A fast, resource efficient, and reliable rule-based system for COVID-19 symptom identification.
With COVID-19, there was a need for a rapidly scalable annotation system that facilitated real-time integration with clinical decision support systems (CDS). Current annotation systems suffer from a high-resource utilization and poor scalability limiting real-world integration with CDS. A potential solution to mitigate these issues is to use the rule-based gazetteer developed at our institution. Performance, resource utilization, and runtime of the rule-based gazetteer were compared with five annotation systems: BioMedICUS, cTAKES, MetaMap, CLAMP, and MedTagger. This rule-based gazetteer was the fastest, had a low resource footprint, and similar performance for weighted microaverage and macroaverage measures of precision, recall, and f1-score compared to other annotation systems. Opportunities to increase its performance include fine-tuning lexical rules for symptom identification. Additionally, it could run on multiple compute nodes for faster runtime. This rule-based gazetteer overcame key technical limitations facilitating real-time symptomatology identification for COVID-19 and integration of unstructured data elements into our CDS. It is ideal for large-scale deployment across a wide variety of healthcare settings for surveillance of acute COVID-19 symptoms for integration into prognostic modeling. Such a system is currently being leveraged for monitoring of postacute sequelae of COVID-19 (PASC) progression in COVID-19 survivors. This study conducted the first in-depth analysis and developed a rule-based gazetteer for COVID-19 symptom extraction with the following key features: low processor and memory utilization, faster runtime, and similar weighted microaverage and macroaverage measures for precision, recall, and f1-score compared to industry-standard annotation systems.


Systematic review of risk and protective factors for suicidal and self-harm behaviors among children and adolescents involved with cyberbullying.
Cyberbullying is associated with increased risk of suicidal and self-harm behaviors in children and adolescents. However, no review to date has explored factors that exacerbate and mitigate this relationship. This systematic review concerns research on factors that influence the impact of cyberbullying on suicidal and self-harm behaviors. Four bibliographic databases were explored and references in included articles were searched. We identified 727 articles and retained 66 that met inclusion criteria. Research has identified multiple risk factors which have been associated with increased suicide risk in general (mental health problems, substance abuse, loneliness, stress, sexual orientation/gender identity issues and violent behaviors). Others risk factors more specific to cyberbullying were: Autism Spectrum Disorder, Intellectual and Developmental Disorders, obesity, having asthma and severity of cyberbullying. Fewer studies concern protective factors. School connectedness, restrictive style of parenting, parental support, life satisfaction, having a healthy diet, personal skills and having family dinners were associated with less risk of suicidal and self-harm behaviors following cyberbullying. These protective factors suggest prevention strategies to reduce the impacts of cyberbullying by teaching better personal skills, promoting school social connections and proposing family interventions. More research is needed including exploration of the differential impacts of different forms of cyberbullying, and evaluations of the impacts of programs to increase personal skills, improve family relationships and foster school connectedness to reducing suicidal and self-harm behaviors in this vulnerable population.


Cytopathology of follicular lesions of the thyroid gland.
Fine needle biopsy is generally considered unreliable in the differential diagnosis of follicular lesions of the thyroid gland. To test this hypothesis, we correlated fine needle biopsy diagnoses with surgical diagnoses in 379 follicular lesions. From nuclear characteristics (especially size) and the architectural pattern of tissue fragments, the following observations were made. Differentiation of goiters (including hyperplastic ones) from neoplastic thyroid disease is quite accurate and no more than 1 to 2% of cancers should be missed. The specific cytologic diagnosis of follicular carcinoma is 75% accurate, and that of follicular variant of papillary carcinoma is over 95% accurate. Of histologically proved follicular carcinomas, almost three-quarters should be diagnosed as such or strongly suspected by fine needle biopsy. The remainder will be identified as cellular follicular adenomas, reaffirming the overlap of cytologic features of benign and malignant neoplastic disease. From cytologic and surgical pathologic data for each fine needle biopsy diagnosis of follicular lesion, a probability of cancer can be stated that is useful in management decisions.


[Effect of copper supplementation on lipid profile of Venezuelan hyperlipemic patients].
It has been assumed that most Western diets satisfy the requirement of copper/day because of ubiquitous presence of this element in most foods. Recent studies have shown that dietary copper (Cu) may often fall below the estimated daily requirements, what could determine a deficiency of this trace element. This deficiency is associated with hypercholesterolemia and hypertrigliceridemia, both in human and experimental animals. In the present intervention study was examined the effect of the administration of 5 mg of Cu/day in 73 patients (treated group), of both genders, with ages between 26 and 48 years, with high serum levels of total cholesterol and triglycerides without pharmacological treatment and compared with 73 hyperlipemic subjects non-treated with copper (control group) who were matched by gender, age, body weight, smoking habits, calories and fat intake, and physical activity. Before copper administration, a sample of blood was obtained for serum determinations of copper, zinc and lipids. At the end of the experimental period (45 days), a new sample of blood was taken for the corresponding determinations. The results suggest the existence of a marginal deficiency of the trace element in 38% of the subjects and demonstrate that copper supplementation decreases (p < 0.05) serum levels of total cholesterol (r = -0.976), triglycerides (r = -0.972), LDL-cholesterol (r = -0.961) and zinc (r = -0.980) with a slight increment (r = 0.894) of HDL-cholesterol. These findings demonstrate that copper can be used in the treatment of the patients with hypercholesterolemia and hypertriglyceridemia. The mechanisms by which Cu determines these changes are not known.


Surgical smoke and the anesthesia provider.
Surgical smoke generated by use of electrosurgical units (ESUs), lasers, and ultrasonic scalpels constitutes a physical, chemical, and biological hazard for anesthesia personnel. Inhalation of particulate matter with inflammatory consequences, pulmonary injury from products of tissue pyrolysis, exposure to mutagens and carcinogens, and the transmission of human papillomavirus (HPV) and possibly other pathogens represent a spectrum of adverse effects associated with the occupational exposure to surgical plume. While adequate operating room ventilation and use of high filtration-efficiency masks offer some protection from these conditions, the most effective method of safeguarding against surgical smoke involves its removal with a dedicated smoke evacuation device (SED). Despite the fact that many professional and governmental agencies have endorsed widespread usage of SEDs, anesthesia providers have been largely silent on this subject, with few reports within the field of anesthesiology and perioperative medicine regarding these hazards. SED use is relatively infrequent in most surgeries, and this condition reflects surgeons' reluctance to employ these devices, likely resulting from lack of education and less than optimal technology. Anesthesia societies and academic centers can serve critical roles in advocating employment of SEDs in much the same way that they have supported perioperative smoking cessation.


Iterative blip-summed path integral for quantum dynamics in strongly dissipative environments.
The iterative decomposition of the blip-summed path integral [N. Makri, J. Chem. Phys. 141, 134117 (2014)] is described. The starting point is the expression of the reduced density matrix for a quantum system interacting with a harmonic dissipative bath in the form of a forward-backward path sum, where the effects of the bath enter through the Feynman-Vernon influence functional. The path sum is evaluated iteratively in time by propagating an array that stores blip configurations within the memory interval. Convergence with respect to the number of blips and the memory length yields numerically exact results which are free of statistical error. In situations of strongly dissipative, sluggish baths, the algorithm leads to a dramatic reduction of computational effort in comparison with iterative path integral methods that do not implement the blip decomposition. This gain in efficiency arises from (i) the rapid convergence of the blip series and (ii) circumventing the explicit enumeration of between-blip path segments, whose number grows exponentially with the memory length. Application to an asymmetric dissipative two-level system illustrates the rapid convergence of the algorithm even when the bath memory is extremely long.


The effect of omitting an early population-based vision screen in the Netherlands: A micro-simulation model approach.
Objective To estimate the effect of omitting an individual screen from a child vision screening programme on the detection of amblyopia in the Netherlands. A previous study (Rotterdam Amblyopia Screening Effectiveness Study) suggested that the three screens carried out between 6 and 24 months contributed little. Methods We developed a micro-simulation model that approximated the birth-cohort data from the previous study, in which 2964 children had completed follow-up at age 7, and 100 amblyopia cases were detected. Detailed data on screens, referrals, and orthoptic follow-up, including the cause of amblyopia, were available. The model predicted the number of amblyopia cases detected for each screen and for the entire screening programme, and the effect of omitting screens. Incidence curves for all types of amblyopia caused by strabismus, refractive anomalies or by both were estimated by approximation of the observational data, in conjunction with experts' estimations and the literature. Results We calculated mean actual sensitivity per screen per type of amblyopia, and the effect per screen. Screening at 24 months was found to be least effective. The impact on the screening programme, estimated by summing the effectiveness per screen, omitting the 24-month screen, was a reduction of 3.4% (57 vs. 59 cases) in the number of detected cases of amblyopia at age 5. Conclusion The effectiveness of the Dutch vision screening programme would hardly be affected by omission of the 24-month screening examination. A disinvestment study is warranted.


[Hemorrhage in erosive gastritis].
The authors have examined 381 patients admitted with acute hemorrhage from the upper portion of the gastrointestinal tract. In 58 patients erosive gastritis was found by means of urgent gastroduodenoscopy. The clinical picture of this severe affection, the possibilities of diagnosis and the policy of treatment are described. Electron-microscopic studies of the gastric mucosa in erosive gastritis have evidenced different genesis of the erosions.


