[Clinical observation of Cookgas intubating laryngeal airway in anticipating difficult tracheal intubation].
To compare the clinical effects of Cookgas intubating laryngeal airway (CILA) in facilitating fiberoptic bronchoscope (FOB) and Shikani optical stylet (SOS)-guided intubations in anticipating difficult tracheal intubation. Totally 60 anticipated difficult tracheal intubation patients undergoing selective plastic surgery under general anesthesia were allocated to FOB group (n = 30) and SOS group (n = 30). After anesthesia induction and CILA insertion, the patients were treated with FOB or SOS-guided intubation via CILA. The time of intubation and CILA removal and the time and the success rate of CILA insertion were recorded. Noninvasive blood pressure and heart rate were recorded before and after anesthesia induction at CILA insertion, at intubation, at CILA removal, and every minute thereafter for 5 minutes. CILA was inserted successfully in all patients. The first intubation attempt succeeded in all but two who succeeded in the second and the third attempt respectively in FOB group. In SOS group, 18 patients were successfully intubated in the first attempt, and 7 patients were successfully intubated in the second attempt; SOS failed in 5 patients with severe cervical scars, and then FOB was successfully used to intubate. The time of the intubation [(60.2 +/- 29.6) vs. (92.4 +/- 47.9)s] and CILA removal [(104.6 +/- 39.9) vs. (130.0 +/- 51.9) s] in SOS group were significantly longer than in FOB group (P < 0.05). Hemodynamic changes during the intubation with CILA in these two groups were minimal. FOB and SOS-guided tracheal intubation via CILA is safe and effective in anticipating the outcome of difficult airway management. Compare to SOS-guided intubation, the time of FOB-guided intubation is shorter and the success rate is higher.


Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways.
Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose 3 hub key events (KEs) for use in AOP network development. Each event, "tissue resident cell activation", "increased pro-inflammatory mediators", and "leukocyte recruitment/activation," is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub KEs, it was possible to link together a series of AOPs that previously had no shared KEs. Significant challenges remain with regard to accurate prediction of inflammation-related toxicological outcomes even if a broader and more connected network of inflammation-centered AOPs is developed. Nonetheless, the current proposal addresses one of the major hurdles associated with representation of inflammation in AOPs and may aid fit-for-purpose evaluations of other AOPs operating in a network context.


[Philosophical perspectives about the use of technology in critical care nursing].
The context of health assistance has been influenced by changes which are produced in the dimension of technology. They have triggered a lot of inquietude and questioning regarding benefits, risks, and relations constructed among workers and sick, and the use of machines as indispensable tools for care. This paper aims at reflecting on the use of technology in nursing care given to the critical sick in the intensive care unit. It is expected that this reflection can minimize doubts which permeate technological environments, such as the intensive care unit, and the conceptions of nursing care since it involves the use of machines and equipment which provide advanced life support in this field of health assistance.


The impact of under coding of cardiac severity and comorbid diseases on the accuracy of hospital report cards.
Hospital report cards usually are based on administrative discharge abstracts. However, cardiac severity and comorbidities generally are under-reported in administrative data. We sought to determine how undercoding of cardiac severity and comorbidities affects the determination that some hospitals are high-mortality outliers. Simulations using retrospective data on 18,795 patients admitted with an acute myocardial infarction (AMI) to 109 acute care hospitals in Ontario. Change in the number of hospitals that remained high-mortality outliers after adjusting for potentially increased prevalence of as many as 9 separate measures of cardiac severity and comorbid conditions, individually or together. For most measures of cardiac severity and comorbidities, increasing the prevalence of each factor to the highest observed hospital-specific prevalence seldom altered the status of high-mortality outlier hospitals. Increases in the prevalence of cardiogenic shock or acute renal failure to even the median level led to reclassification of up to 4 of the 12 high-mortality outlier hospitals to nonoutlier status. Most high-mortality outlier hospitals were reclassified if the maximum prevalence was imputed for these 2 factors. Simultaneously increasing the prevalence of all comorbidities to the median level typically converted the status of about half the outlier hospitals. Not until the prevalence of all measures of cardiac severity and comorbidities were simultaneously increased to the maximum observed hospital-specific prevalence, did all hospitals initially classified as high-mortality outliers revert to nonoutlier status. Undercoding of severity and comorbidities in administrative data in itself is very unlikely to account for the outlier status of most hospitals. However, some potential for misclassification of individual institutions exists if influential factors are variably coded.


Streptococcus pneumoniae: an old bug with significant maternal-newborn implications.
Streptococcus pneumoniae is an uncommon organism identified in neonatal bacteremia, but when it occurs, it has serious implications for both the infant and the mother. Despite the similarities in the manifestations between group B streptococcus and S. pneumoniae sepsis, the latter appears to be more virulent and of marked severity, resulting in significant neonatal mortality. In the absence of a routine maternal screening protocol for S. pneumoniae colonization, aggressive newborn management constitutes the mainstay of treatment.


Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy.
Cancer is the second leading cause of death and is becoming the leading one in old age. Vegetable and fruit consumption is inversely associated with cancer incidence and mortality. Currently, interest in a number of fruits high in polyphenols has been raised due to their reported chemopreventive and/or chemotherapeutic potential. Pomegranate has been shown to exert anticancer activity, which is generally attributed to its high content of polyphenols. This review provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of pomegranate polyphenols as future anticancer agents. Pomegranate evokes antiproliferative, anti-invasive, and antimetastatic effects, induces apoptosis through the modulation of Bcl-2 proteins, upregulates p21 and p27, and downregulates cyclin-cdk network. Furthermore, pomegranate blocks the activation of inflammatory pathways including, but not limited to, the NF-κB pathway. The strongest evidence for its anticancer activity comes from studies on prostate cancer. Accordingly, some exploratory clinical studies investigating pomegranate found a trend of efficacy in increasing prostate-specific antigen doubling time in patients with prostate cancer. However, the genotoxicity reported for pomegranate raised certain concerns over its safety and an accurate assessment of the risk/benefit should be performed before suggesting the use of pomegranate or its polyphenols for cancer-related therapeutic purposes.


Skin conductance reflects drug-induced changes in blood levels of cortisol, adrenaline and noradrenaline in dogs.
To verify availability of skin conductance (SC) as an indicator for the sympathetic nervous system (SNS) activity in dogs, the changes in SC and blood levels of stress-related hormones induced by drugs were compared. SC and cortisol, adrenaline and noradrenaline levels were measured in 5 dogs on 4 occasions with or without drug-induced sedation at 7-day intervals (no treatment, intramuscular medetomidine 0.01 mg/kg, intramuscular acepromazine 0.1 mg/kg and intravenous fentanyl 0.02 mg/kg). The fentanyl treatment produced significantly higher levels of SC and plasma cortisol and adrenaline compared with the other 3 treatments. The plasma noradrenaline level also tended to be higher following the fentanyl treatment. These results indicate that SC may reflect changes in the SNS activities in dogs.


Aspects of crystal structure prediction: some successes and some difficulties.
Attention is called to some little-discussed aspects of crystal structure prediction. It is pointed out that the structures of metal-organic frameworks can often be correctly predicted. This allows designed synthesis of materials with targeted pore size and functionality. For more-conventional inorganic materials, predicting the lowest energy state can be made difficult by two problems. First, the difference in energy between competing structures can be very small. Second, the unit cells of materials with simple compositions may be very large. Examples are given for both cases.


Ecological biomechanics of benthic organisms: life history, mechanical design and temporal patterns of mechanical stress.
We can gain biomechanical insights if we couple knowledge of the environments, ecological roles and life history strategies of organisms with our laboratory analyses of their mechanical function or fluid dynamics, as illustrated by studies of the mechanical design of bottom-dwelling marine organisms. Obviously, measurements of the spatial and temporal distribution of loads on an organism in nature reveal the magnitudes and rates at which biomechanical tests should be performed in the laboratory. Furthermore, knowledge of the population biology and ecological interactions of the organisms being studied is crucial to determine when during the life of an individual particular aspects of mechanical performance should be measured; not only can the size, shape and material properties of an individual change during ontogeny, but so can its habitat, activities and ecological role. Such ecological information is also necessary to determine whether the aspects of mechanical performance being studied are biologically important, i.e. whether they affect the survivorship or fitness of the organisms. My point in raising these examples is to illustrate how ecological studies can enhance or change our understanding of biomechanical function.


[The black widow spider--its appearance and control].
Between 1995 and 2002, a massive appearance of black widow (Latrodectus mactans tredecimguttatus, Rossi 1790) was recorded along the Croatia coast. This paper gives a historical review of latrodectism and observations from Istria and Dalmatia, paying particular attention to the spider's habitat. There are several reasons for the black widow to appear in a new habitat such as the introduction of leguminous plants, watermelons and melons where crops were grown earlier. Black widow can also be found near buildings and gardens. Human contacts with the spider are usually without consequences for humans, thanks to education and a relatively good visibility of the spider. The authors describe their experience in fighting black widow and emphasise the importance of education in preventing lactrodectism.


Discrimination of saccharides with a fluorescent molecular imprinting sensor array based on phenylboronic acid functionalized mesoporous silica.
A fluorescent indicator-displacement molecular imprinting sensor array based on phenylboronic acid functionalized mesoporous silica was developed for discriminating saccharides. D-Fructose imprinted material (FruIM), D-xylose imprinted material (XylIM) together with a control blank nonimprinted material (NIM) were synthesized as the elements of the imprinting sensor array. Spectrofluorimetric titrations of the three materials with eight selected saccharides were carried out, and Stern-Volmer quenching constants (K(SV)) of NIM, FruIM, and XylIM with the eight selected saccharides were obtained to investigate the interaction of the materials with saccharides. The present approach couples molecular imprinting technique to indicator-displacement strategy with the use of one conventional saccharide receptor (phenylboronic acid) and one commercially available fluorescent dye (Alizarin Red S., ARS) as the indicator, and allows identifying two template saccharides (D-fructose and D-xylose) plus eight nontemplate saccharides (D-arabinose, D-glucose, D-galactose, D-mannose, L-sorbose, D-ribose, L-rhamnose and sucrose). The principal component analysis (PCA) plot shows a clear discrimination of the 10 tested saccharides at 100 mM and the first principal component possesses 94.8% of the variation. Besides, the developed saccharide imprinted sensor array is successfully applied to discriminating three brands of orange juice beverage.


