care approach.


Many lifetime growth trajectories for a single mammal.
Despite their importance in shaping life history tactics and population dynamics, individual growth trajectories have only been rarely explored in the wild because their analysis requires multiple measurements of individuals throughout their lifetime and some knowledge of age, a key timer of body growth. The availability of long-term longitudinal studies of two wild boar populations subjected to contrasting environments (rich vs. poor) provided an opportunity to analyze individual growth trajectories. We quantified wild boar growth trajectories at both the population and the individual levels using standard growth models (i.e., Gompertz, logistic, and monomolecular models) that encompass the expected range of growth shapes in determinate growers. Wild boar is a rather altricial species, with a polygynous mating system and is strongly sexually dimorphic in size. According to current theories of life history evolution, we thus expect wild boar to display a sex-specific Gompertz type growth trajectory and lower sexual size dimorphism in the poorer environment. While wild boar displayed the expected Gompertz type trajectory in the rich site at the population level, we found some evidence for potential differences in growth shapes between populations and individuals. Asymptotic body mass, growth rate and timing of maximum growth rate differed as well, which indicates a high flexibility of growth in wild boar. We also found a cohort effect on asymptotic body mass, which suggests that environmental conditions early in life shape body mass at adulthood in this species. Our findings demonstrate that body growth trajectories in wild boar are highly diverse in relation to differences of environmental context, sex and year of birth. Whether the intermediate ranking of wild boar along the precocial-altricial continuum of development at birth may explain the ability of this species to exhibit this high diversity of growth patterns remains to be investigated.


Folded edge of turbulence in a pipe.
The results of an experimental investigation into the threshold boundary between laminar and disordered pipe flow are presented. Complex features have been uncovered using a highly refined experimental approach where an intermediate periodic state forms an integral part of the transition sequence. In accord with the suggestions produced by a numerical investigation, the boundary is found to be folded with a complicated structure. This raises important questions about accepted definitions of threshold amplitudes in this long-standing problem.


Reference chart derived from post-stent-implantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography.
Intravascular ultrasound (IVUS)-guided stent implantation and the availability of a reference chart to predict the expected in-stent restenosis rate based on operator-dependent IVUS parameters may interactively facilitate optimal stent placement. The use of IVUS guidance protects against undue risks of dissection or rupture. IVUS-determined post-stent-implantation predictors of 6-month in-stent restenosis on quantitative coronary angiography (QCA) were identified by logistic regression analysis. These predictors were used to construct a reference chart that predicts the expected 6-month QCA restenosis rate. IVUS and QCA data were obtained from 3 registries (MUSIC [Multicenter Ultrasound Stenting in Coronaries study], WEST-II [West European Stent Trial II], and ESSEX [European Scimed Stent EXperience]) and 2 randomized in-stent restenosis trials (ERASER [Evaluation of ReoPro And Stenting to Eliminate Restenosis] and TRAPIST [TRApidil vs placebo to Prevent In-STent intimal hyperplasia]). In-stent restenosis was defined as luminal diameter stenosis >50% by QCA. IVUS predictors were minimum and mean in-stent area, stent length, and in-stent diameter. Multiple models were constructed with multivariate logistic regression analysis. The model containing minimum in-stent area and stent length best fit the Hosmer-Lemeshow goodness-of-fit test. This model was used to construct a reference chart to calculate the expected 6-month restenosis rate. The expected 6-month in-stent restenosis rate after stent implantation for short lesions in relatively large vessels can be predicted by use of in-stent minimal area (which is inversely related to restenosis) and stent length (which is directly related to restenosis), both of which can be read from a simple reference chart.


Early atherosclerosis exhibits an enhanced procoagulant state.
Thrombin generation in vivo may be important in regulating atherosclerotic progression. In the present study, we examined for the first time the activity and presence of relevant coagulation proteins in relation to the progression of atherosclerosis. Both early and stable advanced atherosclerotic lesions were collected pairwise from each individual (n=27) during autopsy. Tissue homogenates were prepared from both total plaques and isolated plaque layers, in which the activity of factors (F) II, X, and XII and tissue factor was determined. Microarray analysis was implemented to elucidate local messenger RNA synthesis of coagulation proteins. Part of each specimen was paraffin embedded, and histological sections were immunohistochemically stained for multiple coagulation markers with the use of commercial antibodies. Data are expressed as median (interquartile range [IQR]). Tissue factor, FII, FX, and FXII activities were significantly higher in early atherosclerotic lesions than in stable advanced atherosclerotic lesions. Endogenous thrombin potential and thrombin-antithrombin complex values consolidated a procoagulant profile of early atherosclerotic lesions (endogenous thrombin potential, 1240 nmol/L x min [IQR, 1173 to 1311]; thrombin-antithrombin complex, 1045 ng/mg [IQR, 842.6 to 1376]) versus stable advanced atherosclerotic lesions (endogenous thrombin potential, 782 nmol/L x min [IQR, 0 to 1151]; thrombin-antithrombin complex, 718.4 ng/mg [IQR, 508.6 to 1151]). Tissue factor, FVII, and FX colocalized with macrophages and smooth muscle cells. In addition, multiple procoagulant and anticoagulant proteases were immunohistochemically mapped to various locations throughout the atherosclerotic vessel wall in both early and advanced atherosclerotic stages. This study shows an enhanced procoagulant state of early-stage atherosclerotic plaques compared with advanced-stage plaques, which may provide novel insights into the role of coagulation during atherosclerotic plaque progression.