An overview and analysis of theories employed in telemedicine studies. A field in search of an identity.
This study asks: What theories are employed in telemedicine studies? How might they be categorized in ways that help distinguish the knowledge base of telemedicine? Theories in use were identified from a database of telemedicine-related publications between 1990 and 2005. Eighty-three (5% of 1615) articles referred to a theoretical concept. Grounded Theory procedures were used to analyze and categorize theories, while descriptive statistics were used for supplementary information. The proportion of studies with theory was 3% in 1999 and 7% in 2005. The 83 articles were dispersed among 48 of the in total 795 different journals in the original sample. Identified theories were grouped into two main categories; 'shared' (used in two or more studies) and 'lone ranger'. All of the shared theories are social science theories employed without notable adjustments to any uniquely defining features of telemedicine; diffusion, technology acceptance, health behavior, science and technology studies (STS), and economics. Theoretical concepts within the lone ranger category may well address unique features of telemedicine, but have yet to attract the attention of colleagues. The theories identified as 'shared' play an important role, but are inadequate in illuminating any unique features of telemedicine. The future of telemedicine as a field will need to identify its underlying theoretical components. Frameworks employed in the field of evaluation may aid in identifying the types of theories worth articulating in telemedicine.


Evolutionary forces shaping genomic islands of population differentiation in humans.
Levels of differentiation among populations depend both on demographic and selective factors: genetic drift and local adaptation increase population differentiation, which is eroded by gene flow and balancing selection. We describe here the genomic distribution and the properties of genomic regions with unusually high and low levels of population differentiation in humans to assess the influence of selective and neutral processes on human genetic structure. Individual SNPs of the Human Genome Diversity Panel (HGDP) showing significantly high or low levels of population differentiation were detected under a hierarchical-island model (HIM). A Hidden Markov Model allowed us to detect genomic regions or islands of high or low population differentiation. Under the HIM, only 1.5% of all SNPs are significant at the 1% level, but their genomic spatial distribution is significantly non-random. We find evidence that local adaptation shaped high-differentiation islands, as they are enriched for non-synonymous SNPs and overlap with previously identified candidate regions for positive selection. Moreover there is a negative relationship between the size of islands and recombination rate, which is stronger for islands overlapping with genes. Gene ontology analysis supports the role of diet as a major selective pressure in those highly differentiated islands. Low-differentiation islands are also enriched for non-synonymous SNPs, and contain an overly high proportion of genes belonging to the 'Oncogenesis' biological process. Even though selection seems to be acting in shaping islands of high population differentiation, neutral demographic processes might have promoted the appearance of some genomic islands since i) as much as 20% of islands are in non-genic regions ii) these non-genic islands are on average two times shorter than genic islands, suggesting a more rapid erosion by recombination, and iii) most loci are strongly differentiated between Africans and non-Africans, a result consistent with known human demographic history.


[Analysis of concrete and abstract cues as a function of different hemispheres in the white rat].
In experiments on 92 Wistar albino rats performed by the motor alimentary method of conditioning, the following models were used: reflexes to relation, transfer of conditioned reflexes and invariant recognition of visual images. Functional elimination of the cerebral cortex was achieved by means of spreading depression. It was shown that in a rat population, reflexes to rather wide relations of areas of geometrical figures or lengths of straight lines are equally disturbed after elimination of the right or the left hemisphere. In conditioned reflexes to relation of areas of some other geometrical figures or of their multitudes, as well as in finer reflexes to relation of lines lengths, elimination of the right hemisphere disturbs predominantly the analysis of concrete stimuli characteristics, while elimination of the left hemisphere disturbs analysis of abstract characteristics. The transfer of conditioned reflexes to other geometrical figures is predominantly disturbed following the inactivation of the left hemisphere. Invariant recognition of visual images is more affected following the elimination of the left hemisphere than that of the right one. It has been suggested that the animals' right hemisphere analyses in the main concrete characteristics of the stimuli, while the left one--their abstract characteristics.


Leveraging technology for the treatment of type 1 diabetes in pregnancy: A review of past, current, and future therapeutic tools.
The significant risks associated with pregnancies complicated by type 1 diabetes (T1D) were first recognized in the medical literature in the mid-twentieth century. Stringent glycemic control with hemoglobin A1c (HbA1c) values ideally less than 6% has been shown to improve maternal and fetal outcomes. The management options for pregnant women with T1D in the modern era include a variety of technologies to support self-care. Although self-monitoring of blood glucose (SMBG) and multiple daily injections (MDI) are often the recommended management options during pregnancy, many people with T1D utilize a variety of different technologies, including continuous glucose monitoring (CGM), continuous subcutaneous insulin infusion (CSII), and CSII including automated delivery or suspension algorithms. These systems have yielded invaluable diagnostic and therapeutic capabilities and have the potential to benefit this understudied higher-risk group. A recent prospective, multicenter study evaluating pregnant patients with T1D revealed that CGM significantly improves maternal glycemic parameters, is associated with fewer adverse neonatal outcomes, and minimizes burden. Outcome data for CSII, which is approved for use in pregnancy and has been utilized for several decades, remain mixed. Current evidence, although limited, for commercially available and emerging technologies for the management of T1D in pregnancy holds promise for improving patient and fetal outcomes.


[Reliability and accuracy of reported causes of death from cancer. II. Accuracy of stomach cancer reported in the municipality of Rio de Janeiro County, Brazil]
Quality of data is a central concern in epidemiological studies, particularly when using secondary data. This study aims to carry out on reliability and accuracy of stomach cancer mortality data in the city of Rio de Janeiro. A simple random sample of 97 death certificates was obtained from a total of 645 stomach cancer deaths in 1990, and was used for validation. A questionnaire specifically designed to obtain clinical and laboratory data was completed for each case. Two physicians read this questionnaire and completed the new death certificates, allowing analysis of the instrument's reliability. A total of 86 cases were studied as a consequence of 11 losses (11.3%). Reliability analysis of questionnaires revealed 90.7% agreement according to stomach cancer diagnosis (kappa = 0.73). Accuracy was calculated by positive predictive value: 90.7%. Eight cases were discharged after clinical and laboratory revision. The study concludes that mortality data by stomach cancer in the city of Rio de Janeiro are very reliable, and that their level of accuracy is adequate for use in epidemiological studies.


Derivation of the inverse Schulze-Hardy rule.
The inverse Schulze-Hardy rule was recently proposed based on experimental observations. This rule describes an interesting situation of the aggregation of charged colloidal particles in the presence of the multivalent coions. Specifically, it can be shown that the critical coagulation concentration is inversely proportional to the coion valence. Here the derivation of the inverse Schulze-Hardy rule based on purely theoretical grounds is presented. This derivation complements the classical Schulze-Hardy rule, which describes the multivalent counterion systems.


Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected].
The aim of the study was to determine the properties of a standardized extract of ginseng root in inducing a higher immune response in vaccination against influenza. Attention was also paid to the common cold in this multicentre, two-arm, randomized, placebo-controlled, double-blind investigation. A total of 227 volunteers who visited 3 private practices in Milan received daily oral capsule doses of either placebo (113) or 100 mg of standardized ginseng extract Ginsana G 115 (114) for a period of 12 weeks within which they received an anti-influenza polyvalent vaccination at week 4. As a result, while the frequency of influenza or common cold between weeks 4 and 12 was 42 cases in the placebo group, it was only 15 cases in the G115 group, the difference being statistically highly significant (p < 0.001). Whereas antibody titres by week 8 rose to an average of 171 units in the placebo group, they rose to an average of 272 units in the G115 group (p < 0.0001). Natural killer (NK) activity levels at weeks 8 and 12 were nearly twice as high in the G115 group as compared to the placebo group (p < 0.0001). In all the volunteers, laboratory values of 24 safety parameters showed no significant differences between the end and the beginning of the 12-week study in either of the groups. There were only 9 adverse events in the study, the principal one being insomnia.


Prevalence of allergy symptoms and total IgE in a New York City cohort and their association with birth order.
An inverse association between birth order and allergic disease has been widely observed, but has not been examined in the high asthma prevalence, inner-city populations of the United States. As part of an ongoing prospective birth cohort study, the prevalence of early phenotypes of asthma and/or allergy was compared with those reported in other studies, and the association with birth order was evaluated. Children of Dominican and African-American mothers living in Northern Manhattan underwent detailed periodic questionnaires. Total IgE from the mothers (n = 321) and the children at birth (n = 291) and at ages 24 (n = 244) and 36 (n = 155) months was measured. The association between birth order and allergy symptoms was evaluated at 12 (n = 350), 24 (n = 290) and 36 (n = 247) months. Total serum IgE was detectable (>0.5 IU/ml) in 35% of the children's cord blood and averaged 15 and 21 IU/ml at ages 24 and 36 months, respectively. They were not significantly different at any age between children with and without older siblings. Additionally, at these ages, there were no consistent associations between birth order and either wheeze, itchy eyes or eczema. Despite a substantially higher prevalence of asthma in the Northern Manhattan community compared with other areas, total IgE levels at ages 24 and 36 months, but not cord blood, are similar to those reported in other areas of the world. In this community, results at this age do not support a protective effect of higher birth order.


