Swelling and Orientation Behavior of End-Grafted Polymer Chains by In Situ Attenuated Total Reflection Fourier Transform Infrared Spectroscopy Complementing In Situ Ellipsometry.
The literature lacks established concrete parameters for assigning grafted chain regimes. In this context, dichroic in situ attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and in situ ellipsometry were used complementarily, offering new opportunities for conformational analysis of end-grafted polymer chains. Especially polymer chain orientation was studied as a new parameter, among others, for proper chain regime assignment in this report. Alkyne-functionalized poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) with a molecular weight of 49.8 kg/mol and a contour length of around 80 nm was grafted to self-assembled monolayers bearing triazole end groups as reported. Different chain regimes were generated by using three different grafting densities. ATR-FTIR spectroscopy based on the ν(C═O) stretching vibration at around 1728 cm-1 provided a new direct approach to determine the GD of polymer chains. Significant shifts in the position of the ν(C═O) band comparing dry and wet states were observed, caused by increased hydrogen bonding interactions between PDMAEMA and water. Finally, the averaged orientation of PDMAEMA chains along the z-axis was determined using dichroic ATR-FTIR spectroscopy based on the dichroic ratios of the ν(C═O) band and molecular order parameters SZ,MOL calculated thereof. High SZ,MOL values were found for the wet state compared to the dry state, confirming that all GD PDMAEMA samples are in the brush regime in the swollen state.


Dual Tracer Test to measure tissue-specific insulin action in individual mice identifies in vivo insulin resistance without fasting hyperinsulinemia.
The ability of metabolically active tissues to increase glucose uptake in response to insulin is critical to whole-body glucose homeostasis. This report describes the Dual Tracer Test, a robust method involving sequential retro-orbital injection of 14C-2-deoxyglucose (14C-2DG) alone, followed 40 min later by injection of 3H-2DG with a maximal dose of insulin to quantify both basal and insulin-stimulated 2DG uptake in the same mouse. The collection of both basal and insulin-stimulated measures from a single animal is imperative for generating high-quality data since differences in insulin action may be misinterpreted mechanistically if basal glucose uptake is not accounted for. The approach was validated in a classic diet-induced model of insulin resistance and a novel transgenic mouse with reduced GLUT4 expression that, despite ubiquitous peripheral insulin resistance, did not exhibit fasting hyperinsulinemia. This suggests that reduced insulin-stimulated glucose disposal is not a primary contributor to chronic hyperinsulinemia. The Dual Tracer Test offers a technically simple assay that enables the study of insulin action in many tissues simultaneously. By administering two tracers and accounting for both basal and insulin-stimulated glucose transport, this assay halves the required sample size for studies in inbred mice and demonstrates increased statistical power to detect insulin resistance, relative to other established approaches using a single tracer. The Dual Tracer Test is a valuable addition to the metabolic phenotyping toolbox.


Protein and amino acid requirements of the laboratory rabbit.
The arginine requirement of the growing rabbit has been re-investigated and found to vary depending upon the pattern of the indispensable amino acids other than arginine. The requirement was higher on a pattern simulating isolated soy protein than on a pattern that contributed essentially the requirement pattern. The rabbit has been found sensitive to protein quality in the same way as other monogastric animals, including the rat and the chick. Interestingly, soy protein appears to provide a superior amino acid pattern to whole egg. Also, casein may be limiting in arginine for the growing rabbit.


Anterior biopercular syndrome caused by unilateral infarction.
The anterior biopercular syndrome is characterized by facio-pharyngo-glosso-masticatory diplegia, with automatic dissociation of movements. It generally translates bilateral opercular lesion, often of vascular etiology. There are very few cases described with unilateral lesions. We present the case of a patient with a bilateral anterior opercular syndrome caused by unilateral infarction.


Models of mental health problems: a quasi-systematic review of theoretical approaches.
Mental health and mental illness have been contested concepts for decades, with a wide variety of models being proposed. To date, there has been no exhaustive review that provides an overview of existing models. To conduct a quasi-systematic review of theoretical models of mental health problems. We searched academic databases, reference lists, and an electronic bookshop for literature that proposed, endorsed, reviewed, or critiqued such models. Papers, book chapters, and books were included with material by researchers, clinicians, non-medical professions, and service users writing between 2000 to June 2020 being considered. The study was registered with the Open Science Framework (No. osf.io/r3tjx). Based on 110 publications, we identified 34 different models which were grouped into five broader categories. Many models bridged two or more categories. Biological and psychological approaches had the largest number of models while social, consumer and cultural models were less diversified. Due to the non-empirical nature of the publications, several limitations in terms of search and quality appraisal apply. We conclude that mental health care needs to acknowledge the diversity of theoretical models on mental health problems.


Heptad repeat 2-based peptides inhibit avian sarcoma and leukosis virus subgroup a infection and identify a fusion intermediate.
Fusion proteins of enveloped viruses categorized as class I are typified by two distinct heptad repeat domains within the transmembrane subunit. These repeats are important structural elements that assemble into the six-helix bundles characteristic of the fusion-activated envelope trimer. Peptides derived from these domains can be potent and specific inhibitors of membrane fusion and virus infection. To facilitate our understanding of retroviral entry, peptides corresponding to the two heptad repeat domains of the avian sarcoma and leukosis virus subgroup A (ASLV-A) TM subunit of the envelope protein were characterized. Two peptides corresponding to the C-terminal heptad repeat (HR2), offset from one another by three residues, were effective inhibitors of infection, while two overlapping peptides derived from the N-terminal heptad repeat (HR1) were not. Analysis of envelope mutants containing substitutions within the HR1 domain revealed that a single amino acid change, L62A, significantly reduced sensitivity to peptide inhibition. Virus bound to cells at 4 degrees C became sensitive to peptide within the first 5 min of elevating the temperature to 37 degrees C and lost sensitivity to peptide after 15 to 30 min, consistent with a transient intermediate in which the peptide binding site is exposed. In cell-cell fusion experiments, peptide inhibitor sensitivity occurred prior to a fusion-enhancing low-pH pulse. Soluble receptor for ASLV-A induces a lipophilic character in the envelope which can be measured by stable liposome binding, and this activation was found to be unaffected by inhibitory HR2 peptide. Finally, receptor-triggered conformational changes in the TM subunit were also found to be unaffected by inhibitory peptide. These changes are marked by a dramatic shift in mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, from a subunit of 37 kDa to a complex of about 80 kDa. Biotinylated HR2 peptide bound specifically to the 80-kDa complex, demonstrating a surprisingly stable envelope conformation in which the HR2 binding site is exposed. These experiments support a model in which receptor interaction promotes formation of an envelope conformation in which the TM subunit is stably associated with its target membrane and is able to bind a C-terminal peptide.


Survey of sulfites in wine and various Turkish food and food products intended for export, 2007-2010.
Surveys were carried out between 2007 and 2010 to determine the total levels of sulfites in 1245 samples of wines, dried apricots, dried vegetables, nuts, juices and purees, frozen foods and cereals containing dried fruit supplied by food inspectors and by food producers for testing or for export certification. Sulfite analysis of wine was carried out using the Ripper method with an LOQ of 5 mg l(-1) and for dried and other foods the Monier-Williams distillation procedure was employed with an LOQ of 10 mg kg(-1). In the survey all wines contained measurable sulfites, but with the exception of one sample of white wine they were otherwise below Turkish Food Codex limits of 160 mg kg(-1) for red wine, 210 mg kg(-1) to white wine and 235 mg kg(-1) for sparkling wine. None of the cereal products, frozen foods, juices or purees contained sulfites above 10 mg kg(-1). However, all dried apricot samples contained significant levels of sulfite with around 40% having levels exceeding the Turkish limit of 2000 mg kg(-1). Significant levels of sulfite were found in other samples of dried fruit with even a fruit and nut bar containing 1395 mg kg(-1) of sulfite, suggesting the dried fruit ingredients contained levels above regulatory limits.