Low Subjective Cardiovascular Disease Risk Perceptions among Hypertensive Patients in Addis Ababa, Ethiopia.
Accurate cardiovascular disease (CVD) risk appraisal is essential for hypertensive patients to identify correctly their risk status and take efficient behavioral measures timely to avoid major adverse outcomes. However, hypertensive patients' risk perceptions of CVD events in Ethiopia are unknown. Thus, the study aimed to compare the subjective CVD risk perception level of patients with the nonlaboratory Framingham Risk Score (nl-FRS). A cross-sectional design was used. The Attitudes and Beliefs about Cardiovascular Disease Risk Questionnaire and the nl-FRS were used to compare subjective versus objective measures of CVD risk. Agreement between participants' risk perceptions and the nl-FRS were examined using the kappa statistic. Bivariate chi-square test and multinomial logistic regression analyses were run to identify factors associated with risk perceptions. The statistical significance was set at a p-value < 0.05 level. Participants (n=377) had a mean age of 53.61 ± 12.80-years, range (18-82 years), 51.2% were males, 42.7% had less than high school education, 45.1% achieved target BP control, and mean HTN duration was 8.01 ± 6.07 years. The majority (58.62%) of the participants had a low subjective risk perception of CVD events (mean 17.79, 95% CI: 17.43-18.15). Approximately three-fourths (72.4%) had a moderate nl-FRS risk calculation (mean, 13.84, 95% CI: 13.36-14.33). Agreement between participants perceived-risk and the nl-FRS was poor (kappa = 0.0002, standard error = 0.023, p =0.99). Participants' CVD risk-perception inaccuracy was also high (76%) primarily due to underestimation. Hypertension duration, frequency of physician visits, and level of diabetes control were significant predictors of CVD risk underestimation. Hypertensive patients had inaccurate and low subjective risk perceptions of CVD events compared to moderate objective risks identified using the nl-FRS. Planned education on HTN and CVD risk factors is essential to improve patients' CVD risk perception to reduce adverse CVD events.


The reovirus sigma1 aspartic acid sandwich: a trimerization motif poised for conformational change.
Reovirus attachment protein sigma1 mediates engagement of receptors on the surface of target cells and undergoes dramatic conformational rearrangements during viral disassembly in the endocytic pathway. The sigma1 protein is a filamentous, trimeric molecule with a globular beta-barrel head domain. An unusual cluster of aspartic acid residues sandwiched between hydrophobic tyrosines is located at the sigma1 subunit interface. A 1.75-A structure of the sigma1 head domain now reveals two water molecules at the subunit interface that are held strictly in position and interact with neighboring residues. Structural and biochemical analyses of mutants affecting the aspartic acid sandwich indicate that these residues and the corresponding chelated water molecules act as a plug to block the free flow of solvent and stabilize the trimer. This arrangement of residues at the sigma1 head trimer interface illustrates a new protein design motif that may confer conformational mobility during cell entry.


[Allogeneic tendoplasty in surgery of the locomotor system].
Allogenic tendotransplants were used in the treatment of different lesions and diseases of the locomotor apparatus in 410 patients. Good anatomical and functional results were obtained in 84% of the patients. Unsatisfactory results were noted in 7% of cases. The method of preservation of allogenic tendons had no influence upon the results.


Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization.
Synaptic GTPase-activating protein (SynGAP) is a neuronal-specific Ras/Rap-GAP that increases the hydrolysis rate of GTP to GDP, converting Ras/Rap from the active into the inactive form. The Ras protein family modulates a wide range of cellular pathways including those involved in sensitization of sensory neurons. Since GAPs regulate Ras activity, SynGAP might be an important regulator of peripheral sensitization and pain. Therefore, we evaluated excitability, stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP), and nociception from wild-type (WT) mice and those with a heterozygous mutation of the SynGAP gene (SynGAP(+/-)). Our results demonstrate that SynGAP is expressed in primary afferent sensory neurons and that the capsaicin-stimulated CGRP release from spinal cord slices was two-fold higher from SynGAP(+/-) mice than that observed from WT mouse tissue, consistent with an increase in expression of the capsaicin receptor, transient receptor potential cation channel subfamily V member 1 (TRPV1), in SynGAP(+/-) dorsal root ganglia. However, there was no difference between the two genotypes in potassium-stimulated release of CGRP, the number of action potentials generated by a ramp of depolarizing current, or mechanical hypernociception elicited by intraplantar injection of capsaicin. In contrast, capsaicin-induced thermal hypernociception occurred at lower doses of capsaicin and had a longer duration in SynGAP(+/-) mice than WT mice. These results provide the first evidence that SynGAP is an important regulator of neuropeptide release from primary sensory neurons and can modulate capsaicin-induced hypernociception, demonstrating the importance of GAP regulation in signaling pathways that play a role in peripheral sensitization.


Decompositional odor analysis database.
This study, conducted at the University of Tennessee's Anthropological Research Facility (ARF), describes the establishment of the Decompositional Odor Analysis (DOA) Database for the purpose of developing a man-portable, chemical sensor capable of detecting clandestine burial sites of human remains, thereby mimicking canine olfaction. This "living" database currently spans the first year and a half of burial, providing identification, chemical trends and semi-quantitation of chemicals liberated below, above and at the surface of graves 1.5 to 3.5 ft deep (0.45 to 1.0 m) for four individuals. Triple sorbent traps (TSTs) were used to collect air samples in the field and revealed eight major classes of chemicals containing 424 specific volatile compounds associated with burial decomposition. This research is the first step toward identification of an "odor signature" unique to human decomposition with projected ramifications on cadaver dog training procedures and in the development of field portable analytical instruments which can be used to locate human remains buried in shallow graves.


