Coordination tending towards an anti-phase relationship determines greater sway reduction during entrainment with a simulated partner.
The increased risk of falls in the older aged population demands the development of assistive robotic devices capable of effective balance support. For the development and increased user acceptance of such devices, which provide balance support in a human-like way, it is important to understand the simultaneous occurrence of entrainment and sway reduction in human-human interaction. However, sway reduction has not been observed yet during a human touching an external, continuously moving reference, which rather increased human body sway. Therefore, we investigated in 15 healthy young adults (27.20±3.55 years, 6 females) how different simulated sway-responsive interaction partners with different coupling modes affect sway entrainment, sway reduction and relative interpersonal coordination, as well as how these human behaviours differ depending on the individual body schema accuracy. For this, participants were lightly touching a haptic device that either played back an average pre-recorded sway trajectory ("Playback") or moved based on the sway trajectory simulated by a single-inverted pendulum model with either a positive (Attractor) or negative (Repulsor) coupling to participant's body sway. We found that body sway reduced not only during the Repulsor-interaction, but also during the Playback-interaction. These interactions also showed a relative interpersonal coordination tending more towards an anti-phase relationship, especially the Repulsor. Moreover, the Repulsor led to the strongest sway entrainment. Finally, a better body schema contributed to a reduced body sway in both the "reliable" Repulsor and the "less reliable" Attractor mode. Consequently, a relative interpersonal coordination tending more towards an anti-phase relationship and an accurate body schema are important to facilitate sway reduction.


A multiple regression approach to study optical components of myopia in Singapore school children.
Previous studies on the optical components of childhood myopia adjusted only for age and gender or reported only the change of individual components with time. We perform a study to assess the association of the optical components of the eye contributing to the degree of myopia by building a statistical model which can better assess the individual effects of each optical component. Children 6-12 years old with myopia of -1 to -6 D were used in this study. Autokeratometry was performed to determine the mean corneal power in two perpendicular meridia. Ultrasonography was used to determine the vitreous chamber depth (VCD). Ultrasonography and Scheimflug biometry were used to determine lens thickness (LT) and anterior chamber depth. A stepwise multiple linear regression was used to determine statistically significant independent variables that explain the variation in the mean spherical equivalent of the left eye. The independent variables investigated were anterior chamber length, LT, VCD, mean corneal power, age and gender. The first regression model used measurements of anterior chamber depth and LT from ultrasonography, while the second model used measurements from Scheimflug photography. Statistical significance was set at p < 0.05. Both statistical models have the same significant independent variables - VCD, LT and gender, with similar estimates. In both models, VCD was found to have the strongest partial association with mean spherical equivalent, followed by gender and LT. A more myopic refractive error was associated with (1) a longer eye, (2) an increased LT, and (3) female gender. Myopia was associated with a longer vitreous chamber. This remained the primary determinant of myopia in Chinese children after consideration of other optical components. The effect of gender and LT on myopia requires further study. These results are in agreement with multiple regression analyses in Singapore adults.


Multifunctional silk vinyl sulfone-based hydrogel scaffolds for dynamic material-cell interactions.
Biochemical and mechanical interactions between cells and the surrounding extracellular matrix influence cell behavior and fate. Mimicking these features in vitro has prompted the design and development of biomaterials, with continuing efforts to improve tailorable systems that also incorporate dynamic chemical functionalities. The majority of these chemistries have been incorporated into synthetic biomaterials, here we focus on modifications of silk protein with dynamic features achieved via enzymatic, "click", and photo-chemistries. The one-pot synthesis of vinyl sulfone modified silk (SilkVS) can be tuned to manipulate the degree of functionalization. The resultant modified protein-based material undergoes three different gelation mechanisms, enzymatic, "click", and light-induced, to generate hydrogels for in vitro cell culture. Further, the versatility of this chemical functionality is exploited to mimic cell-ECM interactions via the incorporation of bioactive peptides and proteins or by altering the mechanical properties of the material to guide cell behavior. SilkVS is well-suited for use in in vitro culture, providing a natural protein with both tunable biochemistry and mechanics.


Chemical Biology Approaches to Genome Editing: Understanding, Controlling, and Delivering Programmable Nucleases.
Programmable DNA nucleases have provided scientists with the unprecedented ability to probe, regulate, and manipulate the human genome. Zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeat-Cas9 system (CRISPR-Cas9) represent a powerful array of tools that can bind to and cleave a specified DNA sequence. In their canonical forms, these nucleases induce double-strand breaks at a DNA locus of interest that can trigger cellular DNA repair processes that disrupt or replace genes. The fusion of these programmable nucleases with a variety of other protein domains has led to a rapidly growing suite of tools for activating, repressing, visualizing, and modifying loci of interest. Maximizing the usefulness and therapeutic relevance of these tools, however, requires precisely controlling their activity and specificity to minimize potentially toxic side effects arising from off-target activities. This need has motivated the application of chemical biology principles and methods to genome-editing proteins, including the engineering of variants of these proteins with improved or altered specificities, and the development of genetic, chemical, optical, and protein delivery methods that control the activity of these agents in cells. Advancing the capabilities, safety, effectiveness, and therapeutic relevance of genome-engineering proteins will continue to rely on chemical biology strategies that manipulate their activity, specificity, and localization.


Smoking as a risk factor for chronic musculoskeletal complaints is influenced by age. The HUNT study.
Chronic musculoskeletal complaints (MSCs) are among the major health problems, and cross-sectional studies suggest an association between smoking and MSCs. The causal relationship, however, is not known. The present study is designed to assess the association between smoking and chronic MSCs, and is based on data from a large longitudinal cohort study of all inhabitants ⩾20years in Nord-Trøndelag County (Helse Undersøkelsen i Nord-Trøndelag -HUNT), conducted in 1995-97 (HUNT 2) and 2006-08 (HUNT 3). The study population consisted of 15,134 subjects without chronic MSCs and valid exposure data on smoking at baseline (HUNT 2). The outcome was defined as presence of chronic MSCs at follow-up (HUNT 3). The results show that smoking at baseline represents a 20% increased risk (IRR=1.20, 95% CI 1.14-1.27, P=0.0001) for chronic MSCs at follow-up. The risk for chronic MSCs by daily smoking decreased with increasing age up to 50years; after this, there was no significant association. The results show that modifiable risk factors like smoking should be included in public health intervention programs for MSCs.


Calibrating the BOLD signal during a motor task using an extended fusion model incorporating DOT, BOLD and ASL data.
Multimodal imaging improves the accuracy of the localization and the quantification of brain activation when measuring different manifestations of the hemodynamic response associated with cerebral activity. In this study, we incorporated cerebral blood flow (CBF) changes measured with arterial spin labeling (ASL), Diffuse Optical Tomography (DOT) and blood oxygen level-dependent (BOLD) recordings to reconstruct changes in oxy- (ΔHbO(2)) and deoxyhemoglobin (ΔHbR). Using the Grubb relation between relative changes in CBF and cerebral blood volume (CBV), we incorporated the ASL measurement as a prior to the total hemoglobin concentration change (ΔHbT). We applied this ASL fusion model to both synthetic data and experimental multimodal recordings during a 2-s finger-tapping task. Our results show that the new approach is very powerful in estimating ΔHbO(2) and ΔHbR with high spatial and quantitative accuracy. Moreover, our approach allows the computation of baseline total hemoglobin concentration (HbT(0)) as well as of the BOLD calibration factor M on a single subject basis. We obtained an average HbT(0) of 71 μM, an average M value of 0.18 and an average increase of 13% in cerebral metabolic rate of oxygen (CMRO(2)), all of which are in agreement with values previously reported in the literature. Our method yields an independent measurement of M, which provides an alternative measurement to validate the hypercapnic calibration of the BOLD signal.


Multiomics analysis of human peripheral blood reveals marked molecular profiling changes caused by one night of sleep deprivation.
Sleep insufficiency is associated with various disorders; the molecular basis is unknown until now. Here, 14 males and 18 females were subjected to short-term (24 h) sleep deprivation, and donated fasting blood samples prior to (day 1) and following (days 2 and 3) short-term sleep deprivation. We used multiple omics techniques to examine changes in volunteers' blood samples that were subjected to integrated, biochemical, transcriptomic, proteomic, and metabolomic analyses. Sleep deprivation caused marked molecular changes (46.4% transcript genes, 59.3% proteins, and 55.6% metabolites) that incompletely reversed by day 3. The immune system in particular neutrophil-mediated processes associated with plasma superoxidase dismutase-1 and S100A8 gene expression was markedly affected. Sleep deprivation decreased melatonin levels and increased immune cells, inflammatory factors and c-reactive protein. By disease enrichment analysis, sleep deprivation induced signaling pathways for schizophrenia and neurodegenerative diseases enriched. In sum, this is the first multiomics approach to show that sleep deprivation causes prominent immune changes in humans, and clearly identified potential immune biomarkers associated with sleep deprivation. This study indicated that the blood profile following sleep disruption, such as may occur among shift workers, may induce immune and central nervous system dysfunction.


A Novel Flap for Dynamic Reanimation of Facial Paralysis: Microvascular Sternohyoid Muscle Free Flap.
The main objectives of facial reanimation procedures include restoring facial symmetry at resting state and regaining facial mobility. Static procedures usually provide unsatisfactory results, especially in younger patients. For this reason, over the years, several different surgical alternatives based on autologous, locoregional, or muscle free flaps have been proposed. The gracilis muscle is the gold standard technique for dynamic reanimation of long-standing facial paralysis. The excessive muscle bulk and the differences regarding the type of predominant muscle fiber were compared with the zygomaticus major force reconstructive surgeons to search for alternatives to the gracilis as a potential free flap for reanimation. One of them is the sternohyoid muscle flap. We report a patient with long-standing facial paralysis who underwent a dynamic facial reanimation by using a sternohyoid muscle free flap, thus proposing the procedure as an alternative to the conventional gracilis muscle flap.