A Benzimidazole Proton Pump Inhibitor Increases Growth and Tolerance to Salt Stress in Tomato.
Pre-treatment of tomato plants with micromolar concentrations of omeprazole (OP), a benzimidazole proton pump inhibitor in mammalian systems, improves plant growth in terms of fresh weight of shoot and roots by 49 and 55% and dry weight by 54 and 105% under salt stress conditions (200 mM NaCl), respectively. Assessment of gas exchange, ion distribution, and gene expression profile in different organs strongly indicates that OP interferes with key components of the stress adaptation machinery, including hormonal control of root development (improving length and branching), protection of the photosynthetic system (improving quantum yield of photosystem II) and regulation of ion homeostasis (improving the K+:Na+ ratio in leaves and roots). To our knowledge OP is one of the few known molecules that at micromolar concentrations manifests a dual function as growth enhancer and salt stress protectant. Therefore, OP can be used as new inducer of stress tolerance to better understand molecular and physiological stress adaptation paths in plants and to design new products to improve crop performance under suboptimal growth conditions. Highlight: Omeprazole enhances growth of tomato and increases tolerance to salinity stress through alterations of gene expression and ion uptake and transport.


Incidence of deep vein thrombosis related to peripherally inserted central catheters in children and adolescents.
Peripherally inserted central catheters (PICC) in children and adolescents are being used with increasing frequency. We sought to determine the incidence and characterize risk factors of deep vein thrombosis associated with peripherally inserted central catheters in a pediatric population. We conducted a prospective study involving consecutive patients referred to the radiology department of a tertiary care university-affiliated hospital for insertion of a peripherally inserted central catheter. We included patients aged 18 years or less who weighed more than 2.5 kg and had a peripherally inserted central catheter successfully inserted in his or her arm between June 2004 and November 2005. The primary outcome was the occurrence of partial or complete deep vein thrombosis evaluated by clinical examination, ultrasonography and venous angiography. A total of 214 patients (101 girls, 113 boys) were included in the study. Partial or complete deep vein thrombosis occurred in 20 patients, for an incidence of 93.5 per 1000 patients and 3.85 per 1000 catheter-days. Only 1 of the cases was symptomatic. In the univariable analyses, the only variable significantly associated with deep vein thrombosis was the presence of factor II mutation G20210A (odds ratio 7.08, 95% confidence interval 1.11-45.15, p = 0.04), a genetic mutation that increases the risk of a blood clot and that was present in 5 (2.3%) of the 214 patients. The incidence of deep vein thrombosis related to peripherally inserted central catheters in our study was lower than the incidence related to centrally inserted venous catheters described in the pediatric literature (11%-50%).


Vascular profile characterization of liver tumors by magnetic resonance imaging using hemodynamic response imaging in mice.
Recently, we have demonstrated the feasibility of using hemodynamic response imaging (HRI), a functional magnetic resonance imaging (MRI) method combined with hypercapnia and hyperoxia, for monitoring vascular changes during liver pathologies without the need of contrast material. In this study, we evaluated HRI ability to assess changes in liver tumor vasculature during tumor establishment, progression, and antiangiogenic therapy. Colorectal adenocarcinoma cells were injected intrasplenically to model colorectal liver metastasis (CRLM) and the Mdr2 knockout mice were used to model primary hepatic tumors. Hepatic perfusion parameters were evaluated using the HRI protocol and were compared with contrast-enhanced (CE) MRI. The hypovascularity and the increased arterial blood supply in well-defined CRLM were demonstrated by HRI. In CRLM-bearing mice, the entire liver perfusion was attenuated as the HRI maps were significantly reduced by 35%. This study demonstrates that the HRI method showed enhanced sensitivity for small CRLM (1-2 mm) detection compared with CE-MRI (82% versus 38%, respectively). In addition, HRI could demonstrate the vasculature alteration during CRLM progression (arborized vessels), which was further confirmed by histology. Moreover, HRI revealed the vascular changes induced by rapamycin treatment. Finally, HRI facilitates primary hepatic tumor characterization with good correlation to the pathologic differentiation. The HRI method is highly sensitive to subtle hemodynamic changes induced by CRLM and, hence, can function as an imaging tool for understanding the hemodynamic changes occurring during CRLM establishment, progression, and antiangiogenic treatment. In addition, this method facilitated the differentiation between different types of hepatic lesions based on their vascular profile noninvasively.


Asthma morbidity 6 yrs after an effective asthma self-management programme in a Maori community.
A 6-month Maori community-based asthma self-management programme, involving a "credit card" asthma self-management plan, has previously been shown to be an effective and acceptable system for reducing asthma morbidity. The effectiveness of the asthma self-management programme and participants' self-management behaviour was assessed 6 yrs after the formal end of the programme. Participants were surveyed at the time of enrollment, and 1, 2, and 6 yrs after completing the programme. In each survey, participants were questioned on markers of asthma morbidity and use of medical services during the previous 12 months. Self-management behaviour was assessed using a questionnaire at 2 years and 6 yrs. Of the 69 original participants, 47 (68%) were surveyed after 6 yrs. They generally had reduced severe asthma morbidity and emergency use of health services from baseline. In particular, the proportion who had an emergency visit to a general practitioner had decreased from 41% to 18% (p=0.02). However, the percentage of nights woken due to asthma had returned to preintervention levels, and the proportion of participants taking prescribed regular inhaled steroid had decreased from 91% to 53% (p<0.001). Compared with 2 yrs after completion of the asthma programme, self-management behaviour had also deteriorated, with 29% versus 73% (p<0.001) using their peak flow meter daily when their asthma was "getting bad" and 41% versus 86% (p<0.001) using the "credit card" plan to increase the amount of inhaled steroids in the last year. Although the programme participants were still experiencing reduced morbidity from their asthma 6 yrs after the end of the self-management programme, the benefits were less than those observed at 2 yrs. These findings suggest that under-recognition and under-treatment of asthma with appropriate amounts of inhaled steroids is a major factor contributing to asthma morbidity in this indigenous rural community. To obtain enduring benefits from a self-management system of care continued reinforcement of self-management skills seems to be an essential component of any follow-up.


Responses of lymphocytes to anisotonic media: volume-regulating behavior.
The regulatory responses elicited in lymphoid cells suspended in anisotonic media are reviewed. The immediate response approximates osmometric behavior. In addition, in hypotonic media, the initial osmometric swelling is followed by a regulatory volume decrease (RVD), which is associated with KCl loss. The volume-induced effluxes of K+ and Cl- are mediated by two independent conductive pathways. Ca2+-depletion experiments and studies of inhibitor susceptibility suggest that Ca2+ may mediate the activation of the K+ pathway. The responses of the two main lymphocyte subpopulations to hypotonic challenge are different. RVD is much more rapid in T- than in B-cells, regardless of their tissue of origin. Under certain conditions, shrunken lymphocytes will regain their initial volume. This regulatory volume increase (RVI) is due to NaCl uptake, followed by a secondary exchange of Na+ for K+ via the Na+-K+ pump. Na+ is primarily taken up in exchange for H+ through an amiloride-sensitive pathway, whereas Cl- enters in exchange for HCO-3 (or OH-). Anion and cation fluxes responsible for RVI are electroneutral. Some of the volume-sensitive pathways can also be activated in isotonic cells. The conductive K+ pathway is activated by Ca2+ plus ionophore A23187, and the Na+-H+ exchanger can be activated by cytoplasmic acidification. The responses of lymphocytes to anisotonic challenge are compared with those of other cells, and the possible significance of the volume-induced fluxes is discussed.


Factor analytic models of clustered multivariate data with informative censoring.
This article describes a general class of factor analytic models for the analysis of clustered multivariate data in the presence of informative missingness. We assume that there are distinct sets of cluster-level latent variables related to the primary outcomes and to the censoring process, and we account for dependency between these latent variables through a hierarchical model. A linear model is used to relate covariates and latent variables to the primary outcomes for each subunit. A generalized linear model accounts for covariate and latent variable effects on the probability of censoring for subunits within each cluster. The model accounts for correlation within clusters and within subunits through a flexible factor analytic framework that allows multiple latent variables and covariate effects on the latent variables. The structure of the model facilitates implementation of Markov chain Monte Carlo methods for posterior estimation. Data from a spermatotoxicity study are analyzed to illustrate the proposed approach.


Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1.
Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1alpha, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1alpha-null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1alpha is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.


Protostellar feedback halts the growth of the first stars in the universe.
The first stars fundamentally transformed the early universe by emitting the first light and by producing the first heavy elements. These effects were predetermined by the mass distribution of the first stars, which is thought to have been fixed by a complex interplay of gas accretion and protostellar radiation. We performed radiation-hydrodynamics simulations that followed the growth of a primordial protostar through to the early stages as a star with thermonuclear burning. The circumstellar accretion disk was evaporated by ultraviolet radiation from the star when its mass was 43 times that of the Sun. Such massive primordial stars, in contrast to the often-postulated extremely massive stars, may help explain the fact that there are no signatures of the pair-instability supernovae in abundance patterns of metal-poor stars in our galaxy.


Hemagglutinin Stalk Immunity Reduces Influenza Virus Replication and Transmission in Ferrets.
We assessed whether influenza virus hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 influenza virus infection. Immunization of ferrets by a universal influenza virus vaccine strategy based on viral vectors expressing chimeric hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no virus replication at all following natural exposure to influenza virus.


