A Gabor-block-based kernel discriminative common vector approach using cosine kernels for human face recognition.
In this paper a nonlinear Gabor Wavelet Transform (GWT) discriminant feature extraction approach for enhanced face recognition is proposed. Firstly, the low-energized blocks from Gabor wavelet transformed images are extracted. Secondly, the nonlinear discriminating features are analyzed and extracted from the selected low-energized blocks by the generalized Kernel Discriminative Common Vector (KDCV) method. The KDCV method is extended to include cosine kernel function in the discriminating method. The KDCV with the cosine kernels is then applied on the extracted low-energized discriminating feature vectors to obtain the real component of a complex quantity for face recognition. In order to derive positive kernel discriminative vectors, we apply only those kernel discriminative eigenvectors that are associated with nonzero eigenvalues. The feasibility of the low-energized Gabor-block-based generalized KDCV method with cosine kernel function models has been successfully tested for classification using the L(1), L(2) distance measures; and the cosine similarity measure on both frontal and pose-angled face recognition. Experimental results on the FRAV2D and the FERET database demonstrate the effectiveness of this new approach.


Spatial imputation for air pollutants data sets via low rank matrix completion algorithm.
Incomplete observation of hourly air-pollutants concentration data is a common issue existing in urban air quality monitoring networks. This research proposes a spatial interpolation method to impute missing values presented in air pollutants data sets based on low rank matrix completion (LRMC). It considers air pollutants data of high correlation and consistency in its spatial distribution. We evaluate the performance of the proposed method when imputing various air pollutants concentration time series (NOx,O3,SO2,PM2.5,PM10) in terms of root mean square error (RMSE), index of agreement (D2), and goodness of fit (R2). It systematically compared with existing established imputation techniques, including nearest neighboring, mean substitution, regression-based method, spline interpolation, spectral method, and regularized expectation maximization algorithm (EM). As a spatial imputation method, LRMC outperforms these methods used in this research under the condition of larger missing ratio (such as 30% removal) on the central air pollutants monitoring station. For all monitoring stations, comprehensive experimental results show that LRMC always generates robust results to replace missing data with reasonable substitutions, and it is not sensitive to the length of missing gaps. The promising imputation performance in terms of the indicator R2 obtained by the proposed LRMC demonstrates that it can effectively impute missing values of air pollutants time series based on their inherent patterns.


Psychosocial factors predicting symptoms of depression and anxiety in allogeneic hematopoietic stem cell transplant recipients in Japan.
We explored whether a patient's psychosocial background before allogeneic hematopoietic stem cell transplantation (allo-HSCT) could predict the occurrence of psychiatric symptoms during treatment and after hospital discharge. Logistic regression analysis was performed using INTERMED, a scale that comprehensively evaluates psychological factors such as psychiatric history, current mental status, and coping skills, and social factors such as social participation status, relationships with others, and living environment, which were used as independent variables. The Center for Epidemiologic Studies Depression Scale was used to measure depression, while the Profile of Mood States was used to measure anxiety and other symptoms. Both measures were used as dependent variables and were administered upon clean room admission, during clean room stay, at clean room discharge, and at 3, 6, and 12 months after hospital discharge. Participants included 70 patients (45 males and 25 females, mean age 53.3 ± 12.3 years). Thirty-eight patients participated in the program for the entire period, up to 12 months after hospital discharge. The total score on the Japanese version of the INTERMED and psychological factor scores assessed at baseline were significant predictors of depressed mood on discharge; however, there were no significant predictors of scores on the Profile of Mood States. A comprehensive pretransplant evaluation of psychosocial background can help predict the appearance of psychiatric symptoms after allo-HSCT. In patients who are expected to develop psychiatric symptoms after allo-HSCT, it is important to consider early intervention by a specialist and close monitoring by a medical team.


Gender Prototypes Hinder Bystander Intervention in Women's Sexual Harassment.
Bystander intervention is a powerful response to sexual harassment that reduces victims' burden to respond. However, gender prototypes depicting sexual harassment victims as prototypical women (i.e., stereotypically feminine) may hinder intervention when harassment targets women who deviate from this prototype. Across four preregistered experiments (N = 1,270 Americans), we test whether bystanders intervene less readily in nonprototypical (vs. prototypical) women's sexual harassment. Participants observed a man manager ask a series of increasingly sexually harassing job interview questions toward either a gender prototypical or nonprototypical woman by traits (Studies 1-3) or gender identity (Study 4). Participants were instructed to intervene to stop the interview if/when they judged the questions as inappropriate. A meta-analysis revealed participants had a greater threshold for intervention when harassment targeted a nonprototypical (vs. prototypical) woman-a small but meaningful effect. Efforts to foster bystander intervention in sexual harassment would benefit by recognizing this neglect of nonprototypical women.


Hedgerows interact with forests to shape the abundance of mesopredators and their predation rate on eggs in farmland landscapes.
Nest predation is the main cause of reproductive failure, particularly in ground-nesting birds on farmlands. Understanding the links between nest predation and habitat change can help design effective management schemes to constrain the negative impact of predation pressure on birds. However, the mechanisms underlying the relationships between landscape attributes, predator distribution, and nest predation are still unclear. Here, we use an experimental approach to examine the effects of distance to the hedgerow as well as hedgerow and forest densities on the abundance of major mesopredators of ground nests of our study area (i.e., corvids) and on the predation rate of artificial ground nests (n = 2576). We found evidence that landscape configuration influenced predation patterns differently depending on the predator species. Nest predation by corvids was more likely in homogeneous and open agricultural landscapes with a low density of forest and hedgerows, whereas predation by other predators was more likely close to hedgerows. Nest predation by corvids and the abundance of corvids also tended to be lower in landscapes dominated by grasslands. Other variables such as road density and distance to human settlements had contrasted effects on the likelihood of a nest being depredated by corvids, i.e., no effect with proximity to human settlements and decreasing trend with road density. Altogether, our results suggest that landscape features interact with mesopredator distribution and their predation rates of ground nests. Therefore, from a conservation and management perspective, a heterogeneous agricultural landscape that includes a mixture of crops associated with patches of forests, hedgerows, and grasslands offering alternative food to generalist predators should contribute to reducing ground-nesting bird predation.


Study on relationship between erythrocyte filtration and other risk factors in diabetic angiopathy.
Red blood cell filtration test has been performed in 37 insulin dependent diabetics (IDD) and 35 controls matched for age and sex and subdivided into age groups. IDD have been classified according to the presence of vascular complications, either affecting small and/or large vessels, assessed by clinical and instrumental methods. Results evidence a close correlation between age, fibrinogen, smoking and filtration index, both in IDD and in controls. The presence and type of vascular complication in diabetics parallels the increase in the filtration index, being the blood of macroangiopathic diabetics less filtrable than that of non angiopathics and/or controls. Metabolic control, recorded as glycosylated haemoglobin shows a slight correlation with filtration index, while blood glucose of the same specimen does not. Filtration index appears to be an useful datum for assessing angiopathic risk in diabetics. Nineteen IDD have been treated with pentoxifylline, 400 mg per os 3 times daily for 20 days and filtration time, and other metabolic variables have been assessed. Data evidenced a marked improvement in the filtration time without any change in the other metabolic variables suggesting that the effect of this drug is mainly exerted on the RBC deformability and not on plasma viscosity. The drug has been very well tolerated and revealed itself an effective therapeutic mean for influencing RBC filtration, thus preventing angiopathic phenomena.


The round window membrane in otitis media: effect of pneumococcal proteins.
To determine whether mutants of Streptococcus pneumoniae that are deficient in pneumococcal surface protein A (PspA), pneumococcal surface antigen A (PsaA), or pneumolysin (Ply) are less virulent and less likely to penetrate the round window membrane (RWM). Histopathologic comparison of wild-type S. pneumoniae and its mutants deficient in PspA, PsaA, and Ply. Otopathology Laboratory, Department of Otolaryngology, University of Minnesota Medical School, Minneapolis. Forty young chinchillas (weight, 250-350 g) with normal external auditory canals and tympanic membranes. Animals were divided into 3 groups and bullae inoculated with wild-type S. pneumoniae serotype 2, strain D39, or its mutants deficient in PspA, PsaA, or Ply. Two days after inoculation, bullae were processed for light microscopy and transmission electron microscopy. Comparison of inflammatory cell infiltration and penetration of bacteria into the round window membrane and adjacent scala tympani. Histopathologic findings using wild-type S. pneumoniae and Ply(-) mutant were similar and included otitis media and the presence of inflammatory cells and damage to and passage of bacteria through the RWM. Although otitis media was seen with the PspA(-) and PsaA(-) mutants, we observed no passage of bacteria through the RWM. Both PspA and PsaA affect the ability of S. pneumoniae to penetrate the RWM. Understanding the role of S. pneumoniae virulence proteins in the pathogenesis of the middle ear, RWM, and inner ear will provide new strategies for the prevention and treatment of otitis media and its complications.


Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021.
Botulism is a rare, neurotoxin-mediated, life-threatening disease characterized by flaccid descending paralysis that begins with cranial nerve palsies and might progress to extremity weakness and respiratory failure. Botulinum neurotoxin, which inhibits acetylcholine release at the neuromuscular junction, is produced by the anaerobic, gram-positive bacterium Clostridium botulinum and, rarely, by related species (C. baratii and C. butyricum). Exposure to the neurotoxin occurs through ingestion of toxin (foodborne botulism), bacterial colonization of a wound (wound botulism) or the intestines (infant botulism and adult intestinal colonization botulism), and high-concentration cosmetic or therapeutic injections of toxin (iatrogenic botulism). In addition, concerns have been raised about the possibility of a bioterrorism event involving toxin exposure through intentional contamination of food or drink or through aerosolization. Neurologic symptoms are similar regardless of exposure route. Treatment involves supportive care, intubation and mechanical ventilation when necessary, and administration of botulinum antitoxin. Certain neurological diseases (e.g., myasthenia gravis and Guillain-Barré syndrome) have signs and symptoms that overlap with botulism. Before the publication of these guidelines, no comprehensive clinical care guidelines existed for treating botulism. These evidence-based guidelines provide health care providers with recommended best practices for diagnosing, monitoring, and treating single cases or outbreaks of foodborne, wound, and inhalational botulism and were developed after a multiyear process involving several systematic reviews and expert input.


Residues Distal to the Active Site Contribute to Enhanced Catalytic Activity of Variant and Hybrid β-Lactamases Derived from CTX-M-14 and CTX-M-15.
A variety of CTX-M-type extended-spectrum β-lactamases (ESBLs), including hybrid ones, have been reported in China that are uncommon elsewhere. To better characterize the substrate profiles and enzymatic mechanisms of these enzymes, we performed comparative kinetic analyses of both parental and hybrid CTX-M enzymes, including CTX-M-15, -132, -123, -64, -14 and -55, that are known to confer variable levels of β-lactam resistance in the host strains. All tested enzymes were susceptible to serine β-lactamase inhibitors, with sulbactam exhibiting the weakest inhibitory effects. CTX-M-55, which differs from CTX-M-15 by one substitution, A(77)V, displayed enhanced catalytic activity (kcat/Km) against expanded-spectrum cephalosporins (ESCs). CTX-M-55 exhibits higher structure stability, most likely by forming hydrophobic interactions between A(77)V and various key residues in different helices, thereby stabilizing the core architecture of the helix cluster, and indirectly contributes to a more stable active site conformation, which in turn shows higher catalytic efficiency and is more tolerant to temperature change. Analyses of the hybrids and their parental prototypes showed that evolution from CTX-M-15 to CTX-M-132, CTX-M-123, and CTX-M-64, characterized by gradual enhancement of catalytic activity to ESCs, was attributed to introduction of different substitutions to amino acids distal to the active site of CTX-M-15. Similarly, the increased hydrolytic activities against cephalosporins and sensitivity to β-lactamase inhibitors, clavulanic acid and sulbactam, of CTX-M-64 were partly due to the amino acids that were different from CTX-M-14 and located at both the C and N termini of CTX-M-64. These data indicate that residues distal to the active site of CTX-Ms contributed to their enhanced catalytic activities to ESCs.


WITHDRAWN: Bed rest for acute low-back pain and sciatica.
Low-back pain (LBP) is a common reason for consulting a general practitioner, and advice on daily activities is an important part of the primary care management of low-back pain. To assess the effects of advice to rest in bed for patients with acute LBP or sciatica. We searched the Cochrane Back Group Specialized Registry, CENTRAL, MEDLINE, EMBASE, Sport, and SCISEARCH to March 2003, reference lists of relevant articles, and contacted authors of relevant articles. Randomised or controlled clinical trials with quasi-randomisation (alternate allocation, case record numbers, dates of birth, etc.), in any language, where the effectiveness of advice to rest in bed was evaluated. The main outcomes of interest were pain, functional status, recovery and return to work. Two authors independently selected trials for inclusion, assessed the internal validity of included trials and extracted data. Investigators were contacted to obtain missing information. Eleven trials (1963 patients) were included in this updated version. There is high quality evidence that people with acute LBP who are advised to rest in bed have a little more pain [Standardised Mean Difference (SMD) 0.22 (95% Confidence Interval (CI): 0.02, 0.41)] and a little less functional recovery [SMD 0.29 (95% CI: 0.05, 0.45)] than those advised to stay active. For patients with sciatica, there is high quality evidence of little or no difference in pain [SMD -0.03 (95% CI: -0.24, 0.18)] or functional status [SMD 0.19 (95% CI: -0.02, 0.41)], between bed rest and staying active.For patients with acute LBP, there is moderate quality evidence of little or no difference in pain intensity or functional status between bed rest and exercises. For patients with sciatica, there is moderate quality evidence of little or no difference in pain intensity between bed rest and physiotherapy, but small improvements in functional status [Weighted Mean Difference 6.9 (on a 0-100 scale) (95% CI: 1.09, 12.74)] with physiotherapy. There is moderate quality evidence of little or no difference in pain intensity or functional status between two to three days and seven days of bed rest. For people with acute LBP, advice to rest in bed is less effective than advice to stay active. For patients with sciatica, there is little or no difference between advice to rest in bed and advice to stay active. There is little or no difference in the effect of bed rest compared to exercises or physiotherapy, or seven days of bed rest compared with two to three.


Correlates of safer sex communication among college students.
Correlates of safer sex communication among college students The purpose of this study was to examine factors that are thought to promote communication about safer sex and HIV among college students in the United States of America and to determine the extent to which communication about safer sex is important in the use of condoms. A better understanding of factors associated with safer sex communication can be helpful in developing HIV and STD prevention programmes for college students. Following approval from the institutional review boards of the six participating colleges and universities, researchers collected data from a random sample of students. The study included participant responses if participants were 18-25 years of age, single and sexually active. For the sample of 1349 participants, the mean age was 20.6 years. Sixty-three per cent of the sample was female, 50.5% white, 42.3% African-American, and the remainder of other ethnic groups. Over 50% of respondents reported frequent condom use, with 28% noting that they used a condom every time and 30.6% reporting condom use almost every time they had sex. Only 9.6% indicated that they never used a condom. The results of hierarchical multiple regression analysis revealed that the perception of quality of general communication with parents, the perception of a partner's attitude towards communication, communication self-efficacy, and communication outcome expectancies, were associated with safer sex communication. However, the association between safer sex communication and condom use was weak, suggesting that other factors excluded from this study are important in determining condom use for this sample of respondents. The findings provide some implications for HIV interventions. Interventions that enhance self-efficacy and positive outcome expectancies related to communication about safer sex are likely to foster discussion with a sexual partner. However, they might not lead to actual condom use.


Phylogeny of the beetle supertribe Trechitae (Coleoptera: Carabidae): Unexpected clades, isolated lineages, and morphological convergence.
Using data from two nuclear ribosomal genes and four nuclear protein-coding genes, we infer a well-resolved phylogeny of major lineages of the carabid beetle supertribe Trechitae, based upon a sampling of 259 species. Patrobini is the sister group of Trechitae, but the genus Lissopogonus appears to be outside of the Patrobini + Trechitae clade. We find that four enigmatic trechite genera from the Southern Hemisphere, Bembidarenas, Argentinatachoides, Andinodontis, and Tasmanitachoides, form a clade that is the sister group of Trechini; we describe this clade as a new tribe, Bembidarenini. Bembidarenini + Trechini form the sister group of remaining trechites. Within Trechini, subtribe Trechodina is not monophyletic, as three trechodine genera from Australia (Trechobembix, Paratrechodes, Cyphotrechodes) are the sister group of subtribe Trechina. Trechini appears to have originated in the continents of the Southern Hemisphere, with almost all Northern Hemisphere lineages representing a single radiation within the subtribe Trechina. We present moderate evidence that the geographically and phylogenetically isolated genera Sinozolus (six species in the mountains of China), Chaltenia (one species in Argentina and Chile), and Phrypeus (one species in western North America) also form a clade, the tribe Sinozolini. The traditionally recognized tribe Bembidiini sens. lat., diagnosed by the presence of a subulate terminal palpomere, is shown to be polyphyletic; subulate palpomeres have arisen five times within Trechitae. Anillini is monophyletic, and the sister group of Tachyini + Pogonini + Bembidiini + Zolini + Sinozolini; within anillines, we confirm earlier results indicating the eyed New Zealand genus Nesamblyops as the sister to the rest. Sampled New World Pogonini are monophyletic, rendering the genus Pogonus non-monophyletic. Tachyina and Xystosomina are sister groups. Within Xystosomina, the New World members are monophyletic, and are sister to an Australia-New Zealand clade. The latter consists of the genus Philipis as well as taxa not previously recognized as xystosomines: Kiwitachys, the "Tachys" ectromioides group, and "Tachys" mulwalensis. Within Tachyina, the subgenus Elaphropus is not closely related to other subgenera previously placed in the genus Elaphropus; we move the other subgenera into the genus Tachyura. Tachyina with a bifoveate mentum do not form a clade; in fact, a bifoveate mentum is found in Xystosomina, Sinozolini, Trechini, Trechitae and its sister group, Patrobini. Extensive homoplasy in the morphological characters previously used as key indicators of relationship is supported by our results: in addition to multiple origins of subulate palpomeres and bifoveate menta, a concave protibial notch has arisen independently in Anillina, Xystosomina, and Tachyina. Phylogenetically and geographically isolated, species-poor lineages in Trechini, Bembidarenini, and Sinozolini may be relicts of more widespread faunas; many of these are found today on gravel or sand shores of creeks and rivers, which may be an ancestral habitat for portions of Trechitae. In addition to the description of Bembidarenini, we present a diagnosis of the newly delimited Sinozolini, and keys to the tribes of Trechitae.


More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients.
The clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection. To study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19. One hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome. Although the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14-8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19. These findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs. https://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584.