[Evoked potentials of the dog sensomotor cortex following systematic application of series of electrocutaneous stimuli].
Standard 5-member series of weak electro-cutaneous stimulations of the fore-paw were applied in chronic experiments to two dogs with implanted cortical electrodes. The stimuli caused no apparent motor reactions and were not reinforced by any other type of stimulation. Evoked potentials (EP) in the sensorimotor cortex were gradually forming in the course of experiments in such a way that the amplitude of averaged EPs to the extreme stimuli of the series became larger than those to the middle ones. The elaborated U-shaped dependence of the averaged EP amplitudes in the sensorimotor cortex on the ordinal number of the electrical stimuli correlates with the same EP dependence observed in the auditory cortex of dogs in response to series of clicks. The described form of EP organization in response to the stimuli of one modality facilitates the elaboration of the same type of organization in response to the stimuli of an other modality.


The prevalence of headache and migraine in atopic children: an epidemiological study in general practice.
The lifetime prevalence of headache and migraine was assessed in an unselected sample of atopic (asthma, eczema or rhinitis) children in a general practice population of known socio-economic and age/sex composition. Maternal migraine was also recorded. The prevalence of both headache and migraine was significantly and proportionally higher in children with atopic disorders compared to those without. Childhood migraine was associated with atopy and the association was strongest with rhinitis. Rhinitis in children was associated with maternal migraine. A history of atopy (especially rhinitis) supports the diagnosis of migraine in young children with paroxysmal headaches.


Correlation between apparent diffusion coefficient and viscoelasticity of articular cartilage in a porcine model.
Quantitative MR imaging techniques of degenerative cartilage have been reported as useful indicators of degenerative changes in cartilage extracellular matrix, which consists of proteoglycans, collagen, non-collagenous proteins, and water. Apparent diffusion coefficient (ADC) mapping of cartilage has been shown to correlate mainly with the water content of the cartilage. As the water content of the cartilage in turn correlates with its viscoelasticity, which directly affects the mechanical strength of articular cartilage, ADC can serve as a potentially useful indicator of the mechanical strength of cartilage. The aim of this study was to investigate the correlation between ADC and viscoelasticity as measured by indentation testing. Fresh porcine knee joints (n = 20, age 6 months) were obtained from a local abattoir. ADC of porcine knee cartilage was measured using a 3-Tesla MRI. Indentation testing was performed on an electromechanical precision-controlled system, and viscosity coefficient and relaxation time were measured as additional indicators of the viscoelasticity of cartilage. The relationship between ADC and viscosity coefficient as well as that between ADC and relaxation time were assessed. ADC was correlated with relaxation time and viscosity coefficient (R(2) = 0.75 and 0.69, respectively, p < 0.01). The mean relaxation time values in the weight-bearing and non-weight-bearing regions were 0.61 ± 0.17 ms and 0.14 ± 0.08 ms, respectively. This study found a moderate correlation between ADC and viscoelasticity in the superficial articular cartilage. Both molecular diffusion and viscoelasticity were higher in weight bearing than non-weight-bearing articular cartilage areas.


The value of a perception and control test in predicting performance in dental students and ancillary personnel.
A test designed to measure basic manual perception and control skills, assumed to be less susceptible to the effects of haphazard and unplanned training, was developed and used with groups of dental students and ancillary personnel. The test was similar to one reported to be successful in predicting practical ability in American dental students. Statistical techniques were used to compare the results of the perception and control test with practical and theory examination results. The results show that the perception and control test is not a reliable predictor of performance with British dental students but was more successful with the ancillary groups and particularly with dental auxiliaries.


Rapid toxicity prediction of organic chemicals to Chlorella vulgaris using quantitative structure-activity relationships methods.
This paper presents the results of an optimization study on the toxicity of 91 aliphatic and aromatic compounds as well as a small subset of pesticides to algae Chlorella vulgaris, which was accomplished by using quantitative structure-activity relationships (QSAR). The linear (HM) and the nonlinear method radial basis function neural networks (RBFNN) were used to develop the QSAR models and both of them can give satisfactory prediction results. At the same time, by interpreting the descriptors, we can get some insight into structural features (molecular surface area, electrostatic repulsion, and hydrogen bonds) related to the toxic action. Finally, a detailed analysis on the model application domain defined the compounds, whose estimation can be accepted with confidence. The results of this study suggest that the proposed approaches could be successfully used as a general tool for the estimate of novel toxic compounds.


Gerontechnology for better elderly care and life quality: a systematic literature review.
Gerontechnology as multidisciplinary research has expanded in recent years due to its significant role in ensuring better care and improved quality of life for older adults and their caregivers. With a substantial increase in studies on reasons behind less inclination of older individuals to accept gerontechnology, barriers to its non-acceptance appear to be persistent. In addition, there is a dearth of research on the adoption of gerontechnology from the perspectives of social caregivers, given that caregivers bear a substantial burden in the form of chronic stress, which adversely affects their health and that of older people. Therefore, the aim of this study is to present a holistic perspective of older adults and their caregivers by systematically reviewing literature on gerontechnology acceptance. Adopting the preferred reported items for systematic and meta-analysis (PRISMA) framework, publications specifically on gerontechnology from 2002 to 2022 in Scopus, Web of Science and PubMed, that focused on older people (50 years and above) and caregivers (informal and formal) were reviewed. We critically evaluated 25 publications and synthesised them thematically. The results highlight that gerontechnology acceptance by older adults and their social caregivers is highly contingent on certain personal, physical, socio-cultural and technological indicators. However, this paper concludes that a generalised policy approach for gerontechnology and a better quality of life may be ineffective, considering that older adults and social caregivers constitute two heterogeneous groups.


Acinetobacter infections in a tertiary level intensive care unit in northern India: epidemiology, clinical profiles and outcomes.
Nosocomial Acinetobacter infections are an increasing concern in intensive care units (ICU). To study the demographic and clinical characteristics and the outcomes of ICU patients with Acinetobacter infections. A retrospective, 1-year audit of all Acinetobacter infections diagnosed in ICU patients between January 1 and December 31, 2009. Acinetobacter infection occurred in 94 patients (108 episodes). The most common site of infection was the respiratory tract (83 patients, 76.85%), with medical patients being more susceptible than surgical patients to Acinetobacter lung infections (P=0.04), particularly late-onset ventilator-associated pneumonia (VAP) (P=0.04). The majority (63.8%) of infections were acquired in the ICU, and patients with ICU acquired infections were intubated significantly longer than the other patients (P=0.02). Seventy percent of the infections were caused by multidrug-resistant (MDR) strains, and the overall crude mortality rate was over 70%. The most important factors affecting mortality were the duration of intubation (P=0.001) and the inappropriate use of antibiotics (P=0.021) after diagnosis of the infection. Acinetobacter infections are highly prevalent in the ICU, with medical patients being more susceptible to lung infections, particularly late-onset VAP. The early and appropriate selection of antibiotics is the most important determinant of survival among these patients.


Experimental and theoretical thermal equations of state of MgSiO3 post-perovskite at multi-megabar pressures.
The MgSiO3 post-perovskite phase is the most abundant silicate phase in a super-Earth's mantle, although it only exists within the Earth's lowermost mantle. In this study, we established the thermal equation of state (EoS) of the MgSiO3 post-perovskite phase, which were determined by using both laser-heated diamond anvil cell and density-functional theoretical techniques, within a multi-megabar pressure range, corresponding to the conditions of a super-Earth's mantle. The Keane and AP2 EoS models were adopted for the first time to extract meaningful physical properties. The experimentally determined Grüneisen parameter, which is one of the thermal EoS parameters, and its volume dependence were found to be consistent with their theoretically obtained values. This reduced the previously reported discrepancy observed between experiment and theory. Both the experimental and theoretical EoS were also found to be in very good agreement for volumes at pressures and temperatures of up to 300 GPa and 5000 K, respectively. Our newly developed EoS should be applicable to a super-Earth's mantle, as well as the Earth's core-mantle boundary region.


Frequencies of the Common MEFV Gene Mutations in Adiyaman, Southeast Anatolia, Turkey.
Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by fever and serosal inflammation. The reasons for the disorder are mutations in the Mediterranean fever (MEFV) gene; the most common of which are M694V, M680I, M694I and V726A. In this study, we aimed to screen these common mutations of the MEFV gene and then determine the prevalence of FMF according to these mutations in Adıyaman, Southeast Anatolia, Turkey. Seven hundred and sixty-seven healthy individuals from the region of Adıyaman participated in the study. Polymerase chain reaction-amplification refractory mutation system (PCR-ARMS) methods were used to determine the common mutations of the MEFV gene. Twenty-six (3.9%) individuals had only one mutation in the MEFV gene, 25 individuals were heterozygous and one person was homozygous for the V726A mutation (0.15%). In the present study, the V726A mutation (50.0%) was the most frequent, followed by M694V (38.5%), M680I (7.7%) and M694I (3.8%). It was seen that the carrier rate was very low and the prevalence of FMF was 0.15%, according to the common mutations of the MEFV gene in Adıyaman, Southeast Anatolia, Turkey.


Participation in a food assistance program and excessive weight gain: an evaluation of the Brazilian Worker's Food Program in male and female manufacturing workers.
Several published studies have reported an association between participation in a food assistance program and greater prevalence of overweight/obesity. Our aim was to compare nutritional status and nutrient consumption between workers from manufacturing companies participant and non-participant in the Brazilian Workers' Food Program (WFP). Cross-sectional survey, based on a probability sample of manufacturing workers in Brazil obtained by stratified two-stage sampling, comparative between WFP and non-WFP participating companies. Body mass index (BMI), waist circumference (WC), and nutrient consumption (24-hour recall) were collected by trained nutritionists. Statistical analysis was done separately in each sex with mixed effects multilevel linear regression model including sampling weights and covariate adjustment. Thirty-three companies were randomly selected from all companies in three different economic activity sectors (food and beverages, non-metallic minerals, and textiles) in North-eastern Brazil, with stratification by company size, and a random sample of 929 workers (484 from non-WFP and 445 from WFP companies) was obtained from those companies. In males, the WFP group had higher BMI (+ 1.08 kg/m2, p < 0.001), greater WC (+ 3.27 cm, p < 0.001) and greater prevalence of obesity (OR 1.67, p < 0.001). In females, no statistical significant differences were observed in anthropometric parameters, but the WFP group had lower prevalence of obesity (OR 0.49, p = 0.05). Among workers in companies that provide lunch, males from WFP companies have greater consumption of carbohydrates (+ 39.5 kcal, p = 0.02) and protein (+ 11.1 kcal, p = 0.08), while females have lower protein consumption (- 14.2 kcal, p = 0.04) and also lower total daily consumption of carbohydrates (- 59.3 Kcal, p = 0.05) and total lipids (- 14.2 Kcal, p = 0.04). Participation in the WFP is associated with increased BMI and WC among male workers; however, this association was not found in females. Compared to the non-WFP group, in the WFP group, males have greater consumption of carbohydrates and protein at lunch, while women have lower protein intake. These results indicate the need that proposals for public policies aimed to the improvement of the nutritional status of populations take into consideration the different effects of food assistance programs in males and females.