Connectomic reconstruction predicts the functional organization of visual inputs to the navigation center of the Drosophila brain.
Many animals, including humans, navigate their surroundings by visual input, yet we understand little about how visual information is transformed and integrated by the navigation system. In Drosophila melanogaster , compass neurons in the donut-shaped ellipsoid body of the central complex generate a sense of direction by integrating visual input from ring neurons, a part of the anterior visual pathway (AVP). Here, we densely reconstruct all neurons in the AVP using FlyWire, an AI-assisted tool for analyzing electron-microscopy data. The AVP comprises four neuropils, sequentially linked by three major classes of neurons: MeTu neurons, which connect the medulla in the optic lobe to the small unit of anterior optic tubercle (AOTUsu) in the central brain; TuBu neurons, which connect the anterior optic tubercle to the bulb neuropil; and ring neurons, which connect the bulb to the ellipsoid body. Based on neuronal morphologies, connectivity between different neural classes, and the locations of synapses, we identified non-overlapping channels originating from four types of MeTu neurons, which we further divided into ten subtypes based on the presynaptic connections in medulla and postsynaptic connections in AOTUsu. To gain an objective measure of the natural variation within the pathway, we quantified the differences between anterior visual pathways from both hemispheres and between two electron-microscopy datasets. Furthermore, we infer potential visual features and the visual area from which any given ring neuron receives input by combining the connectivity of the entire AVP, the MeTu neurons' dendritic fields, and presynaptic connectivity in the optic lobes. These results provide a strong foundation for understanding how distinct visual features are extracted and transformed across multiple processing stages to provide critical information for computing the fly's sense of direction.


Hydrogen storage in a highly interpenetrated and partially fluorinated metal-organic framework.
A partially fluorinated metal-organic framework, Zn(bpe)(tftpa)·cyclohexanone [bpe = 1,2-bis(4-pyridyl)ethane; tftpa = tetrafluoroterephthalate], has been synthesized, and its H2 storage properties are reported. The structure is highly interpenetrated yet contains templating cyclohexanone molecules, which can be easily removed to give a porous material with fluorine atoms exposed to the pore surface. The material adsorbs 1.04 wt % H2 at 77 K and 1 atm with an adsorption enthalpy (Qst) of 6.2 kJ/mol, which represents a slight enhancement in the binding strength due to the presence of fluorine atoms over comparable metal-organic frameworks, which bind through purely physisorptive methods.


Baicalein protects isoproterenol induced myocardial ischemic injury in male Wistar rats by mitigating oxidative stress and inflammation.
The aim of the present study was to investigate the cardioprotective effects of baicalein, main bioactive constituent from roots of Scutellaria baicalensis and Scutellaria lateriflora, on isoproterenol (ISO) induced acute myocardial infarction model in rats and to explore the underlying mechanisms. Rats were treated with baicalein (50 mg/kg and 100 mg/kg) orally for 14 days and on 13th and 14th day, myocardial injury was induced by ISO injection (100 mg/kg, subcutaneous) at an interval of 24 h. Our study showed that ISO administration resulted in significant elevations in the levels of cardiac injury biomarkers such as cardiac troponin I, creatine kinase-MB, AST and ALT. Concentrations of reactive nitrogen species and reactive oxygen species in the heart tissue increased significantly while antioxidant enzymes level declined. The levels of tissue pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6 were significantly increased after ISO administration. Pretreatment with baicalein significantly reversed these alterations induced by ISO administration. Exploration of the underlying mechanisms of protective effect of baicalein pretreatment revealed that it repressed the expression of nuclear factor kappa B and restored the ISO induced elevation of pro-inflammatory cytokines, oxidative and nitrosative stress. We found that baicalein pretreatment enhanced the level of antioxidant defense enzymes like SOD, catalase and GSH. Furthermore, the present study also demonstrated cardioprotective effects of baicalein by the histopathological findings. Taken together, our findings demonstrated that baicalein pretreatment might have a potential benefit in prevention and terminating ischemic heart diseases like myocardial infarction.


Characterization of the fibronectin synthesized by human germ cell tumors.
The ability of the human germ cell tumor cell lines Tera 1, Tera 2, PA-1, LICR LON HT 39/7, LICR LON HT3B1, and LICR LON HT 53 to synthesize and secrete fibronectin has been studied. The presence of cellular fibronectin was examined using indirect immunofluorescence, whereas the synthesis and secretion of the protein were studied using specific immunoprecipitation from cultures radioactively labeled with [35S]methionine. Two of the cell lines, LICR LON HT 39/7 and Tera 1, did not synthesize fibronectin, whereas all the other cell lines did. Plasma membrane fibronectin could not be demonstrated on any of the cell lines, although cytoplasmic fibronectin was easily demonstrable. The cells appear therefore to synthesize fibronectin but not retain it. Sodium dodecyl sulfate:polyacrylamide gel electrophoresis of the secreted fibronectin produced by the human teratoma cell lines showed that it had an apparent molecular weight greater than that produced by adult human breast fibroblasts or human plasma fibronectin. Peptide mapping of this secreted germ cell tumor fibronectin, by partial proteolytic cleavage, yielded peptide patterns similar to those obtained from either human plasma fibronectin or adult human breast fibroblast fibronectin. The difference in molecular weight between the fibronectins may therefore be due to changes in their patterns of glycosylation.


Applying Lean Six Sigma to Improve Depression Screening and Follow-Up in Oncology Clinics.
Depression is a common and serious illness that impairs the health of individuals and societies globally. It is associated with a significant economic burden, with productivity losses exceeding $40 billion dollars annually in the United States (U.S.) alone. This project focused on the use of a systematic, data-driven approach to improve the screening rate for depression in an academic, metropolitan cancer center located in North Texas. A multidisciplinary team collaboratively applied Lean Six Sigma education, methods, and tools within oncology and psychiatry clinics to address the increased risk of depression among oncology patients. Improving the standardization of screening and follow-up processes, resulted in a 44% sustained increase in the depression screening and follow-up performance rate. This improvement was verified to be statistically significant through the use of control charts toward the end of the project.


MPK6, sphinganine and the LCB2a gene from serine palmitoyltransferase are required in the signaling pathway that mediates cell death induced by long chain bases in Arabidopsis.
Long chain bases (LCBs) are sphingolipid intermediates acting as second messengers in programmed cell death (PCD) in plants. Most of the molecular and cellular features of this signaling function remain unknown. We induced PCD conditions in Arabidopsis thaliana seedlings and analyzed LCB accumulation kinetics, cell ultrastructure and phenotypes in serine palmitoyltransferase (spt), mitogen-activated protein kinase (mpk), mitogen-activated protein phosphatase (mkp1) and lcb-hydroxylase (sbh) mutants. The lcb2a-1 mutant was unable to mount an effective PCD in response to fumonisin B1 (FB1), revealing that the LCB2a gene is essential for the induction of PCD. The accumulation kinetics of LCBs in wild-type (WT) and lcb2a-1 plants and reconstitution experiments with sphinganine indicated that this LCB was primarily responsible for PCD elicitation. The resistance of the null mpk6 mutant to manifest PCD on FB1 and sphinganine addition and the failure to show resistance on pathogen infection and MPK6 activation by FB1 and LCBs indicated that MPK6 mediates PCD downstream of LCBs. This work describes MPK6 as a novel transducer in the pathway leading to LCB-induced PCD in Arabidopsis, and reveals that sphinganine and the LCB2a gene are required in a PCD process that operates as one of the more effective strategies used as defense against pathogens in plants.


Free microvascular fibular transfer for idiopathic femoral head necrosis: long-term follow-up.
The authors discuss free microvascular bone transfers in general, and propose a new classification for idiopathic femoral head necrosis. They then present a technique they have been using for 11 years, with the goals of providing both mechanical support and an improved blood supply to the femoral head. This technique involves clearing the necrotic area of the femoral head, filling the area with cancellous bone taken from the greater and lesser trochanters, and transferring a fibular microvascular graft. The approach is transtrochanteric and spares the capsule. Vascular anastomosis is done with the lateral branches of the deep femoral artery, sparing the anterior circumflex artery which is important to the blood supply of the femoral head. Forty-five cases have been surgically managed over 11 years. Eighteen cases with follow-up longer than five years were analyzed, providing an 84 percent successful outcome with both very good and good results.


Exploring an EAP writing teacher's adaptive expertise and adaptive teaching practices from a CDST perspective.
Teachers' adaptive expertise (TAE) has received increasing attention in the current English as foreign language (EFL) teaching field, however, it has seldom been examined with adaptive practices by teachers in on-going classes among existing literature. Adopting a mixed-method design with data triangulation, this study was conducted to explore the complexity of teachers' adaptive expertise (TAE) and adaptive teaching practices that an EAP writing teacher demonstrated in academic writing courses, from a Complex Dynamic Systems Theory (CDST) perspective. Semi-structured interviews, classroom observations, and questionnaires were arranged to collect qualitative and quantitative data from an EAP writing teacher and 43 EFL learners in a Chinese university. Thematic analysis and SPSS were mainly used in the current work for data analysis. Our findings confirmed (1) the complexity of TAE and ATP with specific features of non-linearity, interconnectedness, and self-organization, which are classic CDST characteristics; (2) the TAE evolved with meta-cognitive, cognitive, affective and social components that are intertwined and contributed to the teacher's adaptive teaching practices (ATP) in her academic writing course; (3) being facilitated by TAE, the teacher's adaptive teaching practices significantly enhanced EFL learners, learning motivation of academic writing and their learning efficiency. Findings of the current work pave the way for future studies in researching TAE and ATP with a thorough consideration of language teachers, students and contexts from the CDST perspective. Moreover, pedagogical contributions are highlighted through the detailed examinations of the EAP writing teacher's ATP, including the class design, teaching plans, and methods, which would be fruitful for the development of tertiary EAP writing research.