Gene regulatory network reconstruction by Bayesian integration of prior knowledge and/or different experimental conditions.
There have been various attempts to improve the reconstruction of gene regulatory networks from microarray data by the systematic integration of biological prior knowledge. Our approach is based on pioneering work by Imoto et al. where the prior knowledge is expressed in terms of energy functions, from which a prior distribution over network structures is obtained in the form of a Gibbs distribution. The hyperparameters of this distribution represent the weights associated with the prior knowledge relative to the data. We have derived and tested a Markov chain Monte Carlo (MCMC) scheme for sampling networks and hyperparameters simultaneously from the posterior distribution, thereby automatically learning how to trade off information from the prior knowledge and the data. We have extended this approach to a Bayesian coupling scheme for learning gene regulatory networks from a combination of related data sets, which were obtained under different experimental conditions and are therefore potentially associated with different active subpathways. The proposed coupling scheme is a compromise between (1) learning networks from the different subsets separately, whereby no information between the different experiments is shared; and (2) learning networks from a monolithic fusion of the individual data sets, which does not provide any mechanism for uncovering differences between the network structures associated with the different experimental conditions. We have assessed the viability of all proposed methods on data related to the Raf signaling pathway, generated both synthetically and in cytometry experiments.


Effortful swallowing training combined with electrical stimulation in post-stroke dysphagia: a randomized controlled study.
We tested the effect of effortful swallow combined with surface electrical stimulation used as a form of resistance training in post-stroke patients with dysphagia. Twenty post-stroke dysphagic patients were randomly divided into two groups: those who underwent effortful swallow with infrahyoid motor electrical stimulation (experimental group, n = 10) and effortful swallow with infrahyoid sensory electrical stimulation (control group, n = 10). In the experimental group, electrical stimulation was applied to the skin above the infrahyoid muscle with the current was adjusted until muscle contraction occurred and the hyoid bone was depressed. In the control group, the stimulation intensity was applied just above the sensory threshold. The patients in both groups were then asked to swallow effortfully in order to elevate their hyolaryngeal complex when the stimulation began. A total of 12 sessions of 20 min of training for 4 weeks were performed. Blinded biomechanical measurements of the extent of hyolaryngeal excursion, the maximal width of the upper esophageal sphincter (UES) opening, and the penetration-aspiration scale before and after training were performed. In the experimental group, the maximal vertical displacement of the larynx was increased significantly after the intervention (p < 0.05). The maximal vertical displacement of the hyoid bone and the maximal width of the UES opening increased but the increase was not found to be significant (p = 0.066). There was no increase in the control group. Effortful swallow training combined with electrical stimulation increased the extent of laryngeal excursion. This intervention can be used as a new treatment method in post-stroke patients with dysphagia.


Effect of thermal cycling on microleakage of a fissure sealant polymerized with different light sources.
The purpose of this study was to examine the effect of thermal cycling on microleakage of a fissure sealant after it was bonded with different bonding agents and polymerized with different light curing units. To this end, two bonding agents (Xeno III, iBond), three light curing units (Astralis 3, Elipar free-light, Elipar free-light 2), and a fissure sealant (Fissurit FX) were used. Microleakage was then evaluated using a dye penetration method after thermal cycling. When the fissure sealant was polymerized with Elipar free-light and Elipar free-light 2, microleakage at 10,000 cycles was significantly increased compared with that at 5,000 cycles. In terms of comparison among the curing units, the best microleakage score was observed with Astralis 3 (p<0.05). In terms of comparison between the two bonding agents, no significant differences in microleakage score were observed (p>0.05). Further, it was concluded that in order to evaluate microleakage scores appropriately, it was necessary for specimens to be subjected to thermocycling of 10,000 times or more.


The Role of Illness Perception and Its Association With Posttraumatic Stress at 3 Months Following Acute Myocardial Infarction.
Background: The aim of this study was to investigate the relationship between illness perception and posttraumatic stress disorder (PTSD) symptoms at three months following acute myocardial infarction (MI). Methods: Patients (n = 96) were examined within 48 h and 3 months after the illness episode. The brief revised illness perception questionnaire (Brief-IPQ) was used to assess patients' cognitive representation of their MI. At 3-month follow-up, the Posttraumatic Diagnostic Scale (PDS) and the Clinician-Administered PTSD Scale (CAPS) were used to assess the level of PTSD symptoms. Results: The subjective perception of the illness, including higher harmful consequences (r > 0.35, p < 0.01), higher illness concerns (r > 0.24, p < 0.05) and more emotional impairment (r > 0.23, p < 0.05), was associated with both self-rated and clinician-rated PTSD symptoms. Beliefs regarding harmful consequences after acute MI were independently associated with levels of PTSD symptoms assessed with both the self-rated PDS and CAPS interview (standardized β coefficient = 0.24; P < 0.05) adjusted for demographic factors, cognitive depressive symptoms, fear of dying during MI, factors related to study design, and illness severity. Conclusions: The findings suggest that initial perception of acute MI is significantly associated with PTSD symptoms attributable to MI at 3 months follow-up.


Exposure, epidemiology, and mechanism of the environmental toxicant manganese.
It has become increasingly apparent that global manganese (Mn) pollution to air and water is a significant threat to human health. Despite this recognition, research is only beginning to comprehend the detrimental effects of exposure. Mn, while essential, is particularly harmful to the central nervous system, and overexposure is symptomatic of several neurological disorders. At-risk populations have been identified, but it is still unclear whether typical exposure levels have any long-term consequences. Those at an elevated risk have diminished intellectual function, learning and memory, and mental development. While the overall mechanism of toxicity is undetermined, Mn has been found to induce oxidative stress, exacerbate mitochondrial dysfunction, dysregulate autophagy, and promote apoptosis, ultimately enhancing neurodegeneration. Extrapolation of this in vitro and in vivo data to humans is difficult. There is a definite need to correlate epidemiological studies with causative effects. It is imperative that research efforts endure, so threats are appropriately identified and exposure properly regulated.


Relationship between perceived exertion during exercise and subsequent recovery measurements.
The return towards resting homeostasis in the post-exercise period has the potential to represent the internal training load of the preceding exercise bout. However, the relative potential of metabolic and autonomic recovery measurements in this role has not previously been established. Therefore the aim of this study was to investigate which of 4 recovery measurements was most closely associated with Borg's Rating of Perceived Exertion (RPE), a measurement widely acknowledged as an integrated measurement of the homeostatic stress of an exercise bout. A heterogeneous group of trained and untrained participants (n = 36) completed a bout of exercise on the treadmill (3 km at 70% of maximal oxygen uptake) followed by 1 hour of controlled recovery. Expired respiratory gases and heart rate (HR) were measured throughout the exercise and recovery phases of the trial with recovery measurements used to calculate the magnitude of excess post-exercise oxygen consumption (EPOCMAG), the time constant of the EPOC curve (EPOCτ), 1 min heart rate recovery (HRR60s) and the time constant of the HR recovery curve (HRRτ) for each participant. RPE taken in the last minute of exercise was significantly associated with HRR60s (r=-0.69), EPOCτ (r=0.52) and HRRτ (r=0.43) but not with EPOCMAG. This finding suggests that, of the 4 recovery measurements under investigation, HRR60s shows modest potential to represent inter-individual variation in the homeostatic stress of a standardized exercise bout, in a group with a range of fitness levels.


Developmental switch of leptin signaling in arcuate nucleus neurons.
Leptin is well known for its role in the regulation of energy homeostasis in adults, a mechanism that at least partially results from the inhibition of the activity of NPY/AgRP/GABA neurons (NAG) in the arcuate nucleus of the hypothalamus (ARH). During early postnatal development in the rodent, leptin promotes axonal outgrowth from ARH neurons, and preautonomic NAG neurons are particularly responsive to leptin's trophic effects. To begin to understand how leptin could simultaneously promote axonal outgrowth from and inhibit the activity of NAG neurons, we characterized the electrochemical effects of leptin on NAG neurons in mice during early development. Here, we show that NAG neurons do indeed express a functional leptin receptor throughout the early postnatal period in the mouse; however, at postnatal days 13-15, leptin causes membrane depolarization in NAG neurons, rather than the expected hyperpolarization. Leptin action on NAG neurons transitions from stimulatory to inhibitory in the periweaning period, in parallel with the acquisition of functional ATP-sensitive potassium channels. These findings are consistent with the idea that leptin provides an orexigenic drive through the NAG system to help rapidly growing pups meet their energy requirements.


Regulation of ion transport in the porcine intestinal tract by enteric neurotransmitters and hormones.
In the present paper, the mechanisms underlying the neural and hormonal regulation of mucosal ion transport in the pig intestinal tract are reviewed. The active transport of NaCl by isolated sheets of porcine intestinal mucosa is modulated by cholinergic and non-cholinergic neurons of undetermined neurochemical identity that lie in the submucosa. The application of electrical field stimulation to mucosa-submucosa preparations from porcine jejunum, ileum, or colon produces rapid elevations in short-circuit current which are inhibited by tetrodotoxin or omega-conotoxin GVIA, blockers of neuronal Na+ and Ca2+ channels, respectively. In porcine ileum, these elevations in current are mimicked in large part by cholinergic agonists and have been attributed to anion secretion. The majority of classical neurotransmitters and gut peptides that have been examined to date increase active transepithelial anion secretion through interactions with G protein-coupled receptors associated with submucosal neurons or situated on the basolateral membranes of epithelial cells. A small number of neuropeptides interact with neuronal receptors to augment NaCl absorption or decrease anion secretion. Noradrenergic control of intestinal transport differs in the porcine small and large intestines, and displays considerable inter-species variability in its cellular underpinnings. Transport regulation by bombesin-like peptides may be mediated by receptors distributed in both the apical and basolateral membrane domains of epithelial cells in porcine colon. The transport process affected by these peptides may be linked to epithelial growth and differentiation. The pig intestinal tract appears to be a useful biological model for resolving the cellular mechanisms by which gut neurotransmitters and hormones act in regulating transepithelial ion fluxes. Its general relevance to human intestinal function is discussed.