Effects of immunization against luteinizing hormone-releasing hormone and treatment with trenbolone acetate on reproductive function of beef bulls and steers.
The objectives of this study were 1) to evaluate the ability of trenbolone acetate (TBA) administered in tandem with LHRH immunization to suppress reproductive function in bulls and 2) to examine the effects of LHRH and androgen (TBA) signaling on pituitary gland function. Forty-four Angus × Hereford crossbred calves (BW=225 ± 2 kg; age=187 ± 6 d) received castration, LHRH immunization, or TBA administration in a 2 × 2 × 2 factorial design. Treatment groups receiving LHRH immunization contained 6 animals, whereas other treatment groups contained 5 animals. Animals immunized against LHRH received a primary injection and 2 booster injections of ovalbumin-LHRH-7 fusion protein on d 0, 42, and 196, respectively. Animals treated with TBA were implanted on d 224. Serum LHRH antibodies increased (P<0.05) after each booster for immunized animals, but were negligible in nonimmunized animals throughout the experiment. Serum testosterone concentration (P<0.001) and scrotal circumference (P<0.05) were depressed in LHRH-immunized bulls compared with nonimmunized bulls by d 84 and 168 of the experiment, respectively. Treatment with TBA tended (P=0.08) to decrease serum testosterone concentrations of nonimmunized bulls. Weights of testes at slaughter were decreased (P<0.001) for LHRH-immunized (232 ± 41 g) compared with nonimmunized (752 ± 45 g) bulls, but did not differ (P=0.80) between TBA-implanted (500 ± 49 g) and nonimplanted bulls (484 ± 36 g). Both LHRH immunization and castration decreased pituitary gland stores of LH and FSH (P<0. 001). There was no effect (P>0.10) of TBA on pituitary gland FSH content and only a tendency (P=0.09) to increase pituitary gland LH content. Immunization against LHRH decreased expression of LH β-subunit and common α-subunit genes (P<0.001). Castration increased expression of LH β-subunit and common α-subunit genes (P=0.02). Treatment with TBA further suppressed (P=0.04) α-subunit mRNA expression in LHRH-immunized steers. In summary, LHRH immunization decreased synthesis and storage of LH and decreased storage, but not synthesis of FSH in bulls. The increased synthesis of LH and FSH in nonimmunized, but not LHRH-immunized steers suggests that castration removes the negative feedback on gonadotropin synthesis but that LHRH is still needed for release of these hormones. Androgen replacement with TBA did not restore the negative feedback control of gonadotropin synthesis.


Effects of acculturation on a culturally adapted diabetes intervention for Latinas.
To inform the refinement of a culturally adapted diabetes intervention, we evaluated acculturation's association with variables at several sequential steps: baseline measures of diet and physical activity, intervention engagement, putative mediators (problem solving and social resources), and outcomes (fat consumption and physical activity). Latina women (N = 280) recruited from health organizations were randomly assigned to a culturally adapted lifestyle intervention (¡Viva Bien!) or usual care. A brief version of the Acculturation Rating Scale for Mexican Americans-II (ARSMA-II) acculturation scales (Anglo and Latina orientations) was administered at baseline. Assessments at baseline, 6 months, and 12 months included social supportive resources for diet and exercise, problem solving, saturated fat consumption, and physical activity. Latina orientation was negatively related to saturated fat intake and physical activity at baseline. Latina orientation also was positively related to session attendance during Months 6-12 of the intervention. Independent of 6-month intervention effects, Anglo orientation was significantly positively related to improvements in problem solving and dietary supportive resources. Anglo orientation related negatively to improved physical activity at 6 and 12 months. There were no Acculturation × Intervention interactions on putative mediators or outcomes. The cultural adaptation process was successful in creating an engaging and effective intervention for Latinas at all levels of acculturation. However, independent of intervention effects, acculturation was related to putative mediating variables (problem solving and social resources) and an outcome variable (physical activity), an indication of acculturation's general influence on lifestyle and coping factors.


Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.
Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.


LINE-1 as a therapeutic target for castration-resistant prostate cancer.
Prostate cancer is the third leading cause of death by cancer in men. Surgery or hormone deprivation usually contains the progression of the local forms of the disease. In metastatic situations, chemotherapy or second generation hormone therapies are used with an overall survival that never exceeds 36 months when tumors become resistant to castration. In the search for new alternatives, clinical trials with various classes of anticancer drugs have been performed, including chemotherapies, targeted therapies with kinase inhibitors, radium-223, or immunotherapies with somehow limited efficacy. Targeting LINE-1 with reverse transcriptase inhibitors was also proposed as an attractive strategy as retrotransposons may play a role in the initiation and the progression of prostate cancers. After reviewing the biological rational to use RT inhibitors in the treatment of prostate cancers, we will discuss the results of the phase II trial evaluating the efficacy of Efavirenz in the treatment of castration-resistant prostate cancers with a particular emphasis on pharmacokinetics data that were obtained. We will also discuss the positioning of other RT inhibitors in the current therapeutic armamentarium.


Modeling colorectal cancer evolution.
Understanding cancer evolution provides a clue to tackle therapeutic difficulties in colorectal cancer. In this review, together with related works, we will introduce a series of our studies, in which we constructed an evolutionary model of colorectal cancer by combining genomic analysis and mathematical modeling. In our model, multiple subclones were generated by driver mutation acquisition and subsequent clonal expansion in early-stage tumors. Among the subclones, the one obtaining driver copy number alterations is endowed with malignant potentials to constitute a late-stage tumor in which extensive intratumor heterogeneity is generated by the accumulation of neutral mutations. We will also discuss how to translate our understanding of cancer evolution to a solution to the problem related to therapeutic resistance: mathematical modeling suggests that relapse caused by acquired resistance could be suppressed by utilizing clonal competition between sensitive and resistant clones. Considering the current rate of technological development, modeling cancer evolution by combining genomic analysis and mathematical modeling will be an increasingly important approach for understanding and overcoming cancer.


Differences in resting corticolimbic functional connectivity in bipolar I euthymia.
We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low-frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically important imaging biomarker.


Association of polymorphic alleles of the calcium-sensing receptor gene with parathyroid hormone secretion in hemodialysis patients.
The present study was performed to investigate the association of calcium-sensing receptor (CaSR) genotypes with parathyroid hormone (PTH) secretion in hemodialysis patients. Subjects were 122 Japanese hemodialysis patients, including 39 patients with diabetes mellitus (DM). The CaSR polymorphisms tested were codon 990 in intracellular domain (A/A, A/G, and G/G groups) as well as T to C base change of intron 4 (T/T, T/C, and C/C groups). Statistical analysis of these polymorphisms revealed that the serum PTH level was significantly higher in the A/A group than in the G/G group in the former. In addition, the serum PTH level was also significantly higher in patients displaying C allele, as compared with the T/T group in the latter. This association of two polymorphisms with the serum PTH level was observed only in non-DM patients. Although two polymorphisms affected the PTH level independently, patients who possessed both genotypes (AAC+) had a markedly high level of PTH not only in the non-DM group but also in the DM group. The present findings indicate the possibility of the prediction for the extensive progression of secondary hyperparathyroidism through analyzing the CaSR polymorphisms in chronic hemodialysis patients.