Antioxidant activities of extracts from Barkleyanthus salicifolius (Asteraceae) and Penstemon gentianoides (Scrophulariaceae).
Various extracts of the aerial parts of Barkleyanthus salicifolius (Asteraceae) and Penstemon gentianoides (Scrophulariaceae) have been used in folk medicine to treat many ailments, particularly inflammation and migraine. Neither the bioactive components responsible nor the mechanisms involved have been evaluated. Here are reported antioxidant activities of their methanol, dichloromethane, and ethyl acetate extracts. Samples were evaluated for oxygen radical absorption capacity (ORAC), ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging, and inhibition of the formation of thiobarbituric acid reactive species (TBARS), a measure of lipid peroxidation. Antioxidant activities were strongly correlated with total polyphenol content. The most active extracts from P. gentianoides in scavenging DPPH radicals and inhibiting TBARS formation were the methanol extract (A) and a further ethyl acetate extract of this (E). Partition E was further divided into eight fractions, and both E and the fractions were compared for activity against butylated hydroxytoluene, quercetin, and tocopherol. Partition E and the most active fractions, 5 and 6, were found to have I(50) values of 14.1, 38.6, and 41.8 ppm, respectively, against DPPH and 18.5, 26.0, and 12.7 ppm, respectively, against TBARS formation. Consistent with this finding, partition E and fractions 4-6 had the greatest ORAC and FRAP values. These results show that these plants could be useful antioxidant sources.


DynaMiTES - A dynamic cell culture platform for in vitro drug testing PART 2 - Ocular DynaMiTES for drug absorption studies of the anterior eye.
In the present study, a formerly designed Dynamic Micro Tissue Engineering System (DynaMiTES) was applied with our prevalidated human hemicornea (HC) construct to obtain a test platform for improved absorption studies of the anterior eye (Ocular DynaMiTES). First, the cultivation procedure of the classic HC was slightly adapted to the novel DynaMiTES design. The obtained inverted HC was then compared to classic HC regarding cell morphology using light and scanning electron microscopy, cell viability using MTT dye reaction and epithelial barrier properties observing transepithelial electrical resistance and apparent permeation coefficient of sodium fluorescein. These tested cell criteria were similar. In addition, the effects of four different flow rates on the same cell characteristics were investigated using the DynaMiTES. Because no harmful potential of flow was found, dynamic absorption studies of sodium fluorescein with and without 0.005%, 0.01% and 0.02% benzalkonium chloride were performed compared to the common static test procedure. In this proof-of-concept study, the dynamic test conditions showed different results than the static test conditions with a better prediction of in vivo data. Thus, we propose that our DynaMiTES platform provides great opportunities for the improvement of common in vitro drug testing procedures.


Improving Mobility Performance in Wheelchair Basketball.
This study aimed to investigate which characteristics of athlete, wheelchair and athlete-wheelchair interface are the best predictors of wheelchair basketball mobility performance. A total of 60 experienced wheelchair basketball players performed a wheelchair mobility performance test to assess their mobility performance. To determine which variables were the best predictors of mobility performance, forward stepwise linear regression analyses were performed on a set of 33 characteristics, including 10 athlete, 19 wheelchair, and 4 athlete-wheelchair interface characteristics. A total of 8 of the characteristics turned out to be significant predictors of wheelchair basketball mobility performance. Classification, experience, maximal isometric force, wheel axis height, and hand rim diameter-which both are interchangeable with each other and wheel diameter-camber angle, and the vertical distance between shoulder and rear wheel axis-which was interchangeable with seat height-were positively associated with mobility performance. The vertical distance between the front seat and the footrest was negatively associated with mobility performance. With this insight, coaches and biomechanical specialists are provided with statistical findings to determine which characteristics they could focus on best to improve mobility performance. Six out of 8 predictors are modifiable and can be optimized to improve mobility performance. These adjustments could be carried out both in training (maximal isometric force) and in wheelchair configurations (eg, camber angle).


Gastric conduit-preserving, radical pancreaticoduodenectomy with microvascular reconstruction for pancreatic head cancer after esophagectomy: report of a case.
Pancreaticoduodenectomy is a radical treatment for pancreatic head cancer. However, it is sometimes difficult to perform pancreaticoduodenectomy, particularly in patients who have previously undergone esophagectomy with gastric conduit reconstruction. We herein describe a surgical technique for radical pancreaticoduodenectomy with microvascular reconstruction that preserves the gastric conduit. A 72-year-old male with a previous history of esophagectomy and gastric conduit reconstruction for esophageal cancer was referred to our hospital for surgical treatment of advanced pancreatic head cancer. After considering both the cancer curability and preservation of the gastric conduit, we performed a standard pancreaticoduodenectomy, and added a microvascular anastomosis of the gastroduodenal artery to the right gastroepiploic artery. In addition, we also performed reconstruction of the right gastroepiploic vein. This radical pancreaticoduodenectomy with microvascular reconstruction was safely and successfully performed, and it preserved the gastric conduit. The 6-month follow-up showed recurrence-free survival and a good quality of life.


Liquid chromatographic-electrospray tandem mass spectrometric determination of clarithromycin in human plasma.
A rapid, sensitive and specific LC-MS-MS method has been developed for the determination of clarithromycin (CLA) in human plasma using roxithromycin (ROX) as the internal standard. Samples were prepared via liquid-liquid extraction with methyl tert-butyl ether (MTBE) and chromatographed on a Supelco RP(18) (4.6 x 50 mm, 3 microm particle size) column with a mobile phase consisting of acetonitrile:methanol:60 mM (pH 3.5) ammonium acetate buffer (32.5:32.5:35) at a constant flow rate of 0.8 mL/min. The run time was 3 min with retention times of approximately 1.65 and 1.70 min for CLA and ROX, respectively. Detection was performed on a PE Sciex API 365 mass spectrometer equipped with a turboionspray ionization source in multiple reaction monitoring (MRM) mode. The MRM pairs were m/z 748.5 --> m/z 158.2 for CLA and m/z 837.7 --> m/z 679.3 for ROX, respectively, with dwell times of 200 ms for each transition. The validated calibration curve range was 5.00-5000 ng/mL, based on 0.100 mL plasma sample volume with signal-to-noise ratio (S/N) greater than 60 for CLA at the lower limit of quantification level (5.00 ng/mL). The correlation coefficients (r(2)) of the calibration curves were better than or equal to 0.996. The inter-day (n = 18) precision and accuracy of the quality control (QC) samples were less than 3.58% RSD (relative standard deviation) and -10.8% bias, respectively. The intra-day (n = 6) precision and accuracy of the quality control samples were less than 5.0 and 12.6%, respectively. There was no significant deviation from the nominal values after a 10-fold dilution of high concentration QC samples using blank matrix. The QC samples were stable when left on the bench for 24 h or after three freeze-thaw cycles. The processed samples were also stable in HPLC autosampler at 10C for over 72 h. No matrix ionization suppression was observed when extracted blank matrix or reconstitution solvent was injected onto the system with post-column infusion of clarithromycin and roxithromycin. No carryover was observed when an extracted blank plasma sample was injected immediately after a 5000 ng/mL ULOQ (the upper limit of quantification) standard. The mean recovery was 81.5 and 78.3%, respectively, for clarithromycin and internal standard.


[Diathermic endoscopic retrograde cholangiography].
The endoscopic retrograde cholangiography through an artificially formed suprapapillary choledochoduodenal fistula was used in 66 patients with different diseases of bile ducts, liver and pancreas. The results have shown that this method should be recommended after failure of retrograde endoscopic cholangiopancreatography performed by the routine technique.


Impacts of evidence-based quality improvement on depression in primary care: a randomized experiment.
Previous studies testing continuous quality improvement (CQI) for depression showed no effects. Methods for practices to self-improve depression care performance are needed. We assessed the impacts of evidence-based quality improvement (EBQI), a modification of CQI, as carried out by 2 different health care systems, and collected qualitative data on the design and implementation process. Evaluate impacts of EBQI on practice-wide depression care and outcomes. Practice-level randomized experiment comparing EBQI with usual care. Six Kaiser Permanente of Northern California and 3 Veterans Administration primary care practices randomly assigned to EBQI teams (6 practices) or usual care (3 practices). Practices included 245 primary care clinicians and 250,000 patients. Researchers assisted system senior leaders to identify priorities for EBQI teams; initiated the manual-based EBQI process; and provided references and tools. EVALUATION PARTICIPANTS: Five hundred and sixty-seven representative patients with major depression. Appropriate treatment, depression, functional status, and satisfaction. Depressed patients in EBQI practices showed a trend toward more appropriate treatment compared with those in usual care (46.0% vs 39.9% at 6 months, P = .07), but no significant improvement in 12-month depression symptom outcomes (27.0% vs 36.1% poor depression outcome, P = .18). Social functioning improved significantly (mean score 65.0 vs 56.8 at 12 months, P = .02); physical functioning did not. Evidence-based quality improvement had perceptible, but modest, effects on practice performance for patients with depression. The modest improvements, along with qualitative data, identify potential future directions for improving CQI research and practice.