Cross-subsidies and payment for hospital care.
This study uses hospital data from the 1979 American Hospital Association Reimbursement Survey in a multivariate framework to assess the impact of discounts and third-party reimbursement on hospital costs and profitability. Three central issues are addressed: (1) Is a differential payment justified for Medicare, Medicaid, and/or Blue Cross on the basis of differential costs? (2) Have the cost-containment efforts of the dominant payers reduced total payments to hospitals? and (3) What part of the overall savings in payments to hospitals is in the form of reduced costs rather than reduced profits? On the basis of the evidence in this study, we find (1) that the differential payment is not justified; (2) that the cost-containment efforts of the dominant payers have reduced total payments to hospitals somewhat, but a substantial amount of cost-shifting remains; and (3) that the savings is in profits, rather than in costs.


Health benefits and economic advantages associated with increased utilization of a smoking cessation program.
Rationale, aim & objective: The goal of this study was to examine the health and economic impacts related to increased utilization of the Duke Smoking Cessation Program resulting from the addition of two relatively new referral methods - Best Practice Advisory and Population Outreach. Materials & methods: In a companion paper 'Comparison of Referral Methods into a Smoking Cessation Program', we report results from a retrospective, observational, comparative effectiveness study comparing the impact of three referral methods - Traditional Referral, Best Practice Advisory and Population Outreach on utilization of the Duke Smoking Cessation Program. In this paper we take the next step in this comparative assessment by developing a Markov model to estimate the improvement in health and economic outcomes when two referral methods - Best Practice Advisory and Population Outreach - are added to Traditional Referral. Data used in this analysis were collected from Duke Primary Care and Disadvantaged Care clinics over a 1-year period (1 October 2017-30 September 2018). Results: The addition of two new referral methods - Best Practice Advisory and Population Outreach - to Traditional Referral increased the utilization of the Duke Smoking Cessation Program in Primary Care clinics from 129 to 329 smokers and in Disadvantaged Care clinics from 206 to 401 smokers. The addition of these referral methods was estimated to result in 967 life-years gained, 408 discounted quality-adjusted life-years saved and total discounted lifetime direct healthcare cost savings of US$46,376,285. Conclusion: Health systems may achieve increased patient health and decreased healthcare costs by adding Best Practice Advisory and Population Outreach strategies to refer patients to smoking cessation services.


Effect of dietary energy on lipogenesis in turkey hens prior to and after sexual maturity.
An experiment was conducted with 208 Diamond Hybrid Small White turkey hens to determine the role of dietary energy on in vitro lipid metabolism. Young turkey hens were fed diets containing either a high (3100 kcal metabolizable energy) or low (2400 kcal metabolizable energy) energy level from 12 to 30 weeks of age. Both diets contained 12% protein and were fed on an ad libitum basis. Hens were then maintained under a constant (21 degrees C) or cyclic (12 to 27 degrees C) daily temperature regime and fed either a high (47% of the total energy) or low (8% of the total energy) fat diet for a 100-day egg collection period. Hens were killed at the end of the growing phase, after 1 week of receiving the breeder diets and after 2 weeks of stimulatory light (14 hr/day). Hens were also killed following a 100-day egg collection period. In vitro lipid metabolism and enzyme activities were determined at these periods. In vitro fatty acid synthesis was greater (P less than .05) in hens fed the high-energy prebreeder diet although total energy intakes for both groups of birds were similar. Transferring both groups of hens to individual cages in the breeder house decreased (P less than .05) fatty acid synthesis; however, lipogenic rates were higher (P less than .05) after 2 and 18 weeks of stimulatory light. The high-fat diet decreased (P less than .05) in vitro lipogenesis, fatty acid synthesis, malic enzyme and esterification of palmitate. Acetate utilization in the presence of pyruvate was one-half the rate in the absence. Diets fed prior to sexual maturity did not affect egg production or in vitro lipogenesis of mature hens.


Roots.
Many unicellular eukaryotic organisms possess complex fiber systems that organize and anchor the flagellar basal apparatus in the cell [20, 24]. In 1978 we first published the observation that one of these fiber systems, the striated flagellar root of the quadriflagellate green alga Tetraselmis subcordiformis (= Platymonas subcordiformis), is a contractile organelle [31]. We subsequently found that striated flagellar roots are composed, in part, of the Ca(2+)-binding protein centrin [30]. Since that time, centrin has been found to be a ubiquitous component of the flagellar basal apparatus, basal bodies and centrioles, and centrosomes and mitotic spindle poles of eukaryotic cells (for general reviews see [28, 34]). While we have learned a great deal about centrin from other organisms, our earliest success in understanding the biology of centrin was in large part due to the extraordinary extent to which Tetraselmis cells have elaborated their centrin-based organelles. In this paper, I will return attention to several unanswered questions concerning Tetraselmis striated flagellar root behavior and I will suggest several new directions that students may wish to pursue in order to tease fresh insights from this fascinating organism.


Multifrequency focusing and wide angular scanning of terajets.
In the past, it has been demonstrated that it is possible to produce terajets with high resolution at its focus using 3D dielectric cuboids under plane-wave illumination. Here, a systematic study of the harmonic and angular response of terajets using cuboids is performed. Mutifrequency focusing is demonstrated at the fundamental frequency and two higher frequency harmonics showing an intensity enhancement of ∼10, ∼18, and ∼14 for each case. This capability to use 3D dielectric cuboids to produce terajets at the fundamental frequency and first harmonic is experimentally evaluated at sub-THz frequencies, with good agreement with numerical results. Moreover, a robust angular response is demonstrated numerically and experimentally showing that the intensity at the focal position is maintained in a wide angular range (from 0° to 45°), demonstrating the capability to work as a wide scanning terajet-focusing lens. The results here presented may be scaled at different frequency bands such as optical frequencies and may be used in microscopy techniques and sensors.


Concomitant pneumococcal appendicitis, peritonitis, and meningitis.
A 9-year-old boy developed pneumococcal meningitis and peritonitis following appendectomy. Subsequent pathologic examination showed Gram-positive diplococci in the appendix. Cultures of the peritoneal fluid, blood, and spinal fluid showed Diplococcus pneumoniae. The experience illustrates the danger of assuming that all pneumococcus peritonitis is the primary variety and the advisability of routine Gram stain of the peritoneal fluid at operation in order to select the appropriate antibiotic.


Conformational sensitivity of beta-93 cysteine SH to ligation of hemoglobin observed by FT-IR spectroscopy.
The SH vibrational absorption of cysteine F9(beta-93) in concentrated aqueous solutions of native liganded hemoglobin (human HbA, horse, and bovine) has been observed by use of Fourier transform infrared spectroscopy. The pattern of beta-93 SH absorption intensity is ligand dependent. In bovine hemoglobin derivatives the SH absorption intensity pattern is (carbonmonoxy)hemoglobin (HbCO) greater than oxyhemoglobin (HbO2) = cyanomethemoglobin (HbCN) much greater than aquomethemoglobin (metHb) and deoxyhemoglobin (deoxyHb). In horse and human hemoglobin derivatives the pattern is HbCO greater than or equal to HbO2 greater than HbCN greater than metHb. The bovine metHb beta-93 SH shows a much lower absorptivity than that of horse or human metHb, and thus it has a different local tertiary equilibrium conformation than does horse or human hemoglobin. X-ray diffraction studies have shown the beta-93 SH in carbon monoxide or oxygen bound hemoglobin to be situated within a nonpolar pocket between the F, G, and H helices. The higher than usual SH absorption frequency (2592 cm-1) that we observe implies there is no hydrogen bonding for this thiol group while situated within this nonpolar pocket. A similar beta-93 SH absorption has been observed in the beta-chain tetramer (thalassemic hemoglobin H in vivo). The beta-112 SH stretching band, previously observed in the alpha 2 beta 2 tetramer, was observed for the first time in the beta-chain tetramer. A band at 2610 cm-1 that is not due to SH was resolved and found to be ligand dependent.