Identification and Expression Analysis of LncRNAs Reveal the Immune Mechanism of Visceral White-Nodules Disease Resistance in Large Yellow Croaker.
Long non-coding RNAs (lncRNAs) have several known functions in fish growth processes and signal transduction, but their possible roles in response to bacterial diseases remain largely unresolved. In this study, we report a comprehensive cold-water bacterial disease-responsive lncRNA expression profile for understanding the transcriptional regulatory mechanisms of visceral white-nodules disease resistance in large yellow croaker. A total of 2534 high-confidence lncRNAs were identified by a rigorous filtering pipeline as a basic sequence set for comparative transcriptional analysis. In addition, a total of 10,200 lncRNA-mRNA pairs with high correlation coefficients were identified by expressions level correlation analysis, including non-redundant 381 DE lncRNAs and 2590 differential expressed genes. MSTRG_11084_1 and MSTRG_20402_1 were linked to a large number of target genes and may be involved in important functions in immune regulation. We further revealed the conserved and idiosyncratic features of the disease response process between the technical control strain (TCS) and the resistant strain (RS). Immune-related pathways were enriched in GO terms and KEGG pathways, among which cytokine-cytokine receptor interaction, MAPK signaling pathway, and NF-kappa B signaling pathway may play a key role in VWND resistance in large yellow croaker. Protein-protein interaction network (PPI) analysis revealed that immune-related target genes such as il-10, met, acta2, myc, cav1, and ntrk1, as well as growth and metabolism-related target genes such as pik3r2, igf1, sc5d, hmgcr, and lss were considered the main hub genes. This study represents the first characterization of lncRNAs involved in VWND resistance in large yellow croaker and provides new clues for elucidating the disease response mechanism of large yellow croaker.


Weekly iron and folic acid supplementation with counseling reduces anemia in adolescent girls: a large-scale effectiveness study in Uttar Pradesh, India.
Weekly iron-folic acid supplementation in small-scale research trials and as administered in institutions has been demonstrated to be effective in reducing anemia in adolescent girls. To assess the effectiveness of weekly iron-folic acid supplementation in a large-scale project in reducing the prevalence of anemia in adolescent girls. The project provided weekly iron-folic acid tablets, family life education, and deworming tablets every 6 months to 150,700 adolescent school girls and non-schoolgirls of a total district population of 3,647,834. Consumption of the iron-folic acid tablets was supervised for schoolgirls but not for non-schoolgirls. Hemoglobin levels were assessed in a random sample of non-schoolgirls at 6 and 12 months and schoolgirls at 6 months. The effect of supplementation on the prevalence of anemia and the compliance rate were assessed over a 4-year period. In 4 years, the overall prevalence of anemia was reduced from 73.3% to 25.4%. Hemoglobin levels and anemia prevalence were influenced significantly at 6 months. No difference in the impact on hemoglobin or anemia prevalence was observed between supervised and unsupervised girls. Counseling on the positive effects of regular weekly iron-folic acid intake contributed to a high compliance rate of over 85%. The cost of implementation was US$0.36 per beneficiary per year. Weekly iron-folic acid supplementation combined with monthly education sessions and deworming every 6 months is cost-effective in reducing the prevalence of anemia in adolescent girls. Appropriate counseling, irrespective of supervision, is critical for achieving positive outcomes.


Pharmacokinetics and Dosing of Ceftobiprole Medocaril for the Treatment of Hospital- and Community-Acquired Pneumonia in Different Patient Populations.
Hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP) are among the most common infections treated in the hospital setting, and together they place a significant burden on healthcare systems. Successful management of HAP and CAP depends on rapid initiation of empirical antibiotic therapy with broad-spectrum antibiotics. Ceftobiprole is a new-generation, broad-spectrum cephalosporin antibiotic for the treatment of HAP (excluding ventilator-associated pneumonia) and CAP. It displays potent in vitro activity against a broad range of pathogens important in pneumonia. This review summarizes the pharmacokinetic profile of ceftobiprole, and considers the pharmacokinetic parameters and pharmacodynamics underlying the choice of dosing regimen. Ceftobiprole shows linear pharmacokinetics after single and multiple doses and is eliminated predominantly through the kidneys. Ceftobiprole is administered as a 500 mg intravenous infusion over 2 h every 8 h, and steady-state concentrations are reached on the first day of dosing. Dose adjustment is recommended for patients with moderate or severe renal impairment and for those with end-stage renal disease. Extending the infusion time of ceftobiprole to 4 h is recommended to optimize drug exposure in critically ill patients with augmented renal clearance. However, there is no need for dose adjustments based on age, sex or ethnicity, or for patients with severe obesity. Population pharmacokinetic modelling and Monte Carlo simulations were used to determine the optimal dosing regimen for ceftobiprole in special patient populations, including paediatric patients. Future studies of ceftobiprole in patients with HAP and CAP would be of interest.


Evaluation of ER-α, ER-Β1 and ER-Β2 expression and correlation with clinicopathologic factors in invasive luminal subtype breast cancers.
Luminal subtype breast cancer is defined as oestrogen receptor (ER)- and/or progesterone receptor (PR)- positive breast cancer. We detected the expression of ER-α, ER-Β1 and ER-Β2 in the tissue samples of invasive luminal subtype breast cancer patients, evaluated the correlations between these ER statuses and prognosis, and tried to clarify whether the status of ER-α isoforms provides clinically useful information further to what is already provided by the traditional ER-α/PR assay. The expression of ER-α, ER-Β1 and ER-Β2 in the paraffin-embedded sections of 162 invasive luminal subtype breast cancer patients was detected with an immunohistochemical staining method. With mid-long-term follow-up, the features of ER-α, ER-Β1 and ER-Β2 status and the correlations between clinical characteristics and the prognosis were analysed. ER-Β1-positive status was correlated with PR (rs=0.217, p<0.01). The median follow-up time was 92 months (range, 4-98 months). Univariate analysis suggested that ER-Β1 status was significantly correlated to diseasefree survival (DFS) time (log rank=3.98, p=0.046), especially in patients with positive lymph nodes (log rank=6.20, p=0.013). In patients with smaller tumour size (=20 mm), negative ER-Β2 status was significantly correlated to overall survival time (log rank=3.87, p=0.049). In invasive luminal subtype breast cancers, ER-Β1 is correlated with good prognosis and could be regarded as one of the factors for evaluating DFS time, especially in lymph node-positive patients. There may be some interactions between ER-Β1 and PR. In clinical practice, besides routine detection of ER-α and PR in invasive luminal subtype breast cancers, immunohistochemical staining of ER-Β1 and ER-Β2 should be considered in order to achieve more useful information. Further studies are needed to confirm our findings.


The joint contribution of early parental warmth, communication and tracking, and early child conduct problems on monitoring in late childhood.
The relationship of parental warmth, communication, and tracking (WCT), and child conduct problems in early elementary school (age 5.5 years) to monitoring in late elementary school (age 9.5 years) was longitudinally examined in a sample of 267 boys and girls. WCT in kindergarten was associated with lower kindergarten levels and less growth of conduct problems into the first grade, and was prospectively associated with effective monitoring in the third and fourth grades. Overt and covert conduct problems in kindergarten and growth in covert problems during kindergarten and first grade were associated with less effective later monitoring. Early conduct problems mediated the prospective association of WCT on later monitoring. The results are described in a transactional model of parent-child relationships and child problem behavior.


Calculated versus measured albumin-creatinine ratio to predict kidney failure and death in people with chronic kidney disease.
Albumin-to-creatinine ratio (ACR), the preferred method to quantify proteinuria, can be calculated from urine dipstick protein or protein-to-creatinine ratio (PCR). The performance of calculated vs. measured ACR in predicting kidney failure and death without kidney failure in people with chronic kidney disease (CKD) is unknown. Here, we used population-based data from Alberta, Canada, to identify adults with incident moderate-severe CKD (sustained for more than 90 days) from 2008-04-01 to 2017-03-31, who had same-day measures of ACR and urine dipstick (ACR-dipstick cohort) or PCR (ACR-PCR cohort) in the two years before cohort entry. We followed participants until 2019-03-31 and trained competing risk models of kidney failure and death without kidney failure including age, sex, estimated glomerular filtration rate, diabetes, cardiovascular disease, and either measured or calculated ACR. Model performance was tested in cohorts created using the same algorithm in Manitoba, Canada. The ACR-dipstick and ACR-PCR cohorts included 18,731 and 4,542 people (training cohorts) and 821 and 1,831 people (testing cohorts), respectively. In internal and external testing, there was closer agreement between predictions based on measured vs. PCR-calculated ACR than between those based on measured vs. dipstick-calculated ACR. The dipstick-calculated ACR had higher Brier scores than measured ACR from year three for both outcomes, indicating worsening calibration. Models including measured or calculated ACR had similar discrimination: year one-to-five area under the receiver operating characteristic curve of 83-89% for kidney failure and 69-75% for mortality. Thus, if confirmed in different ethnic groups, calculated ACR can be used for risk predictions when the measured ACR is not available. PCR-calculated ACR may have superior performance to dipstick-calculated ACR.