Nerve injury-induced c-Jun activation in Schwann cells is JNK independent.
We investigated (a) if activation of the mitogen activated protein kinase (MAPK) pathway was linked to the stress activated protein kinase (SAPK) pathway and (b) if JNK was required for activation of c-Jun in Schwann cells of rat sciatic nerve following injury. To this aim, ERK1/2 and the transcription factors c-Jun and ATF-3 were studied by immunohistochemistry in segments of transected nerves. We utilized pharmacological inhibitors of both signal transduction pathways in vitro to determine the effects on downstream signalling events, such as c-Jun activation, and on Schwann cell survival and proliferation. A transection induces c-Jun and ATF-3 transcription in Schwann cells. These events are followed by Schwann cell activation of c-Jun in the injured nerve. The MAPK inhibitor U0126 blocked ERK1/2 activation and reduced Schwann cell proliferation as well as induction of c-Jun transcription. The JNK inhibitor SP600125 reduced Schwann cell proliferation, but did not affect the expression of ERK1/2 or injury-induced increases in c-Jun or ATF-3 levels. Importantly, nerve injury induces Schwann cell activation of c-Jun by phosphorylation, which, in contrast to in sensory neurons, is JNK independent. MAP kinases, other than JNK, can potentially activate c-Jun in Schwann cells following injury; information that is crucial to create new nerve reconstruction strategies.


Injectable nanospheres from a novel multiblock copolymer: cytocompatibility, degradation and in vitro release studies.
The aim was to develop and characterize nanospheres made from a newly synthesized poly (D,L-lactide-co-ethyleneglycol) (-PLA-PEG-PLA-)n multiblock copolymer. Nanospheres were prepared under optimized conditions of modified emulsion-solvent evaporation technique in a continuous flow process using rhodamine B as a drug model. They were characterized for size distribution, zeta (zeta) potential, porosity and morphology. Drug loading and yield were also determined. In vitro degradation studies of the copolymer were conducted in phosphate buffer (pH 7.4) at 37 degrees C. The cytotoxic properties of the polymer and vector were analysed by dimethylthiazoldiphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays on the B16 mouse cell line. Release of rhodamine B from the nanospheres was assayed in vitro using a dialysis bag in isotonic phosphate buffer (pH 7.4) at 37 degrees C. Spherical and non-porous nanospheres with mean size less than 800 nm could be prepared. The (zeta) potential was neutral. The average yield was approximately 70% with 7% rhodamine loading. A total of 50% of the multiblock underwent initial degradation after 4 weeks, while degradation was complete after 16 weeks. Cellular proliferation was not inhibited as no cytotoxicity was observed with the copolymers and nanospheres. Rhodamine B was released in a stepwise pattern. The initial burst was 20%, and release was prolonged thereafter for 29 days. Thus, injectable nanospheres with prolonged rhodamine B release have been designed and characterized as a potential drug-delivery system.


Polynuclear Cu(i) and Ag(i) phosphine complexes containing multi-dentate polytopic ligands: syntheses, crystal structures and photoluminescence properties.
A series of polynuclear metal complexes, [Cu2(L1)(PPh3)4](ClO4)2 (1), [Cu3(L2)(PPh3)6](ClO4) (2), [Cu3(L3)(PPh3)6] (3), [Ag2(L1)(PPh3)4](BF4)2 (4), [Ag4(L2)2(PPh3)6] (5) and [Ag3(L3)(PPh3)5] (6), have been obtained from the reactions of the highly conjugated bridging ligands 2,3-bis(2-pyridyl)pyrazine (L1), 2,3-bis(2-tetrazoyl)pyrazine (H2L2) and 2,3-bis(2-tetrazoyl)imidazole (H3L3) with [Cu(MeCN)4]ClO4 and AgBF4, respectively. Their crystal structures have been determined by X-ray crystallography and their photophysical properties have been investigated in detail. Complexes 1 and 3 show photoluminescence in CH2Cl2 solution, while all the complexes exhibit obvious luminescence in the solid state; detailed photophysical studies and density functional theory calculations of these complexes have revealed that their lowest energy absorptions and emissions are predominantly derived from either metal-to-ligand charge-transfer (MLCT) or intraligand (IL) excited states.


Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer.
Patients diagnosed with triple-negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, which is a driver of tumor metastasis and resistance and a target for cancer vaccine approaches. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions. A strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provide rationale for using brachyury-targeting immunotherapy approaches for the treatment of TNBC.


Identification of pumping influences in long-term water level fluctuations.
Identification of the pumping influences at monitoring wells caused by spatially and temporally variable water supply pumping can be a challenging, yet an important hydrogeological task. The information that can be obtained can be critical for conceptualization of the hydrogeological conditions and indications of the zone of influence of the individual pumping wells. However, the pumping influences are often intermittent and small in magnitude with variable production rates from multiple pumping wells. While these difficulties may support an inclination to abandon the existing dataset and conduct a dedicated cross-hole pumping test, that option can be challenging and expensive to coordinate and execute. This paper presents a method that utilizes a simple analytical modeling approach for analysis of a long-term water level record utilizing an inverse modeling approach. The methodology allows the identification of pumping wells influencing the water level fluctuations. Thus, the analysis provides an efficient and cost-effective alternative to designed and coordinated cross-hole pumping tests. We apply this method on a dataset from the Los Alamos National Laboratory site. Our analysis also provides (1) an evaluation of the information content of the transient water level data; (2) indications of potential structures of the aquifer heterogeneity inhibiting or promoting pressure propagation; and (3) guidance for the development of more complicated models requiring detailed specification of the aquifer heterogeneity.