Bifunctional backbone modified squaramide dipeptides as amyloid beta (Aβ) aggregation inhibitors.
Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (Aβ) peptide plaques and higher concentrations of bio-metals such as copper (Cu), zinc (Zn), and iron (Fe) are the most significant hallmarks of AD observed in the brains of AD patients. Therefore simultaneous inhibition of Aβ peptide aggregation and reduction of metal stress may serve as an effective therapeutic approach for treating Alzheimer's disease. A series of bifunctional dipeptides bearing squaramide backbone were synthesized and investigated for their ability to chelate metal ions and prevent Aβ peptide aggregation. Dipeptides with Valine (V) and Threonine (T) substitutions at the C-terminus exhibited preferential chelation with Cu(II), Zn(II), and Fe(III) metal ions in the presence of other metal ions. They were also found to inhibit the aggregation of Aβ peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the Aβ peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the Aβ peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of Aβ peptide aggregation, the selected dipeptides were found to possess anti-oxidant properties. Therefore, the squaramide backbone-modified dipeptides may serve as an active bifunctional scaffold towards the development of new chemical entities for the treatment of Alzheimer's disease.


Complex Neck Loading and Injury Tolerance in Lateral Bending With Head Rotation From Human Cadaver Tests.
Advancements in automated vehicles may position the occupant in postures different from the current standard posture. It may affect human tolerance responses. The objective of this study was to determine the lateral bending tolerance of the head-cervical spine with initial head rotation posture using loads at the occipital condyles and lower neck and describe injuries. Using a custom loading device, head-cervical spine complexes from human cadavers were prepared with load cells at the ends. Lateral bending loads were applied to prerotated specimens at 1.5 m/s. At the occipital condyles, peak axial and antero-posterior and medial-lateral shear forces were: 316-954 N, 176-254 N, and 327-508 N, and coronal, sagittal, and axial moments were: 27-38 N·m, 21-38 N·m, and 9.7-19.8 N·m, respectively. At the lower neck, peak axial and shear forces were: 677-1004 N, 115-227 N, and 178-350 N, and coronal, sagittal, and axial moments were: 30-39 N·m, 7.6-21.3 N·m, and 5.7-13.4 N·m, respectively. Ipsilateral atlas lateral mass fractures occurred in four out of five specimens with varying joint diastasis and capsular ligament involvements. Acknowledging that the study used a small sample size, initial tolerances at the occipital condyles and lower neck were estimated using survival analysis. Injury patterns with posture variations are discussed.


A subset of flavaglines inhibits KRAS nanoclustering and activation.
The RAS oncogenes are frequently mutated in human cancers and among the three isoforms (KRAS, HRAS and NRAS), KRAS is the most frequently mutated oncogene. Here, we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations. Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid-enriched plasma membrane domains. We further demonstrate that plasma membrane-associated prohibitins directly interact with KRAS, phosphatidylserine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by the structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied the rocaglamide-mediated effects on KRAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and that treatment with rocaglamide reduces non-small-cell lung carcinoma (NSCLC) tumour nodules in autochthonous KRAS-driven mouse models without severe side effects. Our data suggest that it will be promising to further develop flavagline derivatives as specific KRAS inhibitors for clinical applications.


[Johanson-Blizzard syndrome: the importance of differential diagnostic in pediatrics].
To promote a clinical entity that could be part of differential diagnosis of most disorders that affect the pediatric age group. We describe a Brazilian girl affected by Johanson-Blizzard syndrome and review the literature. Johanson-Blizzard syndrome is an autosomal recessive condition characterized by hypoplastic alae nasi, scalp defect, deafness and pancreatic insufficiency with malabsorption. Looking at the major signs, this disorder should be considered as differential diagnosis in several pediatric diseases.


DNA damage in normally and prematurely aged mice.
Steady-state levels of spontaneous DNA damage, the by-product of normal metabolism and environmental exposure, are controlled by DNA repair pathways. Incomplete repair or an age-related increase in damage production and/or decline in repair could lead to an accumulation of DNA damage, increasing mutation rate, affecting transcription, and/or activating programmed cell death or senescence. These consequences of DNA damage metabolism are highly conserved, and the accumulation of lesions in the DNA of the genome could therefore provide a universal cause of aging. An important corollary of this hypothesis is that defects in DNA repair cause both premature aging and accelerated DNA damage accumulation. While the former has been well-documented, the reliable quantification of the various lesions thought to accumulate in DNA during aging has been a challenge. Here, we quantified inhibition of long-distance PCR as a measure of DNA damage in liver and brain of both normal and prematurely aging, DNA repair defective mice. The results indicate a marginal, but statistically significant, increase in spontaneous DNA damage with age in normal mouse liver but not in brain. Increased levels of DNA damage were not observed in the DNA repair defective mice. We also show that oxidative lesions do not increase with age. These results indicate that neither normal nor premature aging is accompanied by a dramatic increase in DNA damage. This suggests that factors other than DNA damage per se, for example, cellular responses to DNA damage, are responsible for the aging phenotype in mice.


Novel modification to leaded eyewear results in significant operator eye radiation dose reduction.
Ocular radiation exposure from fluoroscopically guided interventions (FGIs) can cause cataracts. Standard lead eyewear may not significantly reduce eye radiation dose as the majority of scattered radiation penetrates the operator's eye obliquely. Our aim was to evaluate the efficacy of standard leaded eyewear and a customized eyewear design in lowering eye radiation dose to vascular surgeons. The attenuating efficacy of three forms of leaded eyewear (standard eyewear, eyewear with built-in leaded side shields, and our modified eyewear) was tested in both a simulated setting and clinical practice. The modified design consisted of safety eyewear with 0.75 mm of added lead shielding attached to the lateral and inferior borders of the eyewear frame to attenuate oblique radiation. We performed simulated experiments using an anthropomorphic head phantom (ATOM model 701; CIRS, Norfolk, Va) positioned to represent a primary operator performing right femoral access. Optically stimulated, luminescent nanoDot detectors (Landauer, Glenwood, Ill) were placed inside the phantom's ocular spaces and at the surface of the left eye within and outside the leaded glasses to measure the eye radiation dose reduction provided by each eyewear type. All three eyewear types were also tested during clinical FGIs by placing nanoDots below the operator's left eye, inside and outside of the eyewear coverage. Means and standard errors were calculated using a pooled linear mixed model with repeated measurements. This prospective, single-center study included 60 FGIs, 30 with traditional eyewear and 30 with our modified design. There was no significant eye radiation dose reduction (P > .05) with the standard eyewear or leaded side shield eyewear in both the simulated and clinical settings. In the simulated environment, our modified design resulted in an 86% radiation dose reduction to the surface of the left eye and an 80% reduction in left lens radiation dose (P < .0001). In the clinical FGIs, the modified eyewear led to a 62% left ocular radiation dose reduction (P < .0001). Standard lead-equivalent glasses are ineffective at reducing ocular radiation dose during FGIs. Eyewear modification with lateral and inferior lead shielding molded to the operator's face significantly decreases radiation exposure to the eye closest to the X-ray source.


Dynamic combinatorial chemistry: a tool to facilitate the identification of inhibitors for protein targets.
Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen.


Factors associated with mental health of young children during the COVID-19 pandemic in the Netherlands.
The COVID-19 pandemic and accompanying societal measures have impacted children and their families all over the world. Little is known about the factors associated with mental health outcomes in young children (i.e., 1 to 6 years old) during the pandemic. The current study aimed to examine associations with potential risk and protective factors, i.e., direct COVID-19 exposure factors as well as within-family characteristics. Caregivers of children aged 1-6 years old were recruited in the Netherlands to participate in an ongoing longitudinal research project. In the current study, baseline data-collected during the 1st year of the pandemic-are reported. The final sample consisted of 2762 caregivers who answered questionnaires assessing negative and positive dimensions of their children's mental health (i.e., anxiety, depressive symptoms, anger, sleep problems, positive affect, and self-regulation). Furthermore, caregivers provided information regarding: (1) Direct COVID-19 related factors, i.e., parental infection and death of a family member or close friend due to COVID-19, (2) Family related COVID-19 factors, i.e., parental perceived impact of the pandemic and COVID-19 related parent-child emotion regulation strategies (i.e., active, avoidant and information-focused strategies), (3) General caregiver's distress, i.e., parental mental health, parental feelings of rejection towards their child. Regression analyses were used to examine associations with children's mental health. Direct COVID-19 related factors were not associated with more mental health problems in the children, though parental COVID-19 infections were related with less anger in children. Family related COVID-19 factors and caregiver's distress were related with children's mental health. Higher parental perceived negative impact of the pandemic, lower parental perceived positive impact of the pandemic, more avoidant as well as more active and information-focused parent-child emotion regulation strategies, more caregiver's mental health problems and more parental feelings of rejection towards their child were related with more mental health problems in the child. Direct exposure to COVID-19 was not related with more mental health problems in the child. Family related COVID-19 factors and caregiver's distress appear to play a more important role for young children's mental health. Findings may inform prevention and intervention programs for potential future global crises as well as other stressful events.


Medical education - beyond tomorrow? The new doctor - Asclepiad or Logiatros?
Against a background of the theoretical basis for the contextual approach to medical education, this paper examines and supports the changes that are occurring in undergraduate medical education throughout the world, before putting up for discussion the suggestion that the changes have not gone far enough. Consideration is given to a model of apprenticeship learning within undergraduate medical education, to the benefits it may offer, and to some of the challenges inherent in its implementation.