Early Lung Adenocarcinoma in Mice: Micro-Computed Tomography Manifestations and Correlation with Pathology.
Lung cancer is the most common fatal malignancy for both men and women and adenocarcinoma is the most common histologic type. Early diagnosis of lung cancer can significantly improve the survival rate of patients. This study aimed to investigate the micro-computed tomography (micro-CT) manifestations of early lung adenocarcinoma (LAC) in mice and to provide a new perspective for early clinical diagnosis. Early LAC models in 10 mice were established by subcutaneously injecting 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) solution. Micro-CT scan and multiple planar reconstruction (MPR) were used for mouse lungs. Micro-CT features of early LAC, especially the relationships between tumor and bronchus, were analyzed and correlated with pathology. Micro-CT findings of early LAC were divided into three types: non-solid (n = 8, 6%), partly solid (n = 85, 64%) and totally solid (n = 39, 30%). Tumor-bronchus relationships, which could be observed in 110 of 132(83%) LAC, were classified into four patterns: type I (n = 16, 15%), bronchus was truncated at the margin of the tumor; type II (n = 33, 30%), bronchus penetrated into the tumor with tapered narrowing and interruption; type III (n = 38, 35%), bronchus penetrated into the tumor with a patent and intact lumen; type IV (n = 99, 90%), bronchus ran at the border of the tumor with an intact or compressed lumen. Micro-CT manifestations of early LAC correlated well with pathological findings. Micro-CT can clearly demonstrate the features of mouse early LAC and bronchus-tumor relationships, and can also provide a new tool and perspective for the study of early LAC.


Effects of N-Glycan Composition on Structure and Dynamics of IgG1 Fc and Their Implications for Antibody Engineering.
Immunoglobulin G1 (IgG1), a subclass of human serum antibodies, is the most widely used scaffold for developing monoclonal antibodies to treat human diseases. The composition of asparagine(N)297-linked glycans can modulate the binding affinity of IgG1 Fc to Fc γ receptors, but it is unclear how the structural modifications of N-glycan termini, which are distal from the binding interface, contribute to the affinity. Through atomistic molecular dynamics simulations of a series of sequentially truncated high-mannose IgG1 Fc glycoforms, we found that the C'E loop and the Cγ2-Cγ3 orientation are highly dynamic, and changes in N-glycan composition alter their conformational ensembles. High-mannose glycoform preferentially samples conformations that are more competent to FcγRIIIa binding, compared to the truncated glycoforms, suggesting a role of IgG1 Fc N-glycan in optimizing the interface with the Fc receptor for efficient binding. The trajectory analyses also reveal that the N-glycan has large amplitude motions and the carbohydrate moiety interconverts between Fc-bound and unbound forms, enabling enzymatic modification of the glycan termini.


Flow cytometric analysis of duodenal intraepithelial lymphocytes (celiac lymphogram): A diagnostic test for celiac disease.
Celiac disease (CD) diagnosis in adults and certain cases of children mainly relies on the assessment of histopathological features in duodenal biopsies. However, none of the histological findings that characterize CD are pathognomonic. This, in addition to the clinical heterogeneity of the disease and the presence of seronegative forms, makes the diagnosis of CD still a challenge. A hallmark of the celiac mucosa is the elevated number of TCRγδ intraepithelial lymphocytes (IEL) in the epithelium, which may remain increased even long after gluten withdrawal. Active disease is also characterized by the decreased CD3- IEL subset. The use of flow cytometry enables a precise cell counting and phenotyping, allowing the ascertainment of both TCRγδ+ and CD3- IEL subsets, what is known as the "IEL lymphogram." Although determination of this lymphogram has become a routine evaluation tool in numerous hospitals, standardization of the technical method will guarantee an accurate performance in order to become a pivotal technique for CD diagnosis. Here we describe the protocol to process duodenal biopsies in order to obtain the IELs from the mucosa and to characterize lymphocyte populations by flow cytometry to obtain the IEL lymphogram.


Differences in family caregiver experiences and expectations of end-of-life heart failure care across providers and settings: a systematic literature review.
Heart failure impacts patients' quality of life and life expectancy and significantly affects the daily behaviours and feelings of family caregivers. At the end-of-life, the burden for family caregivers depends on their emotional and sentimental involvement, as well as social costs. The aim of this work is to determine whether and how family caregivers' experiences and expectations vary in relation to the places of care and teams involved in heart failure management. A systematic literature review was conducted, by screening manuscripts dealing with the experience of Family Care Givers' (FCGs) of patients with Advanced Heart failure. Methods and results were reported following the PRISMA rules. Papers were searched through three databases (PubMed, Scopus and Web of Science). Seven topics were used to synthetize results by reporting qualitative information and quantitative evidence about the experience of FCGs in places of care and with care teams. Thirty-one papers, dealing with the experience of 814 FCGs, were selected for this systematic review. Most manuscripts came from the USA (N = 14) and European countries (N = 13) and were based on qualitative methods. The most common care setting and provider profile combination at the end of life was home care (N = 22) and multiprofessional teams (N = 27). Family caregivers experienced "psychological issues" (48.4%), impact of patients' condition on their life (38,7%) and "worries for the future" (22.6%). Usually, when family caregivers were unprepared for the future, the care setting was the home, and there was a lack of palliative physicians on the team. At the end-of-life, the major needs of chronic patients and their relatives are not health related. And, as we observed, non-health needs can be satisfied by improving some key components of the care management process that could be related to care team and setting of care. Our findings can support the design of new policies and strategies.


Temperature dependence of plasma membrane physical state in living Madin-Darby canine kidney cells.
Using 1-[4-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene (TMA-DPH) as a probe, we have done fluorescence anisotropy experiments to estimate, in situ, the temperature dependence of the lipid order of the plasma membrane of MDCK cells. In intact monolayers, anisotropy vs temperature biphasic curves were obtained, indicative of discontinuous change in lipid physical state starting around 27 degrees C, in the apical domain of the plasma membrane. The very high anisotropy values (r greater than 0.33) determined below this temperature strongly suggested it corresponded to a phase separation phenomenon. Biphasic curves with similar critical temperatures zone were also obtained when measuring anisotropy or fluorescence lifetime of suspensions of MDCK cells. This suggests that changes in lipid physical state might be involved in the marked dependence on temperature of tight junction formation and of electrical conductance in MDCK monolayers.


Association of Pentachlorophenol with Fetal Risk of Prolonged Bradycardia: A Systematic Review and Meta-Analysis.
This study explored the systematic evaluation and meta-analysis of different concentrations of PCP on the risk of long-term bradycardia in fetuses. Cochrane Library, Embase, PubMed, China Biomedical Literature Service, CNCNKI, and Wanfang database were computerized to collect all case-control studies on the association between variety classes and different concentrations of environmental pollutant gas to fetal of prolonged bradycardia. After evaluating the quality of the inclusion study and extracting valid data, meta-analysis was performed using Stata15 software. Relative hazards were calculated using the Mantel-Haenszel method and the random effect model, and P values and I 2 values were used for heterogeneity evaluation. When heterogeneity occurs, subgroup analysis and sensitivity analysis were used to explore the sources. A total of 15 studies were included, including 1202 patients with fetal of prolonged bradycardia and 1380 in the control population. Meta-analysis showed that there was no statistical difference in PCP < 0.1 mg/L between the experimental group and control group (OR = 1.03, 95% CI (0.62, 1.72), P=0.90, I 2 = 0%, Z = 0.13), but there was a statistical difference in PCP > 5 mg/L (OR = 1.73, 95% CI (1.15, 2.58), P=0.008, I 2 = 0%, Z = 2.65), PCP > 10 mg/L (OR = 1.75, 95% CI (1.19, 2.57), P=0.004, I 2 = 14%, Z = 2.85), and PCP >15 mg/L (OR = 2.02, 95% CI (1.38, 2.95), P=0.0003, I 2 = 77%, Z = 3.61). In this study, we found that different concentrations of PCP increased the risk of long-term bradycardia in fetuses, and the risk coefficient increased with the increase of PCP concentration.


Thyroid antigen associated immune complex glomerulonephritis in Graves' disease.
A 60 year old hyperthyroid black woman with long-standing Graves' disease treated with methimazole presented with anasarca and congestive heart failure. She was found to have the nephrotic syndrome with a urinary protein excretion of 32 g/day. Light and electron microscopy revealed a stage II membranous glomerulopathy. Direct and indirect immunofluorescence demonstrated immunoglobulin G (IgG), immunoglobulin M (IgM), third component of complement and thyroglobulin in a granular diffuse pattern consistent with an immune complex glomerulonephritis. Total thyroidectomy led to a decrease in proteinuria with little change in glomerular filtration rate during an 11 month follow-up period. We believe this to be the first report of immune complex glomerulonephritis associated with thyroid antigen in Graves' disease.


Changes in geometry of actively shortening unipennate rat gastrocnemius muscle.
Muscle geometry of the unipennate medial gastrocnemius (GM) muscle of the rat was examined with photographic techniques during isometric contractions at different muscle lengths. It was found that the length of fibers in different regions of GM differs significantly, and proximal aponeurosis length varies significantly from distal aponeurosis length; the angle of the aponeurosis with the muscular action differs significantly among regions at short muscle lengths (full contraction). These data support the idea that the unipennate GM cannot be represented by a parallelogram in a two-dimensional analysis. As the muscle shortens, the area of the mid-longitudinal plane of the GM decreases by 24%, a decrease that may be explained by assuming fiber diameter to increase in all directions. The angle between fiber and aponeurosis is determined by more than fiber length. Hence, such important assumptions as a parallelogram with constant area and fiber angle gamma changes determined by fiber length changes, frequently used in the theoretical analysis of the morphological mechanism of unipennate muscle contraction, do not hold for the unipennate GM of the rat. Length of the sarcomere within the mid-longitudinal plane of GM varies from 1.92 to 2.14 microns among the different muscle regions at muscle optimum length (length at which force production is highest), whereas shortening to 6 mm less than optimum length produces a range of sarcomere lengths from 0.89 to 1.52 microns. These data suggest that fibers located in different regions of the GM reach their optimum and slack lengths at various muscle lengths.