Selecting an Endourology Society Fellowship Program: The Candidates' Perspectives.
Introduction: Understanding the factors that influence the decision of urology residents to pursue an Endourology Society (ES) fellowship and the criteria used by applicants to rank programs may help residents and program directors (PDs) optimize the match process. In the present study, we surveyed current ES fellows to gain better insight surrounding their decision-making process. Materials and Methods: A survey was emailed to all ES fellows, comprising Endourology and Stone Disease (ESD), Laparoscopic and Robotic Surgery (MIS), and combination of ESD/MIS (COM) programs. A Likert scale ranging from 1 to 5 was used. The survey captured demographics such as geographic region, program type, duration, applicants' reasons for pursuing fellowship, criteria for ranking programs, and perceived improvements in surgical comfort levels at the end of their training. Results: Out of the 60 fellows who were surveyed, 40 (66.7%) responded. Among the respondents, 9 (22.5%) pursued ESD, 10 (25%) pursued MIS, and 21 (52.5%) pursued COM programs. The primary reason for seeking a fellowship was to improve surgical skills while increasing earning potential and enhancing research opportunities were deemed the least important. Fellows enrolled in 1-year programs were less likely to pursue fellowships for academic reasons. The two most significant factors in selecting a program were both related to gaining operative experience. Lastly, there was an increase in the level of comfort performing all endourological surgeries independently after fellowship. Conclusions: ES fellowship is seen as an opportunity to hone surgical skills and increase job competitiveness. When selecting a program, operative experience is the most important factor, and fellowship improves operative confidence. The information obtained from this study may mutually help guide future applicants and PDs in the decision process of the Endourology Match.


A systematic review of instruments that measure attitudes toward homosexual men.
Scientific interest in the measurement of homophobia and internalized homophobia has grown over the past 30 years, and new instruments and terms have emerged. To help researchers with the challenging task of identifying appropriate measures for studies in sexual-minority health, we reviewed measures of homophobia published in the academic literature from 1970 to 2012. Instruments that measured attitudes toward male homosexuals/homosexuality or measured homosexuals' internalized attitudes toward homosexuality were identified using measurement manuals and a systematic review. A total of 23 instruments met criteria for inclusion, and their features were summarized and compared. All 23 instruments met minimal criteria for adequate scale construction, including scale development, sampling, reliability, and evidence of validity. Validity evidence was diverse and was categorized as interaction with gay men, HIV/AIDS variables, mental health, and conservative religious or political beliefs. Homophobia was additionally correlated with authoritarianism and bias, gender ideology, gender differences, and reactions to homosexual stimuli. Internalized homophobia was validated by examining relationships with disclosing one's homosexuality and level of homosexual identity development. We hope this review will make the process of instrument selection more efficient by allowing researchers to easily locate, evaluate, and choose the proper measure based on their research question and population of interest.


Conflicts Between Women's Religiosity and Sense of Free Will in the Context of Elective Abortion: A Qualitative Study in the Worst Period of Italy's COVID-19 Crisis.
This qualitative study considers the relationship between abortion, bereavement, and the effects of the COVID-19 lockdown nine women who had undergone an elective abortion, which is voluntarily termination of a pregnancy at the woman's request. These women were interviewed in three time points (1 month, 6 months, and 1 year after the event) to consider the possible evolution of their experience. The third phase was concurrent with the COVID-19 pandemic and particularly with Pope Francis's Easter declaration against abortion. All the interviews were conducted and analysed through qualitative research in psychology. Results showed that the abortion experience led to physical, relational, and psychological suffering, similar to perinatal grief. Participants were non-practising Catholics and religiosity did not help them to overcome their sorrow. Though religiosity is a possible resilience factor in other stressful conditions, in this case it is a factor that aggravated suffering. Finally, we discuss the difficulties experienced by Catholic women who choose to have an abortion and assert the necessity of psychological and spiritual interventions to support these women.


Assessment of the control measures of the category A diseases of Animal Health Law: Burkholderia mallei (Glanders).
EFSA received a mandate from the European Commission to assess the effectiveness of some of the control measures against diseases included in the Category A list according to Regulation (EU) 2016/429 on transmissible animal diseases ('Animal Health Law'). This opinion belongs to a series of opinions where these control measures will be assessed, with this opinion covering the assessment of control measures for glanders. In this opinion, EFSA and the AHAW Panel of experts review the effectiveness of: (i) clinical and laboratory sampling procedures, (ii) monitoring period and (iii) the minimum radius of the protection and surveillance zone, and the minimum length of time the measures should be applied in these zones. The general methodology used for this series of opinions has been published elsewhere. Considering the epidemiology and distribution of glanders, it was foreseen that three different situations could lead to a suspicion of the disease. Sampling procedures were defined for each of the three different suspicion types, which can also be applied in most of the other scenarios assessed. The monitoring period (6 months) was assessed as effective in all scenarios. The AHAW Panel of experts considered the minimum radius and duration of the existing protection and surveillance zone, set at the establishment level, effective. Recommendations provided for each of the scenarios assessed aim to support the European Commission in the drafting of further pieces of legislation, as well as for plausible ad hoc requests in relation to glanders.


A survey of β-lactamase and 16S rRNA methylase genes among fluoroquinolone-resistant Escherichia coli isolates and their horizontal transmission in Shandong, China.
The prevalence of β-lactamase, 16S rRNA methylase genes, and plasmid-mediated fluoroquinolone-resistance (PMQR) determinants (qnrC and qnrD) was determined by polymerase chain reaction in fluoroquinolone-resistant Escherichia coli isolated from a chicken farm, a pig farm, and a hospital in Shandong, China in 2007. The bla(TEM) and bla(CTX-M) were the most prevalent β-lactamase genes in isolates from chickens (88.4%, 175/198 and 81.3%, 161/198) and hospitalized patients (87.8%, 122/139 and 69.1%, 96/139). The bla(TEM) was the most prevalent β-lactamase gene observed in isolates from pigs (98.5%, 135/137). The gene bla(CMY-2) was also predominant among isolates from chickens (20.2%, 40/198). The bla(LAP-1) gene was first detected in one strain from chickens and humans (pig farm workers) in China. Only one strain from hospitalized patients was found to possess bla(SHV). The rmtB was the most prevalent 16S rRNA methylase gene detected in isolates from chickens (19.7%, 39/198) and hospitalized patients (15.8%, 22/139). To our knowledge, this is the first report of the detection of the qnrD gene in E. coli from chickens and pigs in China. The qnrC and bla(KPC) genes were not detected in any of the isolates. Results of southern hybridization revealed that PMQR determinants, β-lactamases, and 16S rRNA methylase genes were located on the same plasmid in E. coli strains derived from patients. Also, PMQR determinants and β-lactamase genes were localized on the same plasmid in an E. coli strain of animal origin. Results of conjugation experiments revealed that all of these plasmid-based resistance genes can be transferred by conjugation through horizontal transmission.