Physiologic and hypertonic saline solutions impair ciliary activity in vitro.
Physiologic saline (NaCl 0.9%) is commonly used in treating acute and chronic rhinosinusitis. Moreover, physiologic saline is used as a control medium, vehicle, or solvent in studies on ciliary beat frequency (CBF). Hypertonic saline (NaCl 7% and 14.4%) has been applied in attempts to enhance mucociliary transport in patients with cystic fibrosis or asthma and in healthy subjects. Therefore the objective of this study is to document in vitro effects of saline solutions in different concentrations on CBF. Experimental, in vitro. The effects on CBF of cryopreserved mucosa of the sphenoidal sinus was measured by a photoelectrical method. Initial frequencies, measured in Locke-Ringer's solution (LR), were compared with CBF after exposure to NaCl in concentrations of 0.9%, 7.0%, and 14.4% (w/v). NaCl 0.9% has a moderately negative effect on CBF. The 7% solution leads to a complete ciliostasis within 5 minutes, although this effect turns out to be reversible after rinsing with LR. A hypertonic solution of 14.4% has an irreversible ciliostatic effect. LR is an isotonic solution that has no effect on CBF. Therefore it is probable that this solution is more appropriate than saline for nasal irrigation and nebulization or antral lavage. Moreover, the results of this study suggest that mucolytic effects induced by hyperosmolarity should be attained preferably with hypertonic saline 7% in patients with cystic fibrosis or asthma. At this concentration, the ciliostatic effect is reversible, whereas irreversible changes are to be expected at higher concentrations.


[Changes in the enzyme activity of flavinogenesis in the process of culturing the fungus Eremothecium ashbyii].
The activity of enzymes involved in the beginning (GTP cyclohydrolase) and terminal steps (riboflavin synthase EC 184.108.40.206, riboflavin kinase EC 188.8.131.52 and FMN adenyltransferase EC 18.104.22.168) of flavinogenesis was studied in the mycelium of Erenmothecium ashbyii of different age. The activity of GTP cyclohydrolas, riboflavin kinase and FMN adenyltransferase was low in the young mycelium and increased in the process of growth, which was accompanied by the acceleration of flavinogenesis. The activity of riboflavin synthase was high in the young mycelium and changed only slightly in the process of subsequent cultivation of the fungus. 8-Azaadenine and 8-hydroxyquinoline added to the young culture of E. ashbyii inhibited the flavinogenesis of the mycelium and the increase of the enzyme activity.


A longitudinal case-control study on goals in adolescents with cancer.
This study examined whether: (1) the goals of adolescents with cancer at 3 months post-diagnosis (T1) and healthy peers differed in terms of content, valuation, and abstraction level, (2) the content, valuation and abstraction level of the goals of the adolescents with cancer differed between 3 and 12 months post-diagnosis (T2). Thirty-three adolescents with cancer and 66 matched controls completed the Personal Project Analysis Inventory. After nine months, the adolescents with cancer completed the measure again. Compared to controls, adolescents with cancer at 3 months post-diagnosis (T1) reported more intrinsic than extrinsic goals, appraised intrinsic goals as more important than extrinsic goals and reported more concrete goals. Within the adolescents with cancer, the content, valuation and abstraction level of the goals did not differ between T1 and T2. Adolescents recently diagnosed with cancer set different types of goals than healthy peers and continue to set these types of goals until one year post-diagnosis. Future research can help determine how the personal goals of adolescents with cancer develop in the long term and to what extent personal goal setting during cancer influences the attainment of age-graded developmental tasks and well-being.


Safety of live attenuated influenza vaccine in atopic children with egg allergy.
Live attenuated influenza vaccine (LAIV) is an intranasal vaccine recently incorporated into the United Kingdom immunization schedule. However, it contains egg protein and, in the absence of safety data, is contraindicated in patients with egg allergy. Furthermore, North American guidelines recommend against its use in asthmatic children. We sought to assess the safety of LAIV in children with egg allergy. We performed a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom. Children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited. LAIV was administered under medical supervision, with observation for 1 hour and telephone follow-up 72 hours later. Four hundred thirty-three doses were administered to 282 children with egg allergy (median, 4.9 years; range, 2-17 years); 115 (41%) had experienced prior anaphylaxis to egg. A physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. There were no systemic allergic reactions (upper 95% CI for population, 1.3%). Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%; 95% CI for population, 6.2% to 13.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze. None of these episodes required medical intervention beyond routine treatment. In contrast to current recommendations, LAIV appears to be safe for use in children with egg allergy. Furthermore, the vaccine appears to be well tolerated in children with a diagnosis of asthma or recurrent wheeze.


Symposium on the etiology of hypertension--summarizing studies in 20th century. 1. Hypertension and genes.
Under classical strategy, scientists have tried first to find a physiological phenomenon specific for essential hypertension, then to identify the protein underlying the physiological abnormality, and finally to clarify the causative gene which encoded the protein. On the other hand, under the reverse genetic approach, the correlation between hypertension and genetic abnormality is identified first, and then the pathogenesis is clarified-in reverse order. Therefore, it is not extraordinary for unexpected results to be obtained in the correlation between a gene and a disease, suggesting that this approach has a possibility to be a breakthrough in the chaos of hypertension research.


The evolution of trade-offs: where are we?
Trade-offs are a core component of many evolutionary models, particularly those dealing with the evolution of life histories. In the present paper, we identify four topics of key importance for studies of the evolutionary biology of trade-offs. First, we consider the underlying concept of 'constraint'. We conclude that this term is typically used too vaguely and suggest that 'constraint' in the sense of a bias should be clearly distinguished from 'constraint' in the sense of proscribed combinations of traits or evolutionary trajectories. Secondly, we address the utility of the acquisition-allocation model (the 'Y-model'). We find that, whereas this model and its derivatives have provided new insights, a misunderstanding of the pivotal equation has led to incorrect predictions and faulty tests. Thirdly, we ask how trade-offs are expected to evolve under directional selection. A quantitative genetic model predicts that, under weak or short-term selection, the intercept will change but the slope will remain constant. Two empirical tests support this prediction but these are based on comparisons of geographic populations: more direct tests will come from artificial selection experiments. Finally, we discuss what maintains variation in trade-offs noting that at present little attention has been given to this question. We distinguish between phenotypic and genetic variation and suggest that the latter is most in need of explanation. We suggest that four factors deserving investigation are mutation-selection balance, antagonistic pleiotropy, correlational selection and spatio-temporal variation, but as in the other areas of research on trade-offs, empirical generalizations are impeded by lack of data. Although this lack is discouraging, we suggest that it provides a rich ground for further study and the integration of many disciplines, including the emerging field of genomics.


How to review a paper on medical education.
This article was migrated. The article was marked as recommended. There has been a substantial increase in the number of medical and health professional education manuscripts being submitted to an increasing number of journals in this field. More reviews and more reviewers are needed to facilitate discussion of both relevance and quality of those manuscripts. MedEdPublish relies on readers and Review Panel members to contribute to this process, thereby helping to maintain standards in medical and health professional education publishing. This article provides guidance that is most relevant to reviewers and potential authors for MedEdPublish, but may be relevant to publishing in other medical and health professional journals.


Immunofluorescence staining for detection of variola virus.
In September 1975 Bangladesh was the only country in the world with endemic variola major, and the eradication of the disease was imminent. A rapid and accurate laboratory diagnostic method was required to supplement immunodiffusion in agar gel and culture on chorioallantoic membrane of embryonated egg available at the Institute of Public Health in Dacca, Bangladesh. To determine its effectiveness, a new, improved immunofluorescence (IF) staining technique was introduced. Laboratory specimens (scabs or vesicular or pustular impressions) were collected from patients who had, or were suspected of having, smallpox. Seventy-eight of 144 specimens collected were found to be IF positive for smallpox. As the number of laboratory-positive cases far exceeded the number of clinically diagnosed smallpox cases, IF-positive cases were reinvestigated and subsamples of the IF-positive specimens were tested at a World Health Organization poxvirus reference laboratory at the Centers for Disease Control in Atlanta, Ga. The results indicated 100% sensitivity for the IF technique (no false-negative results) in diagnosing variola major but also showed a high rate of false-positive results. Consequently, IF could not be recommended as a routine screening test for smallpox.


Nosocomial outbreak of Crimean-Congo haemorrhagic fever.
We report a nosocomial outbreak of Crimean-Congo haemorrhagic fever (CCHF) that affected six patients in June 2009 in Ghaem Hospital, Mashhad, Iran, apparently related to one index case. The last four cases were healthcare workers. Infection was spread by percutaneous exposure to two cases, and probably by direct contact with blood, clothes and sheets, to three others. The diagnosis in the two fatal cases was not confirmed virologically. The diagnosis in four cases who survived was confirmed by specific reverse transcription polymerase chain reaction. The patients were treated with ribavirin. In endemic areas, every patient presenting with a febrile haemorrhagic syndrome should be considered to have a viral haemorrhagic fever until proven otherwise. Patients who meet the criteria for probable CCHF should be admitted to hospital and treated with ribavirin. Appropriate isolation precautions should be immediately initiated.


