Cellular Concentrations of Nucleotide Diphosphate-Chelated Magnesium Ions Accelerate Catalysis by RNA and DNA Enzymes.
RNAs are involved in myriad cellular events. In general, RNA function is affected by cellular conditions. For instance, molecular crowding promotes RNA folding through compaction of the RNA. Metabolites generally destabilize RNA secondary structure, which improves RNA folding cooperativity and increases the fraction of functional RNA. Our recent studies demonstrate that cellular concentrations of amino acid-chelated magnesium (aaCM) stimulate RNA folding and catalysis while protecting RNAs from magnesium ion-induced degradation. However, effects of other cellular magnesium ion chelators on RNA function have not been tested. Herein, we report that nucleotide diphosphate-chelated magnesium, which is of intermediate strength, promotes RNA catalysis much like aaCM. Nucleotides are some of the major metabolites in cells and have one to three phosphates, which have increasingly tight binding of magnesium. On the basis of binding calculations, ∼85% ATP, ∼40% ADP, and only 5% AMP are estimated to possess a magnesium ion under cellular conditions of 0.50 mM Mg2+free. We tested the self-cleaving activity of the hammerhead ribozyme in the presence of these chelated magnesium species. Our results indicate that NTP-chelated magnesium and NMP-chelated magnesium do not appreciably stimulate RNA catalysis, whereas NDP-chelated magnesium promotes RNA catalysis up to 6.5-fold. Inspired by NDP, we observed similar stimulatory effects for several other Mg2+ diphosphate-containing metabolites, including UDP-GlcNAC and UDP-Glc; in addition, we found similar effects for a DNAzyme. Thus, rate stimulatory effects are general with respect to the diphosphate and nucleic acid enzyme. These results implicate magnesium-chelated diphosphate metabolites as general facilitators of RNA function inside cells.


Visualizing Risk Prediction Models.
Risk prediction models can assist clinicians in making decisions. To boost the uptake of these models in clinical practice, it is important that end-users understand how the model works and can efficiently communicate its results. We introduce novel methods for interpretable model visualization. The proposed visualization techniques are applied to two prediction models from the Framingham Heart Study for the prediction of intermittent claudication and stroke after atrial fibrillation. We represent models using color bars, and visualize the risk estimation process for a specific patient using patient-specific contribution charts. The color-based model representations provide users with an attractive tool to instantly gauge the relative importance of the predictors. The patient-specific representations allow users to understand the relative contribution of each predictor to the patient's estimated risk, potentially providing insightful information on which to base further patient management. Extensions towards non-linear models and interactions are illustrated on an artificial dataset. The proposed methods summarize risk prediction models and risk predictions for specific patients in an alternative way. These representations may facilitate communication between clinicians and patients.


Reductions in Children's Vicariously Learnt Avoidance and Heart Rate Responses Using Positive Modeling.
Recent research has indicated that vicarious learning can lead to increases in children's fear beliefs and avoidance preferences for stimuli and that these fear responses can subsequently be reversed using positive modeling (counterconditioning). The current study investigated children's vicariously acquired avoidance behavior, physiological responses (heart rate), and attentional bias for stimuli and whether these could also be reduced via counterconditioning. Ninety-six (49 boys, 47 girls) 7- to 11-year-olds received vicarious fear learning for novel stimuli and were then randomly assigned to a counterconditioning, extinction, or control group. Fear beliefs and avoidance preferences were measured pre- and post-learning, whereas avoidance behavior, heart rate, and attentional bias were all measured post-learning. Control group children showed increases in fear beliefs and avoidance preferences for animals seen in vicarious fear learning trials. In addition, significantly greater avoidance behavior, heart rate responding, and attentional bias were observed for these animals compared to a control animal. In contrast, vicariously acquired avoidance preferences of children in the counterconditioning group were significantly reduced post-positive modeling, and these children also did not show the heightened heart rate responding to fear-paired animals. Children in the extinction group demonstrated comparable responses to the control group; thus the extinction procedure showed no effect on any fear measures. The findings suggest that counterconditioning with positive modelling can be used as an effective early intervention to reduce the behavioral and physiological effects of vicarious fear learning in childhood.


Temporal patterns of self-weighing behavior and weight changes assessed by consumer purchased scales in the Health eHeart Study.
Self-weighing may promote attainment and maintenance of healthy weight; however, the natural temporal patterns and factors associated with self-weighing behavior are unclear. The aims of this secondary analysis were to (1) identify distinct temporal patterns of self-weighing behaviors; (2) explore factors associated with temporal self-weighing patterns; and (3) examine differences in percent weight changes by patterns of self-weighing over time. We analyzed electronically collected self-weighing data from the Health eHeart Study, an ongoing longitudinal research study coordinated by the University of California, San Francisco. We selected participants with at least 12 months of data since the day of first use of a WiFi- or Bluetooth-enabled digital scale. The sample (N = 1041) was predominantly male (77.5%) and White (89.9%), with a mean age of 46.5 ± 12.3 years and a mean BMI of 28.3 ± 5.9 kg/m2 at entry. Using group-based trajectory modeling, six distinct temporal patterns of self-weighing were identified: non-users (n = 120, 11.5%), weekly users (n = 189, 18.2%), rapid decliners (n = 109, 10.5%), increasing users (n = 160, 15.4%), slow decliners (n = 182, 17.5%), and persistent daily users (n = 281, 27.0%). Individuals who were older, female, or self-weighed 6-7 days/week at week 1 were more likely to follow the self-weighing pattern of persistent daily users. Predicted self-weighing trajectory group membership was significantly associated with weight change over time (p < .001). In conclusion, we identified six distinct patterns of self-weighing behavior over the 12-month period. Persistent daily users lost more weight compared with groups with less frequent patterns of scale use.


Approaches Based on Artificial Intelligence and the Internet of Intelligent Things to Prevent the Spread of COVID-19: Scoping Review.
Artificial intelligence (AI) and the Internet of Intelligent Things (IIoT) are promising technologies to prevent the concerningly rapid spread of coronavirus disease (COVID-19) and to maximize safety during the pandemic. With the exponential increase in the number of COVID-19 patients, it is highly possible that physicians and health care workers will not be able to treat all cases. Thus, computer scientists can contribute to the fight against COVID-19 by introducing more intelligent solutions to achieve rapid control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease. The objectives of this review were to analyze the current literature, discuss the applicability of reported ideas for using AI to prevent and control COVID-19, and build a comprehensive view of how current systems may be useful in particular areas. This may be of great help to many health care administrators, computer scientists, and policy makers worldwide. We conducted an electronic search of articles in the MEDLINE, Google Scholar, Embase, and Web of Knowledge databases to formulate a comprehensive review that summarizes different categories of the most recently reported AI-based approaches to prevent and control the spread of COVID-19. Our search identified the 10 most recent AI approaches that were suggested to provide the best solutions for maximizing safety and preventing the spread of COVID-19. These approaches included detection of suspected cases, large-scale screening, monitoring, interactions with experimental therapies, pneumonia screening, use of the IIoT for data and information gathering and integration, resource allocation, predictions, modeling and simulation, and robotics for medical quarantine. We found few or almost no studies regarding the use of AI to examine COVID-19 interactions with experimental therapies, the use of AI for resource allocation to COVID-19 patients, or the use of AI and the IIoT for COVID-19 data and information gathering/integration. Moreover, the adoption of other approaches, including use of AI for COVID-19 prediction, use of AI for COVID-19 modeling and simulation, and use of AI robotics for medical quarantine, should be further emphasized by researchers because these important approaches lack sufficient numbers of studies. Therefore, we recommend that computer scientists focus on these approaches, which are still not being adequately addressed.


Leukotriene inhibitors and antagonists in asthma.
This article reviews the literature on the effects of leukotrienes in asthma. In particular, the ability of recently developed receptor antagonists and synthesis inhibitors to attenuate the asthma-causing effects of leukotrienes is examined. Published literature on the role of leukotrienes in asthma was reviewed. Reports of research on agents that inhibit the synthesis of leukotrienes or block leukotriene receptors were also studied. Leukotrienes are endogenous molecules formed by the breakdown of a membrane constituent, arachidonic acid, via the 5-lipoxygenase enzyme pathway. This pathway ultimately produces several species of leukotrienes with various biologic activities, including generalized inflammatory effects associated with asthma: increased vascular permeability, enhanced mucous production, and decreased mucociliary transport. Particularly important in asthma, leukotriene receptors on the airways mediate a potent bronchoconstriction. Two general types of drugs have been developed with the goal of attenuating the leukotrienes' effects in inflammation and asthma: the leukotriene receptor blockers and the leukotriene synthesis inhibitors (eg, 5-lipoxygenase inhibitors). The antileukotriene drugs attenuated the responses to inhaled leukotrienes and allergen challenges. These agents produced beneficial effects in cold-, exercise-, and aspirin-induced asthma, as well as clinical asthma. Many of these medications appear to be effective in the treatment of asthma; however, further clinical research is needed to determine which patients would benefit most from their use.


Gain manipulation of a slotted sphere using general bi-isotropic coating.
The gain characteristics of a general bi-isotropic (BI) coated slotted sphere have been studied using numerical calculations. An eigenfunction expansion method has been used to derive analytical expressions for the radiated electric and magnetic fields. The effects of various BI and Tellegen coatings upon the gain pattern are investigated. It is proven that the chirality and Tellegen parameters of the coating can significantly modify the gain. It is found that a lossless BI coating has the highest gain in the forward direction as compared to lossless dielectric, Tellegen, and chiral coatings. Such type of enhanced gains in the forward direction are desirable for point-to-point communication. It is further shown that the Tellegen coating guides most of the radiated field from the slot toward polar directions and reduces the gain in the forward direction provided that the Tellegen parameter is not close to unity. For a Tellegen coating whose Tellegen parameter is close to unity, the maximum gain in the forward direction is found. The proposed theory is also extended to realistic BI and low-loss dielectric coatings. It is investigated that by using a proper selection of coating thickness, the forward direction gain of a realistic BI coating can be enhanced or diminished as compared to a low-loss dielectric coating.