Burkholderia mimosarum sp. nov., isolated from root nodules of Mimosa spp. from Taiwan and South America.
Fourteen strains were isolated from nitrogen-fixing nodules on the roots of plants of the genus Mimosa growing in Taiwan, Brazil and Venezuela. On the basis of 16S rRNA gene sequence similarities, all of the strains were previously shown to be closely related to each other and to belong to the genus Burkholderia. A polyphasic approach, including DNA-DNA reassociation, whole-cell protein analysis, fatty acid methyl ester analysis and extensive biochemical characterization, was used to clarify the taxonomic position of these strains: all 14 strains were classified as representing a novel species, for which the name Burkholderia mimosarum sp. nov. is proposed. The type strain, PAS44(T) (=LMG 23256(T) =BCRC 17516(T)), was isolated from Mimosa pigra nodules in Taiwan.


The physical and chemical features of Cannabis plants grown in the United Kingdom of Great Britain and Northern Ireland from seeds of known origin--Part II: second generation studies.
A second generation of Cannabis plants has been grown from seeds produced by first generation plants which were raised in the United Kingdom of Great Britain and Northern Ireland from seeds taken from imported cannabis of known geographical origin and chemistry. The gross physical appearance of the second generation plants, in general, resembled their parents and the cannabis produced therefrom was not usually distinguishable from that derived from first generation plants. Although cannabinoid patterns were, in some cases, similar to those of both parents and original seedstock cannabis, there were many exceptions. The yields of cannabis were significantly higher than from first generation plants, but the tetrahydrocannabinol contents were lower. Although higher than in the original imported cannabis, the tetrahydrocannabinolic acid to tetrahydrocannabinol ratios in cannabis from second generation plants were lower than in cannabis produced from first generation plants.


[Validation of a Short Telephone Test (T3MS) for the Diagnosis of Cognitive Impairment].
The identification of cognitive impairment in general practice requires short but accurate tests. For epidemiologic surveys and genetic family studies cognitive tests are desirable which can be administered over the telephone. We assessed the ability of a telephone version of the Modified Mini Mental State Examination (T3MS) to identify mild cognitive impairment (MCI) and mild dementia in Alzheimer's disease (AD) and compared it with the diagnostic accuracy of the conventional Mini Mental State Examination (MMSE). The study refers to 34 patients of the outpatient clinic for cognitive disorders of the technical university of Munich of whom 18 had MCI and 16 had mild dementia in AD, respectively. The study also included 14 cognitively unimpaired age-matched probands. The T3MS and MMST were validated against an expert diagnosis base on a comprehensive diagnostic workup. Statistical analysis was performed using the receiver-operator-characteristics (ROC) method. The T3MS outperformed the MMST in the distinction between MCI patients and cognitively unimpaired individuals. In the separation between cognitively unimpaired probands and patients with mild AD the T3MS achieved a sensitivity and specificity of 100 %. The T3MS is a short and practical but accurate telephone test for the identification of mild dementia in AD for use in epidemiological surveys and genetic family studies. The interview achieves higher diagnostic precision than the MMSE and contributes to a valid assessment of cognitive performance. For the identification of mild cognitive impairment, however, the T3MS was less appropriate.


Understanding assessment on a hospital ward for older people: A qualitative study.
To explore assessment on a hospital ward for older people from the perspectives of patients and healthcare professionals. A qualitative study drawing on grounded theory was undertaken between February 2015 - January 2016. Interviews with 15 patients and 22 healthcare professionals, a focus group with six healthcare professionals, 45 hr of observation and review of 18 sets of patient notes. Analysis was conducted using initial and focused coding, continuously comparing data, emerging codes and themes. The core category was navigating, constructed through three themes: containing complexity, networking, and situating the process. Navigating assessment was a complex, flexible, context dependent, and social process where healthcare professionals used a combination of formal, informal, visible, and invisible ways of working. Registered nurses were at the centre of networking and focused on gathering and sharing information in the multi-disciplinary team, whilst patients had a passive role despite a variety of preferences about their involvement. Navigating the assessment of older people is contextually situated, includes networking and a professional focus on containing complexity. This process may be enhanced by: (a) making informal assessment visible to others; (b) developing the nurses' role beyond chasing information towards coordinating care; and (c) asking patients and acting on how they would like to be involved in decision-making. Acknowledging that navigating assessment is a social, flexible and complex process, including different ways of working to meet patient needs, may enhance the usability of current assessment guidelines and their development.


Let-7c-5p inhibits cell proliferation and induces cell apoptosis by targeting ERCC6 in breast cancer.
In this study, we found that let-7c-5p expression was clearly downregulated in breast cancer tissues compared with that of corresponding adjacent tissues. Furthermore, overexpression of let-7c-5p in MCF-7 breast cancer cells could significantly inhibit cell proliferation and induce cell apoptosis. The target genes of let-7c-5p were predicted by the way of bioinformatics, and validated by dual luciferase reporter assay and western blotting demonstrating that excision repair cross complementing 6 (ERCC6) gene was a direct target. Collectively, the present study suggested that let-7c-5p acted as a tumor suppressor in breast cancer possibly by negatively regulating ERCC6, which took an important part in nucleotide excision repair and it may provide a new potential strategy for breast cancer therapy.


[Growing up with congenital heart disease: neurocognitive outcome, psychopathology and quality of life].
Thank to medical and surgical improvements, a very high percentage of children with congenital heart disease (CHD; about 1% of newborn) reaches adulthood. This population of young surgical and medical patients opens up new challenges in clinical management, including evaluation and optimization of psychosocial functioning and quality of life. Data regarding neurocognitive and psychopathological adaptation, personality and quality of life of CHD patients are rather extensive but still insufficient to guide management approaches to these subjects and to address the numerous emerging problems. The present review analyzes extensively the research literature to find out those variables that may influence development of CHD children. It emerges that a multi-factorial process seems involved in the poor outcome of neurocognitive development in many patients. Notwithstanding the attempts to define risk factors, current researches do not consent definitive conclusions about the determinants of developmental problems in CHD children. An improvement of existential outcome for CHD subjects may be achieved if adequate interventions are carried out. In fact, psychopathological and quality of life in CHD subjects may result even better if elaboration of disease by CHD subjects is adequately supported. On one hand, genetic factors that may contribute to unfavourable evolutions suggest the need for early recognition of subjects at risk. On the other, research should be addressed to the identification of those protective and risk factors related to personality, environmental and relational aspects entailed in the development of CHD subjects.


Least-inclusive taxonomic unit: a new taxonomic concept for biology.
Phylogenetic taxonomy has been introduced as a replacement for the Linnaean system. It differs from traditional nomenclature in defining taxon names with reference to phylogenetic trees and in not employing ranks for supraspecific taxa. However, 'species' are currently kept distinct. Within a system of phylogenetic taxonomy we believe that taxon names should refer to monophyletic groups only and that species should not be recognized as taxa. To distinguish the smallest identified taxa, we here introduce the least-inclusive taxonomic unit (LITU), which are differentiated from more inclusive taxa by initial lower-case letters. LITUs imply nothing absolute about inclusiveness, only that subdivisions are not presently recognized.