Population-based 3D genome structure analysis reveals driving forces in spatial genome organization.
Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization.


Increased angiogenesis and VEGF expression correlates with disease severity in prurigo patients.
Vascular endothelial growth factor-A (VEGF-A) is known as the major skin angiogenesis factor and can be produced by various resident skin cells including keratinocytes. To identify and characterize the role of VEGF-A in the pathogenesis of prurigo. Expression of VEGF, VEGFR2, CD-31, and D2-40 was analyzed in the skin of eleven prurigo patients and seven healthy controls by immunohistochemistry. VEGF immunoreactivity (IR) was markedly increased in the epidermis, dermis and subcutis of prurigo patients, whereas expression of the main receptor for VEGF-A in the skin, VEGFR2, was comparable to that of healthy controls. The increased VEGF expression in the skin was associated with a marked increase in the number (12.8 ± 2.1 vs 5.6 ± 0.5, P < 0.05) but not in the size of blood vessels, as assessed by staining of the endothelial cell marker CD31. This increase in small blood vessels correlated closely with increases in the epidermal thickness in prurigo lesions. The number of lymphatic vessels as assessed by D2-40 staining was found to be similar in prurigo patients and healthy controls. Based on these findings, we speculate that the observed profound vascular remodelling in prurigo might contribute to the pathogenesis of prurigo and the corresponding clinical symptoms and that targeting of VEGF may present a novel therapeutic strategy in the treatment of prurigo patients.


[Coagulative capacity of the blood and anti-aggregative activity of the vascular wall in rats subjected to immobilization stress].
An immobilizing stress increases the vascular coagulative activity, causes significant changes in the microcirculatory hemostasis. High effectiveness of the adaptive mechanism permits increasing the activity of antioxidant enzymes.


LH-dependent steroid production and protein phosphorylation in culture of rat tumour Leydig cells.
The possible cause of the decreased responsiveness of cultured Leydig cells to stimulation with LH was investigated with rat tumour Leydig cells cultured at 32 degrees C for 2 days. Pregnenolone production and phosphorylation of proteins were studied in combination with the activity of cyclic AMP-dependent protein kinase. Pregnenolone production in cultured tumour Leydig cells decreased from 45 +/- 16 on day 0 to 14 +/- 7 on day 2 (ng/60 min/mg protein) under basal conditions and from 226 +/- 108 on day 0 to 30 +/- 24 on day 2 (ng/60 min/ng protein) under LH-stimulated conditions (means +/- SD, n = 4). This decrease may be accounted for by decreased capacity of cholesterol side-chain cleavage which decreased (in the presence of 25-hydroxycholesterol) from 1.68 +/- 0.26 on day 0 to 0.74 +/- 0.48 on day 2 (microgram/60 min/mg protein; mean +/- SD, n = 4) and decreased activity of cyclic AMP-dependent protein kinase (as apparent from a direct assay of protein kinase activity and the extent of phosphorylation of LH-dependent phosphoproteins).


Some thoughts on the relationship between vitamin A and cancer.
Retinoids clearly show both prophylactic and therapeutic effects against many kinds of neoplasm. Vitamin A deficiency and vitamin A excess, which are very different states clinically and metabolically, should be separately considered relative to carcinogenesis. The anticancer effects of retinoids and related compounds may be more closely related to their chemical structure than to their similarity to the structure and function of vitamin A. Retinoids act on cells and tissues in a number of ways. Although many interesting ideas have been proposed to clarify their mode of action, no single hypothesis adequately explains their many molecular interactions and responses. Investigation of early molecular interactions between retinoids and cells and the subsequent metabolism of retinoids in neoplastic and normal cells may aid in the clarification of their action as antineoplastic agents.


Donor site morbidity following vascularized fibular grafting.
We examined donor site morbidity in thirty-nine patients with avascular necrosis of the femoral head treated by curettage and transplantation of a free ipsilateral fibular graft. Utilising our donor site morbidity questionnaire, scar, functional loss, wound healing, complications, and pain were analysed. Subjective complaints and objective findings were evaluated and compared. Subjective complaints were common and included a sense of instability in 42% and a sense of weakness in 37%. However, objective findings were limited. No clinical instability could be elicited and only great toe flexion (29%) and extension (43%) were found to be mildly weak. Only one patient required reoperation for a donor site problem (2%). Eighty-nine percent were pain free at time of follow-up, and 93% felt the scar was good. Range of motion of the knee and ankle of the donor site leg was not different from the nonoperated leg. Donor site morbidity for avascular necrosis of the femoral head is low.


Naftifine cream 1% versus econazole cream 1% in the treatment of tinea cruris and tinea corporis.
Data from 104 subjects with tinea cruris or tinea corporis were evaluated in this double-blind, randomized study. The subjects applied naftifine cream 1% or econazole nitrate cream 1% to affected areas twice daily for 4 weeks. After 1 week of treatment naftifine had an overall cure rate of 19% compared with 4% for econazole (p = 0.03). A difference in favor of naftifine, although not statistically significant after the first week, persisted throughout treatment. Two weeks after the end of treatment both medications had overall cure rates of approximately 80%. Three percent of the naftifine-treated subjects had side effects compared with 13% of the econazole-treated subjects. In two subjects using econazole, the side effects were severe enough to warrant discontinuation of treatment.


High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism.
Biallelic pathogenic variants of the Sar1b gene cause chylomicron retention disease (CRD) whose central phenotype is the inability to secrete chylomicrons. Patients with CRD experience numerous clinical symptoms such as gastrointestinal, hepatic, neuromuscular, ophthalmic, and cardiological abnormalities. Recently, the production of mice expressing either a targeted deletion or mutation of Sar1b recapitulated biochemical and gastrointestinal defects associated with CRD. The present study was conducted to better understand little-known aspects of Sar1b mutations, including mouse embryonic development, lipid profile, and lipoprotein composition in response to high-fat diet, gut and liver cholesterol metabolism, sex-specific effects, and genotype-phenotype differences. Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities. On high-fat diet, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol, non-HDL cholesterol and polyunsaturated fatty acids than those on the regular Chow diet. Divergences were also noted in lipoprotein lipid composition, lipid ratios (serving as indices of particle size) and lipoprotein-apolipoprotein distribution. Sar1b defects significantly reduce gut cholesterol accumulation while altering key players in cholesterol metabolism. Noteworthy, variations were observed between males and females, and between Sar1b deletion and mutation phenotypes. Overall, mutant animal findings reveal the importance of Sar1b in several biochemical, metabolic and developmental processes.


Reduced expression of peptide-loaded HLA class I molecules on multiple sclerosis lymphocytes.
Lymphocytes from patients with HLA class II-linked autoimmune diseases such as type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, and Graves' have recently been shown to have a decrease in the expression of self-peptide-filled HLA class I antigens on the surface of peripheral lymphocytes. The human demyelinating diseases of multiple sclerosis in some cases are also associated with the presence of certain HLA class II genes, which may in turn be linked to genes in the class II region that control class I expression. Hence, we studied fresh peripheral blood mononuclear cells (PBMCs) and newly produced Epstein-Barr virus (EBV)-transformed cell lines from multiple sclerosis patients for the class I defect. Unseparated PBMCs, as well as T cells, B cells, and macrophages from multiple sclerosis patients had a decrease in the amount of conformationally correct peptide-filled HLA class I molecules on the cell surface compared with matched controls detectable by flow cytometry. To demonstrate the independence of this defect from exogenous serum factors, newly produced EBV-transformed cell lines from B cells of patients with multiple sclerosis maintained the defect. In addition, DR2 +/+, +/-, and -/- EBV-transformed B cells from these patients similarly demonstrated the self-antigen presentation defect. Analysis of a set of discordant multiple sclerosis twins revealed the class I defect was exclusively found on the affected twin lymphocytes, suggesting a role of this class I complex in disease expression. These data indicate that multiple sclerosis patients have abnormal presentation of self-antigens.(ABSTRACT TRUNCATED AT 250 WORDS)


Distribution, sources and ecological risk assessment of polycyclic aromatic hydrocarbons in water and sediments from Tiber River and estuary, Italy.
The concentration, source and ecological risk of polycyclic aromatic hydrocarbons (PAHs) in the Tiber River and its environmental impact on the Tyrrhenian Sea (Central Mediterranean Sea) were estimated. The 16 priority PAHs were determined in the water dissolved phase (DP), suspended particulate matter (SPM) and sediments collected from 21 sites in four different seasons. Total concentrations of PAHs ranged from 10.3 to 951.6ngL(-1) and from 36.2 to 545.6ngg(-1) in water (sum of DP and SPM) and in sediment samples, respectively. The compositions of PAHs showed that 2- to 4-ring PAHs were abundant in DP, 4- to 6-ring PAHs were predominant in SPM samples, and 4- to 5-ring PAHs were abundant in sediments. The diagnostic ratio analysis indicated that the PAHs mainly had a pyrolytic source. The toxic equivalent concentration of carcinogenic PAHs was 45.3ngTEQg(-1), suggesting low carcinogenic risk for Tiber River. Total PAHs loads into the sea were calculated in about 3161.7kgyear(-1) showing that this river is one of the main contribution sources of these contaminants to the Tyrrhenian Sea.


Efficient iterative solutions to complex-valued nonlinear least-squares problems with mixed linear and antilinear operators.
We consider a setting in which it is desired to find an optimal complex vector x ∈ C N that satisfies A (x) ≈ b in a least-squares sense, where b ∈ C M is a data vector (possibly noise-corrupted), and A (·) : C N → C M is a measurement operator. If A (·) were linear, this reduces to the classical linear least-squares problem, which has a well-known analytic solution as well as powerful iterative solution algorithms. However, instead of linear least-squares, this work considers the more complicated scenario where A (·) is nonlinear, but can be represented as the summation and/or composition of some operators that are linear and some operators that are antilinear. Some common nonlinear operations that have this structure include complex conjugation or taking the real-part or imaginary-part of a complex vector. Previous literature has shown that this kind of mixed linear/antilinear least-squares problem can be mapped into a linear least-squares problem by considering x as a vector in R 2N instead of C N . While this approach is valid, the replacement of the original complex-valued optimization problem with a real-valued optimization problem can be complicated to implement, and can also be associated with increased computational complexity. In this work, we describe theory and computational methods that enable mixed linear/antilinear least-squares problems to be solved iteratively using standard linear least-squares tools, while retaining all of the complex-valued structure of the original inverse problem. An illustration is providedtodemonstratethatthisapproachcansimplifytheimplementationandreduce the computational complexity of iterative solution algorithms.