Testing for pediatric obstructive sleep apnea when health care resources are rationed.
Evaluation of pediatric obstructive sleep apnea in resource-limited health care systems necessitates testing modalities that are accurate and more cost-effective than polysomnography. To trace the clinical pathway of children referred to our sleep laboratory for possible obstructive sleep apnea who were evaluated using nocturnal pulse oximetry and the McGill Oximetry Score. This was a retrospective cohort study of children 2 to 17 years old with suspected obstructive sleep apnea due to adenotonsillar hypertrophy, conducted at a Canadian pediatric tertiary care center. Nocturnal pulse oximetry studies scored using the McGill Oximetry Score. For children who underwent adenotonsillectomy we determined the length of time from oximetry to surgery, postoperative length of stay, postoperative readmissions, and emergency department visits in the month following surgery and major surgical complications. We analyzed these outcomes by oximetry result. We compared the cost savings of our diagnostic approach with those of other diagnostic models. Among 362 children, the median age was 4.8 years (interquartile range, 3.3-6.7), and 61% were male. Two-hundred-sixty-six (73%) and 96 (27%), respectively, had inconclusive and abnormal oximetry results. Eighty of 96 of children with abnormal oximetry results (83%) and 81 of 266 children with inconclusive oximetry results (30%) underwent adenotonsillectomy. Thirty-three of 266 children (12%) underwent further evaluation with polysomnography; of 14 diagnosed as having OSA, 12 underwent adenotonsillectomy. Children with abnormal oximetry results were operated on soonest after testing and triaged based on oximetry results. No child with an inconclusive oximetry result required hospitalization for more than 1 night postoperatively; 14% of children (11 of 80) with an abnormal oximetry result required hospitalization for 2 or 3 nights (χ2 = 12.0; P = .001). Rates of readmissions and emergency department visits were low, irrespective of oximetry results (whether inconclusive or abnormal). We show that our oximetry-based diagnostic approach results in considerable cost savings compared with a polysomnography-for-all approach. Oximetry studies evaluated with the McGill Oximetry Score expedite diagnosis and treatment of children with adenotonsillar hypertrophy referred for suspected sleep-disordered breathing. When resources for testing for sleep-disordered breathing are rationed or severely limited, our proposed diagnostic approach can help maximize cost-savings and allows sleep laboratories to focus resources on medically complex children requiring polysomnographic evaluation of suspected sleep disorders.


The Mental Health of Elite Athletes: A Narrative Systematic Review.
The physical impacts of elite sport participation have been well documented; however, there is comparatively less research on the mental health and psychological wellbeing of elite athletes. This review appraises the evidence base regarding the mental health and wellbeing of elite-level athletes, including the incidence and/or nature of mental ill-health and substance use. A systematic search of the PubMed, EMBASE, SPORTDiscus, PsycINFO, Cochrane and Google Scholar databases, up to and including May 2015, was conducted. The search yielded a total of 2279 records. Following double screening, 60 studies were included. The findings suggested that elite athletes experience a broadly comparable risk of high-prevalence mental disorders (i.e. anxiety, depression) relative to the general population. Evidence regarding other mental health domains (i.e. eating disorders, substance use, stress and coping) is less consistent. These results are prefaced, however, by the outcome of the quality assessment of the included studies, which demonstrated that relatively few studies (25 %) were well reported or methodologically rigorous. Furthermore, there is a lack of intervention-based research on this topic. The evidence base regarding the mental health and wellbeing of elite athletes is limited by a paucity of high-quality, systematic studies. Nonetheless, the research demonstrates that this population is vulnerable to a range of mental health problems (including substance misuse), which may be related to both sporting factors (e.g. injury, overtraining and burnout) and non-sporting factors. More high-quality epidemiological and intervention studies are needed to inform optimal strategies to identify and respond to player mental health needs.


Apathy in dementia: an examination of the psychometric properties of the apathy evaluation scale.
The psychometric properties of the clinician, informant, and self-rated versions of the Apathy Evaluation Scale (AES-C/I/S) were examined using data on 121 outpatients seen in a behavioral neurology clinic for the assessment of dementia and associated neuropsychiatric disorders. Two factors, apathy and interest, were identified for the AES-C and the AES-I. The AES-S had only an apathy factor. The AES-C was found to have fairly good psychometric properties. However, from a diagnostic point of view, the AES-I provided the greatest sensitivity and the strongest positive and negative predictive values. Generally, the AES-S performed poorly compared with the AES-C and AES-I.


Interactions of fluorinated gases with ionic liquids: solubility of CF4, C2F6, and C3F8 in trihexyltetradecylphosphonium bis(trifluoromethylsulfonyl)amide.
The interactions between ionic liquids and totally fluorinated alkanes are investigated by associating gas solubility measurements with molecular simulation calculations. Experimental values for the solubility of perfluoromethane, perfluoroethane, and perfluoropropane in one ionic liquidtrihexyltetradecylphophonium bis(trifluoromethylsulfonyl)amide [P 6,6,6,14][Ntf 2]are reported between 303 and 343 K and close to atmospheric pressure. All mole fraction solubilities decrease with increasing temperature. From the variation of Henry's law constants with temperature, the thermodynamic functions of solvation were calculated. The precision of the experimental data, considered as the average absolute deviation of the Henry's law constants from appropriate smoothing equations, is always better than +/-3%. By the analysis of the differences between the solute-solvent radial distribution functions of perfluoromethane and perfluoropropane obtained by molecular simulation, it was possible to explain why solubility increases with the size of the perfluoroalkane. The trend of solubility is explained on the basis of the location of the solute with respect to the solvent ions as well as on the differences in the solute-solvent energies of interaction.


CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant.
Many genomic analyses of cortisol-producing adrenocortical carcinoma (ACC) have been reported, but very few have come from East Asia. The first objective of this study is to verify the genetic difference with the previous reports by analyzing targeted deep sequencing of 7 Japanese ACC cases using next-generation sequencing (NGS). The second objective is to compare the somatic variant findings identified by NGS analysis with clinical and pathological findings, aiming to acquire new knowledge about the factors that contribute to the poor prognosis of ACC and to find new targets for the treatment of ACC. DNA was extracted from ACC tissue of seven patients and two reference blood samples. Targeted deep sequencing was performed using the MiSeq system for 12 genes, and the obtained results were analyzed using MuTect2. The hypothesis was obtained by integrating the somatic variant findings with clinical and pathological data, and it was further verified using The Cancer Genome Atlas (TCGA) dataset for ACC. Six possible pathogenic and one uncertain significance somatic variants including a novel PRKAR1A (NM_002734.4):c.545C>A (p.T182K) variant were found in five of seven cases. By integrating these data with pathological findings, we hypothesized that cases with TP53 variants were more likely to show atypical mitotic figures. Using TCGA dataset, we found that atypical mitotic figures were associated with TP53 somatic variant, and mRNA expression of CCNB2 and AURKA was significantly high in TP53 mutated cases and atypical mitotic figure cases. We believe this is the first report that discusses the relationship between atypical mitotic figures and TP53 somatic variant in ACC. We presumed that overexpression of CCNB2 and AURKA mRNA may cause atypical mitosis in TP53 somatic mutated cases. Because AURKA is highly expressed in atypical mitotic cases, it may be an appropriate indicator for AURKA inhibitors.


Fibronectins in vascular morphogenesis.
Fibronectin is an extracellular matrix protein found only in vertebrate organisms containing endothelium-lined vasculature and is required for cardiovascular development in fish and mice. Fibronectin and its splice variants containing EIIIA and EIIIB domains are highly upregulated around newly developing vasculature during embryogenesis and in pathological conditions including atherosclerosis, cardiac hypertrophy, and tumorigenesis. However, their molecular roles in these processes are not entirely understood. We review genetic studies examining functions of fibronectin and its splice variants during embryonic cardiovascular development, and discuss potential roles of fibronectin in vascular disease and tumor angiogenesis.


Comparison of 1-deoxynojirimycin and aqueous mulberry leaf extract with emphasis on postprandial hypoglycemic effects: in vivo and in vitro studies.
Carbohydrate digestion by α-glucosidase and subsequent glucose uptake at the brush border are critical for postprandial blood glucose control. Any specific inhibitors are useful as hyperglycemia modulating agents. In this study, it was postulated that an array of active components in mulberry leaf extract (MLE) may provide higher potency in inhibiting intestinal glucose absorption compared to the single component 1-deoxynojirimycin (DNJ), which is recognized as a promising inhibitor of intestinal glucose absorption. Both MLE and DNJ were active in inhibiting α-glucosidase. However, in Caco-2 cells, only MLE showed significant inhibition of 2-deoxyglucose uptake, whereas DNJ was ineffective. For glucose loading, co-administration of MLE resulted in potent inhibitions of glucose responses compared to those by DNJ in Sprague Dawley (SD) rats, but this was not found for maltose loading. These novel findings add evidence that the unabsorbed phytochemicals in MLE compete with glucose for intestinal glucose transporters, but DNJ itself does not. We also evaluated the timing of MLE consumption. By administering MLE for 30 min before glucose loading, the incremental area under the curve (IAUC) was significantly lowered in the rats, as compared to a simultaneously administered group. Similarly, cellular glucose uptake was significantly reduced in Caco-2 cells following pretreatment.


Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors.
Protease inhibitor (PI) therapy for patients infected with the human immunodeficiency virus has been associated with lipid disorders and insulin resistance. We compared the incidence of myocardial infarction (MI) among participants receiving treatment with PIs with or without nucleoside reverse transcriptase inhibitors (nRTIs) to nRTI therapy alone in 30 phase II/III double-blind, randomized studies conducted before 1999 for the first 4 PI drugs. In most trials included in this analysis, participants could receive combination therapy with a PI plus nRTIs in open-label extensions after the blinded phase concluded. Person-years (PY) of follow-up were calculated from treatment initiation to the diagnosis of MI, or to the end of the randomized phases for nRTI-only therapy or to the conclusion of the studies for PI-containing regimens. Separate analyses were conducted for the randomized and the randomized-plus-extension phases. Among 10,986 participants, 7951 (72%) received PI drugs at some point for an average duration of 12 months. There were 10 MIs (1.31/1000 PY) in the randomized phases and 19 MIs (1.63/1000 PY) in the randomized-plus-extension phases. The overall stratified relative risk of MI for PI-containing (1.82 MI/1000 PY) versus nRTI-only (1.05 MI/1000 PY) regimens of 1.69 was not significantly increased (95% confidence interval [CI], 0.54 to 7.48). The absolute difference in MI risk was +0.77 (95% CI, -0.71 to +2.26) MIs/1000 PY. Compared with NRTI-only therapy, patients receiving PI-containing regimens for an average of 1 year did not have significantly more MIs, but the upper bound of the 95% CI indicates there may be up to 2.3 additional MIs per 1000 PY. Although studies with a longer duration of PI therapy are in progress to assess whether a later increase in MI incidence occurs, our analysis did not demonstrate a dramatic increase in MI risk during the first year of PI therapy.


Effectiveness of Natural Antioxidants against SARS-CoV-2? Insights from the In-Silico World.
The SARS CoV-2 pandemic has affected millions of people around the globe. Despite many efforts to find some effective medicines against SARS CoV-2, no established therapeutics are available yet. The use of phytochemicals as antiviral agents provides hope against the proliferation of SARS-CoV-2. Several natural compounds were analyzed by virtual screening against six SARS CoV-2 protein targets using molecular docking simulations in the present study. More than a hundred plant-derived secondary metabolites have been docked, including alkaloids, flavonoids, coumarins, and steroids. SARS CoV-2 protein targets include Main protease (MPro), Papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), Spike glycoprotein (S), Helicase (Nsp13), and E-Channel protein. Phytochemicals were evaluated by molecular docking, and MD simulations were performed using the YASARA structure using a modified genetic algorithm and AMBER03 force field. Binding energies and dissociation constants allowed the identification of potentially active compounds. Ligand-protein interactions provide an insight into the mechanism and potential of identified compounds. Glycyrrhizin and its metabolite 18-β-glycyrrhetinic acid have shown a strong binding affinity for MPro, helicase, RdRp, spike, and E-channel proteins, while a flavonoid Baicalin also strongly binds against PLpro and RdRp. The use of identified phytochemicals may help to speed up the drug development and provide natural protection against SARS-CoV-2.


Posaconazole-Induced Pseudohyperaldosteronism.
A woman in her late 60s with disseminated histoplasmosis was treated with posaconazole because first-line therapies were not tolerated. She subsequently presented with decompensated heart failure, hypertension, and hypokalemia. Laboratory tests revealed low renin and aldosterone levels. A potential mechanism is inhibition of the enzyme 11β-hydroxysteroid dehydrogenase 2, with resultant apparent mineralocorticoid excess.


Chinese Ultrasound Doctors Association Guideline on Operational Standards for 2-D Shear Wave Elastography Examination of Musculoskeletal Tissues.
The Ultrasound Physician Branch of the Chinese Medical Doctor Association sought to develop evidence-based recommendations on the operational standards for 2-D shear wave elastography examination of musculoskeletal tissues. A consensus panel of 22 Chinese musculoskeletal ultrasound experts reviewed current scientific evidence and proposed a set of 12 recommendations for 13 key issues, including instruments, operating methods, influencing factors and image interpretation. A final consensus was reached through discussion and voting. On the basis of research evidence and expert opinions, the strength of recommendation for each proposition was assessed using a visual analog scale, while further emphasizing the best available evidence during the question-and-answer session. These expert consensus guidelines encourage facilitation of the standardization of clinical practices for collecting and reporting shear wave elastography data.


Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation.
Mutations in one or more genes encoding complement-regulatory proteins predispose to atypical hemolytic uremic syndrome (aHUS) and its recurrence following kidney transplantation. We evaluated plasma complement level and performed a screening for mutations in genes encoding complement Factors H and I (CFH, CFI) and membrane cofactor protein (MCP) in 24 kidney transplant recipients experiencing de novo thrombotic microangiopathy (TMA). Six patients presented with low C3 and/or low Factor B levels suggestive complement alternative pathway. A mutation in the CFH or CFI gene was found in 7/24 patients (29%), two of whom had a mutation in both genes. On the contrary, no mutation was identified in a control kidney transplant patients group (n = 25) without TMA. Patients with or without mutations were similar with regard to clinical features. Eight out of 24 patients lost their graft within 1 year of posttransplantation including six patients with a CFH mutation or a decrease of C3 or CFB in plasma. To conclude, kidney transplant patients with de novo TMA exhibit an unexpectedly high frequency of CFH and CFI mutations. These results suggest that genetic abnormalities may represent risk factors for de novo TMA after kidney transplantation and raise the question of the best therapeutic strategy.


Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.
Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.


Validity and relative validity of a novel digital approach for 24-h dietary recall in athletes.
We developed a digital dietary analysis tool for athletes (DATA) using a modified 24-h recall method and an integrated, customized nutrient database. The purpose of this study was to assess DATA's validity and relative validity by measuring its agreement with registered dietitians' (RDs) direct observations (OBSERVATION) and 24-h dietary recall interviews using the USDA 5-step multiple-pass method (INTERVIEW), respectively. Fifty-six athletes (14-20 y) completed DATA and INTERVIEW in randomized counter-balanced order. OBSERVATION (n = 26) consisted of RDs recording participants' food/drink intake in a 24-h period and were completed the day prior to DATA and INTERVIEW. Agreement among methods was estimated using a repeated measures t-test and Bland-Altman analysis. The paired differences (with 95% confidence intervals) between DATA and OBSERVATION were not significant for carbohydrate (10.1%, -1.2-22.7%) and protein (14.1%, -3.2-34.5%) but was significant for energy (14.4%, 1.2-29.3%). There were no differences between DATA and INTERVIEW for energy (-1.1%, -9.1-7.7%), carbohydrate (0.2%, -7.1-8.0%) or protein (-2.7%, -11.3-6.7%). Bland-Altman analysis indicated significant positive correlations between absolute values of the differences and the means for OBSERVATION vs. DATA (r = 0.40 and r = 0.47 for energy and carbohydrate, respectively) and INTERVIEW vs. DATA (r = 0.52, r = 0.29, and r = 0.61 for energy, carbohydrate, and protein, respectively). There were also wide 95% limits of agreement (LOA) for most method comparisons. The mean bias ratio (with 95% LOA) for OBSERVATION vs. DATA was 0.874 (0.551-1.385) for energy, 0.906 (0.522-1.575) for carbohydrate, and 0.895(0.395-2.031) for protein. The mean bias ratio (with 95% LOA) for INTERVIEW vs. DATA was 1.016 (0.538-1.919) for energy, 0.995 (0.563-1.757) for carbohydrate, and 1.031 (0.514-2.068) for protein. DATA has good relative validity for group-level comparisons in athletes. However, there are large variations in the relative validity of individuals' dietary intake estimates from DATA, particularly in athletes with higher energy and nutrient intakes. DATA can be a useful athlete-specific, digital alternative to conventional 24-h dietary recall methods at the group level. Further development and testing is needed to improve DATA's validity for estimations of individual dietary intakes.


The Tolerability and Efficacy of Oral Isotonic Solution versus Plain Water in Dengue Patients: A Randomized Clinical Trial.
Plasma leakage plays an important role in dengue infection, and this condition can lead to hemoconcentration, hypovolemia, and shock. Fluid replacement is the main treatment for dengue. There is a lack of evidence to support certain oral fluid therapy as a treatment for dengue patients. The objective of this study is to evaluate tolerability and efficacy of oral isotonic solution (OIS) compared to plain water as a fluid replacement in dengue patients. A randomized, clinical trial with single-blinded groups was conducted to compare tolerability and efficacy of OIS and plain water in dengue patients. We evaluated gastrointestinal disturbances (nausea, vomiting, and bloating), body temperature, mean arterial pressure (MAP), fluid balance, hematocrit, Na+, and K+ levels. Data were analyzed with SPSS 20.0, and figures were made with GraphPad Prism version 5.01. Twenty four subjects were included and divided equally into two groups. Our results showed that there are no significant differences but indicate several noteworthy trends. The intervention group (OIS) experienced less nausea, less vomiting, had positive fluid balance and higher MAP, and became afebrile faster compared to the control group (plain water). Although not statistically significant, this study shows the trend that OIS is well-tolerated and effective for dengue patients compared to plain water.


Spectral response characterization of an InP:Fe photorefractive wavelength-self-tunable single-sideband filter.
We report the characterization of the spectral response of a wavelength-self-tunable single-sideband filter operating at 16-GHz radio frequency. We demonstrate, for what we believe to be the first time, simultaneous generation of three dynamic Bragg gratings inside the InP:Fe photorefractive crystal of such a filter. In addition, two signal processing configurations are tested. Finally, measurements are confronted with simulations on the device, which is dedicated to chromatic dispersion compensation in fiber-radio systems.