Extracellular traps are evident in Romanowsky-stained smears of bronchoalveolar lavage from children with non-cystic fibrosis bronchiectasis.
The importance of extracellular traps (ETs) in chronic respiratory conditions is increasingly recognized but their role in paediatric bronchiectasis is poorly understood. The specialized techniques currently required to study ETs preclude routine clinical use. A simple and cost-effective ETs detection method is needed to support diagnostic applications. We aimed to determine whether ETs could be detected using light microscopy-based assessment of Romanowsky-stained bronchoalveolar lavage (BAL) slides from children with bronchiectasis, and whether the ETs cellular origin could be determined. Archived Romanowsky-stained BAL slides from a cross-sectional study of children with bronchiectasis were examined for ETs using light microscopy. The cellular origin of individual ETs was determined based on morphology and physical contact with surrounding cell(s). ETs were observed in 78.7% (70/89) of BAL slides with neutrophil (NETs), macrophage (METs), eosinophil (EETs) and lymphocyte (LETs) ETs observed in 32.6%, 51.7%, 4.5% and 9%, respectively. ETs of indeterminate cellular origin were present in 59.6% of slides. Identifiable and indeterminate ETs were co-detected in 43.8% of slides. BAL from children with bronchiectasis commonly contains multiple ET types that are detectable using Romanowsky-stained slides. While specialist techniques remain necessary to determining the cellular origin of all ETs, screening of Romanowsky-stained slides presents a cost-effective method that is well-suited to diagnostic settings. Our findings support further research to determine whether ETs can be used to define respiratory endotypes and to understand whether ETs-specific therapies may be required to resolve airway inflammation among children with bronchiectasis.


WOx channel engineering of Cu-ion-driven synaptic transistor array for low-power neuromorphic computing.
The multilevel current states of synaptic devices in artificial neural networks enable next-generation computing to perform cognitive functions in an energy-efficient manner. Moreover, considering large-scale synaptic arrays, multiple states programmed in a low-current regime may be required to achieve low energy consumption, as demonstrated by simple numerical calculations. Thus, we propose a three-terminal Cu-ion-actuated CuOx/HfOx/WO3 synaptic transistor array that exhibits analogously modulated channel current states in the range of tens of nanoamperes, enabled by WO3 channel engineering. The introduction of an amorphous stoichiometric WO3 channel formed by reactive sputtering with O gas significantly lowered the channel current but left it almost unchanged with respect to consecutive gate voltage pulses. An additional annealing process at 450 °C crystallized the WO3, allowing analog switching in the range of tens of nanoamperes. The incorporation of N gas during annealing induced a highly conductive channel, making the channel current modulation negligible as a function of the gate pulse. Using this optimized gate stack, Poole-Frenkel conduction was identified as a major transport characteristic in a temperature-dependent study. In addition, we found that the channel current modulation is a function of the gate current response, which is related to the degree of progressive movement of the Cu ions. Finally, the synaptic characteristics were updated using fully parallel programming and demonstrated in a 7 × 7 array. Using the CuOx/HfOx/WO3 synaptic transistors as weight elements in multilayer neural networks, we achieved a 90% recognition accuracy on the Fashion-MNIST dataset.


Laser vs bur for bone cutting in impacted mandibular third molar surgery: A randomized controlled trial.
The aim of this study was to assess the feasibility of Er: YAG laser in bone cutting for removal of impacted lower third molar teeth and compare its outcomes with that of surgical bur. The study comprised 40 subjects requiring removal of impacted mandibular third molar, randomly categorized into two equal groups of 20 each, who had their impacted third molar removed either using Er: YAG laser or surgical bur as per their group, using standard methodology of extraction of impacted teeth. Clinical parameters like pain, bleeding, time taken for bone cutting, postoperative swelling, trismus, wound healing and complications were compared for both groups. Clinical parameters like pain, bleeding and swelling were lower in laser group than bur group, although the difference was statistically not significant. However, postoperative swelling showed significant difference in the two groups. Laser group required almost double the time taken for bone cutting with bur. Trismus persisted for a longer period in laser group. Wound healing and complications were assessed clinically and there was no significant difference in both the groups. Based on the results of our study, the possibility of bone cutting using lasers is pursued, the osteotomy is easily performed and the technique is better suited to minimally invasive surgical procedures. The use of Er: YAG laser may be considered as an alternative tool to surgical bur, specially in anxious patients.


Pasteurisation and the control of milkborne infection in Britain.
Infections carried in milk, particularly salmonellosis and campylobacter enteritis, have continued to feature in Great Britain in recent years. Less commonly reported infections included an outbreak in 1984 in England due to Streptococcus zooepidemicus, in which 12 people, eight of whom died, were admitted to hospital. The implementation of legislation in 1983 requiring heat treatment of cows' milk for sale to the public reduced the incidence of milkborne infection in Scotland compared with previous years and compared with England and Wales, where, without legislative control, outbreaks continue to occur. Until compulsory pasteurisation is introduced throughout Britain and dairy farming communities can be persuaded to drink only heat treated milk outbreaks of milkborne infection will continue.


Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: a pilot study of six candidate genes.
The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted.


Strikingly different effects of hydrogen bonding on the photodynamics of individual nucleobases in DNA: comparison of guanine and cytosine.
Ab initio surface hopping dynamics calculations were performed to study the photophysical behavior of cytosine and guanine embedded in DNA using a quantum mechanical/molecular mechanics (QM/MM) approach. It was found that the decay rates of photo excited cytosine and guanine were affected in a completely different way by the hydrogen bonding to the DNA environment. In case of cytosine, the geometrical restrictions exerted by the hydrogen bonds did not influence the relaxation time of cytosine significantly due to the generally small cytosine ring puckering required to access the crossing region between excited and ground state. On the contrary, the presence of hydrogen bonds significantly altered the photodynamics of guanine. The analysis of the dynamics indicates that the major contribution to the lifetime changes comes from the interstrand hydrogen bonds. These bonds considerably restricted the out-of-plane motions of the NH(2) group of guanine which are necessary for the ultrafast decay to the ground state. As a result, only a negligible amount of trajectories decayed into the ground state for guanine embedded in DNA within the simulation time of 0.5 ps, while for comparison, the isolated guanine relaxed to the ground state with a lifetime of about 0.22 ps. These examples show that, in addition to phenomena related to electronic interactions between nucleobases, there also exist relatively simple mechanisms in DNA by which the lifetime of a nucleobase is significantly enhanced as compared to the gas phase.


Effects of Tryptophan Supplementation and Exercise on the Fate of Kynurenine Metabolites in Mice and Humans.
The kynurenine pathway of tryptophan (TRP) degradation (KP) generates metabolites with effects on metabolism, immunity, and mental health. Endurance exercise training can change KP metabolites by changing the levels of KP enzymes in skeletal muscle. This leads to a metabolite pattern that favors energy expenditure and an anti-inflammatory immune cell profile and reduces neurotoxic metabolites. Here, we aimed to understand if TRP supplementation in untrained vs. trained subjects affects KP metabolite levels and biological effects. Our data show that chronic TRP supplementation in mice increases all KP metabolites in circulation, and that exercise reduces the neurotoxic branch of the pathway. However, in addition to increasing wheel running, we did not observe other effects of TRP supplementation on training adaptations, energy metabolism or behavior in mice. A similar increase in KP metabolites was seen in trained vs. untrained human volunteers that took a TRP drink while performing a bout of aerobic exercise. With this acute TRP administration, TRP and KYN were higher in the trained vs. the untrained group. Considering the many biological effects of the KP, which can lead to beneficial or deleterious effects to health, our data encourage future studies of the crosstalk between TRP supplementation and physical exercise.