Use of a clinical model for safe management of patients with suspected pulmonary embolism.
The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. To determine the safety of a clinical model for patients with suspected pulmonary embolism. Prospective cohort study. Five tertiary care hospitals. 1239 inpatients and outpatients with suspected pulmonary embolism. A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.


Retinal ganglion cells resistant to advanced glaucoma: a postmortem study of human retinas with the carbocyanine dye DiI.
The present study was conducted to examine whether the morphology of the retinal ganglion cells is altered in advanced glaucoma. Perikaryal, axonal, and dendritic alterations were monitored in glaucoma-resistant retinal ganglion cells by postvitam application of the fluorescent dye DiI. The retinas of four amaurotic glaucomatous eyes and four normal eyes enucleated after death were used in this study. The retinas were freed from surrounding tissue, prepared as flatmounts on a nitrocellulose filter, and fixed overnight in 4% paraformaldehyde. The retinal ganglion cells were labeled by introducing crystals of the fluorescent carbocyanine dye DiI, into the optic fiber layer. This dye diffuses along membranes of ganglion cell axons, completely labeling them and their cell bodies and dendrites. Further characterization of the retinas and optic nerves included hematoxylin-eosin and van Gieson histochemical staining as well as immunohistochemistry against glial fibrillary acidic protein. Because of the advanced stage of the disease, the retinas were almost completely depleted of ganglion cells, which had degenerated and therefore could not be stained. The few remaining ganglion cells were considered to be resistant to glaucoma. They showed drastic morphologic alterations, such as abnormal axonal beading, the cell bodies were normal in size but had irregular silhouettes or swellings, and there were fewer dendritic bifurcations. The size of the dendritic trees was smaller, implicating pruning of smaller dendritic branches. Glial cells were also detected immunocytochemically indicating their involvement in the pathologic course of glaucoma. The data suggest that the few ganglion cells that survive the elevated intraocular pressure associated with loss of visual function display morphologic changes that are manifested both on the cell body and on their intraretinal processes, including axons and dendrites.


A Phylogenetic Analysis of Behavioral Neuro-ontogeny in Precocial and Nonprecocial Mammals.
Studies of the postnatal development of two groups of mammals are discussed in relation to behavioral change correlated with neurophysiological and anatomical data. The precocial mammals include especially the ruminants (sheep, cow; also horse and guineapig) while the nonprecocial mammals, which require a long period of nursing, include man and the primates, carnivores and rodents. Common features of certain neurological aspects of development are closely compared in this latter group to emphasize the importance of selected age studies to give correlative data from a wide variety of altricious species. For example, the relative age of a 1-2 week old mouse is equivalent to a 3-4 week old dog or 3 months in man in some behavioral features. The postnatal development of these several species is closely paralleled, but common features of the mother-offspring relationship, especially in dog and man, are not seen in the precocial mammals which are physiologically more independent at birth. These observations indicate that in the field of comparative medicine there is much to contribute by interpolating and extrapolating correlative data from different species. Some of this data in the neurologic field has been brought together in this paper, for especially in developmental and pediatric studies it is desirable to have cross-species data on relative postnatal ages in relation to the degree of maturity of the organism.


Photosynthetic performance and biochemical adjustments in two co-occurring Mediterranean evergreens, Quercus ilex and Arbutus unedo, differing in salt-exclusion ability.
The responses to mild root zone salinity stress were investigated in two co-occurring Mediterranean woody evergreens, Quercus ilex L. and Arbutus unedo L., which differ in morpho-anatomical traits and strategies to cope with water deficit. The aim was to explore their strategies to allocate potentially toxic ions at organism level, and the consequential physiological and biochemical adjustments. Water and ionic relations, gas exchange and PSII performance, the concentration of photosynthetic pigments, and the activity of antioxidant defences, were measured. Q. ilex displayed a greater capacity to exclude Na+ and Cl- from the leaf than A. unedo, in part as a consequence of greater reductions in transpiration rates. Salt-induced reductions in CO2 assimilation resulted in Q. ilex suffering from excess of light to a greater extent than A. unedo. Consistently, in Q. ilex effective mechanisms of nonphotochemical quenching, also sustained by the lutein epoxide-lutein cycle, operated in response to salinity stress. Q. ilex also displayed a superior capacity to detoxify reactive oxygen species (ROS) than A. unedo. Our data suggest that the ability to exclude salt from actively growing shoot organs depends on the metabolic cost of sustaining leaf construction, i.e. species-specific leaf life-span, and the relative strategies to cope with salt-induced water stress. We discuss how contrasting abilities to restrict the entry and transport of salt in sensitive organs relates with species-specific salt tolerance.


Prognostic significance of urothelial carcinoma with divergent differentiation in upper urinary tract after radical nephroureterectomy without metastatic diseases: A retrospective cohort study.
To evaluate the impact of urothelial carcinoma with divergent differentiation (UCDD) on the prognosis of patients for primary upper urinary tract urothelial carcinoma (UTUC) with pN0/x status treated with radical nephroureterectomy (RNU) and to evaluate the prognostic value of UCDD in different tumor locations (renal pelvis and ureter).Data from a total of 346 patients with UTUC who received RNU between January 2012 and March 2016 in the institution were retrospectively analyzed. Clinicopathological features and prognostic factors age, sex, complaint, height, weight, blood pressure, tumor grade, stage, smoking status, history of adjuvant chemotherapy, tumor location, history of bladder cancer, tumor necrosis, degree of hydronephrosis, tumor size, tumor focality, and preoperative anemia were compared between patients with pure UTUC and patients with UCDD. The endpoints were cancer-specific survival (CSS), overall survival (OS), and intraluminal recurrence-free survival (IRFS).Overall, divergent differentiation was present in 50 patients (14.5%). UCDD was related to different tumor location (P = .01), smoking (P = .04), higher body mass index (P = .02), and advanced tumor grade (P = .01). By Kaplan-Meier analysis, UCDD was found to be significantly correlated with worse IRFS, CSS, and OS (all P < .01). Multivariate analysis demonstrated that UCDD was an independent predictor of IRFS (P < .01), CSS (P = .01), and OS (P = .01). However, 40 patients died for various reasons and the 5-year OS rates were 91.9% in UCDD- group and 68.0% in UCDD+ group, respectively. In patients with ureteral tumors, UCDD was the significant predictor for IRFS, CSS, and OS. However, the prognostic value of UCDD was not observed in pyelocaliceal tumors.The presence of divergent differentiation is associated with inferior survival. UCDD may identify patients at high risks for poor prognosis especially in patients with ureteral tumors. As a result, more attention and follow-up should be given to patients with ureteric urothelial carcinoma.


Late-Stage Halogenation of Peptides, Drugs and (Hetero)aromatic Compounds with a Nucleophilic Hydrazide Catalyst.
Unlike its other halogen atom siblings, chlorination of a bioactive compound can change its physiological characteristics, improve its pharmacological profile, and function as a point of diversification through cross-coupling reactions. As a result, it has been a crucial strategy for drug discovery and development. However, functional groups such as amines, amides, hydroxy groups, or carboxylic acids trap the Cl+ , severely limiting the reactivity and making direct chlorination far too difficult to be practical. Herein, we introduce a nucleophilic sulfonohydrazide catalyst for late-stage halogenation of peptides and drugs. This direct, mild and metal-free protocol shows high functional-group tolerance and is compatible with a range of structurally diverse peptides, drugs and aromatic compounds. Furthermore, DFT studies indicate that the reaction most likely proceeds via a cationic transition state. The gram-scale synthesis, high stability and efficiency of the catalyst provide a facile route for late-stage functionalization and intermediates for further derivatization.


Use of impact fees to incentivize low-impact development and promote compact growth.
Low-impact development (LID) is an innovative stormwater management strategy that restores the predevelopment hydrology to prevent increased stormwater runoff from land development. Integrating LID into residential subdivisions and increasing population density by building more compact living spaces (e.g., apartment homes) can result in a more sustainable city by reducing stormwater runoff, saving infrastructural cost, increasing the number of affordable homes, and supporting public transportation. We develop an agent-based model (ABM) that describes the interactions between several decision-makers (i.e., local government, a developer, and homebuyers) and fiscal drivers (e.g., property taxes, impact fees). The model simulates the development of nine square miles of greenfield land. A more sustainable development (MSD) scenario introduces an impact fee that developers must pay if they choose not to use LID to build houses or apartment homes. Model simulations show homeowners selecting apartment homes 60% or 35% of the time after 30 years of development in MSD or business as usual (BAU) scenarios, respectively. The increased adoption of apartment homes results from the lower cost of using LID and improved quality of life for apartment homes relative to single-family homes. The MSD scenario generates more tax revenue and water savings than does BAU. A time-dependent global sensitivity analysis quantifies the importance of socioeconomic variables on the adoption rate of apartment homes. The top influential factors are the annual pay rates (or capital recovery factor) for single-family houses and apartment homes. The ABM can be used by city managers and policymakers for scenario exploration in accordance with local conditions to evaluate the effectiveness of impact fees and other policies in promoting LID and compact growth.


Harnessing the immunotherapeutic potential of T-lymphocyte co-signaling molecules in transplantation.
Alloantigen-specific T-cell triggered immunopathological events are responsible for rapid allograft rejection. The co-signaling pathways orchestrated by co-stimulatory and co-inhibitory molecules are critical for optimal T-cell effector function. Therefore, selective blockade of pathways that control T-cell immunity may offer an attractive therapeutic strategy to manipulate cell mediated allogenic responses. For example, CD28, CTLA-4 and CD154 receptor blockade have proven beneficial in maintaining T-cell tolerance against transplanted organs in experimental animal models as well as in clinical trials. Conversely, induction of co-inhibitory molecules may result in suppressed effector function. There are several other potential molecules that are known to induce immune tolerance are currently under consideration for clinical studies. In this review, we provide a comprehensive and updated analysis of co-stimulatory and co-inhibitory molecules, their therapeutic potential to prevent graft rejection, and to further improve their long-term survival.