Molecular epidemiology of KPC-producing Klebsiella pneumoniae isolated from patients in two public hospitals in Carabobo and Zulia states, Venezuela.
Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria (K. pneumonia carbapenemase) are the most important causative agents of nosocomial infections worldwide. These isolates have been identified in Venezuela, but little is known about their local spread. The aim of this study was to perform molecular epidemiology of KPC-producing K. pneumoniae isolated from two public hospitals in the Carabobo and Zulia states of Venezuela. Thirty-two K. pneumoniaei solates, phenotypically classified as KPC producers were subjected to PCR to detect the presence of blaKPC genes and their location within transposon Tn4401, and the blaKPC product was sequenced to identify the KPC allele. Genotypic analysis was performed using repeated extragenic palindromic PCR (rep-PCR) and Multi Locus Sequence Typing (MLST). Finally, a conjugation assay determined whether the blaKPC genes were carried on transferable plasmids. The results indicate that the 32 isolates contained the blaKPC-2 variant associated with isoform Tn4401b, and were distributed in nine sequence types (ST), one of which was new. Conjugation assays indicate that 87.5% of the isolates contain the gene blaKPC on mobilizable plasmids. In these hospitals, the blaKPC-2 gene is spreading through the plasmids carrying the transposon Tn4401b. The most common ST belongs to Clonal Complexes CC258 and CC147, which play an important role in the dispersion of resistance to carbapenems worldwide.


TranspoGene and microTranspoGene: transposed elements influence on the transcriptome of seven vertebrates and invertebrates.
Transposed elements (TEs) are mobile genetic sequences. During the evolution of eukaryotes TEs were inserted into active protein-coding genes, affecting gene structure, expression and splicing patterns, and protein sequences. Genomic insertions of TEs also led to creation and expression of new functional non-coding RNAs such as microRNAs. We have constructed the TranspoGene database, which covers TEs located inside protein-coding genes of seven species: human, mouse, chicken, zebrafish, fruit fly, nematode and sea squirt. TEs were classified according to location within the gene: proximal promoter TEs, exonized TEs (insertion within an intron that led to exon creation), exonic TEs (insertion into an existing exon) or intronic TEs. TranspoGene contains information regarding specific type and family of the TEs, genomic and mRNA location, sequence, supporting transcript accession and alignment to the TE consensus sequence. The database also contains host gene specific data: gene name, genomic location, Swiss-Prot and RefSeq accessions, diseases associated with the gene and splicing pattern. In addition, we created microTranspoGene: a database of human, mouse, zebrafish and nematode TE-derived microRNAs. The TranspoGene and microTranspoGene databases can be used by researchers interested in the effect of TE insertion on the eukaryotic transcriptome. Publicly available query interfaces to TranspoGene and microTranspoGene are available at http://transpogene.tau.ac.il/ and http://microtranspogene.tau.ac.il, respectively. The entire database can be downloaded as flat files.


Enhanced mobile hybridization of gold nanoparticles decorated with oligonucleotide in microchannel devices.
Mobile hybridization is a concept proposed and verified herein. We have designed a microfluidic device that is capable of enhancing passive mixing through the morphology of micro-structures, positioned along the channels of the device. We investigated the capability of these structures to promote mobile hybridization of fluorophore-labeled target oligonucleotides to oligonucleotide gold-nanoparticle (Au-NP) probes. This process is monitored with fluorescence through the quenching of the fluorescent signal within the device as the target oligonucleotides become bound to the Au-NP probes. We evaluated the fluorescent intensity of a sample image that showed enhanced probability of mobile hybridization of the samples, which was completed in about 7.2 s. Mobile hybridization is thus much more effective than traditional static hybridization (reaction overnight) limited by molecular diffusion. This approach promises an improved hybridization of samples with these probes, and is beneficial for microfluidic-based systems for biomedical detection.


Engagement in Primary Prevention Program among Rural Veterans With Osteoporosis Risk.
A primary osteoporosis prevention program using a virtual bone health team (BHT) was implemented to comanage the care of rural veterans in the Mountain West region of the United States. The BHT identified, screened, and treated rural veterans at risk for osteoporosis using telephone and United States Postal Service communications. Eligibility was determined by regular use of Veterans Health Administration primary care, age 50 or older, and evidence of fracture risk. This study was conducted to identify demographic and clinical factors associated with the acceptance of osteoporosis screening and the initiation of medication where indicated. A cross-sectional cohort design (N = 6985) was utilized with a generalized estimating equation and logit link function to account for facility-level clustering. Fully saturated and reduced models were fitted using backward selection. Less than a quarter of eligible veterans enrolled in BHT's program and completed screening. Factors associated with a lower likelihood of clinic enrollment included being of older age, unmarried, greater distance from VHA services, having a copayment, prior fracture, or history of rheumatoid arthritis. A majority of veterans with treatment indication started medication therapy (N = 453). In this subpopulation, Fisher's exact test showed a significant association between osteoporosis treatment uptake and a history of two or more falls in the prior year, self-reported parental history of fracture, current smoking, and weight-bearing exercise. The BHT was designed to reduce barriers to screening; however, for this population cost and travel continue to limit engagement. The remarkable rate of medication initiation notwithstanding, low enrollment reduces the impact of this primary prevention program, and findings pertaining to fracture, smoking, and exercise imply that health beliefs are an important contributing factor. Efforts to identify and address barriers to osteoporosis screening and treatment, such as clinical factors, social determinants of health, and health beliefs, may pave the way for effective implementation of population bone health care delivery systems. Published 2022. This article is a U.S. Government work and is in the public domain in the USA. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