[Psychosocial functioning of adults with late diagnosed autism spectrum disorders--a retrospective study].
The first time diagnosis of autism spectrum disorder (ASD) after passing childhood and adolescence is still considered a rare event. However, in recent years an increasing demand for diagnostic clarifications with suspected ASD in adulthood challenges this view. There is insufficient knowledge about the neuropsychological characterisation and psychosocial outcome of this adult subgroup in the autistic spectrum. To determine the psychosocial functioning (living status, partnerships, level of education, psychiatric history) of adult patients with late diagnosed ASD. In a retrospective study, a chart review was conducted on 178 consecutively diagnosed individuals at a specialised outpatient clinic for adults with ASD. Global ratings of psychosocial functioning, assessment of psychiatric history and neuropsychological and psychopathological investigations were evaluated. The majority of patients (92 %) diagnosed with ASD suffered from high-functioning autism (HFA)/Asperger syndrome (AS) according to the criteria of ICD-10 (F84.5). The gender ratio was 2:1 favouring males. Mean age at diagnosis (34.1 ± 9.5 years), general intelligence (HAWIE-R, global-IQ 115 ± 20) and self-rated autistic symptoms (autism spectrum quotient [AQ] 39 ± 6) were not discriminative to gender. The psychiatric history revealed a lifetime consultation rate of 78 %, most frequently with depression (50 %). The self-report instrument Beck depression inventory (BDI) identified 30 % of individuals presenting with depressive symptoms in clinical relevant intensity (BDI > 17). Achievement of an independent living status was reported by 68 % of individuals, 58 % reported about current or past intimate partnerships and almost two-thirds of the patients had achieved a higher educational status. The majority of ASD diagnosed late in lifetime turned out to be HFA/AS, presenting with high psychosocial adjustment with regard to independent living, educational status and partnerships. The high level of global intelligence supports the hypothesis of cognitively compensated autistic disturbances leading to the diagnosis comparably late in lifetime. The lifetime rate of psychiatric consultations is high, reflecting the importance to consider a diagnosis of ASD even late in life.


A gC1qR prevents white spot syndrome virus replication in the freshwater crayfish Pacifastacus leniusculus.
The gC1qR/p32 protein is a multiple receptor for several proteins and pathogens. We cloned a gC1qR homologue in a crustacean, Pacifastacus leniusculus, and analyzed the expression of P. leniusculus C1qR (PlgC1qR) in various tissues. The gC1qR/p32 transcript was significantly enhanced by white spot syndrome virus (WSSV) infection 6 h after viral infection both in vitro in a hematopoietic tissue cell culture (Hpt) and in vivo compared to appropriate controls. Moreover, PlgC1qR silencing in both the Hpt cell culture and live crayfish enhanced the WSSV replication. In addition, by making a recombinant PlgC1qR protein we could show that if this recombinant protein was injected in a crayfish, Pacifastacus leniusculus, followed by injection of WSSV, this significantly reduced viral replication in vivo. Furthermore, if the recombinant PlgC1qR was incubated with Hpt cells and then WSSV was added, this also reduced viral replication. These experiments clearly demonstrate that recombinant PlgC1qR reduce WSSV replication both in vivo and in vitro. The results from a far-Western overlay and glutathione S-transferase pull-down assays showed that PlgC1qR could bind to VP15, VP26, and VP28. Altogether, these results demonstrate a role for PlgC1qR in antiviral activity against WSSV.


Identification of Potential Migrants in Polyethylene Terephthalate Samples of Ecuadorian Market.
Polyethylene terephthalate (PET) is the plastic packaging material most widely used to produce bottles intended for contact with food and beverages. However, PET is not inert, and therefore, some chemical compounds present in PET could migrate to food or beverages in contact, leading to safety issues. To evaluate the safety of PET samples, the identification of potential migrants is required. In this work, eight PET samples obtained from the Ecuadorian market at different phases of processing were studied using a well-known methodology based on a solvent extraction followed by gas chromatography-mass spectrometry analysis and overall migration test. Several chemical compounds were identified and categorized as lubricants (carboxylic acids with chain length of C12 to C18), plasticizers (triethyl phosphate, diethyl phthalate), thermal degradation products (p-xylene, benzaldehyde, benzoic acid), antioxidant degradation products (from Irgafos 168 and Irganox), and recycling indicator compounds (limonene, benzophenone, alkanes, and aldehydes). Additionally, overall migration experiments were performed in PET bottles, resulting in values lower than the overall migration limit (10 mg/dm2); however, the presence of some compounds identified in the samples could be related to contamination during manufacturing or to the use of recycled PET-contaminated flakes. In this context, the results obtained in this study could be of great significance to the safety evaluation of PET samples in Ecuador and would allow analyzing the PET recycling processes and avoiding contamination by PET flakes from nonfood containers.


Suitability of leguminous cover crop pollens as food source for the green lacewing Chrysoperla externa (Hagen) (Neuroptera: Chrysopidae).
Diversification of crops with species that provide suitable pollen for predators may reduce pest population on crops by enhancing predator effectiveness. In this paper we evaluated the suitability of leguminous cover crop pollens to the predatory green lacewing Chrysoperla externa (Hagen). The predator is commonly found in coffee agroecosystems and the plant species tested were pigeon pea and sunn hemp, which are used in organic coffee systems. Newly emerged females and males of C. externa were reared on diets containing pollen of pigeon pea, sunn hemp, or castor bean, used as a control. The reproductive success of C. externa was evaluated when females fed the pollen species and when honey was added to the diets, to verify the predator need for an extra carbohydrate source. Similar intrinsic growth rates were found for females fed on pigeon pea pollen and on sunn hemp pollen but these rates increased significantly when honey was added to the diets. Females fed with pigeon pea pollen plus honey and with sunn hemp pollen plus honey had higher intrinsic growth rates than those fed with castor bean pollen plus honey. Females fed on castor bean pollen only or on honey only, did not oviposit. Leguminous pollen species were equally suitable for C. externa especially when they were complemented with honey. The results suggest that to successfully enhance predator effectiveness, organic coffee plantation should be diversified with plant providing pollen in combination with plant providing nectar.


Expansion and molecular evolution of the interferon-induced 2'-5' oligoadenylate synthetase gene family.
The mammalian 2'-5' oligoadenylate synthetases (2'-5'OASs) are enzymes that are crucial in the interferon-induced antiviral response. They catalyze the polymerization of ATP into 2'-5'-linked oligoadenylates which activate a constitutively expressed latent endonuclease, RNaseL, to block viral replication at the level of mRNA degradation. A molecular evolutionary analysis of available OAS sequences suggests that the vertebrate genes are members of a multigene family with its roots in the early history of tetrapods. The modern mammalian 2'-5'OAS genes underwent successive gene duplication events resulting in three size classes of enzymes, containing one, two, or three homologous domains. Expansion of the OAS gene family occurred by whole-gene duplications to increase gene content and by domain couplings to produce the multidomain genes. Evolutionary analyses show that the 2'-5'OAS genes in rodents underwent gene duplications as recently as 11 MYA and predict the existence of additional undiscovered OAS genes in mammals.


Mitogen-activated protein kinase activation down-regulates a mechanism that inactivates cyclin B-cdc2 kinase in G2-arrested oocytes.
The G2 arrest of oocytes from frogs, clams, and starfish requires that preformed cyclin B-cdc2 complexes [prematuration-promoting factor (MPF)] be kept in an inactive form that is largely due to inhibitory phosphorylation of this pre-MPF. We have investigated the role of mitogen-activated protein (MAP) kinase in the activation of this pre-MPF. The cytoplasm of both frog and starfish oocytes contains an activity that can rapidly inactivate injected MPF. When the MAP kinase of G2-arrested starfish or Xenopus oocytes was prematurely activated by microinjection of c-mos or Ste-11 delta N fusion proteins, the rate and extent of MPF inactivation was much reduced. Both effects were suppressed by expression of the specific MAP kinase phosphatase Pyst 1. These results show that MAP kinase down-regulates a mechanism that inactivates cyclin B-cdc2 kinase in Xenopus oocytes. In starfish oocytes, however, MAP kinase activation occurs only after germinal vesicle breakdown, much after MPF activation. In this case, down-regulation of the cyclin B-cdc2 inhibiting pathway is a sensitive response to hormonal stimulation that does not require MAP kinase activation.