Posttraining injections of MK-801 produce a time-dependent impairment of memory in two water maze tasks.
The role of glutamatergic N-methyl-D-aspartate (NMDA) receptors in memory storage processes was examined using systemic posttraining injections of MK-801. Male Long-Evans rats received an eight-trial (30-s ITI) training session on a spatial or cued water maze task. In the spatial task, a submerged escape platform was located in the same quadrant of the maze on all trials. In the cued task, a visible escape platform was located in a different quadrant of the maze on each trial. Following Trial 8 in both tasks, the rats received a posttraining intraperitoneal injection of the NMDA receptor antagonist MK-801 (0.025, 0.05, 0.1, or 0.2 mg/kg) or saline. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In both tasks, the retention test escape latencies of animals given MK-801 (0.05 and 0.1 mg/kg) were significantly higher than those of saline-injected controls, indicating a drug-induced impairment of memory. Injections of MK-801 (0.05 mg/kg) did not affect retention when administered 2 h posttraining in either task, indicating that the effects of MK-801 on retention are not due to an influence on non-mnemonic factors. Control experiments indicated that the memory impairing effects of MK-801 were due to an influence on memory for the type of discrimination training given (i.e., spatial or cued) and not due to an influence on a mnemonic strategy common to both tasks. The findings indicate a time-dependent role for NMDA receptor function in memory storage processes.


Comparison of high-resolution melting analysis with denaturing high-performance liquid chromatography for mutation scanning in the ABCA4 gene.
Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD), a few cases of autosomal recessive cone-rod dystrophy (arCRD), and autosomal recessive retinitis pigmentosa (arRP). The purpose of this study was to compare high-resolution melting (HRM) analysis with denaturing high-performance liquid chromatography (dHPLC), to evaluate the efficiency of the different screening methodologies. Thirty-eight STGD, 15 arCRD, and 5 arRP unrelated Spanish patients who had been analyzed with the ABCR microarray were evaluated. The results were confirmed by direct sequencing. In patients with either no or only one mutant allele, ABCA4 was further analyzed by HRM and dHPLC. Haplotype analysis was also performed. In a previous microarray analysis, 37 ABCA4 variants (37/116; 31.9%) were found. dHPLC and HRM scanning identified 18 different genotypes in 20 samples. Of the samples studied, 19/20 were identified correctly by HRM and 16/20 by dHPLC. One homozygous mutation was not detected by dHPLC; however, the p.Cys2137Tyr homozygote was distinguished from the wild-type by HRM technique. In the same way, one novel change in exon 5 (p.Arg187His) was found only by means of the HRM technique. In addition, dHPLC identified the mutation p.Trp1724Cys in one sample; however, HRM detected the mutation in two samples. ABCA4 should be analyzed by an optimal screening technique, to perform further characterization of pathologic alleles. The results seemed to show that HRM had better sensitivity and specificity than did dHPLC, with the advantage that some homozygous sequence alterations were identifiable.


Performance of an insect-inspired target tracker in natural conditions.
Robust and efficient target-tracking algorithms embedded on moving platforms, are a requirement for many computer vision and robotic applications. However, deployment of a real-time system is challenging, even with the computational power of modern hardware. As inspiration, we look to biological lightweight solutions-lightweight and low-powered flying insects. For example, dragonflies pursue prey and mates within cluttered, natural environments, deftly selecting their target amidst swarms. In our laboratory, we study the physiology and morphology of dragonfly 'small target motion detector' neurons likely to underlie this pursuit behaviour. Here we describe our insect-inspired tracking model derived from these data and compare its efficacy and efficiency with state-of-the-art engineering models. For model inputs, we use both publicly available video sequences, as well as our own task-specific dataset (small targets embedded within natural scenes). In the context of the tracking problem, we describe differences in object statistics within the video sequences. For the general dataset, our model often locks on to small components of larger objects, tracking these moving features. When input imagery includes small moving targets, for which our highly nonlinear filtering is matched, the robustness outperforms state-of-the-art trackers. In all scenarios, our insect-inspired tracker runs at least twice the speed of the comparison algorithms.


Structure-Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology.
Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity - with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D-AD human neural culture model. Results suggest that the structure-based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α-tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho-tau (p-tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology-based drug discovery in AD.


Long-term prognosis in patients undergoing redo-isolated aortic valve replacement.
Aim: To evaluate clinical outcomes after redo aortic valve replacement (AVR) with sutured valves, versus valve-in-valve transcatheter aortic valve replacement (ViV-TAVR), versus sutureless valves. Methods: We identified 113 consecutive patients undergoing redo AVR with either ViV-TAVR, redo-sutured and redo-sutureless valves between August 2010 to March 2020. Heart-team made the decision whether patient should undergo redo-sutureless versus ViV-TAVR, versus redo-sutured AVR. Results: Preoperatively, redo-sutured (n = 57), ViV-TAVR (n = 31) and redo-sutureless (n = 25) patients were compared. Postoperatively, after propensity-adjustment analysis, the redo surgical aortic valve replacement group had a higher incidence of new postoperative atrial fibrillation (POAF; p = 0.04) compared with redo-sutureless group. Follow-up outcomes analysis did not show differences among groups. Conclusion: Patients undergoing redo-sutureless AVR experienced a higher incidence of POAF compared with patients undergoing redo-sutured.


Prevention of Postoperative Cognitive Dysfunction by Minocycline in Elderly Patients after Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Clinical Trial.
There are no effective pharmacologic interventions for preventing postoperative cognitive dysfunction in daily practice. Since the antibiotic minocycline is known to suppress postoperative neuroinflammation, this study hypothesized and investigated whether minocycline might have a preventive effect on postoperative cognitive dysfunction after noncardiac surgery. This study included patients aged more than 60 yr undergoing total knee arthroplasty under general anesthesia. They were randomly assigned to minocycline and placebo groups, to orally receive 100 mg of minocycline or placebo twice daily from the day before surgery until the seventh day after surgery. Cognitive function was evaluated before surgery, and 1 week and 3 months after surgery, using a battery of four cognitive function tests, including Visual Verbal Learning Test, Trail Making Test, Stroop Color and Word Test, and Letter-Digit Coding Task. Additionally, 30 healthy volunteers were subjected to the same tests as the patients to examine the learning effect of repeated tests. The occurrence of postoperative cognitive dysfunction was judged from the results of the neurocognitive test battery, with consideration of the learning effect. The secondary endpoints were the effects of minocycline on postoperative delirium and postoperative pain. A total of 100 patients were randomized to the minocycline group, and 102 were randomized to the placebo group. The average age of patients was 75 yr. Evaluation showed no significant difference in the incidence of postoperative cognitive dysfunction between the minocycline and placebo groups at both 1 week (8 of 90 [8.9%] vs. 4 of 95 [4.2%]; odds ratio, 2.22 [95% CI, 0.64 to 7.65]; P = 0.240) and 3 months (15.3 of 90 [17.0%] vs. 15.3 of 95 [16.1%]; odds ratio, 1.07 [95% CI, 0.49 to 2.32]; P = 0.889) postoperatively. Missing data 3 months after surgery were corrected by the multiple imputation method. There were no differences between the two groups in postoperative delirium and postoperative pain. Minocycline is likely to have no preventive effect on postoperative cognitive dysfunction.


On the construction and training of reformulated radial basis function neural networks.
Presents a systematic approach for constructing reformulated radial basis function (RBF) neural networks, which was developed to facilitate their training by supervised learning algorithms based on gradient descent. This approach reduces the construction of radial basis function models to the selection of admissible generator functions. The selection of generator functions relies on the concept of the blind spot, which is introduced in the paper. The paper also introduces a new family of reformulated radial basis function neural networks, which are referred to as cosine radial basis functions. Cosine radial basis functions are constructed by linear generator functions of a special form and their use as similarity measures in radial basis function models is justified by their geometric interpretation. A set of experiments on a variety of datasets indicate that cosine radial basis functions outperform considerably conventional radial basis function neural networks with Gaussian radial basis functions. Cosine radial basis functions are also strong competitors to existing reformulated radial basis function models trained by gradient descent and feedforward neural networks with sigmoid hidden units.


Cobalt substitution of mouse R2 ribonucleotide reductase as a model for the reactive diferrous state: spectroscopic and structural evidence for a ferromagnetically coupled dinuclear cobalt cluster.
The R2 dimer of mouse ribonucleotide reductase contains a dinuclear iron-oxygen cluster and tyrosyl radical/subunit. The dinuclear diferrous form reacts with dioxygen to generate the tyrosyl radical essential for the catalytic reaction that occurs at the R1 dimer. It is important to understand how the reactivity toward oxygen is related to the crystal structure of the dinuclear cluster. For the mouse R2 protein, no structure has been available with a fully occupied dinuclear metal ion site. A cobalt substitution of mouse R2 was performed to produce a good model for the very air-sensitive diferrous form of the enzyme. X-band EPR and light absorption studies (epsilon(550 nm) = 100 mm(-1) cm(-1)/Co(II)) revealed a strong cooperative binding of cobalt to the dinuclear site. In perpendicular mode EPR, the axial signal from mouse R2 incubated with Co(II) showed a typical S = 3/2 Co(II) signal, and its low intensity indicated that the majority of the Co(II) bound to R2 is magnetically coupled. In parallel mode EPR, a typical integer spin signal (M(s) = +/-3) with g approximately 12 is observed at 3.6 K and 10 K, showing that the two Co(II) ions (S = 3/2) in the dinuclear site are ferromagnetically coupled. We have solved the 2.4 A crystal structure of the Co(II)-substituted R2 with a fully occupied dinuclear cluster. The bridging Co(II) carboxylate ligand Glu-267 adopts an altered orientation compared with its counterpart Glu-238 in Escherichia coli R2. This might be important for proper O(2) activation of the more exposed native diferrous site in mouse R2 compared with E. coli R2.