Effect of Clothing Fabric on 20-km Cycling Performance in Endurance Athletes.
Purpose: Examine the effect of synthetic fabrics (SYN, 60% polyester: 40% nylon) vs. 100% cotton fabric (CTN) on the 20-km cycling time trial (20 kmCTT) performance of competitive cyclists and triathletes. Methods: In this randomized controlled crossover study, 15 adults (5 women) aged 29.6 ± 2.7 years (mean ± SE) with a peak rate of O2 consumption of 60.0 ± 2.0 ml/kg/min completed a 20 kmCTT under ambient laboratory conditions (24.3 ± 0.7°C and 17 ± 7% relative humidity) with a simulated wind of ~3 m/s while wearing SYN or CTN clothing ensembles. Both ensembles were of snowflake mesh bi-layer construction and consisted of a loose-fitting long-sleeved shirt with full-length trousers. Results: Participants maintained a significantly (p < 0.05) higher cycling speed and power output over the last 6-km of the 20 kmCTT while wearing the SYN vs. CTN ensemble (e.g., by 0.98 km/h and 18.4 watts at the 20-km mark). Consequently, 20 kmCTT duration was significantly reduced by 15.7 ± 6.8 sec or 0.8 ± 0.3% during SYN vs. CTN trials (p < 0.05). Improved 20 kmCTT performance with SYN vs. CTN clothing could not be explained by concurrent differences in esophageal temperature, sweat rate, ratings of perceived exertion and/or cardiometabolic responses to exercise. However, it was accompanied by significantly lower mean skin temperatures (~1°C) and more favorable ratings of perceived clothing comfort and thermal sensation during exercise. Conclusion: Under the experimental conditions of the current study, athletic clothing made of synthetic fabrics significantly improved the 20 kmCTT performance of endurance-trained athletes by optimizing selected thermoregulatory and perceptual responses to exercise.


Soft-shell clam, Mya arenaria, a convenient laboratory animal for screening pathogens of bivalve mollusks.
Attempts to introduce infectious or foreign material into oysters and other bivalve mollusks usually involve force or trauma because of immediate, prolonged adduction of the tightly closing valves. The soft-shell clam, Mya arenaria, is unable to seal its valves completely and relaxes readily, exposing soft tissue and a large siphon. This species is free from fouling organisms and is readily available at all seasons in the New England and mid-Atlantic areas. Suspensions of five strains of Vibrio sp. that cause bacillary necrosis in larval and juvenile bivalve mollusks were injected into the heart, siphon tissue, and the incurrent and excurrent siphon lumina of soft-shell clams. All vibrio strains caused significant mortality, usually within 2 days. Heaviest losses resulted from heart and excurrent siphon injections. No mortality occurred in control clams injected with seawater, broth, Serratia sp., and Escherichia coli. The soft-shell clam appears to be a useful animal for testing the pathogenicity of marine microorganisms for bivalve mollusks.


Role of serotonin in Alzheimer's disease: a new therapeutic target?
Mounting evidence accumulated over the past few years indicates that the neurotransmitter serotonin plays a significant role in cognition. As a drug target, serotonin receptors have received notable attention due in particular to the role of several serotonin-receptor subclasses in cognition and memory. The intimate anatomical and neurochemical association of the serotonergic system with brain areas that regulate memory and learning has directed current drug discovery programmes to focus on this system as a major therapeutic drug target. Thus far, none of these programmes has yielded unambiguous data that suggest that any of the new drug entities possesses disease-modifying properties, and significantly more research in this promising area of investigation is required. Compounds are currently being investigated for activity against serotonin 5-HT(1), 5-HT(4) and 5-HT(6) receptors. This review concludes that most work done in the development of selective serotonin receptor ligands is in the pre-clinical or early clinical phase. Also, while many of these compounds will likely find application as adjuvant therapy in the symptomatic treatment of Alzheimer's disease, there are currently only a few drug entities with activity against serotonin receptors that may offer the potential to alter the progression of the disease.


Alpha 1-adrenergic receptor antibodies in patients with primary hypertension.
Autoimmune mechanisms have been proposed to play a role in the pathogenesis of primary (essential) hypertension. Autoantibodies against the alpha 1-adrenergic receptor have been described in patients with malignant and secondary hypertension. To investigate the incidence of autoantibodies against the alpha 1-adrenoceptor in patients with primary hypertension, we examined the immunoglobulin fractions of sera from 54 patients with primary hypertension and 26 normotensive control subjects for the presence of autoantibodies against the alpha 1-adrenoceptor. Sera from 24 patients (44%) and 3 subjects (12%) were positive. An epitope analysis of 16 autoantibody-positive immunoglobulin fractions revealed that in two thirds of the cases, the antibodies were directed against the first extracellular loop of the alpha 1-adrenoceptor and in one third, against the second. The autoantibodies had a positive chronotropic effect on isolated neonatal rat cardiomyocytes, an effect that was blocked by alpha 1-adrenergic antagonists. Since the functional characteristics of the autoantibodies showed no desensitization phenomena, they may play a role in elevating peripheral vascular resistance and promoting cardiac hypertrophy in patients with primary hypertension.


The influence of seat backrest angle on human performance during whole-body vibration.
This study investigated the effects of reclined backrest angles on cognitive and psycho-motor tasks during exposure to vertical whole-body vibration. Twenty participants were each exposed to three test stimuli of vertical vibration: 2-8 Hz; 8-14 Hz and 14-20 Hz, plus a stationary control condition whilst seated on a vibration platform at five backrest angles: 0° (recumbent, supine) to 90° (upright). The vibration magnitude was 2.0 ms(-2) root-mean-square. The participants were seated at one of the backrest angles and exposed to each of the three vibration stimuli while performing a tracking and choice reaction time tasks; then they completed the NASA-TLX workload scales. Apart from 22.5° seat backrest angle for the tracking task, backrest angle did not adversely affect the performance during vibration. However, participants required increased effort to maintain performance during vibration relative to the stationary condition. These results suggest that undertaking tasks in an environment with vibration could increase workload and risk earlier onset of fatigue. Current vibration standards provide guidance for assessing exposures for seated, standing and recumbent positions, but not for semi-recumbent postures. This paper reports new experimental data systematically investigating the effect of backrest angle on human performance. It demonstrates how workload is elevated with whole-body vibration, without getting affected by backrest angle.