Dead bodies matter: gift giving and the unveiling of body donor monuments in the Netherlands.
Body donors are people who voluntarily donate their entire body, after death, to anatomical science. Based on anthropological fieldwork in the Netherlands this article explores the construction of body donor monuments since 2007. These developments are analyzed by means of gift-giving theories. Body donation is a practice in which the medical and scientific value of the donor bodies has always been praised. Increasingly the fact that the bodies represent real human beings who have mourning relatives has also been acknowledged. This change in attitude has resulted in a desire on the part of anatomical professionals to give back a monument, not only for the donors themselves but also, in particular, for the donors' relatives. The great public interest in the monuments has revealed that many of the bereaved, in the absence of having the physical body of the donor, need a symbolic final resting place for their loved ones.


Distinct roles of MDMX in the regulation of p53 response to ribosomal stress.
Approximately 50% of protein and RNA synthesis in proliferating cells are devoted to ribosomal biogenesis. Coordination between ribosome biogenesis, growth, and proliferation is critical for maintenance of homeostasis and tumor suppression. Aberrant rRNA expression and processing is sensed by p53. Ribosomal stress increases the binding between MDM2 and ribosomal proteins L5, L11, and L23, resulting in p53 stabilization. Our recent study showed that p53 activation by ribosomal stress also involves degradation of MDMX in an MDM2-dependent fashion. Failure to eliminate MDMX due to overexpression results in the sequestration of p53 into inactive complexes, severely impairing p53-dependent cell cycle arrest during ribosomal stress. Furthermore, MDMX overexpression promotes resistance to the chemotherapeutic agent 5-FU, which at low concentrations activates p53 by inhibiting RNA metabolism. Therefore, MDMX is an important regulator of p53 response to ribosomal stress. MDMX overexpression in tumors may significantly influence response to chemotherapy agents that target rRNA biogenesis.


Sequencing and analysis of the internal transcribed spacers (ITSs) and coding regions in the EcoR I fragment of the ribosomal DNA of the Japanese pond frog Rana nigromaculata.
The rDNA of eukaryotic organisms is transcribed as the 40S-45S rRNA precursor, and this precursor contains the following segments: 5' - ETS - 18S rRNA - ITS 1 - 5.8S rRNA - ITS 2 - 28S rRNA - 3'. In amphibians, the nucleotide sequences of the rRNA precursor have been completely determined in only two species of Xenopus. In the other amphibian species investigated so far, only the short nucleotide sequences of some rDNA fragments have been reported. We obtained a genomic clone containing the rDNA precursor from the Japanese pond frog Rana nigromaculata and analyzed its nucleotide sequence. The cloned genomic fragment was 4,806 bp long and included the 3'-terminus of 18S rRNA, ITS 1, 5.8S rRNA, ITS 2, and a long portion of 28S rRNA. A comparison of nucleotide sequences among Rana, the two species of Xenopus, and human revealed the following: (1) The 3'-terminus of 18S rRNA and the complete 5.8S rRNA were highly conserved among these four taxa. (2) The regions corresponding to the stem and loop of the secondary structure in 28S rRNA were conserved between Xenopus and Rana, but the rate of substitutions in the loop was higher than that in the stem. Many of the human loop regions had large insertions not seen in amphibians. (3) Two ITS regions had highly diverged sequences that made it difficult to compare the sequences not only between human and frogs, but also between Xenopus and Rana. (4) The short tracts in the ITS regions were strictly conserved between the two Xenopus species, and there was a corresponding sequence for Rana. Our data on the nucleotide sequence of the rRNA precursor from the Japanese pond frog Rana nigromaculata were used to examine the potential usefulness of the rRNA genes and ITS regions for evolutionary studies on frogs, because the rRNA precursor contains both highly conserved regions and rapidly evolving regions.


Bacteria as a source of oviposition attractant for Aedes aegypti mosquitoes.
Since a safe and effective mass vaccination program against dengue fever is not presently available, a good way to prevent and control dengue outbreaks depends mainly on controlling the mosquito vectors. Aedes aegypti mosquito populations can be monitored and reduced by using ovitraps baited with organic infusions. A series of laboratory experiments were conducted which demonstrated that the bacteria in bamboo leaf infusion produce volatile attractants and contact chemical stimulants attractive to the female mosquitoes. The results showed that the female mosquitoes laid most of their eggs (59.9 ± 8.1 vs 2.9 ± 2.8 eggs, P<0.001) in bamboo leaf infusions when compared to distilled water. When the fresh infusion was filtered with a 0.45 μm filter membrane, the female mosquitoes laid significantly more eggs (64.1 ± 6.6 vs 4.9 ± 2.6 eggs, P<0.001) in unfiltered infusion. However when a 0.8 μm filter membrane was used, the female laid significantly more eggs (62.0 ± 4.3 vs 10.1 ± 7.8 eggs, P<0.001) in filtrate compared to a solution containing the residue. We also found that a mixture of bacteria isolated from bamboo leaf infusion serve as potent oviposition stimulants for gravid Aedes mosquitoes. Aedes aegypti laid significantly more eggs (63.3 ± 6.5 vs 3.1 ± 2.4 eggs, P<0.001) in bacteria suspension compared to sterile R2A medium. Our results suggest microbial activity has a role in the production of odorants that mediate the oviposition response of gravid mosquitoes.


[Dynamics of somatic and psychic manifestations in elderly patients hospitalized for a psychasthenic form of cerebral artery atherosclerosis during the course of hypolipidemic treatment].
Out of a group of patients aged 60 years and more with the diagnosis of psychasthenic form of cerebral arteriosclerosis complicated by hyperlipoproteinaemia three subgroups matched for sex, education, social class and place of residence but differing in disease duration were isolated, and three analogous subgroups were selected from healthy subjects which were regarded as controls in the statistical analysis. As the results of statistical analysis it was found that in elderly patients, taking of hypolipaemic drugs influenced evidently negatively the emotional sphere, and that short duration of neuro- and psychasthenic forms of cerebral artery atherosclerosis had greater influence on the frequency of conflicts in nearest surroundings since short duration of the disease probably made impossible full adaptation and acceptation of the disease. The attention was paid to the necessity of introduction of psychotherapy into hypolipaemic treatment.


Coherent X-ray Imaging: Bridging the Gap between Atomic and Micro-scale Investigations.
We present a review of state-of-the art X-ray imaging techniques based on partially coherent synchrotron radiation. Full-field X-ray tomography, X-ray ptychography, scanning small-angle X-ray scattering, and scanning transmission X-ray microscopy are imaging techniques that gather structural information at spatial resolution ranging from several microns to a few tens of nanometers in both real- and reciprocal space. These methods exploit contrast mechanisms based on absorption, phase, and spectroscopic signals. We provide examples of how these techniques can be applied to address scientific questions ranging from imaging of biological samples, to foam rheology, and cement composition.


Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer: Validation of a Concept Based on Blood Biomarkers.
Programs for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements. The protocol described in this paper focuses on the validation of concepts based on biomarkers in blood in a major population screened by FIT. In Part 1, participants will be identified and included through the Danish CRC Screening Program comprising initial FIT and subsequent colonoscopy to those with a positive result. Blood samples will be collected from 8000 FIT-positive participants, who are offered subsequent colonoscopy. Findings and interventions at colonoscopy together with personal data including co-morbidity will be recorded. Blood samples and data will also be collected from 6000 arbitrarily chosen participants with negative FIT. In Part 2, blood samples and data will be collected from 30,000 FIT-negative participants three times within 4 years. The blood samples will be analyzed using various in-house and commercially available manual and automated analysis platforms. We anticipate Part 1 to terminate late August 2016 and Part 2 to terminate late September 2022. The results from Parts 1 and 2 will be presented within 12 to 18 months from termination. The purpose of this study is to improve the efficacy of identifying participants with neoplastic bowel lesions, to identify false negative participants, to identify participants at risk of interval neoplastic lesions, to improve the compliance in screening sessions, and to establish guidelines for out-patient follow-up of at-risk participants based on combinations of blood-based biomarkers.


The diabetic neuropathic ulcer: an overview.
The leading cause of amputation in patients with diabetes is the nonhealing foot wound and its complications. The effects of peripheral neuropathy, peripheral vascular disease, and infection often combine to facilitate ulcer development that can lead to gangrene and amputation. In many instances, foot ulcers and amputation can be prevented. The literature over the past 5 years has included information on the infrared thermometry in the diagnosis of infection and acute Charcot change. Pressure downloading has been facilitated by computerized foot scanning systems and the use of prefabricated pneumatic walkers as an alternative to the contact cast. Local wound care is enforced by repeated sharp debridement. Nonhealing ulcers can benefit from biologicals: platelet-derived growth factors and a human dermal replacement containing viable fibroblasts. The most successful outcomes are achieved when interdisciplinary teams are formed to provide coordinated care. The goal of this article is to provide healthcare professionals with an overview of the risks of neuropathic foot injury and to offer strategies for prevention, protection, and reduction of recurrences of the diabetic foot ulcer.


Evaluation of the Og34C filter paper technique in lymphatic filariasis prevalence studies.
Currently there are several tests which can be used for monitoring and evaluating lymphatic filariasis prevalence in mass drug administration (MDA) programs with the ICT as most commonly accepted field test. However, other techniques to determine circulating antigen are available that also could be suitable in these programs. Our aim was to determine the suitability of the Og4C3 filter paper technique to determine antigen prevalence for lymphatic filariasis. We compared multiple antigen methods during the course of baseline clinical prevalence studies in Papua, New Guinea in over 800 subjects. We found that the ICT and Og4C3 filter paper techniques and using blood from the ICT card in the Og4C3 ELISA were equivalent in performance and that the serum Og4C3 ELISA test detected significantly more antigenic individuals. In addition, we found that modification of the Og4C3 assay by removing the boiling step did not affect its performance. Our results indicate that the Og4C3 filter paper technique is suitable for use in elimination of transmission of lymphatic filariasis monitoring and evaluation programs, quality control of ICT testing could be accomplished by using blood from the ICT test card, and with appropriate logistics in place, venous sampling and testing by the serum Og4C3 ELISA is achievable in monitoring and evaluation and would better identify areas with low level antigenaemia prevalence and possible ongoing transmission.