Within-task variability on standardized language tests predicts autism spectrum disorder: a pilot study of the Response Dispersion Index.
Qualitatively atypical language development characterized by non-sequential skill acquisition within a developmental domain, which has been called developmental deviance or difference, is a common characteristic of autism spectrum disorder (ASD). We developed the Response Dispersion Index (RDI), a measure of this phenomenon based on intra-subtest scatter of item responses on standardized psychometric assessments, to assess the within-task variability among individuals with language impairment (LI) and/or ASD. Standard clinical assessments of language were administered to 502 individuals from the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Participants were divided into four diagnostic groups: unaffected, ASD-only, LI-only, and ASD + LI. For each language measure, RDI was defined as the product of the total number of test items and the sum of the weight (based on item difficulty) of test items missed. Group differences in RDI were assessed, and the relationship between RDI and ASD diagnosis among individuals with LI was investigated for each language assessment. Although standard scores were unable to distinguish the LI-only and ASD/ASD + LI groups, the ASD/ASD + LI groups had higher RDI scores compared to LI-only group across all measures of expressive, pragmatic, and metalinguistic language. RDI was positively correlated with quantitative ASD traits across all subgroups and was an effective predictor of ASD diagnosis among individuals with LI. The RDI is an effective quantitative metric of developmental deviance/difference that correlates with ASD traits, supporting previous associations between ASD and non-sequential skill acquisition. The RDI can be adapted to other clinical measures to investigate the degree of difference that is not captured by standard performance summary scores.


Structure, magnetism, and theoretical study of a mixed-valence Co(II)3Co(III)4 heptanuclear wheel: lack of SMM behavior despite negative magnetic anisotropy.
A mixed-valence Co(II)/Co(III) heptanuclear wheel [Co(II)3Co(III)4(L)6(MeO)6] (LH2 = 1,1,1-trifluoro-7-hydroxy-4-methyl-5-aza-hept-3-en-2-one) has been synthesized and its crystal structure determined using single-crystal X-ray diffraction. The valence state of each cobalt ion was established by bond valence sum calculations. Studies of the temperature dependence of the magnetic susceptibility and the field dependence of the magnetization evidence ferromagnetic interactions within the compound. In order to understand the magnetic properties of this Co7 wheel, we performed ab initio calculations for each cobalt fragment at the CASSCF/CASPT2 level, including spin-orbit coupling effects within the SO-RASSI approach. The four Co(III) ions were found to be diamagnetic and to give a significant temperature-independent paramagnetic contribution to the susceptibility. The spin-orbit coupling on the three Co(II) sites leads to separations of approximately 200 cm(-1) between the ground and excited Kramers doublets, placing the Co7 wheel into a weak-exchange limit in which the lowest electronic states are adequately described by the anisotropic exchange interaction between the lowest Kramers doublets on Co(II) sites. Simulation of the exchange interaction was done within the Lines model, keeping the fully ab initio treatment of magnetic anisotropy effects on individual cobalt fragments using a recently developed methodology. A good description of the susceptibility and magnetization was obtained for nearest-neighbor (J1) and next-nearest-neighbor (J2) exchange parameters (1.5 and 5.5 cm(-1), respectively). The strong ferromagnetic interaction between distant cobalt ions arises as a result of low electron-promotion energies in the exchange bridges containing Co(III) ions. The calculations showed a large value of the magnetization along the main magnetic axis (10.1 mu(B)), which is a combined effect of the ferromagnetic exchange interaction and negative magnetic anisotropy on the two marginal Co(II) sites. The lack of single-molecule magnet behavior in [Co(II)3Co(III)4(L)6(MeO)6] is explained by relatively large matrix elements of transverse magnetic moments between states of maximal magnetization of the ground Kramers doublet, evidenced by ab initio calculations, and the associated large tunneling rates between these states in the presence of dipolar transverse magnetic fields in the crystal.


Relative importance of the LDL receptor and scavenger receptor class B in the beta-VLDL-induced uptake and accumulation of cholesteryl esters by peritoneal macrophages.
We investigated the mechanism of beta-very low density lipoprotein (beta-VLDL)-induced foam cell formation derived from peritoneal macrophages from control mice and low density lipoprotein (LDL) receptor-deficient mice to elucidate the role of the LDL receptor in this process. The LDL receptor appeared to be of major importance for beta-VLDL metabolism. Consequently, the accumulation of cholesteryl esters in LDL receptor(-)(/)- macrophages is 2.5-fold lower than in LDL receptor(+)(/)(+) macrophages. In the absence of the LDL receptor, however, beta-VLDL was still able to induce cholesteryl ester accumulation and subsequently we characterized the properties of this residual beta-VLDL recognition site(s) of LDL receptor(-)(/)- macrophages. Although the LDL receptor-related protein is expressed on LDL receptor(-)(/)- macrophages, the cell association of beta-VLDL is not influenced by the receptor-associated protein, and treatment of the macrophages with heparinase and chondroitinase was also ineffective. In contrast, both oxidized LDL (OxLDL) and anionic liposomes were able to inhibit the cell association of (125)I-labeled beta-VLDL in LDL receptor(-)(/)- macrophages by 65%. These properties suggest a role for scavenger receptor class B (SR-B), and indeed, in the LDL receptor(-)(/)- macrophages the selective uptake of cholesteryl esters from beta-VLDL was 2.2-fold higher than that of apolipoproteins, a process that could be inhibited by OxLDL, high density lipoprotein (HDL), and beta-VLDL. In conclusion, the LDL receptor on peritoneal macrophages is directly involved in the metabolism of beta-VLDL and the subsequent foam cell formation. When the LDL receptor is absent, SR-B appears to mediate the remaining metabolism of cholesteryl esters from beta-VLDL.


Alternate approaches for assessing impacts of oil sands development on air quality: A case study using the First Nation Community of Fort McKay.
Previous analyses of continuously measured compounds in Fort McKay, an indigenous community in the Athabasca Oil Sands, have detected increasing concentrations of nitrogen dioxide (NO2) and total hydrocarbons (THC), but not of sulfur dioxide (SO2), ozone (O3), total reduced sulfur compounds (TRS), or particulate matter (aerodynamic diameter <2.5 μm; PM2.5). Yet the community frequently experiences odors, dust, and reduced air quality. The authors used Fort McKay's continuously monitored air quality data (1998-2014) as a case study to assess techniques for air quality analysis that make no assumptions regarding type of change. Linear trend analysis detected increasing concentrations of higher percentiles of NO2, nitric oxide (NO), and nitrogen oxides (NOx), and THC. However, comparisons of all compounds between an early industrial expansion period (1998-2001) and current day (2011-2014) show that concentrations of NO2, SO2, THC, TRS, and PM2.5 have significantly increased, whereas concentrations of O3 are significantly lower. An assessment of the frequency and duration of periods when concentrations of each compound were above a variety of thresholds indicated that the frequency of air quality events is increasing for NO2 and THC. Assessment of change over time with odds ratios of the 25th, 50th, 75th, and 90th percentile concentrations for each compound compared with an estimate of natural background variability showed that concentrations of TRS, SO2, and THC are dynamic, higher than background, and changes are nonlinear and nonmonotonic. An assessment of concentrations as a function of wind direction showed a clear and generally increasing influence of industry on air quality. This work shows that evaluating air quality without assumptions of linearity reveals dynamic changes in air quality in Fort McKay, and that it is increasingly being affected by oil sands operations. Understanding the nature and types of air quality changes occurring in a community or region is essential for the development of appropriate air quality management policies. Time-series trending of air quality data is a common tool for assessing air quality changes and is often used to assess the effectiveness of current emission management programs. The use of this tool, in the context of oil sands development, has significant limitations, and alternate air quality change analysis approaches need to be applied to ensure that the impact of this development on air quality is fully understood so that appropriate emission management actions can be taken.


Neural circuits. Labeling of active neural circuits in vivo with designed calcium integrators.
The identification of active neurons and circuits in vivo is a fundamental challenge in understanding the neural basis of behavior. Genetically encoded calcium (Ca(2+)) indicators (GECIs) enable quantitative monitoring of cellular-resolution activity during behavior. However, such indicators require online monitoring within a limited field of view. Alternatively, post hoc staining of immediate early genes (IEGs) indicates highly active cells within the entire brain, albeit with poor temporal resolution. We designed a fluorescent sensor, CaMPARI, that combines the genetic targetability and quantitative link to neural activity of GECIs with the permanent, large-scale labeling of IEGs, allowing a temporally precise "activity snapshot" of a large tissue volume. CaMPARI undergoes efficient and irreversible green-to-red conversion only when elevated intracellular Ca(2+) and experimenter-controlled illumination coincide. We demonstrate the utility of CaMPARI in freely moving larvae of zebrafish and flies, and in head-fixed mice and adult flies.


Psycho-educational interventions designed to prevent deployment-related psychological ill-health in Armed Forces personnel: a review.
Employers such as the Armed Forces (AF) and emergency services, who predictably expose their staff to potentially traumatic events (PTEs), often provide psycho-educational briefings in an attempt to mitigate possible adverse psychological sequelae. Within the military, psycho-educational briefings are widely used, particularly following exposure to PTEs on operations. The aim of this review was to evaluate the efficacy of these interventions and make appropriate recommendations. A search of Medline, PsycINFO and EMBASE was conducted, bibliographies of retrieved articles were searched and experts in the field were consulted. Two surveys and seven intervention studies were identified for inclusion in the review. Only three studies were randomized controlled trials (RCTs). Overall, the review found some evidence of benefit of psycho-educational interventions but it was not consistent across studies or outcomes and effects were small. However, there was also little evidence to suggest that they caused harm. There was some evidence that the beneficial effects may be greater for those who have been exposed to a higher number of PTEs. Given the high operational tempo currently faced by coalition forces personnel, there remains a pressing need to identify the most effective way of minimizing the impact of exposure to potentially traumatic deployment incidents. To date, few psycho-educational interventions designed to prevent deployment-related psychological ill-health have been evaluated systematically in methodologically robust studies. The review recommends that future interventions are theoretically based and evaluated in cluster RCTs that examine both process and outcome variables.