Traditional Chinese medical treatment to invigorate blood and relieve stasis treatment of schizophrenia: comparison with antipsychotics treatment.
In this study, 80 schizophrenic patients, divided into two groups of 40, were treated with traditional Chinese medicine to invigorate the blood and relieve stasis and antipsychotic drugs, and were observed by the rating methods of BPRS,TESS, CGI scale and hemorheology test. The results show that such traditional Chinese medicine to invigorate blood and relieve stasis has fewer side effects on schizophrenic patients than do antipsychotic drugs, and there is objective evidence of hemorheology changes. Traditional Chinese medicine is superior to antipsychotic drugs in the effects of anti-anxiety-depression and antipsychomotor inhibition, but it is less effective in controlling psychomotor excitation compared with antipsychotic drugs.


Meshed capillary vessels by use of narrow-band imaging for differential diagnosis of small colorectal polyps.
Although microvascular vessels on the surface of colorectal polyps are observed by narrow-band imaging (NBI) with magnification, its clinical usefulness is still uncertain. Our purpose was to evaluate the usefulness of meshed capillary (MC) vessels observed by NBI magnification for differentiating between nonneoplastic and neoplastic colorectal lesions. Prospective polyp study. National Cancer Center Hospital East, Chiba, Japan. A total of 702 consecutive patients who underwent total colonoscopy between September and December 2004 were prospectively evaluated. Patients with polyps >10 mm and those with polyps previously evaluated by histologic examination or colonoscopy were excluded. Lesions were classified into 2 groups: polyps with invisible or faintly visible MC vessels as nonneoplastic and polyps with clearly visible MC vessels as neoplastic. Lesions judged as nonneoplastic were subjected to biopsy and those as neoplastic were removed endoscopically. Histologic analysis was performed in all lesions. Visible or invisible surface MC vessels, prediction of histologic diagnosis. Of 92 eligible patients enrolled in this study, 150 lesions, including 39 (26%) hyperplastic polyps and 111 (74%) adenomatous polyps, were detected. Observation of MC vessels detected 107 of 111 neoplastic polyps and 36 of 39 nonneoplastic polyps. The overall diagnostic accuracy, sensitivity, and specificity were 95.3%, 96.4%, and 92.3%, respectively. MC vessel judgment performed by a single colonoscopist with extensive experience in magnifying NBI. Observation of surface MC vessels by magnifying NBI is a useful and simple method for differentiating colorectal nonneoplastic and neoplastic polyps.


Inverse-QSPR for de novo Design: A Review.
The use of computer tools to solve chemistry-related problems has given rise to a large and increasing number of publications these last decades. This new field of science is now well recognized and labelled Chemoinformatics. Among all chemoinformatics techniques, the use of statistical based approaches for property predictions has been the subject of numerous research reflecting both new developments and many cases of applications. The so obtained predictive models relating a property to molecular features - descriptors - are gathered under the acronym QSPR, for Quantitative Structure Property Relationships. Apart from the obvious use of such models to predict property values for new compounds, their use to virtually synthesize new molecules - de novo design - is currently a high-interest subject. Inverse-QSPR (i-QSPR) methods have hence been developed to accelerate the discovery of new materials that meet a set of specifications. In the proposed manuscript, we review existing i-QSPR methodologies published in the open literature in a way to highlight developments, applications, improvements and limitations of each.


Failure to embrace the barrier/condom use message.
The objective of this study was to examine the consistency of barrier/condom use among men who have sex with men in the Kansas City metropolitan area. The authors sought to determine if barrier/condom usage patterns were associated with the type of sex act and whether it was insertive or receptive, HIV testing frequency, and number of sexual partners. Data were extracted from a 2003 community health assessment of the gay, lesbian, bisexual, and transgendered community in the metropolitan area. The health assessment instrument was anonymous, self-administered, and distributed at events in that community. Responses from 623 men indicated that consistent use of a barrier/condom was low regardless of the sex act. There was no relationship between barrier/condom usage patterns and HIV testing frequency for any sex act or the number of sex partners, with the exception of anal intercourse. The authors concluded that a different approach is needed to translate the barrier/condom use message into a behavioral response.


Abnormal heart rate tracings and serum creatine phosphokinase in addicted neonates.
Continuous cardiorespirographic (CRG) monitoring was done during the first five postnatal days in 12 infants of drug dependent mothers (IDDM) and 19 normal infants (control). Abnormal heart rate patterns in the IDDM included: (1) significantly (p less than 0.01) higher baseline heart rate (129 +/- 15 vs. 118 +/- 8), beat-to-beat variability (4.4 +/- 2.4 vs. 2.6 +/- 1.6) and long-term variability (15.5 +/- 6.6 vs. 7.0 +/- 3.9), as compared to control and (2) frequent and spontaneous occurrences of large (40 beats per minute), brief rise and fall in heart rate giving a striking "wave-like" appearance to the tracing. These changes were more intense in the IDDM with moderate to severe, as compared to mild withdrawal. Treatment of the infant's withdrawal with drugs resulted in a clinical improvement, but the abnormal heart rate tracings persisted. Serum creatine phosphokinase (CPK) was also elevated (greater than 450 IU/l) in the IDDM (mean +/- SE = 984 +/- 299 IU/l) and 89% of the total CPK was the MM fraction. These infants exhibited tremors and hypertonicity.


Gas exchange abnormalities produced by venous gas emboli.
Bubbles of either He, N2 or SF6 were infused intravenously into anesthetized dogs at a rate of 0.2 ml/kg/min. Alterations in pulmonary gas exchange were quantitated by the invert gas elimination method during control, steady state infusion and resolution phases. The hypoxemia produced was predominantly due to regions of low VA/Q rather than pure shunt, and the increase in physiological dead space was due to the addition of high VA/Q regions rather than 'pure' dead space. The VA/Q distribution returned to normal within 30 minutes of stopping the He or N2 bubbles, but remained abnormal for longer periods with SF6 bubbles. The net elimination of insoluble gases (such as He or N2) was only slightly impaired by bubble emboli, provided the cardiac output remained constant. Early pulmonary edema from bubble embolization was documented by increased wet weight/dry weight ratio, but the increased lung water was not apparent on histological examination. This form of pulmonary embolus is unique in that there is a constant fraction of the vasculature blocked although any given region with embolus is undergoing continuous resportion of the bubble. This produced a partial obstruction of the affected gas exchange units which manifests as regions of high VA/Q rather than pure dead space.


A multivariate solution for cyclic data, applied in modelling locomotor forces.
The variability in dependent biological data (measured as forces at the human foot during pedalling) was reduced, by principal components analysis, to two major components which, combined, accounted for 46% of the variability observed in sets of 26 observations per cycle. On the basis of weightings over the cycle, the components were interpreted as due to Power Production and to Phase Switch from power-generation to recovery. Force measurements were made for three frequencies of leg pedalling (1.00, 1.66, and 2.33 Hz at 10 N ergometer resistance). For each principal component, the mean (or summed) deviation over 75 consecutive cycles was found to increase linearly (p less than 0.05) with velocity of leg movement, by 7% and 85% respectively. Analysis of autocorrelations over cycles of movement showed that, in contrast to the strong interconnections of force measures within a cycle of movement, between-cycle dependence was very low. The statistical technique described provides a useful descriptive and inferential method for analyzing dependent cyclic data. The resulting model of the locomotor forces generated at the foot implies that control of power output is substantially for one cycle of a limb and that variability of force increases at the point when the leg switches from power-generation to recovery.


[Evoked potentials of the brain limbic structures during a change in the motivational state of dogs and during the realization of unconditioned reflex reactions].
In experiments on 6 dogs it has been shown that in the EPs led from the hippocampus in response to electrostimulation of limbic structures and from the latters at the hippocampus stimulation, initial negativity, after positivity and late negative wave are the most stable components. At transition from one functional state to another two latter waves are subjected to the greatest changes. Amplitude-temporal characteristics of intralimbic EPs depend on the level and type of motivation, degree of emotional stress and properties of conditioned reaction.


Effects of the host matrix on the 57Fe-species produced through EC-decay in 57Co-labelled tris(phenanthroline) cobalt (II) perchlorate.
Emission Mössbauer spectroscopic studies of 57Co-labelled [Co(phen)3]clO4)2 in host matrices [M(II)(phen)3](ClO4)2(M=Co, Fe, and Ni) indicate that the relative intensities of the anomalous species produced through the EC-decay depend on the kind of the host matrix. The largest intensity was observed with the cobalt (II) matrix, and the smallest with the iron (II) matrix. Emission spectra of 57Co-labelled [Co(2-CH3-phen)3](ClO4)2 2H2O in the matrix of [Fe(2-CH3-phen)3](ClO4)2 were also studied. The high-spin state (5T2) was predominantly observed at 4.2 K in the emission spectrum, while the low-spin state (1A1) was mainly observed in the absorption spectrum at 78 K. The results are discussed in terms of the stability of the lattice.