Detergent-induced stabilization and improved 3D map of the human heteromeric amino acid transporter 4F2hc-LAT2.
Human heteromeric amino acid transporters (HATs) are membrane protein complexes that facilitate the transport of specific amino acids across cell membranes. Loss of function or overexpression of these transporters is implicated in several human diseases such as renal aminoacidurias and cancer. HATs are composed of two subunits, a heavy and a light subunit, that are covalently connected by a disulphide bridge. Light subunits catalyse amino acid transport and consist of twelve transmembrane α-helix domains. Heavy subunits are type II membrane N-glycoproteins with a large extracellular domain and are involved in the trafficking of the complex to the plasma membrane. Structural information on HATs is scarce because of the difficulty in heterologous overexpression. Recently, we had a major breakthrough with the overexpression of a recombinant HAT, 4F2hc-LAT2, in the methylotrophic yeast Pichia pastoris. Microgram amounts of purified protein made possible the reconstruction of the first 3D map of a human HAT by negative-stain transmission electron microscopy. Here we report the important stabilization of purified human 4F2hc-LAT2 using a combination of two detergents, i.e., n-dodecyl-β-D-maltopyranoside and lauryl maltose neopentyl glycol, and cholesteryl hemisuccinate. The superior quality and stability of purified 4F2hc-LAT2 allowed the measurement of substrate binding by scintillation proximity assay. In addition, an improved 3D map of this HAT could be obtained. The detergent-induced stabilization of the purified human 4F2hc-LAT2 complex presented here paves the way towards its crystallization and structure determination at high-resolution, and thus the elucidation of the working mechanism of this important protein complex at the molecular level.


Loss of bradykinin signaling does not accelerate the development of cardiac dysfunction in type 1 diabetic akita mice.
Bradykinin signaling has been proposed to play either protective or deleterious roles in the development of cardiac dysfunction in response to various pathological stimuli. To further define the role of bradykinin signaling in the diabetic heart, we examined cardiac function in mice with genetic ablation of both bradykinin B1 and B2 receptors (B1RB2R(-/-)) in the context of the Akita model of insulin-deficient type 1 diabetes (Ins2(Akita/+)). In 5-month-old diabetic and nondiabetic, wild-type and B1RB2R(-/-) mice, in vivo cardiac contractile function was determined by left-ventricular (LV) catheterization and echocardiography. Reactive oxygen species levels were measured by 2'-7'-dichlorofluorescein diacetate fluorescence. Mitochondrial function and ATP synthesis were determined in saponin-permeabilized cardiac fibers. LV systolic pressure and the peak rate of LV pressure rise and decline were decreased with diabetes but did not deteriorate further with loss of bradykinin signaling. Wall thinning and reduced ejection fractions in Akita mouse hearts were partially attenuated by B1RB2R deficiency, although other parameters of LV function were unaffected. Loss of bradykinin signaling did not increase fibrosis in Ins2(Akita/+) diabetic mouse hearts. Mitochondrial dysfunction was not exacerbated by B1RB2R deficiency, nor was there any additional increase in tissue levels of reactive oxygen species. Thus, loss of bradykinin B2 receptor signaling does not abrogate the previously reported beneficial effect of inhibition of B1 receptor signaling. In conclusion, complete loss of bradykinin expression does not worsen cardiac function or increase myocardial fibrosis in diabetes.


Azole-Resistance Development; How the Aspergillus fumigatus Lifecycle Defines the Potential for Adaptation.
In order to successfully infect or colonize human hosts or survive changing environments, Aspergillus fumigatus needs to adapt through genetic changes or phenotypic plasticity. The genomic changes are based on the capacity of the fungus to produce genetic variation, followed by selection of the genotypes that are most fit to the new environment. Much scientific work has focused on the metabolic plasticity, biofilm formation or the particular genetic changes themselves leading to adaptation, such as antifungal resistance in the host. Recent scientific work has shown advances made in understanding the natural relevance of parasex and how both the asexual and sexual reproduction can lead to tandem repeat elongation in the target gene of the azoles: the cyp51A gene. In this review, we will explain how the fungus can generate genetic variation that can lead to adaptation. We will discuss recent advances that have been made in the understanding of the lifecycle of A. fumigatus to explain the differences observed in speed and type of mutations that are generated under different environments and how this can facilitate adaptation, such as azole-resistance selection.


Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by localized autonomous cellular proliferation, fluid accumulation within the cysts, and intraparenchymal fibrosis of the kidney. Little is known about the cyst fluid's protein composition. We hypothesized that the complex collection of cyst fluid proteins (cyst fluid proteome) plays a major role in cyst formation/maintenance and contains yet unknown diagnostic and mechanistic features that are common to all forms of PKD. We analyzed five kidney cyst fluids from four patients with ADPKD. Tryptic peptides from plasma-protein immunodepleted (ProteoPrep(R)) and undepleted cyst fluid samples were analyzed by LC-MS/MS. Proteins were identified by SEQUEST and validated via the Trans-Proteomic Pipeline; 391 proteins were identified with >90% confidence; 251 of them in undepleted and 362 in immunodepleted samples. Immunodepletion removed >94% of the cyst fluid protein. A surprisingly large and functionally diverse number of proteins common to most cysts were identified. These proteins may be of mechanistic interest and include Ig gamma, kappa, and fragments; complement components; vitronectin; orosomucoid; prostaglandin D2 synthase; vitamin D-binding protein; clusterin; SERPIN family proteins; hemopexin; and fetuin-A. Additionally, these results suggest that further prefractionation and enhanced chromatographic separation of tryptic peptides is likely to expose an even greater number of relevant proteins.


Distribution and size of mucous glands in the ferret tracheobronchial tree.
A transgenic ferret model of cystic fibrosis has recently been generated. It is probable that malfunction of airway mucous glands contributes significantly to the airway pathology of this disease. The usefulness of the ferret model may therefore depend in part on how closely the airway glands of ferrets resemble those of humans. Here, we show that in the ferret trachea glands are commonest in its most ventral aspect and disappear about half way up the lateral walls; they are virtually absent from the dorsal membranous portion. Further, the aggregate volume of glands per unit mucosal surface declines progressively by about 60% between the larynx and the carina. The average frequency of glands openings for the ferret trachea as a whole is only about one-fifth that in humans (where gland openings are found at approximately the same frequency throughout the trachea). Glands in the ferret trachea are on average about one-third the size of those in the human. Therefore, the aggregate volume of tracheal glands (per unit mucosal surface area) in the ferret is only about 6% that in humans. As in other mammalian species, airway glands in the ferret disappear at an airway internal diameter of ∼1 mm, corresponding approximately in this species to airway generation 6.


Full-width postlaminar optic nerve tumor invasion of retinoblastoma as risk-factor for leptomeningeal spread of retinoblastoma. A case report and review of the literature.
We present a 6-year-old boy with unilateral retinoblastoma of the left eye. MRI showed an intraocular tumor that extended into the optic nerve beyond the lamina cribrosa. The affected eye was enucleated and the optic nerve resection margin proved to be free. Following protocol, this patient received six courses of adjuvant systemic chemotherapy. Unfortunately, after 5 months this patient returned with the leptomeningeal spread of the tumor and died quickly thereafter.Histopathologic analysis of the enucleated eye and distal optic nerve revealed that the postlaminar tumor cells occupied the entire width of the optic nerve, extending all the way up to the pia mater, whereas, more often the tumor invasion is restricted to the center of the optic nerve. This was also visible on the MR images where contrast enhancement occupied the entire nerve width. A resection margin with tumor cells is recognized as a risk factor for metastasis, but perhaps the proximity of tumor cells to the leptomeninges should also be judged with caution as a potential increased risk for metastatic spread.


Fexofenadine effects on cognitive performance in aviators at ground level and simulated altitude.
Antihistamines are used for the treatment of allergic rhinitis (AR) symptoms. However, the cognitive effects of some antihistamines can dramatically impair individuals in occupations that require sustained vigilance. The cognitive effects of fexofenadine were compared to a placebo (passive control) and cetirizine (active control) in healthy naval flight personnel. All subjects received one dose of each treatment in one of six possible sequences with two washout periods in between, and were assessed for aviation-related cognitive skills using the Aeromedical Vigilance Test (AVT) at both ambient atmospheric conditions and normobaric hypoxic conditions. Drowsiness was self-assessed by participants using a visual analog scale (VAS). There was no significant difference between fexofenadine and placebo over the entire 60-min test period, under ambient atmospheric conditions, or under either hypoxic condition. Compared with placebo, cetirizine significantly increased AVT errors over the entire 60-min test period, at 10,000 ft, and at 15,000 ft. No statistical difference was found between treatments under ambient atmospheric conditions, although cetirizine treatment resulted in a greater change from baseline in adjusted average number of AVT errors (0.2124 +/- 0.06) than fexofenadine treatment (0.1989 +/- 0.07) and placebo (0.0745 +/- 0.07). Furthermore, at 10,000 ft there were significantly more AVT errors with cetirizine than with fexofenadine. There were no significant increases in self-reported drowsiness (VAS) for both cetirizine and fexofenadine compared with placebo. Fexofenadine is comparable to placebo in its effect on the cognitive skills important for piloting an aircraft, while cetirizine impairs cognition and may affect piloting ability.