HIV prevention among sex workers in India.
To test the efficacy of a sustainable community-level HIV intervention among sex workers, the Sonagachi Project was replicated, including community organizing and advocacy, peer education, condom social marketing, and establishment of a health clinic. Sex workers were randomly selected in 2 small urban communities in northeastern India (n = 100 each) and assessed every 5-6 months over 15 months (85% retention). Overall condom use increased significantly in the intervention community (39%) compared with the control community (11%), and the proportion of consistent condom users increased 25% in the intervention community compared with a 16% decrease in the control community. This study supports the efficacy of the Sonagachi model intervention in increasing condom use and maintaining low HIV prevalence among sex workers.


Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy.
Lipoprotein glomerulopathy (LPG) is a novel disease characterized by proteinuria, lipoprotein thrombi in the glomeruli, and increased concentration of plasma apolipoprotein (apo) E. It is believed that a genetic disorder of apo E may be present and associated with the disease. Three patients with LPG were examined in this study. The patients' DNA sequences were analyzed, and a nucleotide G to C point mutation in exon 4 of the apo E gene was confirmed in each patient. This missense mutation denotes amino acid substitution of the proline residue for arginine residue at position 145 of apo E. This variant (apo E Sendai) may cause a marked molecular conformational change of the apo E. These findings suggest that a novel variant is etiologically related to LPG.


Puffing frequency and nicotine intake in cigarette smokers.
The smoking behaviour of 36 subjects smoking cigarettes with different filter retention efficiencies for nicotine was studied. Subjects were observed while performing various tasks on a driving simulator and also during a resting period after the tasks. Smokers of cigarettes with high-retention filters took more frequent puffs and obtained nearly the same amount of nicotine as smokers of cigarettes with low-retention filters, both while performing the tasks and during the resting period. Smokers of both types of cigarettes took significantly more puffs and obtained more nicotine per unit time during the resting period than during the tasks. The results are compatible with the possibility that smokers automatically adjust the nicotine dose obtained from a cigarette to some "optimum" level which may vary with different activities.


Probing single cells of purple sulfur bacteria with Raman spectroscopy: carotenoids and elemental sulfur.
We explored the use of Raman spectroscopy to simultaneously monitor the presence of different biomarkers (carotenoids, elemental sulfur) within single cells of the purple sulfur photosynthetic bacteria Allochromatium vinosum and A. warmingii. Raman microspectrometry using excitation at 532 nm allowed the detection of different carotenoids. Raman signals of elemental sulfur appeared soon after feeding starved cells with sulfide. Raman spectroscopy is thus a convenient and sensitive technique to qualitatively and semiquantitatively assess the presence of different compounds of interest within single bacterial cells.


Vocal tract modelling in fallow deer: are male groans nasalized?
Males of several species of deer have a descended and mobile larynx, resulting in an unusually long vocal tract, which can be further extended by lowering the larynx during call production. Formant frequencies are lowered as the vocal tract is extended, as predicted when approximating the vocal tract as a uniform quarter wavelength resonator. However, formant frequencies in polygynous deer follow uneven distribution patterns, indicating that the vocal tract configuration may in fact be rather complex. We CT-scanned the head and neck region of two adult male fallow deer specimens with artificially extended vocal tracts and measured the cross-sectional areas of the supra-laryngeal vocal tract along the oral and nasal tracts. The CT data were then used to predict the resonances produced by three possible configurations, including the oral vocal tract only, the nasal vocal tract only, or combining the two. We found that the area functions from the combined oral and nasal vocal tracts produced resonances more closely matching the formant pattern and scaling observed in fallow deer groans than those predicted by the area functions of the oral vocal tract only or of the nasal vocal tract only. This indicates that the nasal and oral vocal tracts are both simultaneously involved in the production of a non-human mammal vocalization, and suggests that the potential for nasalization in putative oral loud calls should be carefully considered.


Parvovirus B19 antibodies and correlates of infection in pregnant women attending an antenatal clinic in central Nigeria.
Human parvovirus B19 infection is associated with spontaneous abortion, hydrops foetalis, intrauterine foetal death, erythema infectiosum (5th disease), aplastic crisis and acute symmetric polyarthropathy. However, data concerning Nigerian patients with B19 infection have not been published yet. The purpose of this study was to establish the prevalence of B19 IgG and IgM antibodies, including correlates of infection, among pregnant women attending an antenatal clinic in Nigeria. Subsequent to clearance from an ethical committee, blood samples were collected between August-November 2008 from 273 pregnant women between the ages of 15-40 years who have given their informed consent and completed self-administered questionnaires. Recombinant IgG and IgM enzyme linked immunosorbent assay kits (Demeditec Diagnostics, Germany) were used for the assays. Out of the 273 participants, 111 (40.7%) had either IgG or IgM antibodies. Out of these, 75 (27.5%) had IgG antibodies whereas 36 (13.2%) had IgM antibodies, and those aged 36-40 years had the highest prevalence of IgG antibodies. Significant determinants of infection (p < 0.05) included the receipt of a blood transfusion, occupation and the presence of a large number of children in the household. Our findings have important implications for transfusion and foeto-maternal health policy in Nigeria. Routine screening for B19 IgM antibodies and accompanying clinical management of positive cases should be made mandatory for all Nigerian blood donors and women of childbearing age.


Factors associated with suicide attempts in the antecedent illness trajectory of bipolar disorder and schizophrenia.
Factors associated with suicide attempts during the antecedent illness trajectory of bipolar disorder (BD) and schizophrenia (SZ) are poorly understood. Utilizing the Rochester Epidemiology Project, individuals born after 1985 in Olmsted County, MN, presented with first episode mania (FEM) or psychosis (FEP), subsequently diagnosed with BD or SZ were identified. Patient demographics, suicidal ideation with plan, self-harm, suicide attempts, psychiatric hospitalizations, substance use, and childhood adversities were quantified using the electronic health record. Analyses pooled BD and SZ groups with a transdiagnostic approach given the two diseases were not yet differentiated. Factors associated with suicide attempts were examined using bivariate methods and multivariable logistic regression modeling. A total of 205 individuals with FEM or FEP (BD = 74, SZ = 131) were included. Suicide attempts were identified in 39 (19%) patients. Those with suicide attempts during antecedent illness trajectory were more likely to be female, victims of domestic violence or bullying behavior, and have higher rates of psychiatric hospitalizations, suicidal ideation with plan and/or self-harm, as well as alcohol, drug, and nicotine use before FEM/FEP onset. Based on multivariable logistic regression, three factors remained independently associated with suicidal attempts: psychiatric hospitalization (OR = 5.84, 95% CI 2.09-16.33, p < 0.001), self-harm (OR = 3.46, 95% CI 1.29-9.30, p = 0.014), and nicotine use (OR = 3.02, 95% CI 1.17-7.76, p = 0.022). Suicidal attempts were prevalent during the antecedents of BD and SZ and were associated with several risk factors before FEM/FEP. Their clinical recognition could contribute to improve early prediction and prevention of suicide during the antecedent illness trajectory of BD and SZ.


Renal defects and limb deficiencies in 197 infants: is it possible to define the "acrorenal syndrome"?
Dieker and Opitz in 1969 described the simultaneous occurrence of limb deficiencies (LDs) and renal anomalies (RAs) in three patients. Curran and Curran introduced in 1972 the term "acrorenal syndrome." Since then, the term "acrorenal syndrome" is used occasionally, but a well-circumscribed definition has never been established. On the other hand, the concept of an acrorenal polytopic developmental field defect was postulated by Opitz and others to explain the association between RAs and LDs. We undertook this study to investigate whether this acrorenal "syndrome" could be identified in a large group of cases with congenital RAs and a limb deficiency. Eleven birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring (i.e., registries of ICBDMS in Finland, France [Paris and Strasbourg], Israel, Italy [IPIMC and Emilia Romagna], Mexico, Northern Netherlands, South America, Spain, and the United States [Atlanta]) provided data on 815 infants who had a LD and at least one other major congenital anomaly. These 815 cases were ascertained among 5,163,958 births. We selected the 197 cases who had both a limb deficiency and a renal or urinary tract anomaly. In about 50% of these cases a diagnosis or a recognized phenotype was reported, with chromosomal aberrations and VACTERL being most frequent. In the group with no diagnosis or recognized phenotype (95 cases), we looked for (a) clustering of specific types of LDs and RAs, and (b) for clustering of associated anomalies, in order to find evidence for and be able to define better the term "acrorenal syndrome." Our data suggest that an association exists between LDs and RAs, possibly explained by the concept of the acrorenal polytopic developmental field defect. However, our dataset does not yield evidence for the existence of one distinct "syndrome," defined as a pattern of causally related multiple anomalies. Therefore, use of the term "acrorenal syndrome" should be avoided.


Empathy as a moderator of sexual violence perpetration risk factors among college men.
Objective: This study examined if empathy was a significant moderator of several empirically established risk factors for sexual violence perpetration among college men. Participants: Data are from 544 college men who participated in a longitudinal study from 2008 to 2011 at a large, public university. Methods: Participants completed a self-report survey in their first through fourth years in college. A series of generalized linear models were conducted using sexual violence risk factors and empathy during the sophomore year as predictors of sexual violence perpetration frequency during junior year. Results: Empathy was found to be a significant moderator of six out of the 10 sexual violence risk factors tested, such that high levels of empathy were associated with lower sexual violence perpetration rates among high-risk males. Conclusion: Additional research, including the measurement and evaluation of empathy in implementation of college sexual violence prevention and intervention efforts, should be undertaken.