Megakaryocyte maturation in long-term marrow culture.
Evidence has been sought for megakaryocyte maturation in long-term cultures of mouse bone marrow. Cultures up to 14 weeks of age were examined for the presence of megakaryocytes with processes, that is, resembling the morphological appearance seen in vivo prior to platelet liberation. Such cells were found floating just above the adherent stromal layer using low magnification phase contrast microscopy. It was rare to observe as many as 20 of these cells per 25-cm2 flask. At higher magnification, processes were seen to be attenuated with constrictions at intervals along their length. Time-lapse photography was used to follow the development and behavior of the processes. Direct evidence of rupture was very rare; generally the megakaryocytes retracted their processes within 48 h. Careful searching of cultures occasionally revealed the presence of several process fragments, and sometimes individual platelets were found. Ultrastructurally, the processes were seen to contain organelles that are usually associated with platelets. The observations applied to both Dexter and Whitlock-Witte cultures. It is concluded that maturation of megakaryocytes occurs in long-term marrow culture to the point where platelet release appears imminent. Final rupture is rare and may require shearing forces, which in vivo would be provided by blood flow.


Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys.
Rationale: Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and progressive chronic kidney disease (CKD). Exosome-mediated cell-cell communication has been suggested to be involved in various diseases, including renal fibrosis. However, little is known regarding how exosomes regulate renal fibrosis in obstructed kidneys. Methods: We first examined the secretion of exosomes in UUO (unilateral ureteral obstruction) mouse kidneys and TGF-β1-stimulated tubular epithelial cells (NRK-52E). Exosomes from NRK-52E cells were subsequently harvested and incubated with fibroblasts (NRK-49F) or injected into UUO mice via the tail vein. We next constructed Rab27a knockout mice to further confirm the role of exosome-mediated epithelial-fibroblast communication relevant to renal fibrosis in UUO mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of TGFβ1-Exos. The roles of candidate miRNAs, their target genes and relevant pathways were predicted and assessed in vitro and in vivo by setting specific miRNA mimic, miRNA inhibitor, siRNA or miRNA LNA groups. Results: Increased renal fibrosis was associated with prolonged UUO days, and the secretion of exosomes was markedly increased in UUO kidneys and TGF-β1-stimulated NRK-52E cells. Purified exosomes from TGF-β1-stimulated NRK-52E cells could activate fibroblasts and aggravate renal fibrosis in vitro and in vivo. In addition, the inhibition of exosome secretion by Rab27a knockout or GW4869 treatment abolished fibroblast activation and ameliorated renal fibrosis. Exosomal miR-21 was significantly increased in TGFβ1-Exos compared with Ctrl-Exos, and PTEN is a certain target of miR-21. The promotion or inhibition of epithelial exosomal miR-21 correspondingly accelerated or abolished fibroblast activation in vitro, and renal fibrosis after UUO was alleviated by miR-21-deficient exosomes in vivo through the PTEN/Akt pathway. Conclusion: Our findings reveal that exosomal miR-21 from tubular epithelial cells may accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway in obstructed kidneys.


Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review
Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. Over the last few years, we have witnessed several new developments in the pathogenesis, genetic testing, diagnosis, comorbidities, disease related damage and treatment approaches to FMF. Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers. Clinically, although FMF is considered an episodic disease characterized by brief attacks, recent systematic studies have defined several associated chronic inflammatory conditions. Colchicine is the mainstay of FMF treatment, and interleukin (IL)-1 antagonists are the treatment of choice in refractory or intolerant cases. Experience of IL-1 antagonists, anakinra and canakinumab, is now available in thousands of colchicine resistant or intolerant FMF patients. In this contemporary review, we surveyed current FMF knowledge in the light of these recent advances.


Functional angiography.
The discovery of X-rays over a century ago enabled noninvasive examination of the human body. Contrast agents that enhanced X-ray images were soon developed that advanced angiology by allowing exploration of the vascular tree. Starting as a diagnostic tool, angiography underwent technological transformations over the last century and became a basis for interventional therapy as well. Initially a static two-dimensional record of the vasculature on screen films, angiography has evolved to real-time two-dimensional display of the vasculature on television monitors, three-dimensional reconstruction from computerized tomographic (CT) scans, and, more recently, three-dimensional cone-beam reconstruction. Cinematographic angiography is referred to as dynamic angiography in current terminology, but it essentially provides no more than images of vascular structures and changes therein. Although dynamic angiography has facilitated advances in image-guided interventions, the evaluation of blood flow rate, or perfusion, and blood flow velocity using angiography remains elusive. Many lines of research have been pursued toward enabling such evaluations, but none have found their way into clinical practice. This article reviews angiographic flow assessment methods attempted over the past several decades and explores some new avenues that may facilitate the transfer of such methods into the clinical practice of diagnostic and interventional angiography and, eventually, contribute to better patient care.


Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis.
Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, which have key roles in eosinophilic esophagitis. We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (≤6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia). In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P<0.001). In Part B, histologic remission occurred in 47 of 80 patients (59%) with weekly dupilumab, in 49 of 81 patients (60%) with dupilumab every 2 weeks, and in 5 of 79 patients (6%) with placebo (difference between weekly dupilumab and placebo, 54 percentage points; 95% CI, 41 to 66 [P<0.001]; difference between dupilumab every 2 weeks and placebo, 56 percentage points; 95% CI, 43 to 69 [not significant per hierarchical testing]). The mean (±SD) DSQ scores at baseline were 33.6±12.41 in Part A and 36.7±11.22 in Part B; the scores improved with weekly dupilumab as compared with placebo, with differences of -12.32 (95% CI, -19.11 to -5.54) in Part A and -9.92 (95% CI, -14.81 to -5.02) in Part B (both P<0.001) but not with dupilumab every 2 weeks (difference in Part B, -0.51; 95% CI, -5.42 to 4.41). Serious adverse events occurred in 9 patients during the Part A or B treatment period (in 7 who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo) and in 1 patient in the Part A-C group during the Part C treatment period who received placebo in Part A and weekly dupilumab in Part C. Among patients with eosinophilic esophagitis, subcutaneous dupilumab administered weekly improved histologic outcomes and alleviated symptoms of the disease. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03633617.).


[Tuberculous peripheral multifocal choroiditis].
A healthy 57 year-old woman with past untreated pulmonary tuberculosis, disclosed a bilateral uveitic syndrome characte rized by iritis, vitreitis, multiple peripheral retinal punched-out lesions, and cystoid macular edema. Systemic evaluation was unremarkable except for a 30 mm tuberculin skin test. Relapses occurred after oral and periocular corticosteroids were interrupted, but the inflammation completely disappeared after a 6 month course of isoniazid, rifampicin and pyrazinamide. Intraocular tuberculosis should be considered as a treatable cause of peripheral multifocal choroiditis, after ruling out other etiologies.