Deadeye Visualization Revisited: Investigation of Preattentiveness and Applicability in Virtual Environments.
Visualizations rely on highlighting to attract and guide our attention. To make an object of interest stand out independently from a number of distractors, the underlying visual cue, e.g., color, has to be preattentive. In our prior work, we introduced Deadeye as an instantly recognizable highlighting technique that works by rendering the target object for one eye only. In contrast to prior approaches, Deadeye excels by not modifying any visual properties of the target. However, in the case of 2D visualizations, the method requires an additional setup to allow dichoptic presentation, which is a considerable drawback. As a follow-up to requests from the community, this paper explores Deadeye as a highlighting technique for 3D visualizations, because such stereoscopic scenarios support dichoptic presentation out of the box. Deadeye suppresses binocular disparities for the target object, so we cannot assume the applicability of our technique as a given fact. With this motivation, the paper presents quantitative evaluations of Deadeye in VR, including configurations with multiple heterogeneous distractors as an important robustness challenge. After confirming the preserved preattentiveness (all average accuracies above 90%) under such real-world conditions, we explore VR volume rendering as an example application scenario for Deadeye. We depict a possible workflow for integrating our technique, conduct an exploratory survey to demonstrate benefits and limitations, and finally provide related design implications.


Targeting metabolism and autophagy in the context of haematologic malignancies.
Autophagy is a cellular process that maintains the homeostasis of the normal cell. It not only allows for cell survival in times of metabolic stress with nutrient recycling but also is able to lead to cell death when required. During malignant transformation the cell is able to proliferate and survive. This is due to altered cell metabolism and the presence of altered genetic changes that maintain the cell survival. Metabolism was considered an innocent bystander that was a consequence of the increased nutrient requirement for the survival and proliferation of haematological malignancies. The interdependency of metabolism and cellular mechanisms such as autophagy are becoming more evident and important. This interdependence contributes to increased cancer progression and drug resistance. In this paper we aim to discuss autophagy, how it pertains to metabolism in the context of hematologic malignancies, and the implications for therapy.


Functional diversification of vitamin D receptor paralogs in teleost fish after a whole genome duplication event.
The diversity and success of teleost fishes (Actinopterygii) has been attributed to three successive rounds of whole-genome duplication (WGD). WGDs provide a source of raw genetic material for evolutionary forces to act upon, resulting in the divergence of genes with altered or novel functions. The retention of multiple gene pairs (paralogs) in teleosts provides a unique opportunity to study how genes diversify and evolve after a WGD. This study examines the hypothesis that vitamin D receptor (VDR) paralogs (VDRα and VDRβ) from two distantly related teleost orders have undergone functional divergence subsequent to the teleost-specific WGD. VDRα and VDRβ paralogs were cloned from the Japanese medaka (Beloniformes) and the zebrafish (Cypriniformes). Initial transactivation studies using 1α, 25-dihydroxyvitamin D3 revealed that although VDRα and VDRβ maintain similar ligand potency, the maximum efficacy of VDRβ was significantly attenuated compared with VDRα in both species. Subsequent analyses revealed that VDRα and VDRβ maintain highly similar ligand affinities; however, VDRα demonstrated preferential DNA binding compared with VDRβ. Protein-protein interactions between the VDR paralogs and essential nuclear receptor coactivators were investigated using transactivation and mammalian two-hybrid assays. Our results imply that functional differences between VDRα and VDRβ occurred early in teleost evolution because they are conserved between distantly related species. Our results further suggest that the observed differences may be associated with differential protein-protein interactions between the VDR paralogs and coactivators. We speculate that the observed functional differences are due to subtle ligand-induced conformational differences between the two paralogs, leading to divergent downstream functions.


Early aggressive vs. initially conservative treatment in elderly patients with non-ST-elevation acute coronary syndrome: the Italian Elderly ACS study.
Elderly patients represent one-third of all admissions for non-ST-elevation acute coronary syndrome (NSTEACS) in the coronary care units. Despite their high-risk characteristics and worse outcomes, compared with younger patients, the elderly receive less aggressive treatments, also due to less clear evidence regarding the most effective treatment strategy. The Italian Elderly ACS study includes patients older than 74 years of age with NSTEACS in a multicenter randomized clinical trial, comparing an early aggressive and an initially conservative approach. Patients not enrolled due to specific exclusion criteria or any other reason will be enrolled in a Registry. Centers with on-site interventional cathlab and centers without on-site cathlab refering patients to a cathlab within a consolidated percutaneous coronary intervention network. Patients admitted within 48 h of the most recent ischemic symptoms are eligible if they show transient ischemic ECG changes and/or CKMB/Tn elevation. Patients with secondary ischemia, ongoing ischemia, or heart failure, despite optimal therapy or recent coronary intervention, serum creatinine more than 2.5 mg/dl, high bleeding risk, and severe concomitant disease, are excluded from the study. Central randomization to a systematic early aggressive approach (coronary angiography within 48 h of admission and, when indicated, coronary revascularization) or an initially conservative approach (optimal medical therapy with coronary angiography in selected cases with refractory ischemia). Follow-up will include patient visits and ECG at 30 days, 6 months, and 1 year, post randomization. PRIMARY END POINT: The composite of all-cause mortality, myocardial (re)infarction, disabling stroke, and rehospitalization for cardiovascular diseases or severe bleeding within 6 months. Expected primary end point rates of 30% in the conservative arm vs. 20% in the invasive arm. According to these estimates, with two-tailed alpha of 0.05, power will be 80, 85, or 90% with 252, 289, and 338 patients per group, respectively. The goal is to enroll 700 patients from 50 centers.


An immunocytochemical and biochemical study of the microtubule-associated protein MAP-2 during post-lesion dendritic remodeling in the central nervous system of adult rats.
A monoclonal antibody against the microtubule-associated protein MAP-2 was used to examine the fate of this molecule during post-lesion dendritic remodeling in the hippocampus and septum of adult rats. Qualitative and quantitative immunocytochemical analyses were carried out in the dentate gyrus after unilateral destruction of the entorhinal cortex (EC). An increase in MAP-2 immunoreactivity was detected in dendritic processes located in the outer 2/3 of the ipsilateral molecular layer (ML) 2 days after the lesion. whereas dendritic staining decreased considerably in the inner 1/3 of the same ML. The increase of staining was also detected 4, 6 and 8 days after the lesion; it was accompanied by an increase in the immunoreactivity in the inner 1/3 of the ML. After that period, a progressive decrease in anti-MAP-2 staining toward control levels was detected along the whole extent of the ipsilateral ML. This was concurrent with alterations in dendritic orientation, and a decrease in stained dendrites in the inner 1/3 of the ML. By 30 days post-lesion anti-MAP-2 staining was almost identical to that of the contralateral ML, although the alterations in dendritic morphology were still present in the ipsilateral ML. Changes in MAP-2 levels were also evaluated by densitometry of Western blots or dot immunobinding of hippocampal extracts obtained at different post-lesion intervals. The results obtained revealed a pattern of change in MAP-2 levels identical to that observed with the immunohistochemical stain. A similar, immunocytochemical and biochemical, analysis conducted in the lateral septal nucleus after unilateral transection of the fimbria showed no changes in the distribution and/or content of MAP-2 at any post-lesion interval analyzed (2, 10 and 20 days post-lesion). The present observations show that post-lesion dendritic remodeling is concurrent with modifications in the levels and distribution of MAP-2. These modifications suggest that the dendritic cytoskeleton is dynamically changing in response to perturbation of the synaptic environment. In addition, our results indicate that these changes may only occur in those neurons which have the capability to remodel their post-synaptic surface in response to deafferentation.


Cell cannibalism by malignant neoplastic cells: three cases in dogs and a literature review.
Cell cannibalism refers to the engulfment of cells by nonprofessional phagocytic cells. Studies in human medicine have demonstrated a relationship between the presence of cell cannibalism by neoplastic cells and a poor outcome, and have shown a positive correlation with the presence of metastasis at the time of diagnosis. The biologic significance of cell cannibalism is unknown, but it is proposed that it may represent a novel mechanism of tumor immune evasion as a survival strategy in cases of unfavorable microenvironmental conditions. This report describes clinical and morphologic features of 3 cases of dogs with malignant neoplasia in which the presence of cellular cannibalism was observed in cytologic and histologic specimens. In the 1(st) case, a dog with a primary tonsillar squamous cell carcinoma with metastasis to retropharyngeal lymph nodes had neoplastic epithelial cells engulfing neutrophils noted in cytologic examination of the lymph nodes. In the 2(nd) case, neoplastic epithelial cells were seen engulfing each other in fine-needle aspirates from a primary mammary carcinoma with lung metastasis. In the 3(rd) case, poorly differentiated neoplastic mast cells from a recurrent, metastatic grade III mast cell tumor were observed cannibalizing eosinophils. A brief review of the literature describing known cell-into-cell relationships and the possible biologic significance and mechanisms involved in this phenomenon is provided. The relationship between cell cannibalism and distant metastasis should be explored in further studies, as it may prove to be a criterion of malignancy, as it is proposed in human medicine.


Catalyst-Free Transamidation of Aromatic Amines with Formamide Derivatives and Tertiary Amides with Aliphatic Amines.
A simple catalyst- and promoter-free protocol has been developed for the transamidation of weakly nucleophilic aromatic amines with formamide derivatives and low-reactivity tertiary amides with aliphatic amines. This strategy is advantageous because no catalyst or promoters are needed, no additives are required, separation and purification is easy, and the reaction is scalable. Significantly, this strategy was further applied to synthesize several pharmaceutical molecules on a gram scale, and excellent yields were achieved.