Representation of similarity in three-dimensional object discrimination.
How does the brain represent visual objects? In simple perceptual generalization tasks, the human visual system performs as if it represents the stimuli in a low-dimensional metric psychological space (Shepard 1987). In theories of three-dimensional (3D) shape recognition, the role of feature-space representations [as opposed to structural (Biederman 1987) or pictorial (Ullman 1989) descriptions] has long been a major point of contention. If shapes are indeed represented as points in a feature space, patterns of perceived similarity among different objects must reflect the structure of this space. The feature space hypothesis can then be tested by presenting subjects with complex parameterized 3D shapes, and by relating the similarities among subjective representations, as revealed in the response data by multidimensional scaling (Shepard 1980), to the objective parameterization of the stimuli. The results of four such tests, accompanied by computational simulations, support the notion that discrimination among 3D objects may rely on a low-dimensional feature space representation, and suggest that this space may be spanned by explicitly encoded class prototypes.


[Intoxication of a child by an oral nicotine pouch].
Oral nicotine pouches are pouches that contain varying amounts of nicotine. The use of nicotine pouches by adolescents has increased since 2020. Subsequently, there has been an increase in the amount of reports of nicotine intoxications. Acute nicotine intoxications have a biphasic clinical course, during which the initial symptoms may include agitation, tachycardia and vomiting. When large enough doses are used more serious symptoms may emerge. As well as the acute side effects, studies have shown that the use of oral nicotine pouches with tobacco is associated with a younger age at which cigarette smoking is initiated. A 9 year-old boy presented at the Emergency Department with symptoms of nausea, dizziness and shivering following the oral use of one nicotine pouch. Aside from tachycardia the physical examinations showed no abnormalities. The patient was diagnosed with an acute nicotine intoxication and was admitted to the paediatric department for 24 hours. Oral nicotine pouches are commonly used by adolescents. Aside from the addictive nature of nicotine, it is important that clinicians are aware of the symptoms of acute and late-phase intoxications.


Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions.
In recent years, there has been dramatic expansion of the treatment armamentarium for patients with advanced renal cell carcinoma (aRCC), including drugs targeting vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways. Despite these advances, patient outcomes remain suboptimal, underscoring the need for therapeutic interventions with novel mechanisms of action. The advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment landscape for several solid malignancies. Specifically, drugs targeting the programmed death 1 (PD-1) and cytotoxic T-lymphocyte associated antigen (CTLA-4) pathways have demonstrated considerable clinical efficacy and gained regulatory approval as single-agent or combination therapy for the treatment of patients with metastatic melanoma, non-small cell lung cancer, aRCC, advanced squamous cell carcinoma of the head and neck, urothelial cancer and Hodgkin lymphoma. In aRCC, the PD-1 inhibitor nivolumab was approved in both the United States and Europe for the treatment of patients who have received prior therapy, based on improved overall survival compared with the mTOR inhibitor everolimus. Other checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab in combination with several agents, and the PD-L1 inhibitor atezolizumab, are in various stages of clinical development in patients with aRCC. In this review, current evidence related to the clinical use of checkpoint inhibitors for the treatment of patients with aRCC is discussed, including information on the frequency and management of unconventional responses and the management of immune-related adverse events. In addition, perspectives on the future use of checkpoint inhibitors are discussed, including the potential value of treatment beyond progression, the potential use in earlier lines of care or in combination with other agents, and the identification of biomarkers to guide patient selection and enable individualization of therapy.


Hearing levels of secondary school band directors.
Pure-tone AC HTLs were obtained from 52 secondary-school band directors aged 25-58 yrs with 1-28 yrs experience as directors. None reported any history of ear disease or excessive noise exposure other than their musical backgrounds. Groups I, II, and III had mean director experience of 5.3, 12,3, and 20.5 yrs, respectively. The hearing levels of Groups I, II, and III were, respectively, 5, 10, and 15 db less sensitive than those of comparably aged men with no noise exposure (Corso, 1963). SPLs in dbA of typical director locations were assessed. Though the 8-hr time-weighted exposures of the directors were below the "action level" for initiating a hearing conservation program, periodic audiometry was recommended.


Low macular pigment optical density is associated with lower cognitive performance in a large, population-based sample of older adults.
Macular pigment (MP) is comprised of the carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which selectively accumulate at the macula (central retina) of the eye and are neuroprotective. These carotenoids are also present in the brain, and evidence suggests a close correlation between retinal and brain concentrations. We investigated the relationship between MP and cognitive function in 4453 adults aged ≥ 50 years as part of The Irish Longitudinal Study on Aging. Macular pigment optical density (MPOD) was determined using customized heterochromatic flicker photometry-a quick and noninvasive way of measuring the concentration of the pigment. Lower MPOD was associated with poorer performance on the mini-mental state examination (p = 0.026) and on the Montreal cognitive assessment (p = 0.016). Individuals with lower MPOD also had poorer prospective memory (p = 0.011), took longer time to complete a trail-making task (p = 0.003), and had slower and more variable reaction times on a choice reaction time task (p = 0.000 and 0.001). These associations were only slightly attenuated following adjustment for physical and mental health. There was no significant association between MPOD and verbal fluency, word recall, visual reasoning, or picture memory. Overall, the findings support the theory that xanthophyll carotenoids impact on cognitive function, underscoring the need for exploration of novel, noninvasive biomarkers for cognitive vulnerability and preventive strategies.


High-throughput bioluminescence-based mutant screening strategy for identification of bacterial virulence genes.
A high-throughput bioluminescence screening procedure for identification of virulence genes in bacteria was developed and applied to the fish pathogen Edwardsiella ictaluri. A random transposon mutant library expressing bioluminescence was constructed and robotically arrayed on 384-well plates. Mutants were cultivated and mixed with catfish serum and neutrophils in 96-well plates, and bioluminescence was used to detect mutants that are more susceptible to killing by these host factors. The virulence and vaccine efficacy of selected mutants were determined in channel catfish. Transposon insertion sites in 13 mutants attenuated in the natural host were mapped to the E. ictaluri genome. Ten unique genes were mutated, including genes encoding a negative regulator of sigmaE activity, a glycine cleavage system protein, tricarboxylic acid cycle enzymes, an O polysaccharide biosynthesis enzyme, proteins encoded on the native plasmid pEI1, and a fimbrial chaperon protein. Three of these mutants were found to have potential as live attenuated vaccines. This study demonstrates a novel application of bioluminescence to identify bacterial genes required for host resistance; as a result, efficacious and genetically defined live attenuated vaccine candidates were developed.


Congenital cardiac surgery fellowship training: A status update.
In 2007, congenital cardiac surgery became a recognized fellowship by the Accreditation Council of Graduate Medical Education (ACGME) and leads to board certification through the American Board of Thoracic Surgery (ABTS). We highlight the strengths and weaknesses in the current system of accredited training. Data were collected from program directors, the ACGME, and the ABTS. In addition, surveys were sent to training program graduates. Topics included program accreditation status, number of fellows trained per year and per program, match results, fellow operative experience, fellow satisfaction, and post-fellowship employment status. There are twelve active accredited fellowship programs, and 44 trainees have completed accredited training. Each active program has trained a median of 3 fellows (range: 0-7). Operative logs were obtained from 38 of 44 (86%) graduates. The median number of total cases (minimum 75) was 136 (range: 75-236). For complex neonates (minimum 5), the median number of cases was 6 (range: 2-17). Some fellows failed to meet the minimum requirements. Thirty-six (82%) graduates responded to the survey; most were satisfied with their overall operative experience, but less with their neonatal operative experience. Of this total, 84% are currently practicing congenital cardiac surgery, and 74% secured jobs prior to completing their residency. Since 2007, congenital cardiac surgery training has been accredited by the ACGME. In general, the training is uniform, the operative experience is robust, and the fellows are satisfied. Although shortcomings remain, this study highlights the many strengths of the current system.


A new imaging science test object for performance measurements of ultrasonic imaging systems.
We propose a novel test object for ultrasound imaging. The test object, or phantom, is manufactured using thin film techniques allowing precise placement of 'digital scatterers' which can produce sophisticated test targets, similar to those that are widely used in imaging science to evaluate displays, printers and electronic imaging systems. These test objects can be used in conjunction with standard performance evaluation methods and devices to augment and enhance their capabilities and range of application.


The insensitivity of endoscopic markers in celiac disease.
Celiac disease (CD) is characterized by small intestinal inflammation and mucosal atrophy. Endoscopic markers of villous atrophy are reported to be present in 88-100% of untreated celiac patients. In patients being evaluated for iron deficiency anemia (IDA), we examined whether endoscopic markers could predict histological results consistent with CD. One hundred thirteen patients without histories of CD had small bowel biopsies to evaluate IDA using videoendoscopy. Markers suggesting villous atrophy were noted at endoscopy. Biopsy specimens were reviewed for consistency with CD. Endoscopic and histological findings were compared. Seventeen patients were diagnosed with CD, both clinically and histologically. Loss of folds was the most sensitive marker of villous atrophy, present in 47% with CD, with 97% specificity. The mosaic pattern was much less sensitive (12%), with 100% specificity. Nodularity and scalloping had low sensitivities (6%), but specificities of 95% and 100%, respectively. A finding of any endoscopic marker yielded a sensitivity of 59% and specificity of 92% for CD. Although endoscopic markers have been guides for directing small bowel biopsies in patients suspected of having CD, we found sensitivities of these markers to be low and conclude that they should not be relied upon for detecting CD in patients presenting with IDA.