A combined frequency domain near infrared spectroscopy and diffuse correlation spectroscopy system for comprehensive metabolic monitoring of inspiratory muscles during loading.
Mechanical ventilation (MV) is a cornerstone technology in the intensive care unit as it assists with the delivery of oxygen in critical ill patients. The process of weaning patients from MV can be long, and arduous and can lead to serious complications for many patients. Despite the known importance of inspiratory muscle function in the success of weaning, current clinical standards do not include direct monitoring of these muscles. The goal of this project was to develop and validate a combined frequency domain near infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) system for the noninvasive characterization of inspiratory muscle response to a load. The system was fabricated by combining a custom digital FD-NIRS and DCS system. It was validated via liquid phantom titrations and a healthy volunteer study. The sternocleidomastoid (SCM), an accessory muscle of inspiration, was monitored during a short loading period in fourteen young healthy volunteer. Volunteers performed two different respiratory exercises, a moderate and high load, which consisted of a one-minute baseline, a one-minute load, and a six-minute recovery period. The system has low crosstalk between absorption, reduced scattering, and flow when tested in a set of liquid titrations. Faster dynamics were observed for changes in blood flow index (BF i ), and metabolic rate of oxygen (MRO 2 ) compared to hemoglobin + myoglobin (Hb+Mb) based parameters after the onset of loads in males. Additionally, larger percent changes in BF i , and MRO 2 were observed compared to Hb+Mb parameters in both males and females. There were also sex differences in baseline values of oxygenated Hb+Mb, total Hb+Mb, and tissue saturation. The dynamic characteristics of Hb+Mb concentration and blood flow were distinct during loading of the SCM, suggesting that the combination of FD-NIRS and DCS may provide a more complete picture of inspiratory muscle dynamics.


Metatarsus Primus Elevatus Resolution After First Metatarsophalangeal Joint Arthroplasty.
Hallux limitus (HL) is the second-most common pathology associated with the first metatarsophalangeal joint. A common etiology believed to be associated with HL is metatarsus primus elevatus (MPE), although causation has been unsubstantiated by evidence. Historically, correction of MPE is surgically addressed with an osteotomy. However, some believe MPE is a secondary manifestation of HL due to retrograde pressure and lack of dorsiflexion at the first metatarsophalangeal joint. This study sought to determine whether MPE resolves spontaneously after first metatarsophalangeal joint arthroplasty and reinstitution of normal joint dorsiflexion. Twenty-seven weightbearing lateral radiographs from patients with HL were reviewed before and after nonimplant first metatarsophalangeal joint arthroplasty. Radiographs were taken preoperatively and at postoperative visits 1 (mean, 2 weeks) and 2 (mean, 10 weeks). Measurements included first to second metatarsal elevation, Seiberg Index, first to fifth metatarsal distance, sagittal plane first to second metatarsal angle, Meary's angle, metatarsal declination angle, and hallux equinus angle. Statistically significant improvement was seen at both postoperative visits in all of the previously mentioned measurements except first to fifth metatarsal distance, which was reduced but was not statistically significant. Metatarsus primus elevatus was reduced significantly after first metatarsophalangeal joint arthroplasty. Resolution occurred rapidly and was maintained at the final postoperative visit. This could be due to MPE being a manifestation of HL and not a cause. Based on the results of this study, osteotomies may be unnecessary to surgically address MPE because it can spontaneously correct after reinstitution of first metatarsophalangeal joint motion.


Efficacy of Cabazitaxel Treatment in Metastatic Castration Resistant Prostate Cancer in Second and Later Lines. An Experience from Two German Centers.
Purpose: Several new treatment options for patients with metastatic castration resistant prostate cancer (mCRPC) have been approved within the last years - among them cabazitaxel (CAB), abiraterone acetate, enzalutamide, and radium-223. The aim of this study was to assess factors predictive for efficacy of CAB. Methods: We analyzed all patients with mCRPC treated with CAB at our institutions between 2011 and 2016. Data were retrieved retrospectively from the electronical patient chart. Results: 69 patients received CAB (26.1% 2nd line, 36.2% 3rd line, 37.3% >3rd line). Median overall survival (OS) on CAB was 10.0 months (95%CI 7.1-12.9). Median progression free survival (PFS) on CAB was 3.9 months (95%CI 3.0-4.8). There were no differences in OS and PFS regarding treatment line of CAB (2nd vs. higher; 2nd/3rd vs. higher). Duration of remission on 1st line treatment (> 6 months vs. </= 6 months) was associated with a longer PFS with subsequent CAB treatment (4.1 months vs. 3.0 months (95%CI 3.0-5.2; 2.2-3.8); p=0.021). Patients with visceral metastases had a shorter PFS (3.0 months; 95%CI 2.6-3.3) and OS (8.7 months; 95%CI 5.9-11.5) on CAB compared to patients who had bone and/or lymph node lesions only (PFS: 5.8 months; 95%CI 3.2-8.4; p=0.014; OS: 11.7 months; 95%CI 7.5-15.9; p=0.042). Conclusions: Results from our patient cohort suggest that a longer PFS to any 1st line treatment for mCRPC is correlated with a longer PFS to CAB for any later line treatment. Patients with nodal and bone metastases only had a significantly superior PFS and OS with CAB treatment than patients with visceral metastases.


Organochlorine pesticides and polychlorinated biphenyl congeners in lanner Falco biarmicus feldeggli Schlegel chicks and lanner prey in Sicily, Italy.
This paper reports on research conducted to elucidate the risk posed to the Sicilian population of the endangered lanner falcon Falco biarmicus feldeggii Schlegel by organochlorine (OC) pesticides and polychlorinated biphenyls (PCBs), as part of a wider study on contaminant risk to the lanner. Seventeen lanner nest sites were studied in northern and central Sicily. Sampling (in 2005) and analysis were carried out for selected OC pesticides and PCB congeners in lanner chick blood (15 chicks from 6 nest sites) and in two of the main lanner prey species, magpie Pica pica (36 individuals from 6 lanner nest sites) and rock dove Columba livia (10 individuals from 2 lanner nest sites). No OC and PCB residues were found in lanner chick blood above the detection limits, except for one solitary congener PCB153 (21.8 ng g(-1) wet weight), suggesting that these contaminants do not pose a significant risk to lanner chicks in the study area. Magpie and dove appeared mostly free of contamination with OC pesticides, though contamination levels were significantly higher in magpie than in dove. The presence of exceptional DDE and HEOD values in approximately 8% of the P. pica sample, and one P. pica sample showing recent DDT contamination, may indicate a local OC pesticide hazard to some lanner. Future research to further elucidate the contaminant risk to lanner in Sicily is suggested.


Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects.
The extract of the white-skinned sweet potato Ipomoea batatas (Caiapo) has been shown to ameliorate glucose control by improving insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). The present study was designed to further evaluate its mode of action on insulin sensitivity over an extended period of time as well as the effects on fibrinogen and other markers of low-grade inflammation. In this randomized trial, 27 patients with T2DM on diet only received 4 g of Caiapo daily for 5 months; 34 patients placebo. Before and after therapy, insulin sensitivity [oral glucose insulin sensitivity (OGIS), as glucose clearance from oral glucose tolerance test], parameters of diabetes control, lipids, plasma adiponectin, high-sensitivity C-reactive protein (hs-CRP) and fibrinogen were measured. Following Caiapo, we observed an increase in OGIS (293 +/- 15 vs. 321 +/- 12 ml/m(2)/min, p = 0.0072) and adiponectin (5.97 +/- 0.65 to 6.63 +/- 0.70 microg/ml, p = 0.013), while fibrinogen decreased from 3.83 +/- 0.16 to 3.64 +/- 0.18 mg/ml (p = 0.02). This was associated with an improvement in glycated haemoglobin (HbA1c: 6.46 +/- 0.12 vs. 6.25 +/- 0.11%, p = 0.008), fasting glucose (138 +/- 4 vs. 128 +/- 5 mg/dl, p = 0.039) and triglycerides (2.36 +/- 0.22 vs. 2.07 +/- 0.25 mmol/l, p = 0.032). Body weight, lipid levels and hs-CRP were not altered. No changes were observed in the placebo group except for HbA1c, which significantly increased from 6.25 +/- 0.10 to 6.50 +/- 0.12% (p = 0.0001). This study confirms the beneficial effects of Caiapo on glucose and HbA1c control in patients with T2DM after 5 months follow-up. Improvement of insulin sensitivity was accompanied by increased levels of adiponectin and a decrease in fibrinogen. Thus, Caiapo can be considered as natural insulin sensitizer with potential antiatherogenic properties.