Susceptibility of the bruchid Callosobruchus maculatus (Coleoptera: Bruchidae) and its parasitoid Dinarmus basalis (Hymenoptera: Pteromalidae) to three essential oils.
The bruchid Callosobruchus maculatus (F.) causes major losses during the storage of seeds of Vigna unguiculata (Walp.) in West Africa. An endemic parasitoid, the pteromalid Dinarmus basalis (Rond.) reduces the increase in bruchid populations in stores and could be used for biological control. African farmers often introduce essential oils into granaries at harvest time. In Togo, essential oils were extracted from two Gramineae, Cymbopogon nardus (L.) and Cymbopogon schoenanthus (L.) and from a Lamiaceae, Ocimum basilicum (L.). The major components of these essential oils were citronellal in C. nardus, carene-2 and piperitone in C. schoenanthus and estragol in O. basilicum. Cymbopogon schoenanthus was the most toxic oil for C. maculatus adults. D. basalis adults were more susceptible to the three essential oils than the adults of their hosts C. maculatus. In the presence of cowpea seeds, the LC50s of the three essential oils were lower than in their absence, suggesting that the seeds may absorb a part of the volatiles. High doses of three essential oils slightly affected the survival of the fourth instar or the pupae of C. maculatus. This high survival was due to protection of larvae from volatiles by the surrounding seeds. The D. basalis were more affected by the oil volatiles than their hosts. Sub-lethal doses of essential oils reduced the duration of the adult life of both insect species and fecundity of the females. The differences in sensitivity of the host and its parasitoid could influence their population dynamics. The introduction of the essential oils into storage systems potentially could reduce density of parasitoid populations and increase seed losses.


[Semeiotics of incipient forms of vascular diseases of the brain and their diagnosis during preventive examinations of the population].
Using formalized documentation and computerized techniques, the authors analyzed clinical, electrophysiological, and biochemical semiotics in 2180 individuals--healthy subjects, patients with subclinical and initial manifestations of cerebral circulation insufficiency, initial dyscirculatory encephalopathy developing in the presence of neurocirculatory dystonias, atherosclerosis, and arterial hypertension. The author has established characteristics of the semiotics which depend on the nature of the underlying vascular disease, the stage of the process and the patient's age. Tabulated methods and a computerized system of the diagnosis of cerebrovascular disease have been developed. They are based on the employment of a bank of clinical and physiological information used for prophylactic examinations and population screening. The social, medical and economic effectiveness of the proposed methods of the diagnosis and prevention of cerebrovascular diseases allows their recommendation for wide introduction into health care practice.


ABCDP: Approximate Bayesian Computation with Differential Privacy.
We developed a novel approximate Bayesian computation (ABC) framework, ABCDP, which produces differentially private (DP) and approximate posterior samples. Our framework takes advantage of the sparse vector technique (SVT), widely studied in the differential privacy literature. SVT incurs the privacy cost only when a condition (whether a quantity of interest is above/below a threshold) is met. If the condition is sparsely met during the repeated queries, SVT can drastically reduce the cumulative privacy loss, unlike the usual case where every query incurs the privacy loss. In ABC, the quantity of interest is the distance between observed and simulated data, and only when the distance is below a threshold can we take the corresponding prior sample as a posterior sample. Hence, applying SVT to ABC is an organic way to transform an ABC algorithm to a privacy-preserving variant with minimal modification, but yields the posterior samples with a high privacy level. We theoretically analyzed the interplay between the noise added for privacy and the accuracy of the posterior samples. We apply ABCDP to several data simulators and show the efficacy of the proposed framework.


Prenatal diagnosis of beta-thalassemias by amniocentesis: linkage analysis using multiple polymorphic restriction endonuclease sites.
In order to assess the applicability of multiple restriction endonuclease analyses of amniocyte DNA to the prenatal diagnosis of beta-thalassemias in general, we studied 12 consecutive couples at risk. DNA of both members of the 12 couples and a previous offspring of each was analyzed for the presence of 4 polymorphic restriction endonuclease sites: the Hpa I site 3' to the beta-globin gene, the Hind III site in the G gamma gene, the Hind III site in the A gamma gene, and the Bam HI site 3' to the beta-gene. Linkage disequilibrium between these sites and beta A or beta thal genes was not found, presumably due to the heterogeneity of beta thal genes. However, the high frequency of polymorphism at these sites allowed differentiation of beta A-bearing chromosomes from beta thal or beta S-bearing chromosomes in both members of 6 couples. In these couples, complete prenatal diagnosis by linkage analysis of amniocyte DNA would be possible. In the remaining 6 couples, beta A and beta thal chromosomes could be discriminated in one member. In about 50% of the pregnancies of these couples, exclusion of beta-thalassemia is possible by this analysis. These data suggest that when linkage analysis of polymorphic restriction endonuclease sites is carried out, prenatal diagnosis of beta-thalassemia states can be accomplished by amniocentesis alone in 75% of pregnancies at risk.


Runaway sexual selection when female preferences are directly selected.
We introduce models for the runaway coevolution of female mating preferences and male display traits. The models generalize earlier results by allowing for direct natural selection on the preference, arbitrary forms of mate choice, and fairly general assumptions about the underlying genetics. Results show that a runaway is less likely when there is direct selection on the preference, but that it is still possible if there is a sufficiently large phenotypic correlation between the female's preference and the male's trait among mated pairs. Comparison of three preference functions introduced by Lande (1981) shows that open-ended preferences are particularly prone to a runaway, and that absolute preferences require very large differences between females in their preferences. We analyze the causes of the runaway seen in a model developed by Iwasa and Pomiankowski (1995).


Quantifying the efficiency and selectivity of organohalide dechlorination by zerovalent iron.
The efficiency and selectivity of zerovalent iron-based treatments for organohalide contaminated groundwater can be quantified by accounting for redistribution of electrons derived from oxidation of Fe0. Several types of efficiency are reviewed, including (i) the efficiency of Fe(0) utilization, εFe(0), (ii) the electron efficiency of target contaminant reduction, εe, and (iii) the electron efficiency of natural reductant demand (NRD) involving H2O, O2, and co-contaminants such as nitrate, εNRD. Selectivity can then be calculated by using εe/εNRD. Of particular interest is εe and the key to its determination is measuring the total quantity of electrons provided by Fe0 oxidation, which can be based on either the loss of Fe(0), the formation of Fe(ii)/Fe(iii), or the composition of the total reaction products. Recently, many data have accumulated on εe for the treatment of various chlorinated solvents (esp. trichloroethylene, TCE) by zerovalent iron (ZVI), and analysis of these data shows that ZVI particle properties (e.g., stabilization with polymers, bimetallic modification, sulfidation, etc.) and other operational factors have variable effects on εe. Of particular interest is that pre-exposure of ZVI to reduced sulfur species (i.e., sulfidation) consistently improves the εe of contaminant reduction, mainly by suppressing the reduction of water.


Preparedness to care for victims of violence and their families in emergency departments.
To describe the preparedness to provide care for victims of violence and their families in emergency departments (EDs) in Sweden. A web-based questionnaire was sent to all hospital EDs in Sweden (N=66). A total of 46 out of 66 (70%) heads of EDs completed the questionnaire. The results show that most of the EDs are prepared to care for women and children who are victims of violence. However, there seems to be a lack of preparedness to care for other groups of patients, such as victimised men. Very few EDs have routines to identify victims of violence among patients. Results also indicate that nurses play a key role in the care for victims of violence; however, family members are rarely included in care. A lack of general preparedness in EDs to care for all victims of violence, regardless of gender and age, can lead to many patients not receiving appropriate care and treatment. To correct this there is a need to implement guidelines and routines about the care for victims of violence. Further research can shed more light on which measures are needed to improve quality of care for these patients and their families.


High-current stimuli to the spared epicardium of a large infarct induce ventricular tachycardia.
Previous studies have demonstrated that both ventricular tachycardia (VT) and ventricular fibrillation (VF) may begin as figure-eight reentry: VT with a longer cycle length from spared tissue adjacent to an infarct by programmed stimulation and VF with a shorter cycle length from noninfarcted tissue by a large premature S2 stimulus. These results suggest that the type of tissue or cycle length of the arrhythmia rather than the mode of induction determines whether the figure eight becomes sustained VT or degenerates into VF. Thus, a protocol similar to that by which a VF threshold is determined may induce VT rather than VF when performed in the spared tissue over an infarct. In 10 dogs, 4 days after occlusion-reperfusion of the left anterior descending coronary artery, 10 S1 stimuli were delivered from a total of 34 right and left ventricular sites outside the infarct. An epicardial S2 stimulus over the infarct was increased in 10-mA steps and introduced in diastole at decreasing cycle lengths of 5 msec until VT or VF was induced. Sustained monomorphic figure-eight VT was induced from 24 S1 sites and VF from nine (p = 0.03). The mean cycle lengths for the initial six arrhythmic cycles was 152 +/- 33 msec for VT and 115 +/- 13 msec for VF (p less than 0.001). Mean transmural infarct extent was 80% in five dogs with only VT, 63% in three dogs with both VT and VF, and 15% in two dogs with only VF. Different morphologies of VT were induced by changing the S1 site, the S2 strength, or the S1S2 coupling interval. In 25 of the 34 arrhythmias, the central part of the initial figure-eight pathway was oriented opposite the S1 activation sequence in that region. A large S2 stimulus over a nontransmural infarct induces VT if the spared myocardium is thin. This study introduces a useful technique for inducing sustained monomorphic VT in which the location and direction of the figure-eight pathway are known a priori and in which different morphologies of sustained VT can be produced by changing the S1 site.