HIV-1 p17 and IFN-gamma both induce fructose 1,6-bisphosphatase.
The p17 matrix protein of the human immunodeficiency virus type 1 (HIV-1) plays a crucial role in AIDS pathogenesis. It orchestrates viral assembly and directs the preintegration complex to the nucleus of infected cells. Recently, the three-dimensional structure of p17 was shown to resemble that of interferon-gamma (IFN-gamma), suggesting that both proteins might share analogous functions. We demonstrate that in monocytes, p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity and to activate fructose 1,6-bisphosphatase gene expression in the presence of 25-hydroxyvitamin D3. However, p17 does not bind to the IFN-gamma cell membrane receptor and fails to increase expression of IFN-gamma-induced proteins, such as tryptophanyl-tRNA synthetase, Fc gammaRI, and HLA DR or B7/BB1 antigens. Altogether, our results raise the possibility that the structural resemblance between p17 and IFN-gamma causes the selective activation of a common pathway resulting in the production of 1,25-dihydroxyvitamin D3. We also found that unlike IFN-gamma, p17 increases the intracellular ATP content. Since transport of the HIV-1 preintegration complex through the nuclear membrane is an ATP-dependent process, our observation suggests that p17 plays a double role in this active transport, not only by acting as a chaperone molecule but also by recruiting the necessary energy for this process.


Virgins in the wild: mating status affects the behavior of a parasitoid foraging in the field.
In haplodiploid organisms, virgin females can produce offspring, albeit only sons. They may therefore face a trade-off between either: (1) searching for hosts and producing sons immediately; or (2) searching for mates and perhaps producing both sons and daughters later in life. Although this trade-off raises a theoretical interest, it has not been approached experimentally. The objective of this article is thus to document the effect of mating status on the foraging behavior of a haplodiploid parasitoid. For this, we recorded the behavior of virgin and mated female Lysiphlebus testaceipes (Hymenoptera: Braconidae) after being released, in the field, on a colony of their aphid hosts. Half of the virgin females were mated by a wild male after less than 10 min of foraging. Evidently, virgin females attract males while foraging on host patches, so that the two activities are not mutually exclusive. Nonetheless, virgin females stayed motionless more often and for longer periods than mated females. Consequently, they attacked aphids at a lower rate, and in turn, attacked fewer aphids on each patch. Moreover, contrary to mated females, virgins did not aggregate their progeny on large patches. We conclude that in L. testaceipes, the trade-off may not be as hypothesized. By dispersing across patches more than mated females, virgins could promote future mating opportunities for their sons and increase their inclusive fitness. However, by moving too frequently, females may lose immediate mating opportunities for themselves and the immediate advantage of producing offspring of both sexes. The observed behavior of virgin L. testaceipes females on host patches could reflect an optimal solution to such a trade-off.


Modification of O and CO binding on Pt nanoparticles due to electronic and structural effects of titania supports.
Metal oxide supports often play an active part in heterogeneous catalysis by moderating both the structure and the electronic properties of the metallic catalyst particle. In order to provide some fundamental understanding on these effects, we present here a density functional theory (DFT) investigation of the binding of O and CO on Pt nanoparticles supported on titania (anatase) surfaces. These systems are complex, and in order to develop realistic models, here, we needed to perform DFT calculations with up to ∼1000 atoms. By performing full geometry relaxations at each stage, we avoid any effects of "frozen geometry" approximations. In terms of the interaction of the Pt nanoparticles with the support, we find that the surface deformation of the anatase support contributes greatly to the adsorption of each nanoparticle, especially for the anatase (001) facet. We attempt to separate geometric and electronic effects and find a larger contribution to ligand binding energy arising from the former. Overall, we show an average weakening (compared to the isolated nanoparticle) of ∼0.1 eV across atop, bridge and hollow binding sites on supported Pt55 for O and CO, and a preservation of site preference. Stronger effects are seen for O on Pt13, which is heavily deformed by anatase supports. In order to rationalize our results and examine methods for faster characterization of metal catalysts, we make use of electronic descriptors, including the d-band center and an electronic density based descriptor. We expect that the approach followed in this study could be applied to study other supported metal catalysts.


Coenzyme Q10 effects in neurodegenerative disease.
Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson's disease and atypical Parkinson's syndromes, Huntington's disease, Alzheimer disease, Friedreich's ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.


The role of superior temporal cortex in auditory timing.
Recently, there has been upsurge of interest in the neural mechanisms of time perception. A central question is whether the representation of time is distributed over brain regions as a function of stimulus modality, task and length of the duration used or whether it is centralized in a single specific and supramodal network. The answers seem to be converging on the former, and many areas not primarily considered as temporal processing areas remain to be investigated in the temporal domain. Here we asked whether the superior temporal gyrus, an auditory modality specific area, is involved in processing of auditory timing. Repetitive transcranial magnetic stimulation was applied over left and right superior temporal gyri while participants performed either a temporal or a frequency discrimination task of single tones. A significant decrease in performance accuracy was observed after stimulation of the right superior temporal gyrus, in addition to an increase in response uncertainty as measured by the Just Noticeable Difference. The results are specific to auditory temporal processing and performance on the frequency task was not affected. Our results further support the idea of distributed temporal processing and speak in favor of the existence of modality specific temporal regions in the human brain.


Chemotherapy in advanced pancreatic adenosquamous carcinoma: A retrospective multicenter AGEO study.
Pancreatic adenosquamous carcinoma (PASC) account for <5% of pancreatic malignancies. The efficacy of modern chemotherapy regimens in patients with advanced PASC is unknown. Patients with advanced PASC from 2008 to 2021 were consecutively included in this retrospective multicenter study. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Ninety-four PASC from 16 French centers were included (median age, 67.3 years; males, 56.4%; metastatic disease, 85.1%). The first-line treatment was chemotherapy for 79 patients (84.0%) (37 FOLFIRINOX (FX), 7 Gemcitabine-nab paclitaxel (GN) and 35 for all other regimen) or best supportive care (BSC) alone for 15 patients (16.0%). No significant difference was observed between FX and GN in terms of PFS (P = .67) or OS (P = .5). Modern regimens pooled together (FX and GN) as compared to all others chemotherapy regimens showed an improvement of overall response rate (39.5% and 9.7%, P = .002), PFS (median, 7.8 vs 4.7 months, P = .02) and OS (median, 12.7 vs 9.2 months, P = .35). This large study evaluating first-line treatment regimens in advanced PASC suggests that modern regimens as FX or GN may be preferable to all other chemotherapy regimens. These results deserve confirmation in prospective studies.


Foreign-body aspiration mimicking congenital lobar emphysema in a forty-eight-day-old girl.
Foreign-body aspiration (FBA) is a commonly encountered serious problem during childhood, accounting for 7% of lethal accidents in children aged 1-3 years. Bronchoscopy is indicated when a clear history of FBA is present, but the history may be unreliable. Clinical manifestations can be seen in various diseases, and when a history of FBA cannot be obtained, radiologic findings such as hyperaeration can suggest the presence of congenital anomalies, e.g., congenital lobar emphysema. Here, a 48-day-old girl with coconut aspiration is described, to emphasize that a clinical history may not be available and FBA should be among the possible diagnoses, even before 6 months of age.


Relationship of interferon-inducing particle phenotype to encephalomyocarditis virus-induced diabetes mellitus.
The B (nondiabetogenic) and D (diabetogenic) variants of encephalomyocarditis (EMC) virus were studied to further define the role of the interferon (IFN) system in murine virus-induced diabetes mellitus. The relationship between the initial multiplicity of infection with EMC-B and the IFN yield showed that cells infected with one IFN-inducing particle produce a maximum amount of IFN, whereas IFN production is suppressed in cells infected with two or more particles. The IFN yield induced by EMC-D was less than 5% of that induced by EMC-B, allowing the designation of the B and D variants as Ifp+ and Ifp-, respectively. The Ifp+ property of the virion was shown to be responsible for the greater sensitivity of EMC-B to exogenous IFN as a result of primed local IFN induction. The data indicate that different Ifp phenotypes occur in nature and are associated with the development of diabetes in mice.


Immunocytochemical localization of opsin in the inner segment and ciliary plasma membrane of photoreceptors in retinas of rds mutant mice.
Homozygous 020/A mutant mice bearing the rds gene for slow inherited retinal degeneration have been observed to develop normal photoreceptor inner segments connecting cilia and synaptic contacts but fail to form outer segments. Their retinas are responsive to light, however. In order to assess the sources of these physiological responses we investigated the distribution of opsin in photoreceptors by means of immunoelectron microscopy. Opsin was detected in the inner segment plasma membrane and the distal ciliary plasma membrane. Antibody also bound to lamellar and vesicular membranes in the interphotoreceptor space and, in a small fraction of the photoreceptors, to membranes projecting from the distal cilium. These membranes may represent abortive formation of rod discs in this form of retinal degeneration. Failure to form an organized outer segment may contribute to the persistence of opsin in the inner segment plasma membranes of adult mutant mice.