Normal cortisol response to corticotropin in patients with secondary adrenal failure.
A normal plasma cortisol response to exogenous corticotropin has been advanced as a reliable indication of adequate hypothalamic-pituitary-adrenal function in patients suspected of having secondary adrenal failure. We have examined the validity of this diagnostic strategy in five patients who had undergone hypophysectomy and 27 patients recently treated with glucocorticoids. Eleven of the patients had normal adrenal responses to cosyntropin but had subnormal responses when the entire hypothalamic-pituitary-adrenal axis was examined using metyrapone; no patient who responded normally to metyrapone failed to respond to cosyntropin. Inducing hypoglycemia with insulin yielded results concordant with the results induced by metyrapone in four patients tested. A normal cortisol response to corticotropin alone should not be relied on to exclude secondary adrenal insufficiency. To do this it is necessary to demonstrate normal activity of the entire hypothalamic-pituitary-adrenal axis, which can be conveniently examined using metyrapone.


Selenoprotein P is the major selenium transport protein in mouse milk.
Selenium is transferred from the mouse dam to its neonate via milk. Milk contains selenium in selenoprotein form as selenoprotein P (Sepp1) and glutathione peroxidase-3 (Gpx3) as well as in non-specific protein form as selenomethionine. Selenium is also present in milk in uncharacterized small-molecule form. We eliminated selenomethionine from the mice in these experiments by feeding a diet that contained sodium selenite as the source of selenium. Selenium-replete dams with deletion of Sepp1 or Gpx3 were studied to assess the effects of these genes on selenium transfer to the neonate. Sepp1 knockout caused a drop in milk selenium to 27% of the value in wild-type milk and a drop in selenium acquisition by the neonates to 35%. In addition to decreasing milk selenium by eliminating Sepp1, deletion of Sepp1 causes a decline in whole-body selenium, which likely also contributes to the decreased transfer of selenium to the neonate. Deletion of Gpx3 did not decrease milk selenium content or neonate selenium acquisition by measurable amounts. Thus, when the dam is fed selenium-adequate diet (0.25 mg selenium/kg diet), milk Sepp1 transfers a large amount of selenium to neonates but the transfer of selenium by Gpx3 is below detection by our methods.


[Von Recklinghausen osteitis fibrosa cystica. A clinical case].
In Recklinghausen's disease the skeleton lesions are often the first signal of the pathology. The main clinical manifestations are represented by bony lesions which appear as multicystic lesions with loss of the hard lamina and skull malformation and asymmetry. In this disease there is a relevant osteoclastic activity which prevails over the osteoblastic one associated to the fibrous substitution of the marrow, sometimes producing micro or macro cysts. The typical alteration consists of an increase along the endosteal and trabecular surfaces in the number of osteoclasts which can be found in small reabsorption gaps. This is the cause of a cortical and trabecular reduction which can appear as interrupted. Histologic lesions consist in the replacement of bone tissue with fibrous and osteoid tissue. These bony lesions are not characteristic of the disease but to be distinguished from other pathologies such as for example Paget's disease and other forms of fibrous dysplasia (Gardner's syndrome, Leontiasis ossea). A case personally observed is described: a women, 29 years old, suffering from Recklinghausen's disease with face and skull asymmetry, condyles and glenoid cavity deformation, abnormal face reduction. Observing the planigraphy on the right side of the temporomandibular articulation, flattened glenoid cavity and condyles with irregular outlines can be noticed, aplastic coronoid cuts, altered jaw. The patient was submitted to surgery for dental extraction followed by a biopsy which showed some regressive alterations on cellular level of the bony structure.


Comparison of acute exercise responses between conventional video gaming and isometric resistance exergaming.
Exergaming is a relatively new type of entertainment that couples physical activity and video gaming. To date, research that has focused on the physiologic responses to exergaming has been focused exclusively on aerobic-type activities. The purpose of this project was to describe the acute exercise responses (i.e., oxygen uptake [VO(2)], heart rate, and rate of perceived exertion [RPE]) to exergaming using full-body isometric muscle resistance and to determine whether these responses are different during single- versus opponent-based play. Male subjects (n = 32) were randomly and equally divided into either an experimental (EXP) or control (CON) group. Acute exercise responses VO(2), heart rate, and RPE) were measured in all subjects during both solo- and opponent-based video game play. Subjects in the EXP group played using a controller that relied on full-body isometric muscle resistance to manipulate the on-screen character, whereas CON subjects used a conventional handheld controller. During solo play, the EXP group exhibited significantly higher values for VO(2) (9.60 +/-0.50 mL/kg/min) and energy expenditure (3.50 +/- 0.14 kcal/min) than the CON group VO(2) 5.05 +/- 0.16 mL/kg/min; energy expenditure 1.92 +/- 0.07 kcal/min). These changes occurred with no significant differences in RPE or heart rate between the groups. These results suggest that whole-body isometric exergaming results in greater energy expenditure than conventional video gaming, with no increase in perceived exertion during play. This could have important implications regarding long-term energy expenditure in gamers.


The lateral ventromedial thalamic nucleus spreads nociceptive signals from the whole body surface to layer I of the frontal cortex.
Neurons within the lateral ventromedial thalamic nucleus (VMl) convey selectively nociceptive information from all parts of the body. The present experiments were performed in rats and were designed to determine the organization of cortical projections from VMl neurons. In a first series of experiments, these cells were characterized electrophysiologically and individually labelled in a Golgi-like manner following juxtacellular electrophoresis of biotin-dextran. In a second experimental series, topical applications of the tracers fluorogold and tetramethylrhodamine-labelled dextran were placed into both the rostral-most and caudal areas of layer I of the dorsolateral frontal cortex, respectively. All VMl nociceptive neurons were fusiform and their full dendritic arborizations were bipolar, extending in the lateromedial axis. VMl cells are thus particularly well located to receive widespread nociceptive inputs via a brainstem link, viz. the medullary subnucleus reticularis dorsalis. VMl neurons driven by 'whole body' nociceptive receptive fields project to the rostral part of the layer I of the dorsolateral frontal cortex. These projections are widespread because double-labelling data showed a great number of VMl neurons labelled from both rostral and caudal dorsolateral cortices. The VMl comprises a homogeneous, organized subset of thalamic neurons that allow any signals of pain to modify cortical activity in a widespread manner, by interacting with the entire layer I of the dorsolateral neocortex.


Machine learning models for prediction of adverse events after percutaneous coronary intervention.
An accurate prediction of major adverse events after percutaneous coronary intervention (PCI) improves clinical decisions and specific interventions. To determine whether machine learning (ML) techniques predict peri-PCI adverse events [acute kidney injury (AKI), bleeding, and in-hospital mortality] with better discrimination or calibration than the National Cardiovascular Data Registry (NCDR-CathPCI) risk scores, we developed logistic regression and gradient descent boosting (XGBoost) models for each outcome using data from a prospective, all-comer, multicenter registry that enrolled consecutive coronary artery disease patients undergoing PCI in Japan between 2008 and 2020. The NCDR-CathPCI risk scores demonstrated good discrimination for each outcome (C-statistics of 0.82, 0.76, and 0.95 for AKI, bleeding, and in-hospital mortality) with considerable calibration. Compared with the NCDR-CathPCI risk scores, the XGBoost models modestly improved discrimination for AKI and bleeding (C-statistics of 0.84 in AKI, and 0.79 in bleeding) but not for in-hospital mortality (C-statistics of 0.96). The calibration plot demonstrated that the XGBoost model overestimated the risk for in-hospital mortality in low-risk patients. All of the original NCDR-CathPCI risk scores for adverse periprocedural events showed adequate discrimination and calibration within our cohort. When using the ML-based technique, however, the improvement in the overall risk prediction was minimal.


Before and after COVID-19 pandemic: impact on hepatobiliary and pancreatic surgical services in a Singapore Tertiary Hospital.
Reallocation of healthcare resources to prioritize the COVID-19 pandemic-related incremental healthcare needs resulted in longer waiting times for routine elective clinical services. We aimed to analyze the effects of the pandemic on the hepatopancreatobiliary (HPB) unit's surgical workload. The HPB unit's surgical workload for the months of January-June from 2019 to 2022 was extracted, retrospectively compared, and analyzed. This study was registered in ClinicalTrials.gov (NCT05572866) and complies with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Benign elective surgeries were impacted adversely, with elective gallbladder operations decreasing by 45.2% (146 in 2019 vs 80 in 2020, p = 0.89) before slowly increasing to 120 cases in 2021 and rebounding to 179 cases in 2022 (p = 0.001). Elective oncology operations paradoxically increased, with liver resections rising by 12.9% (31 in 2019 vs 35 in 2020, p = 0.002) and maintaining 37 cases in 2021 (p = 0.0337) and 34 cases in 2022 (p = 0.69). Elective pancreatic resections increased by 171.4% (7 in 2019 vs 19 in 2020, p < 0.0001) and were maintained at 15 cases in 2021 (p = 0.013) and 18 cases in 2022 (p = 0.022). The overall emergency workload decreased from 2019 (n = 198) to 2020 (n = 129) to 2021 (n = 122) before recovering to baseline in 2022 (n = 184). The month-on-month volume generally showed similar trends compared to the other years except for February 2022 and May 2021. This audit shows that despite large-scale disruption of the local healthcare system, essential surgeries can still proceed with careful resource planning by steadfast and vigilant clinical teams.


Hydrosalpinx as a Rare Presentation of Synchronous Ovarian and Endometrial Carcinoma - A Case Report.
Hydrosalpinx in postmenopausal woman is rare. Most commonly it is due to primary ovarian malignancy with fallopian tube involvement or primary fallopian tube carcinoma. But hydrosalpinx with no malignancy in the fallopian tube, associated with synchronous malignancy of ovary and endometrium is rare. In a postmenopausal women, hydrosalpinx is commonly due to fallopian tube malignancy or rarely pelvic inflammatory disease. We present a rare and very interesting case of 65-year-old nulliparous postmenopausal women with bilateral hydrosalpinx and pyometra who was found to have papillary serous adenocarcinoma of the ovary and endometroid adenocarcinoma of endomertrium with normal fallopian tube. One should always suspect genital malignancy with this presentation, especially in this age group.