Are Older Adults More Willing to Donate? The Roles of Donation Form and Social Relationship.
Whether older adults are more prosocial than younger adults has been under debate. In the current study, we investigated how age differences in prosocial behaviors varied across different contextual factors, that is, donation form, kinship, and social distance. To achieve this purpose, 89 younger and 66 older adults took part in a hypothetical donation task in which they were asked to donate money and time to relatives and nonrelatives at various social distances. The results showed that, compared to younger adults, (a) older adults donated less to nonrelatives (regardless of the donation form), but donated a similar amount (in money) or even donated more (in time) to relatives; (b) older adults displayed higher levels of kin selection (favoring relatives over nonrelatives) in both monetary and time donations; and (c) older adults showed higher levels of social discounting (favoring socially close over distant others) in monetary but not time donation. The study underscored the importance of contextual factors in understanding age differences in prosocial behaviors such as donation.


UHRF1 phosphorylation by cyclin A2/cyclin-dependent kinase 2 is required for zebrafish embryogenesis.
Ubiquitin-like, containing PHD and RING finger domains 1 (uhrf1) is regulated at the transcriptional level during the cell cycle and in developing zebrafish embryos. We identify phosphorylation as a novel means of regulating UHRF1 and demonstrate that Uhrf1 phosphorylation is required for gastrulation in zebrafish. Human UHRF1 contains a conserved cyclin-dependent kinase 2 (CDK2) phosphorylation site at Ser-661 that is phosphorylated in vitro by CDK2 partnered with cyclin A2 (CCNA2), but not cyclin E. An antibody specific for phospho-Ser-661 recognizes UHRF1 in both mammalian cancer cells and in nontransformed zebrafish cells, but not in zebrafish bearing a mutation in ccna2. Depleting Uhrf1 from zebrafish embryos by morpholino injection causes arrest before gastrulation and early embryonic death. This phenotype is rescued by wild-type UHRF1, but not by UHRF1 in which the phospho-acceptor site is mutated, demonstrating that UHRF1 phosphorylation is essential for embryogenesis. UHRF1 was detected in the nucleus and cytoplasm, whereas nonphosphorylatable UHRF1 is unable to localize to the cytoplasm, suggesting the importance of localization in UHRF1 function. Together, these data point to an essential role for UHRF1 phosphorylation by CDK/CCNA2 during early vertebrate development.


The identification of food patterns: a comparison of principal component and principal axis factoring techniques.
Dietary patterns are based on the concept that food consumed together or by itself is as important as food or nutrient intake. To identify dietary patterns in a sample of nursing professionals and to explore the differences between the patterns found using two techniques: principal components (PC) and principal factorial axis (PAF). The current report was based on data from 309 participants on a nursing team at a public hospital in Rio de Janeiro. A 24-hour dietary recall was used, resulting in 24 food groups. To identify the dietary patterns, we applied a multivariate analysis, specifically the PC and the PAF, followed by a Varimax orthogonal rotation. The Cattell graphic test indicated three factors to be extracted. The communality varied between 0.41 and 0.76. Higher loads than 0.30 were considered in the pattern composition. The two methods identified similar dietary patterns, called traditional patterns. The other two patterns were nominated as healthy and snacks, having inverted position of factors in the applied techniques. The observed differences refer to: the number of food groups that enter the composition of components and factors; the size of the smaller loads in the PAF and the order of the alimentary patterns, especially those derived from loads of a smaller magnitude. However, these differences do not seem to impact the interpretability of dietary patterns in this population.


Analysis of absolute lymphocyte count in patients with COVID-19.
Symptoms of COVID-19 vary in severity and presentation. When admitting patients to the hospital, it is desirable to isolate patients with COVID-19 from those without the disease. However, reliably identifying patients with COVID-19 in the emergency department before hospital admission is often limited by the speed and availability of testing. Previous studies determined a low lymphocyte count is commonly found in patients with COVID-19. We sought to explore the sensitivity of absolute lymphocyte count in patients presenting to the emergency department requiring subsequent hospitalization who were found to have COVID-19. A retrospective chart review was performed on 312 patients with laboratory-confirmed COVID-19 who were admitted to the hospital from the emergency department. The absolute lymphocyte count for these patients was used to calculate sensitivities at various cut-off values. The relationships between absolute lymphocyte count and variables, including age, sex, need for intubation, and mortality, were also explored. Cut-off values for absolute lymphocyte count ranged from 1.1 K/uL to 2.0 K/uL, with sensitivities of 72% and 94%, respectively. Additionally, lower mean absolute lymphocyte counts were identified in males, patients who required intubation, and patients who died. Knowing the sensitivity of absolute lymphocyte count in patients with COVID-19 may help identify patients who are unlikely to have the disease. Additionally, absolute lymphocyte count can be used as a marker of disease severity in patients with COVID-19.


Predicting Simulation Parameters of Biological Systems Using a Gaussian Process Model.
Finding optimal parameters for simulating biological systems is usually a very difficult and expensive task in systems biology. Brute force searching is infeasible in practice because of the huge (often infinite) search space. In this article, we propose predicting the parameters efficiently by learning the relationship between system outputs and parameters using regression. However, the conventional parametric regression models suffer from two issues, thus are not applicable to this problem. First, restricting the regression function as a certain fixed type (e.g. linear, polynomial, etc.) introduces too strong assumptions that reduce the model flexibility. Second, conventional regression models fail to take into account the fact that a fixed parameter value may correspond to multiple different outputs due to the stochastic nature of most biological simulations, and the existence of a potentially large number of other factors that affect the simulation outputs. We propose a novel approach based on a Gaussian process model that addresses the two issues jointly. We apply our approach to a tumor vessel growth model and the feedback Wright-Fisher model. The experimental results show that our method can predict the parameter values of both of the two models with high accuracy.