High prevalence of injection drug use and blood-borne viral infections among patients in an urban emergency department.
The opioid epidemic has led to an increase in the number of persons who inject drugs, and this population accounts for 12% of new human immunodeficiency virus (HIV) and 60% of new hepatitis C virus (HCV) infections in the United States annually. While persons who inject drugs disproportionately utilize the emergency department (ED), accurate data is lacking on the prevalence and patterns of injection drug use, and prevalence of co-occurring HIV and HCV infections among ED patients. The primary outcome was to assess the prevalence of injection drug use and co-occurring HIV and HCV infection among patients presenting to an urban ED. This was a cross sectional study conducted at an urban ED, with an annual census of 65,000 visits. A closed-response questionnaire was developed based on publicly available validated surveys to assess patterns of injection drug use and HIV and HCV infection status, and administered by trained research assistants to all registered adult patients during 4-hour blocks of time. Of the 2,319 eligible patients, 2,200 (94.9%) consented and completed the survey. 241 (11.0%) had ever used injection drugs, 103 (4.7%) currently used injection drugs, and 138 (6.3%) formerly used injection drugs. White patients age 25 to 34 years and white patients age 55 to 64 years had the highest prevalence of current (25.6%) and former (27.1%) injection drug use, respectively. Persons who use injection drugs had a higher prevalence of HCV infection (52.7% vs. 3.4%) and HIV infection (6.2% vs. 1.8%) than the rest of the population. A high prevalence of ED patients report injection drug use, and this population self-reports a high prevalence of HIV and HCV infection. Emergency departments are in a unique position to engage with this population with regards to substance use treatment and linkage to care for HIV and HCV infection.


[Prognosis in radiotherapy of patients with local recurrence of cervix neoplasms].
An analysis of the results of treatment in 231 patients with recurrences of cervical cancer is presented in relation to 5-year survival criterion ("dynamic analysis"). An actual 5-year survival rate was 16.0%. The most important factors determining the prognosis include the stage of the primary process, localization of the secondary tumor, terms of the recurrence and the absorbed dose of radiation given to the recurrence. Standardized rates showed a 3-5 fold improvement of the results of treatment in the presence of favourable prognostic factors. In combinations of favourable prognostic factors the 5-year survival rate of patients with recurrent cervical cancer reached 67.0%. The amount of the absorbed local dosage of radiation is of practical value for improvement of the results of treatment. Radiotherapy is the method of choice in treatment of patients with local recurrences of uterine cervix cancer.


Optimizing risk stratification in portal vein thrombosis after splenectomy and its primary prophylaxis with antithrombin III concentrates and danaparoid sodium in liver cirrhosis with portal hypertension.
Decreased antithrombin III (ATIII) activity and large splenic vein diameter (SVD) are risk factors for portal vein thrombosis (PVT) after splenectomy in liver cirrhosis with portal hypertension. Antithrombin III concentrates can prevent PVT. This study was designed to stratify risks for PVT after splenectomy in cirrhotic patients and to develop prophylactic protocols for PVT. In 53 patients (testing cohort), the cutoff level of preoperative ATIII activity (≤60%) was evaluated for administration of ATIII concentrates. Antithrombin III activity and SVD were re-evaluated as criteria for prophylaxis of PVT. In 57 patients (validation cohort), the risk stratification of PVT and prophylactic protocols were validated. In the testing cohort, 10 (19%) of 53 patients had PVT. Risk level of PVT was stratified and prophylactic protocols were developed. Patients at low risk (ATIII activity ≥70% and SVD <10 mm) were not treated; those at high risk (ATIII activity <70% or SVD ≥10 mm) received ATIII concentrates (1,500 U/day) for 3 days; and those at highest risk (SVD ≥15 mm) received ATIII concentrates for 3 days, followed by danaparoid sodium (2,500 U/day) for 14 days and warfarin. In the validation cohort, 0 of 14 low-risk and 2 of 32 high-risk patients had PVT. Although 8 of 11 patients at highest risk had temporary PVT, it disappeared within 3 months postoperatively. Finally, only 2 (3.5%) of 57 patients had PVT. Risk stratification of PVT after splenectomy and prophylaxis with ATIII concentrates and danaparoid sodium dramatically reduced the incidence of PVT.


Reporting of patient-centred outcomes in heart failure trials: are patient preferences being ignored?
Older people often suffer from multiple diseases. Therefore, universal cross-disease outcomes (e.g. functional status, quality of life, overall survival) are more relevant than disease-specific outcomes, and a range of potential outcomes are needed for medical decision-making. To assess how patient-relevant outcomes have penetrated randomized controlled trials (RCTs), reporting of these outcomes was reviewed in heart failure trials that included patients with multimorbidity. We systematically reviewed RCTs (Jan 2011-June 2012) and evaluated reported outcomes. Heart failure was chosen as condition of interest as this is common among older patients with multimorbidity. The main outcome was the proportion of RCTs reporting all-cause mortality, all-cause hospital admission, and outcomes in four domains of health, i.e. functional, signs and symptoms, psychological, and social domains. Of the 106 included RCTs, 50 (47 %) reported all-cause mortality and cardiovascular mortality and 29 (27 %) reported all-cause hospitalization and cardiovascular hospitalization. Of all trials, 68 (64 %) measured outcomes in the functional domain, 80 (75 %) in the domain of signs and symptoms, 65 (61 %) in the psychological domain, and 59 (56 %) in the social domain. Disease-specific instruments were more often used than non-disease-specific instruments. This review shows increasing attention for more patient-relevant outcomes; this is promising and indicates more awareness of the importance of a variety of outcomes desirable for patients. However, patients' individual goal attainments were universally absent. For continued progress in patient-centred care, efforts are needed to develop these outcomes, study their merits and pitfalls, and intensify their use in research.


Utility of remote wireless pressure sensing for endovascular leak detection after endovascular thoracic aneurysm repair.
The goal of thoracic endovascular aneurysm repair (TEVAR) is to exclude and depressurize the aneurysm sac. Type I and III endovascular leaks (EL) transmit systemic pressure and represent treatment failures. The significance of type II EL is more controversial. Remote pressure sensing is a novel nonradiographic technology for EL detection and monitoring. However, little experience exists with regard to use in the thoracic aorta. We present our experience with the EndoSure wireless pressure measurement system (CardioMEMS, Atlanta, GA) for monitoring aneurysm sac pulse pressure (ASP) after TEVAR. Beginning May 2006, the EndoSure system was routinely implanted in TEVAR patients with suitable anatomy (36 aneurysm patients; 7 chronic dissection patients). The ASP measurements were taken predischarge and at scheduled follow-up visits. Computed tomography angiograms were performed at scheduled follow-up appointments. Data were prospectively maintained in an institutional aortic database. Through June 2008, 43 patients (34% of TEVARs performed during this interval) underwent implantation. In 10 patients (23%), the device was suboptimally positioned between the endovascular graft and the aortic wall, rather than in an area of thrombus-free lumen, with subsequent transmission of systemic pressure despite no radiographic evidence of EL. In patients with well-positioned sensors, predischarge ASP averaged 43% +/- 22% of systemic. In 2 patients, systemic ASP measurements before discharge prompted imaging, confirming type I EL; both patients were treated successfully with cuff extension. One patient exhibited reduced ASP before discharge but exhibited increased ASP (70% systemic) at 1 month; computed tomography scan confirmed a type I EL. Additional TEVAR sealed the EL and reduced ASP to 39% systemic. For all patients at midterm follow-up, ASP decreased further, averaging 19% +/- 12% systemic (p = 0.019); this correlates with computed tomography imaging demonstrating a 5 mm or greater reduction in aortic diameter in 76% of patients (25 of 33) with follow-up of 6 months or longer. No patients manifested a recurrent type I or type III EL at latest follow-up. The device has also been used to follow 8 patients with type II EL with low ASP. Implantation of a wireless ASP sensor provides useful information regarding type I and type III EL after TEVAR and permits serial observation of type II EL. This information may guide clinical therapy and improve outcomes. Longer term follow-up will define sensor reliability in postoperative surveillance.


Misunderstandings in multilingual counselling settings involving school nurses and obese/overweight pupils.
School nurses' counselling is pivotal in stemming the obesity epidemic. Barriers for good counselling such as nurses' misunderstandings and ambiguities when relating to overweight and obesity need to be addressed. In this study, we explored misunderstandings in school nurses' counselling of overweight pupils in multilingual settings, together with how school nurses talk about the condition. Counselling sessions involving eight nurses and 20 pupils (aged 8-16 years) were audio-recorded and analysed using theme-oriented discourse analysis. Statistical methods were used as a complement. The focal themes were misunderstandings and nurses' talk about overweight and obesity. Analytical themes were framing, footing and facework. Data analyses revealed three main origins of misunderstandings occurring in school nurses' counselling of obese and overweight pupils: (1) nurses' illusion that they know what advice the pupils need; (2) nurses' insensitivity to the pupils' and parents' concerns; and (3) lack of lingual understanding. School nurses' apparent difficulties to talk about overweight and obesity suggest a need to reflect on how to name these issues during counselling. School nurses' dominance and pupils'passivity were obvious. We suggest that counselling should be regarded as learning contexts and be subjected to possible quality assurance in the future.


Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells.
IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNgamma and IL-2, but not IL-10. Enhanced secretion of IFNgamma was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.


The Bidirectional Relationship Between Obstructive Sleep Apnea and Metabolic Disease.
Obstructive sleep apnea (OSA) is a common sleep disorder, effecting 17% of the total population and 40-70% of the obese population (1, 2). Multiple studies have identified OSA as a critical risk factor for the development of obesity, diabetes, and cardiovascular diseases (3-5). Moreover, emerging evidence indicates that metabolic disorders can exacerbate OSA, creating a bidirectional relationship between OSA and metabolic physiology. In this review, we explore the relationship between glycemic control, insulin, and leptin as both contributing factors and products of OSA. We conclude that while insulin and leptin action may contribute to the development of OSA, further research is required to determine the mechanistic actions and relative contributions independent of body weight. In addition to increasing our understanding of the etiology, further research into the physiological mechanisms underlying OSA can lead to the development of improved treatment options for individuals with OSA.


Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.
Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10-3 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.


Genome-Wide Selection Scan in an Arabian Peninsula Population Identifies a TNKS Haplotype Linked to Metabolic Traits and Hypertension.
Despite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis.


Splenic contraction during breath-hold diving in the Korean ama.
Major increases of hemoglobin concentration and hematocrit, possibly secondary to splenic contraction, have been noted during diving in the Weddell seal. We sought to learn whether this component of the diving response could be present in professional human breath-hold divers. Splenic size was measured ultrasonically before and after repetitive breath-hold dives to approximately 6-m depth in ten Korean ama (diving women) and in three Japanese male divers who did not routinely practice breath-hold diving. Venous hemoglobin concentration and hematocrit were measured in nine of the ama and all Japanese divers. In the ama, splenic length and width were reduced after diving (P = 0.0007 and 0.0005, respectively) and calculated splenic volume decreased 19.5 +/- 8.7% (mean +/- SD, P = 0.0002). Hemoglobin concentration and hematocrit increased 9.5 +/- 5.9% (P = 0.0009) and 10.5 +/- 4% (P = 0.0001), respectively. In Japanese male divers, splenic size and hematocrit were unaffected by repetitive breath-hold diving and hemoglobin concentration increased only slightly over baseline (3.0 +/- 0.6%, P = 0.0198). Splenic contraction and increased hematocrit occur during breath-hold diving in the Korean ama.


Calorie restriction in humans: An update.
Calorie restriction (CR), a nutritional intervention of reduced energy intake but with adequate nutrition, has been shown to extend healthspan and lifespan in rodent and primate models. Accumulating data from observational and randomized clinical trials indicate that CR in humans results in some of the same metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in animal models of longevity. In particular, moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality. In this paper, we will discuss the effects of CR in non-obese humans on these physiological parameters. Special emphasis is committed to recent clinical intervention trials that have investigated the feasibility and effects of CR in young and middle-aged men and women on parameters of energy metabolism and metabolic risk factors of age-associated disease in great detail. Additionally, data from individuals who are either naturally exposed to CR or those who are self-practicing this dietary intervention allows us to speculate on longer-term effects of more severe CR in humans.


A risk identification model for detection of patients at risk of antidepressant discontinuation.
Between 30 and 68% of patients prematurely discontinue their antidepressant treatment, posing significant risks to patient safety and healthcare outcomes. Online healthcare forums have the potential to offer a rich and unique source of data, revealing dimensions of antidepressant discontinuation that may not be captured by conventional data sources. We analyzed 891 patient narratives from the online healthcare forum, "askapatient.com," utilizing content analysis to create PsyRisk-a corpus highlighting the risk factors associated with antidepressant discontinuation. Leveraging PsyRisk, alongside PsyTAR [a publicly available corpus of adverse drug reactions (ADRs) related to antidepressants], we developed a machine learning-driven algorithm for proactive identification of patients at risk of abrupt antidepressant discontinuation. From the analyzed 891 patients, 232 reported antidepressant discontinuation. Among these patients, 92% experienced ADRs, and 72% found these reactions distressful, negatively affecting their daily activities. Approximately 26% of patients perceived the antidepressants as ineffective. Most reported ADRs were physiological (61%, 411/673), followed by cognitive (30%, 197/673), and psychological (28%, 188/673) ADRs. In our study, we employed a nested cross-validation strategy with an outer 5-fold cross-validation for model selection, and an inner 5-fold cross-validation for hyperparameter tuning. The performance of our risk identification algorithm, as assessed through this robust validation technique, yielded an AUC-ROC of 90.77 and an F1-score of 83.33. The most significant contributors to abrupt discontinuation were high perceived distress from ADRs and perceived ineffectiveness of the antidepressants. The risk factors identified and the risk identification algorithm developed in this study have substantial potential for clinical application. They could assist healthcare professionals in identifying and managing patients with depression who are at risk of prematurely discontinuing their antidepressant treatment.


Fiber-laser-pumped, high-energy, mid-IR, picosecond optical parametric oscillator with a high-harmonic cavity.
We demonstrate the generation of high-energy, mid-IR, picosecond pulses in a high-harmonic-cavity optical parametric oscillator (OPO) that has a relatively compact cavity with a length that is a small fraction of that required to match the pump repetition rate. The OPO, based on an MgO-doped periodically poled LiNbO3 crystal, is pumped by a fiber master-oscillator-power-amplifier system employing direct amplification and delivering 11-μJ, 150-ps pulses at 1035 nm. For a 1.554-m-long OPO cavity, resonating near-infrared signal pulses with a repetition rate that is the 193rd harmonic of the 1-MHz pump are demonstrated. The mid-infrared idler output pulses, tunable from 2300 nm to 3500 nm, are generated at a 1-MHz repetition rate and have energies as high as 1.5 μJ.


The Gfi-1 protooncoprotein represses Bax expression and inhibits T-cell death.
The Gfi-1 protooncogene encodes a nuclear zinc-finger protein that carries a novel repressor domain, SNAG, and functions as a position- and orientation-independent active transcriptional repressor. The Gfi-1 repressor allows interleukin 2 (IL-2)-dependent T cells to escape G1 arrest induced by IL-2 withdrawal in culture and collaborates with c-myc and pim-1 for the induction of retrovirus-induced lymphomas in animals. Here we show that overexpression of Gfi-1 also inhibits cell death induced by cultivation of IL-2-dependent T-cell lines in IL-2-deficient media. Similarly, induction of Gfi-1 in primary thymocytes from mice carrying a metal-inducible Gfi-1 transgene inhibits cell death induced by cultivation in vitro. The protein and mRNA levels of the proapoptotic regulator Bax are down-regulated by Gfi-1 in both immortalized T-cell lines and primary transgenic thymocytes. The repression is direct and depends on several Gfi-1-binding sites in the p53-inducible Bax promoter. In addition to Bax, Gfi-1 also represses Bak, another apoptosis-promoting member of the Bcl-2 gene family. Therefore, Gfi-1 may inhibit apoptosis by means of its repression of multiple proapoptotic regulators. The antiapoptotic properties of Gfi-1 provide a potential explanation for its strong collaboration with c-myc during oncogenesis.


Tactile spatial acuity in childhood: effects of age and fingertip size.
Tactile acuity is known to decline with age in adults, possibly as the result of receptor loss, but less is understood about how tactile acuity changes during childhood. Previous research from our laboratory has shown that fingertip size influences tactile spatial acuity in young adults: those with larger fingers tend to have poorer acuity, possibly because mechanoreceptors are more sparsely distributed in larger fingers. We hypothesized that a similar relationship would hold among children. If so, children's tactile spatial acuity might be expected to worsen as their fingertips grow. However, concomitant CNS maturation might result in more efficient perceptual processing, counteracting the effect of fingertip growth on tactile acuity. To investigate, we conducted a cross-sectional study, testing 116 participants ranging in age from 6 to 16 years on a precision-controlled tactile grating orientation task. We measured each participant's grating orientation threshold on the dominant index finger, along with physical properties of the fingertip: surface area, volume, sweat pore spacing, and temperature. We found that, as in adults, children with larger fingertips (at a given age) had significantly poorer acuity, yet paradoxically acuity did not worsen significantly with age. We propose that finger growth during development results in a gradual decline in innervation density as receptive fields reposition to cover an expanding skin surface. At the same time, central maturation presumably enhances perceptual processing.


Microwave-driven asbestos treatment and its scale-up for use after natural disasters.
Asbestos-containing debris generated by the tsunami after the Great East Japan Earthquake of March 11, 2011, was processed by microwave heating. The analysis of the treated samples employing thermo gravimetry, differential thermal analysis, X-ray diffractometry, scanning electron microscopy, and phase-contrast microscopy revealed the rapid detoxification of the waste by conversion of the asbestos fibers to a nonfibrous glassy material. The detoxification by the microwave method occurred at a significantly lower processing temperature than the thermal methods actually established for the treatment of asbestos-containing waste. The lower treatment temperature is considered to be a consequence of the microwave penetration depth into the waste material and the increased intensity of the microwave electric field in the gaps between the asbestos fibers resulting in a rapid heating of the fibers inside the debris. A continuous treatment plant having a capacity of 2000 kg day(-1) of asbestos-containing waste was built in the area affected by the earthquake disaster. This treatment plant consists of a rotary kiln to burn the combustible waste (wood) and a microwave rotary kiln to treat asbestos-containing inorganic materials. The hot flue gas produced by the combustion of wood is introduced into the connected microwave rotary kiln to increase the energy efficiency of the combined process. Successful operation of this combined device with regard to asbestos decomposition is demonstrated.


[Echocardiographic characteristics of the left heart ventricle in people with different somatotypes].
The objective of this study was to analyze echocardiographic parameters in 143 healthy individuals aged 18-21 years with different somatotypes. The evaluation of somatotype was performed using the the method of R.N. Dorokhov and V.G. Petrukhin (1989). During the echocardiography, left ventricular wall thickness, internal diameter and myocardial mass were measured. The investigation showed marked sex- and somatotype-related differences in left ventricular parameters. The correlations between the studied left ventricular parameters and body mass, length and surface area were demonstrated. The optimal method of the indexation of left ventricular myocardial mass as related to (body length)3, is described.