SLC26A3 (DRA) is stimulated in a synergistic, intracellular Ca2+-dependent manner by cAMP and ATP in intestinal epithelial cells.
In polarized intestinal epithelial cells, downregulated in adenoma (DRA) is an apical Cl-/[Formula: see text] exchanger that is part of neutral NaCl absorption under baseline conditions, but in cyclic adenosine monophosphate (cAMP)-driven diarrheas, it is stimulated and contributes to increased anion secretion. To further understand the regulation of DRA in conditions mimicking some diarrheal diseases, Caco-2/BBE cells were exposed to forskolin (FSK) and adenosine 5'-triphosphate (ATP). FSK and ATP stimulated DRA in a concentration-dependent manner, with ATP acting via P2Y1 receptors. FSK at 1 µM and ATP at 0.25 µM had minimal to no effect on DRA given individually; however, together, they stimulated DRA to levels seen with maximum concentrations of FSK and ATP alone. In Caco-2/BBE cells expressing the Ca2+ indicator GCaMP6s, ATP increased intracellular Ca2+ (Ca2+i) in a concentration-dependent manner, whereas FSK (1 µM), which by itself did not significantly alter Ca2+i, followed by 0.25 µM ATP produced a large increase in Ca2+ that was approximately equal to the elevation caused by 1 µM ATP. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) pretreatment prevented the ATP and FSK/ATP synergistically increased the DRA activity and the increase in Ca2+i caused by FSK/ATP. FSK/ATP synergistic stimulation of DRA was similarly observed in human colonoids. In Caco-2/BBE cells, subthreshold concentrations of FSK (cAMP) and ATP (Ca2+) synergistically increased Ca2+i and stimulated DRA activity with both being blocked by BAPTA-AM pretreatment. Diarrheal diseases, such as bile acid diarrhea, in which both cAMP and Ca2+ are elevated, are likely to be associated with stimulated DRA activity contributing to increased anion secretion, whereas separation of DRA from Na+/H+ exchanger isoform-3 (NHE3) contributes to reduced NaCl absorption.NEW & NOTEWORTHY The BB Cl-/[Formula: see text] exchanger DRA takes part in both neutral NaCl absorption and stimulated anion secretion. Using intestinal cell line, Caco-2/BBE high concentrations of cAMP and Ca2+ individually stimulated DRA activity, whereas low concentrations, which had no/minimal effect, synergistically stimulated DRA activity that required a synergistic increase in intracellular Ca2+. This study increases understanding of diarrheal diseases, such as bile salt diarrhea, in which both cAMP and elevated Ca2+ are involved.


Nasal irrigation efficiently attenuates SARS-CoV-2 Omicron infection, transmission and lung injury in the Syrian hamster model.
Recently, a new variant lineage of SARS-CoV-2, namely Omicron, became the dominant global circulating strain. The multiple antigenic mutations of Omicron largely decrease the efficiency of current vaccines and neutralizing antibodies, which highlights the need for more potent and reachable medical countermeasures. Here, we hypothesize that direct viral clearance by nasal irrigation might be a convenient and alternative option, and perform proof-of-concept experiments in the Syrian hamster model. Interestingly, Omicron shows a different dynamic in the changes of viral RNA, viral titers, and proinflammatory cytokines in nasal rinsing samples when compared with the prototype. Meanwhile, the levels of viral load and proinflammatory cytokines in nasal rinsing samples can indicate the severity of lung injury. Of note, daily nasal irrigation efficiently attenuates inflammation and lung injury in Omicron-infected hamsters by decreasing the viral loads in the respiratory tract organs. Moreover, daily nasal irrigation effectively suppresses viral transmission by close contact.


Measuring leprosy case detection delay and associated factors in Indonesia: a community-based study.
Leprosy is a public health burden in Indonesia with a high number of new cases every year and a high proportion of disability among new cases. Case detection delay (CDD) can contribute to ongoing transmission and increased disability chances among leprosy patients. This study aimed to establish the CDD of leprosy and the factors associated with detection delay in Indonesia. Community-based study with a cross-sectional design. Data were collected through interviews about sociodemographic and behavioral factors, anticipated stigma, and duration of CDD. Leprosy classification and case detection methods were obtained from health service records. A random sample was taken of 126 leprosy patients registered between 1st October 2020 and 31st March 2022 in the Tegal regency in the Central Java Province. Data were analysed by descriptive and analytical statistics using multiple linear regression. The mean CDD, patient delay, and health system delay were 13.0 months, 9.7 months, and 3.2 months, respectively. Factors associated with longer CDD are younger age (below 35 years), male, found through passive case detection, and not having a family member with leprosy. Factors associated with longer patient delay were being younger (below 35 years), being male, not having a family member with leprosy, and anticipated stigma of leprosy. It was not possible to reliably identify factors associated with health system delay. CDD in leprosy should be reduced in Indonesia. The Indonesian National Leprosy Control Program (NLCP) is advised to adopt an integrated intervention programme combining active case detection with targeted health education to reduce CDD and thereby preventing disabilities in people affected by leprosy.


Improvement of Candida sake biocontrol activity against post-harvest decay by the addition of ammonium molybdate.
To improve the efficacy of Candida sake by adding ammonium molybdate to control post-harvest decay in Golden Delicious apples. In laboratory trials, C. sake 2 x 10(6) cfu ml(-)1 plus 5 mmol l(-1) ammonium molybdate greatly reduced Penicillium expansum, Botrytis cinerea or Rhizopus stolonifer in apples stored at 20 degrees C for 7 days, and reduced by more than 90% blue and grey mould in apples stored at 1 degrees C for 60 days. The consistency of these results was maintained in semi-commercial trials at 1 degrees C in air and in a low oxygen atmosphere for 120 days. The pre-harvest application of C. sake 2 x 10(7) cfu ml(-1) plus 1 mmol l(-1) ammonium molybdate did not improve post-harvest biocontrol of blue mould. The population of C. sake significantly decreased in the presence of ammonium molybdate in apple wounds. The addition of ammonium molybdate at 5 mmol l(-1) to C. sake enhanced the efficacy of the antagonist to control post-harvest diseases on apples. Ammonium molybdate significantly reduces the amount of C. sake biomass required to achieve post-harvest disease control, with a consequent reduction in costs. This may be useful in the industrial production of C. sake.


Extrauterine Choriocarcinoma in the Fallopian Tube Following Infertility Treatment: Implications for the Management of Early-Detected Ectopic Pregnancies.
Extrauterine choriocarcinoma in the fallopian tube is very rare and is often diagnosed and treated as an ectopic tubal pregnancy. A 34-year-old woman who initially became pregnant after infertility treatment using ovulation induction with clomiphene citrate and intrauterine insemination was later diagnosed with an extrauterine choriocarcinoma in the left fallopian tube. Because of suspected left ectopic tubal pregnancy based on ultrasonography findings and a high level of β-human chorionic gonadotropin (β-hCG; 7054.3 mIU/mL), the patient underwent diagnostic laparoscopy at a gestational age of 6 weeks. Left salpingectomy was performed based on the operative diagnosis of an ectopic tubal pregnancy. No signs of tubal rupture or leakage of contents from the fallopian tube were observed during the operation. Her serum β-hCG dropped to 10.3 mIU/mL at 15 days postoperatively. Histopathology demonstrated an extrauterine choriocarcinoma in the removed fallopian tube, and the patient was referred to a regional oncologic hospital to receive additional adjuvant chemotherapy. This case indicates that conservative treatment for ectopic pregnancy should be chosen carefully, and that histopathology diagnosis and appropriate β-hCG monitoring following treatment are important not only to diagnose persistent ectopic pregnancy, but also to rule out the possibility of a tubal choriocarcinoma.


A Cross-Sectional Study on the Relationship between Oral Function and Sarcopenia in Japanese Patients with Regular Dental Maintenance.
We aimed to clarify the relationship between oral function assessments regarding oral hypofunction and sarcopenia in patients who had completed treatment for organic dental problems, including oral pain, removable denture fit, and tooth loss. This cross-sectional study included 269 patients aged ≥65 years (mean age 74.9 ± 6.50 years, 133 men, 136 women) who visited a dental clinic between June 2019 and March 2021. We evaluated oral function and sarcopenia and analyzed their relationship using the Jonckheere-Terpstra test, Mantel-Haenszel trend test, and Poisson regression analysis. We diagnosed 132 (49.07%) patients with oral hypofunction, 30 (11.2%) with sarcopenia, and 24 (8.9%) with severe sarcopenia. The number of oral hypofunction items (prevalence rate ratio [PRR] = 1.39, 95%Wald = 0.11 to 0.56) was significantly associated with sarcopenia. For each of the items, tongue-lip motor function [ta] (PRR = 0.80, 95%Wald = -0.44 to -0.02)] [ka] (PRR = 0.76, 95%Wald = -0.53 to -0.03) and tongue pressure (PRR = 0.95, 95%Wald = -0.09 to -0.02) showed a significant association with sarcopenia. However, no significant association was found for other variables. Dentists should not only treat organic dental problems but also consider the relationship between oral function and sarcopenia.


Criteria for detecting significant chronic iliac venous obstructions with duplex ultrasound.
The purpose of this study was to determine the sonographic criteria for diagnosis of iliac venous outflow obstruction by assessing the correlation of this method with intravascular ultrasound (IVUS) in patients with advanced chronic venous insufficiency (CVI). The evaluation included 15 patients (30 limbs; age, 49.4 ± 10.7 years; 1 man) with initial CVI symptoms (Clinical class, Etiology, Anatomy, and Pathophysiology [CEAP] classification, CEAP1-2) in group I (GI) and 51 patients (102 limbs; age, 50.53 ± 14.5 years; 6 men) with advanced CVI symptoms (CEAP3-6) in group II (GII). Patients from both groups were matched by gender, age, and race. The Venous Clinical Severity Score was considered. All patients underwent structured interviews and duplex ultrasound (DU) examination, measuring the flow phasicity, the femoral volume flows and velocities, and the velocity and obstruction ratios in the iliac vein. The reflux multisegment score was analyzed in both groups. Three independent observers evaluated individuals in GI. GII patients were submitted to IVUS, in which the area of the impaired venous segments was obtained and compared with the DU results and then grouped into three categories: obstructions <50%, obstructions between 50% and 79%, and obstructions ≥80%. The predominant clinical severity CEAP class was C1 in 24 of 30 limbs (80%) in GI and C3 in 54 of 102 limbs (52.9%) in GII. Reflux was severe (reflux multisegment score ≥3) in 3 of 30 limbs (10%) in GI and in 45 of 102 limbs (44.1%) in GII (P < .001). There was a moderately high agreement between DU and IVUS findings when they were grouped into three categories (κ = 0.598; P < .001) and high agreement when they were grouped into two categories (obstructions <50% and ≥50%; κ = 0.784; P < .001). The best cutoff points and their correlation with IVUS were 0.9 for the velocity index (r = -0.634; P < .001), 0.7 for the flow index (r = -0.623; P < .001), 0.5 for the obstruction ratio (r = 0.750; P < .001), and 2.5 for the velocity ratio (r = 0.790; P < .001). Absence of flow phasicity was observed in 62.5% of patients with obstructions ≥80%. An ultrasound algorithm was created using the measures and the described cutoff points with accuracy of 86.7% for detecting significant obstructions (≥50%) with high agreement (κ = 0.73; P < .001). DU presented high agreement with IVUS for detection of obstructions ≥50%. The velocity ratio in obstructions ≥2.5 is the best criterion for detection of significant venous outflow obstructions in iliac veins.


Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice.
Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases using fecal microbiota transplant (FMT). It is therefore not surprising that use of FMT, especially for treating relapsed/refractory Clostridioides difficile infections (CDI), has increased over the last decade. Due to the complexity associated with and treatment for these diseases, patients with hematologic and oncologic diseases are particularly susceptible to complications related to altered intestinal microbial composition. Therefore, they are an ideal population for exploring FMT as a therapeutic approach. However, there are inherent factors presenting as obstacles for the use of FMT in these patients. In this review paper, we discussed the principles and biologic effects of FMT, examined the factors rendering patients with hematologic and oncologic conditions to increased risks for relapsed/refractory CDI, explored ongoing FMT studies, and proposed novel uses for FMT in these groups of patients. Finally, we also addressed the challenges of applying FMT to these groups of patients and proposed ways to overcome these challenges.


Consultant opinion on orthodontic treatment plans used by dental practitioners: a pilot study.
Prior to 1987, dental practitioners in England and Wales intending to carry out all but the simplest orthodontic treatment within the National Health Service, were required to submit pretreatment study models, details of the orthodontic assessment and the proposed treatment plan to the Dental Estimates Board prior to starting treatment. Models taken at the end of treatment were required by the Board to enable payment to be made. In this pilot study, the acceptability of orthodontic treatment plans used by practitioners working in the General Dental Services was assessed by eight hospital consultants, using information about 40 cases submitted to the Dental Estimates Board in 1987/88. All consultants considered a high proportion of plans to be unacceptable, but agreement between the consultants was variable and some agreed with one another on very few plans. A single scorer used the weighted PAR (Peer Assessment Rating) index to assess the degree of departure from normal occlusion of both pre- and post-treatment models. Using accepted standards, only nine cases were greatly improved (PAR reduction > 70%) and the mean percentage reduction in PAR score was low. Consultant opinion on the appropriateness of treatment planning was not related to the outcome of orthodontic treatment.


M(3)-S: a genotype calling method incorporating information from samples with known genotypes.
A key challenge in analyzing high throughput Single Nucleotide Polymorphism (SNP) arrays is the accurate inference of genotypes for SNPs with low minor allele frequencies. A number of calling algorithms have been developed to infer genotypes for common SNPs, but they are limited in their performance in calling rare SNPs. The existing algorithms can be broadly classified into three categories, including: population-based methods, SNP-based methods, and a hybrid of the two approaches. Despite the relatively better performance of the hybrid approach, it is still challenging to analyze rare SNPs. We propose to utilize information from samples with known genotypes to develop a two stage genotyping procedure, namely M(3)-S, for rare SNP calling. This new approach can improve genotyping accuracy through clearly defining the boundaries of genotype clusters from samples with known genotypes, and enlarge the call rate by combining the simulated data based on the inferred genotype clusters information with the study population. Applications to real data demonstrates that this new approach M(3)-S outperforms existing methods in calling rare SNPs.


Expression of the nicotinic acetylcholine receptor alpha4 subunit mRNA in the rat cerebellar cortex.
In order to compare the previous immunohistochemical and immunocytochemical data on the distribution of nicotinic acetylcholine receptor alpha4 subunit-like immunoreactivity with the expression of alpha4 mRNA in the rat cerebellar cortex, the present study determined the cellular distribution of alpha4 mRNA in the rat cerebellar cortex. Northern blot analysis revealed two alpha4 mRNA bands in the rat cerebellum and three in the cerebral cortex, hippocampus, hypothalamus and striatum. The total level of these transcripts was lower in the cerebellum than in the other four regions. The expression of alpha4 mRNA was high in Purkinje cells and granular cells, whereas low expression was detected in the molecular layer. These results suggest that the expression of alpha4 mRNA is closely related to the alpha4-like immunoreactivity in the molecular and Purkinje cell layers. In the granular layer, alpha4 mRNA was very highly and broadly expressed in comparison with the alpha4-like immunoreactivity.


Effective Utilization of NIR Wavelengths for Photo-Controlled Polymerization: Penetration Through Thick Barriers and Parallel Solar Syntheses.
This contribution details an efficient and controlled photopolymerization regulated by far-red (λ=680 nm) and NIR (λ=780 and 850 nm) light in the presence of aluminium phthalocyanine and aluminium naphthalocyanine. Initiating radicals are generated by photosensitization of peroxides affording an effective strategy that provides controlled polymerization of a variety of monomers with excellent living characteristics. Critically, long wavelength irradiation provides penetration through thick barriers, affording unprecedented rates of controlled polymerization that can open new and exciting applications. Furthermore, a more optimized approach to performing solar syntheses is presented. By combining the narrow Q-bands of these photocatalysts with others possessing complementary absorptions, layered, independent polymerizations and organic transformations may be performed in parallel under a single broadband emission source, such as sunlight.


Unmasking in neurons of the inferior colliculus of Eptesicus fuscus with binaural stimulation.
171 single inferior colliculus neurons displaying basic auditory properties similar to those described previously were sampled, and 118 of those were tested to determine whether monaurally masked responses (band passed noise of +/- 5 kHz around the best frequency of the pure tone) could be recovered if the masking noise was presented binaurally. 26% of the units tested showed such an improvement in signal detection, i.e. what is called masking level difference (MLD) by psychoacousticians. Signal detection was improved by more than 20 dB in a few cases, but the usual improvement did not exceed 11 dB. The data suggest that MLD occurs only in units showing binaural facilitation in addition to inhibition (I, E/E type), in contrast to the more common binaural I/E types which may only provide basic azimuth information. The neurophysiological results are discussed in view of the findings described in the literature on psychoacoustical MLD and in terms of the biological importance these results have for the bat's acoustical space orientation (echolocation) and this system's excellent resistance to jamming. Since psychoacoustical explanations for the MLD effect appear to be of little relevance on a cellular level, possible neural mechanisms are discussed as well.


Oral health in patients taking psychotropic medications: Results from a pharmacy-based pilot study.
Individuals with mental illness face an increased risk of oral disease compared with those without mental illness. The goals of this study were to examine the self-reported oral health and dental access of individuals filling psychotropic medication prescriptions and to determine whether pharmacy patients would choose to speak with a pharmacist about their oral health if given the option to do so. Pharmacists across 6 community pharmacies within a local chain identified and surveyed adult patients filling prescriptions for psychotropic medications. Surveys included questions about oral health, dry mouth, and dental care utilization. Six community pharmacy locations. Adults (≥18 years of age) filling prescriptions for psychotropic medications. Not applicable. Self-reported oral health, dental utilization, desire to discuss oral health with a pharmacist. Participants (N = 178) filling prescriptions were mostly (65.9%) female with a mean age of 48.2 years (SD 14.3, range 19-82 years). One in 4 (24.9%) said their mouths "always" or "frequently" felt dry; these individuals were significantly more likely to have last seen a dentist for emergency (rather than routine) treatment (P <0.01) and rated their oral health as significantly worse (P <0.001) than participants whose mouths "never" or "occasionally" feel dry. A small percentage (5.7%) requested to speak with pharmacists about oral health; they reported poorer oral health than those who opted not to speak with a pharmacist (P <0.05). One in 4 patients reported having dry mouth, and those with dry mouth reported significantly worse oral health than patients without dry mouth. Although dry mouth and poor oral health were common in this sample of individuals taking psychotropic medications, this did not consistently translate into seeking information regarding oral health. Future research will focus on pharmacist-initiated oral health interventions with high-risk patients.


Developing the Expected Entrustment Score: Accounting for Variation in Resident Assessment.
Clinical competency committees (CCCs) and residency program leaders may find it difficult to interpret workplace-based assessment (WBA) ratings knowing that contextual factors and bias play a large role. We describe the development of an expected entrustment score for resident performance within the context of our well-developed Observable Practice Activity (OPA) WBA system. Observational study PARTICIPANTS: Internal medicine residents MAIN MEASURE: Entrustment KEY RESULTS: Each individual resident had observed entrustment scores with a unique relationship to the expected entrustment scores. Many residents' observed scores oscillated closely around the expected scores. However, distinct performance patterns did emerge. We used regression modeling and leveraged large numbers of historical WBA data points to produce an expected entrustment score that served as a guidepost for performance interpretation.


The Contribution of Neanderthals to Phenotypic Variation in Modern Humans.
Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences. Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day Europeans. Interestingly, multiple Neanderthal alleles at different loci contribute to skin and hair color in present-day Europeans, and these Neanderthal alleles contribute to both lighter and darker skin tones and hair color, suggesting that Neanderthals themselves were most likely variable in these traits.


The spectrum of perinatal group B streptococcal disease.
The progressive unfolding, over four decades, of an understanding of group B Streptococcus (GBS) and its global disease burden support the rationale for maternal immunization as a key strategy to prevent GBS perinatal infections. This review highlights, in historical context, the recognition of GBS as a human pathogen, definition of epidemiologic features of disease, pathogenesis, outcomes, impact of intrapartum antibiotic prophylaxis, development of glycoconjugate vaccines and appreciation of the global scope of GBS perinatal disease. These cumulative advances in the GBS field coupled with an increasing acceptance of immunization during pregnancy suggest the timing is optimal for introduction of a glycoconjugate GBS vaccine for use in pregnant women.