Amblyomma sculptum ticks on a giant otter from the Brazilian Pantanal.
The giant otter (Pteronura brasiliensis) is a semiaquatic carnivore and a top predator in the trophic chain, considered a sentinel of freshwater ecosystems. Ticks are common ectoparasites of worldwide distribution and potential vectors of diseases. In this study, we report the ectoparasitism by ticks on a giant otter carcass found during monitoring activity at the Negro River, that holds a viable population of this endangered species in the Brazilian Pantanal. A total of three tick specimens were collected: two adults were identified as Amblyomma sculptum and a nymph as Amblyomma spp. There is a lack of information about the health of free-ranging giant otters and this report contributes to elucidate some of the host-parasite relationships, although much more research is needed to expand the knowledge about which kinds of pathogens are circulating in the species, especially among those transmitted by ticks.


ALK rearrangement testing by FISH analysis in non-small-cell lung cancer patients: results of the first italian external quality assurance scheme.
The Italian Association of Medical Oncology and the Italian Society of Anatomic Pathology and Diagnostic Cytopathology organized an external quality assessment (EQA) scheme for anaplastic lymphoma kinase (ALK) rearrangement by florescence in situ hybridization (FISH) analysis in non-small-cell lung cancer (NSCLC). Sections from tissue microarrays, each including 10 NSCLC samples with known ALK status, were first validated in five referral laboratories and then provided to 37 participating centers. The laboratories were requested to perform the FISH test, using their usual protocols, and to complete the analysis within 3 weeks. By using a predefined scoring system, two points were assigned in case of correct genotype and zero points to false-negative or false-positive results. The threshold value to pass the EQA scheme was set at 18 points. Two rounds were planned. Thirty-four centers submitted the results within the established deadline. Several errors in the evaluation of genotype (n = 18) were reported, with both false-positive (n = 7) and false-negative (n = 11) results. Test failure occurred in seven cases. Two samples were found to be critical by two referral laboratories and seven participating centers. Twenty-six (70%) laboratories passed the first round and six the second round. Overall, 32 (86%) laboratories passed the ALK EQA scheme. The results of this first EQA scheme for ALK testing in NSCLC cancer patients indicate that ALK analysis is performed with adequate quality in most Italian laboratories and highlight the importance of EQA in revealing methodological problems that need to be addressed to further increase the reproducibility of molecular tests.


Assessing Condom Use and Views on HIV Counselling and Testing among TVET College Students in Limpopo Province, South Africa.
South Africa's population is predominantly young, presenting a powerful resource for the country. Despite this, adolescents and young people remain at the epicentre of the HIV epidemic, particularly adolescent girls and young women (AGYW). There are limited studies that investigate the views on HIV Counselling and Testing (HCT) and condom use among adolescents and young people, and college students in particular, in South Africa. This cross-sectional study assessed condom use among college students and their views and opinions on HCT. Utilising an adapted questionnaire from the Australian Secondary students and the South African Sexual Health survey, the data from 396 students were analysed using univariate and multiple logistic regression performed using Stata IC version 16. The majority of the students (n = 339, 85.8%) had a sexual partner at the time of the study. Our findings reveal a relatively high occurrence of condom use in the last sexual encounter (n = 225, 60%) and high HCT uptake (n = 50, 88.4%). Females were generally more comfortable regarding HIV services compared to their male counterparts. More than half, 54.6% vs. 36.0% were comfortable about testing, 34.0% vs. 48.3% felt very scared about testing for HIV, 3.6% vs. 10.1% reported that they were not ready to take an HIV test, 7.6% vs. 5.6% intended getting tested soon (p = 0.0002). Condom use was significantly associated with the use of a condom during the first sexual encounter (aOR = 4.71, 95% CI: 2.14, 10.37) and knowing their partner's HIV status (aOR = 2.08, 95% CI: 1.19-3.65). The HCT and condom promotion strategies implemented by Higher Health in TVET colleges is showing success and colleges in other parts of the region could emulate these best practices. Program developers should consider tailor-made combinations of prevention interventions that would appeal to both female and male college students to improve condom use and uptake of HIV testing services.


Accuracy and repeatability of long-bone replicas of small animals fabricated by use of low-end and high-end commercial three-dimensional printers.
OBJECTIVE To assess the repeatability and accuracy of polymer replicas of small, medium, and large long bones of small animals fabricated by use of 2 low-end and 2 high-end 3-D printers. SAMPLE Polymer replicas of a cat femur, dog radius, and dog tibia were fabricated in triplicate by use of each of four 3-D printing methods. PROCEDURES 3-D renderings of the 3 bones reconstructed from CT images were prepared, and length, width of the proximal aspect, and width of the distal aspect of each CT image were measured in triplicate. Polymer replicas were fabricated by use of a high-end system that relied on jetting of curable liquid photopolymer, a high-end system that relied on polymer extrusion, a triple-nozzle polymer extrusion low-end system, and a dual-nozzle polymer extrusion low-end system. Polymer replicas were scanned by use of a laser-based coordinate measurement machine. Length, width of the proximal aspect, and width of the distal aspect of the scans of replicas were measured and compared with measurements for the 3-D renderings. RESULTS 129 measurements were collected for 34 replicas (fabrication of 1 large long-bone replica was unsuccessful on each of the 2 low-end printers). Replicas were highly repeatable for all 3-D printers. The 3-D printers overestimated dimensions of large replicas by approximately 1%. CONCLUSIONS AND CLINICAL RELEVANCE Low-end and high-end 3-D printers fabricated CT-derived replicas of bones of small animals with high repeatability. Replicas were slightly larger than the original bones.


A new pathway for salvaging the coenzyme B12 precursor cobinamide in archaea requires cobinamide-phosphate synthase (CbiB) enzyme activity.
The ability of archaea to salvage cobinamide has been under question because archaeal genomes lack orthologs to the bacterial nucleoside triphosphate:5'-deoxycobinamide kinase enzyme (cobU in Salmonella enterica). The latter activity is required for cobinamide salvaging in bacteria. This paper reports evidence that archaea salvage cobinamide from the environment by using a pathway different from the one used by bacteria. These studies demanded the functional characterization of two genes whose putative function had been annotated based solely on their homology to the bacterial genes encoding adenosylcobyric acid and adenosylcobinamide-phosphate synthases (cbiP and cbiB, respectively) of S. enterica. A cbiP mutant strain of the archaeon Halobacterium sp. strain NRC-1 was auxotrophic for adenosylcobyric acid, a known intermediate of the de novo cobamide biosynthesis pathway, but efficiently salvaged cobinamide from the environment, suggesting the existence of a salvaging pathway in this archaeon. A cbiB mutant strain of Halobacterium was auxotrophic for adenosylcobinamide-GDP, a known de novo intermediate, and did not salvage cobinamide. The results of the nutritional analyses of the cbiP and cbiB mutants suggested that the entry point for cobinamide salvaging is adenosylcobyric acid. The data are consistent with a salvaging pathway for cobinamide in which an amidohydrolase enzyme cleaves off the aminopropanol moiety of adenosylcobinamide to yield adenosylcobyric acid, which is converted by the adenosylcobinamide-phosphate synthase enzyme to adenosylcobinamide-phosphate, a known intermediate of the de novo biosynthetic pathway. The existence of an adenosylcobinamide amidohydrolase enzyme would explain the lack of an adenosylcobinamide kinase in archaea.


Using survey results to improve the validity of the standard psychiatric nomenclature.
Measuring the validity of psychiatric diagnoses is still an unsolved problem. Yet, revisions of the Diagnostic and Statistical Manual of Mental Disorders and of chapter V of the International Classification of Diseases are now under way, with the hope of improving the validity of the current systems. This article suggests data that could be used to assist in this goal. This article has 3 objectives. (1) To show that although the validity of the interview protocols used in collecting epidemiologic survey data has not itself been proven, the data banks they have collected are well suited to raising questions about the validity of the existing diagnostic nomenclature. This is the case because they faithfully operationalize the current nomenclature in large interview studies of diverse general populations. (2) To show the kinds of changes that appropriate analysis of these data may suggest as ways to improve the validity of the nomenclature. (3) To show how suggested changes that emerge from such analyses should be tested to learn whether they actually improve validity before they are implemented. The data sets from large epidemiologic studies have hardly been tapped for testing the validity of the current nomenclature. It is feasible to use them for this purpose because they are in the public domain and because they assess the presence or absence of each of the criteria in the manuals before applying the manuals' algorithms for combining them to make a diagnosis. Thus, these data banks allow exploration of the effects of combining and splitting diagnoses, of omitting criteria or reweighting them, and of choosing altered algorithms with respect to age at onset, number of symptoms, and duration of episodes. Assessing the consequences of these alterations can be tested by applying some of the criteria of Robins and Guze and Kendell.