The Co-Occurrence of Intimate Partner Violence and Violence Against Children: A Systematic Review on Associated Factors in Low- and Middle-Income Countries.
Violence against women (VAW) and violence against children (VAC) are public health issues of global concern. Intimate partner violence (IPV) is a commonly occurring form of VAW and there is evidence to suggest that IPV and VAC frequently co-occur within the same families. This systematic literature review searched for studies published in any language between 1st January 2000 to 16th February 2021 and identified 33 studies that provided findings for co-occurring IPV and VAC in 24 low- and middle-income countries (PROSPERO: CRD42020180179). These studies were split into subgroups based on the types of co-occurring violence they present and meta-analyses were conducted to calculate pooled odds ratios (ORs) within these subgroups. Our results indicate a significant association between IPV and VAC, with all pooled ORs showing a significant positive association between the two. Almost half of the studies focused exclusively on co-occurrence between male-to-female IPV and female caregiver-to-child VAC; few authors reported on male caregiver-to-child violence. Only three studies identified risk factors for co-occurring IPV and VAC, and those that did suggested conflicting findings on the risks associated with maternal age, alcohol and drug use, and parental education level. We also found incongruity in the violence definitions and measurements used across studies. Future research should aim to develop more consistent definitions and measurements for co-occurrence and move beyond solely examining dyadic and unidirectional violence occurrence in families; this will allow us to better understand the interrelationships between these different forms of abuse.


Motogenic activity of IGD-containing synthetic peptides.
Although the IGD amino acid motif (iso-gly-asp) is a highly conserved feature of the fibronectin type I module, no biological activity has as yet been ascribed to it. We have previously reported that the gelatin-binding domain of fibronectin stimulates the migration of human skin fibroblasts into native, but not denatured, type I collagen substrata. Two IGD-containing type I modules are present within the gelatin-binding domain. The object of this study was to ascertain whether soluble synthetic peptides containing the IGD motif stimulate fibroblast migration. We found that IGD peptides stimulated fibroblast migration in the following order of activity: IGDS (as present in the ninth type I module) > IGDQ (as present in the seventh type I module) > IGD. The scrambled SDGI peptide and the well-characterised RGDS peptide were devoid of motogenic activity. The migratory response of fibroblasts to IGD-containing peptides consisted of two distinct phases: an initial period of peptide-mediated cell activation and a subsequent period of enhanced migration manifest in the absence of further IGD peptide. Cell activation was substratum-independent (occurring equally well on both native and denatured type I collagen substrata), whilst the manifestation of enhanced migration was persistent and substratum-dependent (being evident only by cells adherent to a native collagen substratum). Our data further indicated that cell activation (1) is elicited by a signal transduction cascade occurring within minutes of cell exposure to IGD-containing peptides, (2) is dependent upon integrin alphavbeta3 functionality, (3) involves the tyrosine phosphorylation of focal adhesion kinase (ppFAK125) and (4) is inhibited by signalling mediated through integrin alpha5beta1. The expression of migration stimulating activity by soluble IGD-containing peptides clearly distinguishes them from their RGD counterparts. This is the first identified biological activity of the highly conserved IGD motif and provides a rational platform for the development of a novel family of therapeutic compounds designed to stimulate cell migration in relevant clinical situations, such as impaired wound healing.


Structural, vibrational, and quasiparticle band structure of 1,1-diamino-2,2-dinitroethelene from ab initio calculations.
The effects of pressure on the structural and vibrational properties of the layered molecular crystal 1,1-diamino-2,2-dinitroethelene (FOX-7) are explored by first principles calculations. We observe significant changes in the calculated structural properties with different corrections for treating van der Waals interactions to Density Functional Theory (DFT), as compared with standard DFT functionals. In particular, the calculated ground state lattice parameters, volume and bulk modulus obtained with Grimme's scheme, are found to agree well with experiments. The calculated vibrational frequencies demonstrate the dependence of the intra and inter-molecular interactions on FOX-7 under pressure. In addition, we also found a significant increment in the N-H...O hydrogen bond strength under compression. This is explained by the change in bond lengths between nitrogen, hydrogen, and oxygen atoms, as well as calculated IR spectra under pressure. Finally, the computed band gap is about 2.3 eV with generalized gradient approximation, and is enhanced to 5.1 eV with the GW approximation, which reveals the importance of performing quasiparticle calculations in high energy density materials.


Estimation of growth yield and maintenance coefficient of plant cell suspensions.
Methodology is presented for the determination of growth yield (Y(g)) and maintenance coefficient (m) for carbon utilization of plant cells grown in suspension culture. Estimation of Y(g) and m requires measurements of specific growth rate (micro) and specific rate of substrate uptake (q) at different growth limiting substrate concentrations. Batch culture of tobacco cells did not permit evaluation of Y(g) and m because micro is constant and maximal during most of the growth cycle. In batch culture, the period of declining specific growth rate is extremely brief because of the rapid transition from logarithmic growth to stationary phase. This occurs because the K(m) for growth is relatively small compared to the initial sucrose concentration. Thus, when the substrate level reaches the K(m), the large mass of cells rapidly depletes the remaining substrate. In contrast, semicontinuous culture facilitates the determination of Y(g) and m because various steady-state growth rates can be achieved. Mathematical expressions were developed to determine the effective values of micro and q over the semicontinuous replacement interval. The validity of this approach was verified by conducting simulations using experimentally determined parameters.


Automatic Tissue Segmentation of Neonate Brain MR Images with Subject-specific Atlases.
Automatic tissue segmentation of the neonate brain using Magnetic Resonance Images (MRI) is extremely important to study brain development and perform early diagnostics but is challenging due to high variability and inhomogeneity in contrast throughout the image due to incomplete myelination of the white matter tracts. For these reasons, current methods often totally fail or give unsatisfying results. Furthermore, most of the subcortical midbrain structures are misclassified due to a lack of contrast in these regions. We have developed a novel method that creates a probabilistic subject-specific atlas based on a population atlas currently containing a number of manually segmented cases. The generated subject-specific atlas is sharp and adapted to the subject that is being processed. We then segment brain tissue classes using the newly created atlas with a single-atlas expectation maximization based method. Our proposed method leads to a much lower failure rate in our experiments. The overall segmentation results are considerably improved when compared to using a non-subject-specific, population average atlas. Additionally, we have incorporated diffusion information obtained from Diffusion Tensor Images (DTI) to improve the detection of white matter that is not visible at this early age in structural MRI (sMRI) due to a lack of myelination. Although this necessitates the acquisition of an additional sequence, the diffusion information improves the white matter segmentation throughout the brain, especially for the mid-brain structures such as the corpus callosum and the internal capsule.


A critical appraisal of stroke evaluation and rating scales.
To judge the efficacy of new, putative stroke therapies, we need a method to measure neurological deficit accurately in groups of patients before and after treatment. No single measurement technique has yet proven to be universally acceptable, but one approach is the use of rating instruments that summarize the neurological deficit found on clinical examination. Currently, stroke assessment scales may be based on the examination of physical deficits, an inventory of activities of daily living, or a global evaluation of functional outcome. Scientific methods for authenticating stroke scales are available in the psychometric and statistical literature. We review currently available stroke scales for their validity and reliability and propose investigations needed to refine further the standardized measurement of neurological deficit following stroke. We suggest that clinical stroke trials include a physical deficit scale and a global rating during the acute phase and that an activities of daily living scale be added at later points in recovery.


Identification of Aurora Kinase A as a Biomarker for Prognosis in Obesity Patients with Early Breast Cancer.
Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. Previous investigation suggested Aurora A kinase was able to partially restore the functionalities of obese adipose-derived mesenchymal stem cells by stabilizing their primary cilia and reestablishing a balance of multiple stemness-associated genes. The association between Aurora A and obesity breast cancer is still unclear. We hypothesized that overexpression of Aurora A was associated with poor survival in obesity breast cancer and the related axis mechanism was involved. A total of 517 primary breast cancer specimens were collected from the First Affiliated Hospital of China Medical University between January 2011 and November 2016. Our independent variable was BMI at baseline, categorized as overweight (BMI ≥25 kg/m2, as obesity cohort), and normal (18.5 ≤ BMI <25 kg/m2, as non-obesity cohort). The immunohistochemical (IHC) staining was performed with Aurora A, Survivin, MMP11, Cyclin B1, and Cathepsin L. Kaplan-Meier curve was used to analyze overall survival in our cohorts and TCGA-BRCA data (GSE3494). Log rank test was used to calculate P values. Protein-protein interaction (PPI) network analysis and MCODE model were used to analyze the Aurora-altered signal pathway from GSE78958. Among 517 breast patients, Aurora A-positive (staining scores ≥4) was significantly higher in obesity breast carcinoma compared with non-obesity cancer carcinoma (χ 2=9.79, P=0.002), with more frequency in hormone receptor-negative (68.4% vs 77.9%, P=0.015) and HER2-positive patients (28.7% vs 17.9%, P=0.003). High Aurora A expression was remarkably and significantly associated with overall survival (OS) (8-year OS ratio: 69.5% vs 81.1%, OR=1.76, 95% CI: 1.03~3.02, P=0.041) in obesity cohort. Interestingly, higher expression of Aurora A was not associated with a shorter overall survival time among the non-obesity breast cancer (8-year OS ratio: 81.4% vs 85.8%, OR=1.40, 95% CI: 0.79~2.45, P=0.229). As for RFS, the expression levels of Aurora A expression genes have no significance with RFS statistically in non-obesity and obesity patients. Aurora A and lymph node metastases were significantly poor prognostic factors for OS, and borderline significance was noted for high BMI. Kaplan-Meier survival analysis from TCGA database confirmed that the high Aurora A expression group had worse prognosis (HR=1.47, 95% CI: 1.14-1.90, P=0.003). The KEGG pathway enrichment results were consistent with GO biological process term analysis, in which CCNB1 was enriched for upregulated Aurora A. In our samples, Aurora A level on tumor cytoplasm had broad connections with Cyclin B1 by IHC correlation analysis (correlation coefficient = 0.227, P=0.001). Our finding demonstrates here for the first time that high expression of Aurora A was notably correlated with early recurrence and poor overall survival in obesity patients with early breast cancer. The Aurora A-Cyclin B1 axis could be a potential promising therapeutic target for cancer intervention and therapy.


Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A.
Neovascularization of the cornea occurs in numerous pathologic states causing decreased visual acuity and blindness and is a major complication of corneal allotransplantation. The purpose of this study was to investigate the effect of topical and systemic cyclosporin A (CsA) on corneal angiogenesis induced by xenotransplantation or by chemical cauterization. The subcutaneous disc angiogenesis system (DAS) also was used to study the effects of CsA on angiogenesis in a nonocular site. Corneal angiogenesis was provoked by either xenotransplantation or chemical cautery. Rats from experiments using both of these models were subdivided into four treatment groups. Topical treatment was administered by using 4% CsA eye drops or vehicle (castor oil) four times daily for 10 days. Systemic therapy consisted of daily (5 mg/kg per day) subcutaneous injections of CsA or vehicle. In the DAS experiments, rats received CsA or vehicle systemically or intradisc. The amount of neovascularization was quantitated by digital image analysis in corneal flat preparations and sections of discs. Rats that received xenografts or cautery manifested less corneal neovascularization than did control animals after topical of subcutaneous CsA treatment. CsA also enhanced the survival of corneal xenografts. A difference between CsA and vehicle-treated animals in the DAS experiments was not detected. CsA effectively retards the growth of new vessels in the cornea after xenotransplantation or chemical cauterization and prolongs xenograft survival. However, CsA does not suppress angiogenesis in all systems, because it was ineffective in blocking vessel growth in the subcutaneous DAS.


Sustained and transient neural modulations in prefrontal cortex related to declarative long-term memory, working memory, and attention.
Common activations in prefrontal cortex (PFC) during episodic and semantic long-term memory (LTM) tasks have been hypothesized to reflect functional overlap in terms of working memory (WM) and cognitive control. To evaluate a WM account of LTM-general activations, the present study took into consideration that cognitive task performance depends on the dynamic operation of multiple component processes, some of which are stimulus-synchronous and transient in nature; and some that are engaged throughout a task in a sustained fashion. PFC and WM may be implicated in both of these temporally independent components. To elucidate these possibilities we employed mixed blocked/event-related functional magnetic resonance imaging (fMRI) procedures to assess the extent to which sustained or transient activation patterns overlapped across tasks indexing episodic and semantic LTM, attention (ATT), and WM. Within PFC, ventrolateral and medial areas exhibited sustained activity across all tasks, whereas more anterior regions including right frontopolar cortex were commonly engaged in sustained processing during the three memory tasks. These findings do not support a WM account of sustained frontal responses during LTM tasks, but instead suggest that the pattern that was common to all tasks reflects general attentional set/vigilance, and that the shared WM-LTM pattern mediates control processes related to upholding task set. Transient responses during the three memory tasks were assessed relative to ATT to isolate item-specific mnemonic processes and were found to be largely distinct from sustained effects. Task-specific effects were observed for each memory task. In addition, a common item response for all memory tasks involved left dorsolateral PFC (DLPFC). The latter response might be seen as reflecting WM processes during LTM retrieval. Thus, our findings suggest that a WM account of shared PFC recruitment in LTM tasks holds for common transient item-related responses rather than sustained state-related responses that are better seen as reflecting more general attentional/control processes.


Tests of stepping as indicators of mobility, balance, and fall risk in balance-impaired older adults.
To determine the relationships between two tests of stepping ability (the maximal step length (MSL) and rapid step test (RST)) and standard tests of standing balance, gait, mobility, and functional impairment in a group of at-risk older adults. Cross-sectional study. University-based laboratory. One hundred sixty-seven mildly balance-impaired older adults recruited for a balance-training and fall-reduction program (mean age 78, range 65-90). Measures of stepping maximally (MSL, the ability to maximally step out and return to the initial position) and rapidly (RST, the time taken to step out and return in multiple directions as fast as possible); standard measures of balance, gait, and mobility including timed tandem stance (TS), tandem walk (TW, both timing and errors), timed unipedal stance (US), timed up and go (TUG), performance oriented mobility assessment (POMA), and 6-minute walk (SMW); measures of leg strength (peak knee and ankle torque and power at slow and fast speeds); self-report measures of frequent falls (>2 per 12 months), disability (Established Population for Epidemiologic Studies of the Elderly (EPESE) physical function), and confidence to avoid falls (Activity-specific Balance Confidence (ABC) Scale). Spearman and Pearson correlation, intraclass correlation coefficient, logistic regression, and linear regression were used for data analysis. MSL consistently predicted a number of self-report and performance measures at least as well as other standard balance measures. MSL correlations with EPESE physical function, ABC, TUG, and POMA scores; SMW; and peak maximum knee and ankle torque and power were at least as high as those correlations seen with TS, TW, or US. MSL score was associated with the risk of being a frequent faller. In addition, the six MSL directions were highly correlated (up to 0.96), and any one of the leg directions yielded similar relationships with functional measures and a history of falls. Relationships between RST and these measures were relatively modest. MSL is as good a predictor of mobility performance, frequent falls, self-reported function, and balance confidence as standard stance tests such as US. MSL simplified to one direction may be a useful clinical indicator of mobility, balance, and fall risk in older adults.


Loss to follow-up in registries of rheumatic patients treated with biologics: a potential information bias in assessing pharmacovigilance and efficacy outcomes.
The information associated with loss to follow-up (LFU) patients may affect real-world data evaluation of the use of biologics that is not being adequately captured in registries. We identified all patients (Pts) treated with biologics in our center who had no visits registered for more than 6 months, in the Rheumatic Diseases Portuguese Register, Reuma.pt. We retrieved baseline information from Reuma.pt and from the hospital electronic clinical record. We then performed a telephonic interview to characterize the reasons for LFU at our day care unit. For Pts unable to be contacted by telephone a letter of invitation to an appointment at the hospital was sent. From a total of 794 Pts registered in Reuma.pt at our center with active biologic therapy 227 did not have any information registered in the last 6 months. Of this, 36 Pts were on biologic therapy prescribed by other departments and maintained follow-up in these departments. 102 Pts had suspended biologic administration by medical indication and this information was registered in the hospital electronic clinical records but not updated in Reuma.pt. For 89 Pts no information could be retrieved from either the hospital electronic clinical record or Reuma.pt and we classified these Pts as true LFU. 26 of these LFU Pts were being followed up in another Rheumatology center. 26 of the LFU Pts died. 11 Pts had an adverse effect. 4 Pts of the LFU were considering to be in remission. We were not able to contact 15 of the LFU pts. Identifying LFU Pts and clarifying the reason for the loss of data in a register contributes to a better knowledge on strategies to discontinue biologics in stable pts, to a better pharmacovigilance of adverse effects and to more efficiency in data capture by registries. Due to data protection reasons it was impossible to have access to the Pts's death certificates.


Neuromyelitis Spectrum Disorders.
The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG-associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG-associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.


[Perspectives of development in anesthesiology and intensive care in oncology].
Despite of anaesthesiology and intensive care progress in oncology there are some problems that need to be solved. These include low individual significance of perioperative risk scale, the lack of approaches for postoperative correction of risk value, estimation of surgical stress value, approach to detection of pain mechanisms etc. The studies which will resolve these problems allow improving the quality of medical care for cancer patients.


The Endoplasmic Reticulum-associated Degradation of Transthyretin Variants Is Negatively Regulated by BiP in Mammalian Cells.
Amyloid fibril formation of mutant transthyretin (TTR) that causes familial amyloid polyneuropathy occurs in the extracellular space. Thus, secretion of TTR variants contributes to the pathogenesis of amyloidosis. However, the molecular mechanisms underlying the endoplasmic reticulum (ER) exit or retention and subsequent degradation of TTR variants remain unclear. Here, we demonstrated that the nonsecreted TTR variants, such as D18G TTR and amyloidogenic TTRs with introduced monomeric mutation (M-TTRs), stably interact with the ER chaperone BiP in mammalian cells. These proteins were co-secreted with the secreted form of BiP in which the KDEL signal was removed, indicating that BiP partially contributes to the ER retention of nonsecreted TTR variants. More interestingly, the degradation efficiency of nonsecreted TTRs was increased when BiP was down-regulated by small interfering RNA. Thus, BiP protects the TTR variants from immediate degradation. Additionally, we showed that the stability of nonsecreted TTR variants is not disturbed in the coat complex II-deficient conditions, which are enough to inhibit the ER export of secreted TTR variants, including wild-type TTR. Therefore, the post-ER retrieval mechanism might not contribute to the ER-associated degradation of nonsecreted TTR variants. These findings suggest that the affinity to the ER-resident protein BiP regulates the fate of TTR variants in the ER.