Comparative effects of different animal and vegetable fats fed before and during carcinogen administration on mammary tumorigenesis, sexual maturation, and endocrine function in rats.
The purpose of this investigation was to determine whether diets high in animal or vegetable fat affected mammary tumorigenesis when fed to rats only prior to and during the initiation phase of carcinogenesis. Weanling 21-day-old female Sprague-Dawley rats were divided into different dietary treatment groups and were allowed to feed and libitum on one of the following diets: 5% (normal fat) corn oil; 20% (high fat) corn oil; 20% palm oil; 20% beef tallow; or 20% lard. At 52 days of age, all rats were given p.o. 7.5 mg 7,12-dimethylbenz(a)anthracene (DMBA). One week following DMBA administration, all rats were switched to the 5% corn oil control diet and were maintained on this diet for the duration of the experiment. Rats fed a 20% lard diet during the treatment period showed a significant increase in mammary tumor incidence and number 19 weeks after DMBA administration, when compared to all other dietary treatment groups. Rats fed a 20% beef tallow diet during this same time period also demonstrated enhanced mammary tumor development, during the 10- to 19-week time period after DMBA. Mammary tumor development in rats fed 20% corn oil or palm oil diets during this treatment period was similar to that of normal fat controls. Estrogens are potent stimulators of mammary tumor growth and development in rats. Because mammary tumorigenesis was enhanced in rats fed high animal, but not vegetable fat diets, it was possible that estrogens present in animal fat might be responsible for this stimulation. Further studies demonstrated however, that increased mammary tumorigenesis in rats fed diets high in animal fat could not be explained on the basis of endocrine stimulation. Average day of vaginal opening for all groups fed 20% fat diets was similar and occurred earlier than in normal fat controls. In addition, 50- to 65-day-old rats in the different dietary treatment groups showed no differences in basal or surge levels of serum prolactin, luteinizing hormone, or estradiol. Rat diestrus uterine weight also showed no significant differences among dietary treatment groups. Thus diets containing high levels of animal fat caused little if any increased estrogenic activity in rats. In conclusion, high dietary intake of lard and beef tallow, but not vegetable fat, fed from weaning until only 1 week after DMBA administration, significantly enhances mammary tumorigenesis in rats. The mechanism(s) by which animal fat induces this stimulation is not clear, but it does not appear to result from endogenous or exogenous endocrine stimulation.


Tomato SlMKK2 and SlMKK4 contribute to disease resistance against Botrytis cinerea.
Mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling modules that mediate the transduction of extracellular stimuli via receptors/sensors into intracellular responses and play key roles in plant immunity against pathogen attack. However, the function of tomato MAPK kinases, SlMKKs, in resistance against Botrytis cinerea remains unclear yet. A total of five SlMKK genes with one new member, SlMKK5, were identified in tomato. qRT-PCR analyses revealed that expression of SlMKK2 and SlMKK4 was strongly induced by B. cinerea and by jasmonic acid and ethylene precursor 1-amino cyclopropane-1-carboxylic acid. Virus-induced gene silencing (VIGS)-based knockdown of individual SlMKKs and disease assays identified that SlMKK2 and SlMKK4 but not other three SlMKKs (SlMKK1, SlMKK3 and SlMKK5) are involved in resistance against B. cinerea. Silencing of SlMKK2 or SlMKK4 resulted in reduced resistance to B. cinerea, increased accumulation of reactive oxygen species and attenuated expression of defense genes after infection of B. cinerea in tomato plants. Furthermore, transient expression of constitutively active phosphomimicking forms SlMKK2DD and SlMKK4DD in leaves of Nicotiana benthamiana plants led to enhanced resistance to B. cinerea and elevated expression of defense genes. VIGS-based knockdown of SlMKK2 and SlMKK4 expression in tomato and gain-of-function transient expression of constitutively active phosphomimicking forms SlMKK2DD and SlMKK2DD in N. benthamiana demonstrate that both SlMKK2 and SlMKK4 function as positive regulators of defense response against B. cinerea.


Automatic method for the dermatological diagnosis of selected hand skin features in hyperspectral imaging.
Hyperspectral imaging has been used in dermatology for many years. The enrichment of hyperspectral imaging with image analysis broadens considerably the possibility of reproducible, quantitative evaluation of, for example, melanin and haemoglobin at any location in the patient's skin. The dedicated image analysis method proposed by the authors enables to automatically perform this type of measurement. As part of the study, an algorithm for the analysis of hyperspectral images of healthy human skin acquired with the use of the Specim camera was proposed. Images were collected from the dorsal side of the hand. The frequency λ of the data obtained ranged from 397 to 1030 nm. A total of 4'000 2D images were obtained for 5 hyperspectral images. The method proposed in the paper uses dedicated image analysis based on human anthropometric data, mathematical morphology, median filtration, normalization and others. The algorithm was implemented in Matlab and C programs and is used in practice. The algorithm of image analysis and processing proposed by the authors enables segmentation of any region of the hand (fingers, wrist) in a reproducible manner. In addition, the method allows to quantify the frequency content in different regions of interest which are determined automatically. Owing to this, it is possible to perform analyses for melanin in the frequency range λE∈(450,600) nm and for haemoglobin in the range λH∈(397,500) nm extending into the ultraviolet for the type of camera used. In these ranges, there are 189 images for melanin and 126 images for haemoglobin. For six areas of the left and right sides of the little finger (digitus minimus manus), the mean values of melanin and haemoglobin content were 17% and 15% respectively compared to the pattern. The obtained results confirmed the usefulness of the proposed new method of image analysis and processing in dermatology of the hand as it enables reproducible, quantitative assessment of any fragment of this body part. Each image in a sequence was analysed in this way in no more than 100 ms using Intel Core i5 CPU M460 @2.5 GHz 4 GB RAM.


Amblyopia: a multidisciplinary approach. Proctor lecture.
Clinically different forms of amblyopia share as common denominators an inability to form well-defined and focused images in one or both eyes and, in the case of unilateral amblyopia, unequal visual input to the brain. This suggests two amblyopiogenic mechanisms which are effective, individually or in unison, in the various forms of amblyopia. The first is lack of adequate visual stimulation during infancy, causing visual deprivation. The second mechanism is based on abnormal binocular interaction. The clinical evidence and data from the animal laboratory will be reviewed in support of this dual etiological concept of amblyopia. An etiological classification of amblyopia suggested in 1972 on hypothetical grounds can be upheld on the basis of information that has accumulated since that time. Amblyopia is not a static condition but has a strong dynamic component since its severity can be modified by the type of stimulation received by the sound eye. Special emphases is placed in this lecture on this unique feature which is based on binocular interaction and is similar to the inhibition of afferent visual stimulation during suppression.


Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5.
Metabotropic glutamate receptors (mGluRs) 1-8 are G protein-coupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca(2+) signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca(2+) oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.


Distribution of chicken anaemia virus in the reproductive tissues of specific-pathogen-free chickens.
The specific-pathogen-free (SPF) flocks of chickens maintained by the Department of Microbiology and Immunology at Cornell University became infected, inadvertently, with chicken anaemia virus (CAV), as demonstrated by seroconversion. Chickens from five flocks representing three different strains were examined for the presence of CAV using nested PCR. Virus was detected in ovaries, infundibula, vas deferentia, testes and spleens. Ovaries were positive in 38 to 72% of the hens in four flocks with 13 to 56 birds examined per flock. Interestingly, the ovaries were often the only positive tissues, while a few hens had only positive spleens. In roosters, the vas deferens was positive in 30 to 79% of the birds with 5 to 19 birds examined per flock; the vas deferens was the only positive tissue in 20 to 37%. Individual cells in the theca externa and rare epithelial cells in the infundibular epithelium were positive for CAV by in situ PCR. Positive cells were not detected in testes or vas deferentia. The SH-1 strain of CAV was isolated from these tissues and partially sequenced. Only minor sequence differences were found compared to CIA-1 and Cux-1. Embryos from matings between persistently infected dams and sire had CAV-positive cells in mesenchyme near the developing vertebral column. The data show that CAV persists in the reproductive tissues far longer than previously thought, and that it can be vertically transmitted from persistently infected birds.


Clinical and molecular heterogeneity in brazilian patients with sotos syndrome.
Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).


Effects of Neighboring Phosphorylation Events on the Affinities of pT181-Tau Antibodies.
A tau variant phosphorylated on threonine 181 (pT181-tau) has been widely investigated as a potential Alzheimer's disease (AD) biomarker in cerebrospinal fluid (CSF) and blood. pT181-tau is present in neurofibrillary tangles (NFTs) of AD brains, and CSF levels of pT181-tau correlate with the overall NFT burden. Various immunobased analytical methods, including Western blotting and ELISA, have been used to quantify pT181-tau in human biofluids. The reliability of these methods is dependent on the affinity and binding specificity of the antibodies used to measure pT181-tau levels. Although both of these properties could, in principle, be affected by phosphorylation within or near the antibody's cognate antigen, such effects have not been extensively studied. Here, we developed a biolayer interferometry assay to determine the degree to which the affinity of pT181-tau antibodies is altered by the phosphorylation of serine or threonine residues near the target epitope. Our results revealed that phosphorylation near T181 negatively affected the binding of pT181-tau antibodies to their cognate antigen to varying degrees. In particular, two of three antibodies tested showed a complete loss of affinity for the pT181 target when S184 or S185 was phosphorylated. These findings highlight the importance of selecting antibodies that have been thoroughly characterized in terms of affinity and binding specificity, addressing the potential disruptive effects of post-translational modifications in the epitope region to ensure accurate biomarker quantitation.


Cardiology residents' attitudes towards clinical supervision: a multi-centered study.
Residents' gender, residency level, and hospital types might influence their attitudes towards clinical supervision (CS); however, reports of its impact on cardiology residency are nonexistent. We explore the effect of gender, residency level, and hospital location's effect on Indonesian cardiology trainees' attitudes towards CS. A multi-centered, cross-sectional study was conducted. We invited 490 Indonesian cardiology residents in September- October 2019 to complete the Cardiology CS Scale. Residents' attitudes, gender, university, and residency year were expressed using descriptive statistics. A Mann-Whitney test analyzed the gender and university location effect on residents' attitudes. Training year and university's impact were subjected to the Kruskal-Wallis test; a p-value of <0.05 reflected a significant result. A total of 388 residents agreed to participate (response rate=79.18%). Most of them were male (n=229 [59,02%]), attended universities in Java Island (n=262 [67,52%]), and were in their 2nd-3rd year of training (n=95 [24.48%], each). There were no significant differences in residents' attitudes between genders (U [Nmale=229, Nfemale=159]=17,908.50, z=-0.27, p=0.78). Generally, their attitudes were significantly affected by the university (H(7)=47.38, p<0.01). However, the university location (located in Java Island or outside Java Island) does not affect residents' attitude towards CS (U [NJava=262, Nnon-Java=126]=15,237.00, z=-1.23, p=0.22). In addition, the residents' training year also affected the residents' response (H(2)=14.278, p<0.01). Cardiology residents' attitudes towards CS are significantly influenced by training year and university but not gender or university location. The results might provide insightful information for further improvement of CS in cardiology training and guide further evaluation.


A proposal to transfer Microbispora bispora (Lechevalier 1965) to a new genus, Thermobispora gen. nov., as Thermobispora bispora comb. nov.
We determined almost complete 16S rRNA gene sequences of two Microbispora bispora (Lechevalier 1965) strains, ATCC 19993T (T = type strain) and JCM 3082. The two sequences were 99% similar to each other but exhibited only 81 to 87.8% similarity with the 16S rRNA gene sequences of seven other Microbispora strains. A phylogenetic analysis revealed that the two sequences clustered not only distantly from other Microbispora strains, but also outside the cluster containing members of the family Streptosporangiaceae. On the basis of the results of our phylogenetic analysis and the results of a comprehensive review of the genus Microbispora by Miyadoh et al. (S. Miyadoh, S. Amano, H. Tohyama, and T. Shomura, J. Gen. Microbiol. 136:1905-1913, 1990) in which chemotaxonomic and DNA-DNA hybridization analyses were performed, we propose that Microbispora bispora should be transferred to a new genus, Thermobispora gen. nov., as Thermobispora bispora comb. nov.


New asymptotics for old wave equations.
Wave equations govern the propagation of acoustical or optical fields in diverse physical settings of interest to oceanographers, geologists, atmospheric scientists, among others. For wavelengths much smaller than all other length scales in the system the wave equation solution is generally expressed as a superposition of waveforms, each of which is determined by properties of the rays of geometrical acoustics or optics. Typically such solutions are accurate except in the vicinity of one or another caustic surface such as those defined as a surface across which a jump in the number of rays tracing through each point occurs. When numerous caustic surfaces exist, which is the generic situation, standard asymptotic solutions prove unsuitable. In this report a new asymptotic expression that overcomes deficiencies in previous approximations is introduced and characterized in an elementary way.


Naturally occurring modified ribonucleosides.
The chemical identity of RNA molecules beyond the four standard ribonucleosides has fascinated scientists since pseudouridine was characterized as the "fifth" ribonucleotide in 1951. Since then, the ever-increasing number and complexity of modified ribonucleosides have been found in viruses and throughout all three domains of life. Such modifications can be as simple as methylations, hydroxylations, or thiolations, complex as ring closures, glycosylations, acylations, or aminoacylations, or unusual as the incorporation of selenium. While initially found in transfer and ribosomal RNAs, modifications also exist in messenger RNAs and noncoding RNAs. Modifications have profound cellular outcomes at various levels, such as altering RNA structure or being essential for cell survival or organism viability. The aberrant presence or absence of RNA modifications can lead to human disease, ranging from cancer to various metabolic and developmental illnesses such as Hoyeraal-Hreidarsson syndrome, Bowen-Conradi syndrome, or Williams-Beuren syndrome. In this review article, we summarize the characterization of all 143 currently known modified ribonucleosides by describing their taxonomic distributions, the enzymes that generate the modifications, and any implications in cellular processes, RNA structure, and disease. We also highlight areas of active research, such as specific RNAs that contain a particular type of modification as well as methodologies used to identify novel RNA modifications. This article is categorized under: RNA Processing > RNA Editing and Modification.


Continuous figure-of-eight suturing in upper and lower gastrointestinal anastomosis.
The optimal technique for gastrointestinal anastomosis is controversial. The three most popular techniques are two layers, one layer and the stapling method. However, there is no universal agreement on the best technique. The aim of this study was to evaluate the safety, feasibility, and efficacy of continuous figure-of-eight suturing in gastrointestinal anastomosis. This was a retrospective study of 170 patients who underwent gastrointestinal anastomosis using continuous figure-of-eight suturing for the first layer and continuous seromuscular suturing for the second layer from August 1993 to January 2006. All operations were performed by a single consultant surgeon. We assessed each anastomosis by checking the integrity, vascularity and patency, and also ensuring tension-free status. Postoperatively, patients were managed by routine care of intravenous fluids and nasogastric tube until they had active bowel sounds and started absorbing. Imaging was arranged for patients who developed clinical signs and symptoms of leak. 170 patients underwent gastrointestinal anastomosis by continuous figure-of-eight suturing for different pathologies over a two-and-a-half-year period. There were 92 (54.1 percent) men and 78 (45.9 percent) women. The mean age of the patients was 56 (range 20-88) years. The median follow-up was 74 months. There were 124 (72.9 percent) small bowel anastomosis and 46 (27.1 percent) large bowel anastomosis. An important complication after gastrointestinal anastomosis was leakage, which was reported in three (1.8 percent) patients. One of them had gastric cancer, one had Crohn's disease and one had intestinal ischaemia. No mortality was reported in relation to anastomotic failure. Two (1.2 percent) patients developed stenosis and 15 (8.8 percent) patients died because of progression of their disease or other pathologies during the follow-up. Continuous figure-of-eight suturing is a simple, easy to learn, safe and satisfactory upper and lower gastrointestinal anastomosis technique.


Sniping Cancer Stem Cells with Nanomaterials.
Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.


Oncologists' reflections on patient rights and access to compassionate use drugs: A qualitative interview study from an academic cancer center.
The U.S. Food and Drug Administration (FDA) allows patients with serious illnesses to access investigational drugs for "compassionate use" outside of clinical trials through expanded access (EA) Programs. The federal Right-to-Try Act created an additional pathway for non-trial access to experimental drugs without institutional review board or FDA approval. This removal of oversight amplifies the responsibility of physicians, but little is known about the role of practicing physicians in non-trial access to investigational drugs. We undertook semi-structured interviews to capture the experiences and opinions of 21 oncologists all with previous EA experience at a major cancer center. We found five main themes. Participants with greater EA experience reported less difficulty accessing drugs through the myriad of administrative processes and drug company reluctance to provide investigational products while newcomers reported administrative hurdles. Oncologists outlined several rationales patients offered when seeking investigational drugs, including those with stronger health literacy and a good scientific rationale versus others who remained skeptical of conventional medicine. Participants reported that most patients had realistic expectations while some had unrealistic optimism. Given the diverse reasons patients sought investigational drugs, four factors-scientific rationale, risk-benefit ratio, functional status of the patient, and patient motivation-influenced oncologists' decisions to request compassionate use drugs. Physicians struggled with a "right-to-try" framing of patient access to experimental drugs, noting instead their own responsibility to protect patients' best interest in the uncertain and risky process of off-protocol access. This study highlights the willingness of oncologists at a major cancer center to pursue non-trial access to experimental treatments for patients while also shedding light on the factors they use when considering such treatment. Our data reveal discrepancies between physicians' sense of patients' expectations and their own internal sense of professional obligation to shepherd a safe process for patients at a vulnerable point in their care.


Induction of apoptosis by retinoids and retinoic acid receptor gamma-selective compounds in mouse thymocytes through a novel apoptosis pathway.
Retinoic acids are morphogenic signaling molecules that are derived from vitamin A and involved in a variety of tissue functions. Two groups of their nuclear receptors have been identified: retinoic acid receptors (RARs) and retinoic acid X receptors (RXRs). All-trans retinoic acid is the high affinity ligand for RARs, and 9-cis retinoic acid also binds to RXRs with high affinity. In cells at high concentrations, all-trans retinoic acid can be converted to 9-cis retinoic acid via unknown mechanisms. It was previously shown that retinoic acids prevents activation-induced death of thymocytes. Here, we report that both all-trans and 9-cis retinoic acid induce apoptosis of mouse thymocytes and purified CD4+CD8+ cells in ex vivo cultures, with 9-cis retinoic acid being 50 times more effective. The induction of apoptosis by retinoic acids is mediated by RARgamma because (a) the phenomenon can be reproduced only by RARgamma-selective retinoic acid analogs, (b) the cell death induced by either retinoic acids or RARgamma analogs can be inhibited by RARgamma-specific antagonists, and (c) CD4+CD8+ thymocytes express RARgamma. In vivo administration of an RARgamma analog resulted in thymus involution with the concomitant activation of the apoptosis-related endonuclease and induction of tissue transglutaminase. The RARgamma pathway of apoptosis is RNA and protein synthesis dependent, affects the CD4+CD8+ double positive thymocytes, and can be inhibited by the addition of either Ca2+ chelators or protease inhibitors. Using various RAR- and RXR-specific analogs and antagonists, it was demonstrated that stimulation of RAR alpha inhibits the RARgamma-specific death pathway (which explains the lack of apoptosis stimulatory effects of all-trans retinoic acid at physiological concentrations) and that costimulation of the RXR receptors (in the case of 9-cis retinoic acid) can neutralize this inhibitory effect. It is suggested that formation of 9-cis retinoic acid may be a critical element in regulating both the positive selection and the "default cell death pathway" of thymocytes.