Pioglitazone-Mediated Peroxisome Proliferator-Activated Receptor γ Activation Aggravates Murine Immune-Mediated Hepatitis.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates target gene expression upon ligand binding. Apart from its effects on metabolism, PPARγ activity can inhibit the production of pro-inflammatory cytokines by several immune cells, including dendritic cells and macrophages. In chronic inflammatory disease models, PPARγ activation delays the onset and ameliorates disease severity. Here, we investigated the effect of PPARγ activation by the agonist Pioglitazone on the function of hepatic immune cells and its effect in a murine model of immune-mediated hepatitis. Cytokine production by both liver sinusoidal endothelial cells (IL-6) and in T cells ex vivo (IFNγ) was decreased in cells from Pioglitazone-treated mice. However, PPARγ activation did not decrease pro-inflammatory tumor necrosis factor alpha TNFα production by Kupffer cells after Toll-like receptor (TLR) stimulation ex vivo. Most interestingly, although PPARγ activation was shown to ameliorate chronic inflammatory diseases, it did not improve hepatic injury in a model of immune-mediated hepatitis. In contrast, Pioglitazone-induced PPARγ activation exacerbated D-galactosamine (GalN)/lipopolysaccharide (LPS) hepatitis associated with an increased production of TNFα by Kupffer cells and increased sensitivity of hepatocytes towards TNFα after in vivo Pioglitazone administration. These results unravel liver-specific effects of Pioglitazone that fail to attenuate liver inflammation but rather exacerbate liver injury in an experimental hepatitis model.


Prognostic prediction models for diabetic retinopathy progression: a systematic review.
With the increasing incidence of diabetic retinopathy and its improved detection, there is increased demand for diabetic retinopathy treatment services. Prognostic prediction models have been used to optimise services but these were intended for early detection of sight-threatening retinopathy and are mostly used in diabetic retinopathy screening services. We wanted to look into the predictive ability and applicability of the existing models for the higher-risk patients referred into hospitals. We searched MEDLINE, EMBASE, COCHRANE CENTRAL, conference abstracts and reference lists of included publications for studies of any design using search terms related to diabetes, diabetic retinopathy and prognostic models. Search results were screened for relevance to the review question. Included studies had data extracted on model characteristics, predictive ability and validation. They were assessed for quality using criteria specified by PROBAST and CHARMS checklists, independently by two reviewers. Twenty-two articles reporting on 14 prognostic models (including four updates) met the selection criteria. Eleven models had internal validation, eight had external validation and one had neither. Discriminative ability with c-statistics ranged from 0.57 to 0.91. Studies ranged from low to high risk of bias, mostly due to the need for external validation or missing data. Participants, outcomes, predictors handling and modelling methods varied. Most models focussed on lower-risk patients, the majority had high risk of bias and doubtful applicability, but three models had some applicability for higher-risk patients. However, these models will also need updating and external validation in multiple hospital settings before being implemented into clinical practice.


Utility of modified Rankin Scale for brain vascular malformations in hereditary hemorrhagic telangiectasia.
Approximately 10% of hereditary hemorrhagic telangiectasia (HHT) patients harbour brain vascular malformations (VMs). Intracranial hemorrhage (ICH) from brain VMs can lead to death or morbidity, while treatment options for brain VMs also have associated morbidity. The modified Rankin Scale (mRS) may provide an approach to identifying HHT-brain VM patients with poor outcomes, and their predictors. We aimed to measure the relationship between mRS score and brain VM, brain VM number, as well as other aspects of HHT, at enrollment and during prospective follow-up. 1637 HHT patients (342 with brain VMs) were recruited from 14 HHT centres of the Brain Vascular Malformation Consortium since 2010 and followed prospectively (mean = 3.4 years). We tested whether the presence of brain VM, other HHT organ involvement, and HHT mutation genotype were associated with worse mRS scores at baseline and during follow-up, using linear mixed models, adjusting for age, sex, and year of visit. Presence of brain VMs was not associated with worse mRS score at baseline and there was no significant worsening of mRS with prospective follow-up in these patients; 92% had baseline mRS of 0-2. HHT-related gastrointestinal (GI) bleeding was associated with worse mRS scores at baseline (0.37, 95% CI 0.26-0.47, p < 0.001), as were history of anemia (0.35, 95% CI 0.27-0.43, p < 0.001) and liver VMs (0.19, 95% CI 0.09-0.30, p < 0.001). Presence of pulmonary arteriovenous malformations (AVMs) was not associated with worse mRS scores at baseline. mRS score was not associated with either HHT genotype (Endoglin vs ACVRL1). Only GI bleeding was associated with a significantly worsening mRS during prospective follow-up (0.64, 95% CI 0.21-1.08, p = 0.004). Most HHT-brain VM patients had good functional capacity (mRS scores 0-2) at baseline that did not change significantly over 3.4 mean years of follow-up, suggesting that mRS may not be useful for predicting or measuring outcomes in these patients. However, HHT patients with GI bleeding, anemia history or liver VMs had worse mRS scores, suggesting significant impact of these manifestations on functional capacity. Our study demonstrates the insensitivity of the mRS as an outcomes measure in HHT brain VM patients and reinforces the continued need to develop outcomes measures, and their predictors, in this group.


Mesangial cells initiate compensatory renal tubular hypertrophy via IL-10-induced TGF-beta secretion: effect of the immunomodulator AS101 on this process.
The present study investigated the role of IL-10 produced by the mesangial cells in postnephrectomy compensatory renal growth and the effect of the immunomodulator AS101 on this process. One hundred forty unilateral nephrectomized and sham-operated male Sprague-Dawley rats were treated by AS101 or PBS before and after surgery. The results show that secretion of IL-10 and TGF-beta by mesangial cells isolated from the remaining kidneys was increased significantly, compared with those of control and sham animals. Moreover, TGF-beta secretion by mesangial cells was increased after the addition of exogenous recombinant IL-10 and inhibited in the presence of neutralizing anti-IL-10 antibodies. In vivo, compensatory growth of the remaining kidneys was associated with significant increase in IL-10 content in renal tissues and plasma. Immunohistochemical studies show that IL-10 was produced by mesangial cells. Elevated IL-10 levels were followed by the rise in TGF-beta content in plasma and renal tissue. AS101 treatment decreased IL-10 and TGF-beta expression in plasma and kidney tissues and results in 25% reduction in the fresh and fractional kidney weight and decreased hypertrophy of tubular cells (protein/DNA ratio, morphometric analysis). Taken together, these data demonstrate that TGF-beta production by mesangial cells is IL-10 dependent. Mesangial cells are the major source of IL-10 in kidneys. AS101, by inhibiting the activity of IL-10, decreases TGF-beta production by mesangial cells, thus limiting compensatory tubular cell hypertrophy.


Rules of order in the retinotectal fascicles of goldfish.
Individual fascicles of retinal axons were labeled in the goldfish tectum with horseradish peroxidase (HRP). The contralateral retina was later processed for HRP histochemistry to mark the cells that had axons in the fascicles. Labeled cells were found in a partial half anulus in ventral hemiretina, centered on the optic disk. The distance of the partial anulus from the disk depended on which tectal fascicle had been labeled; the more rostrocentral the fascicle, the smaller was the annular radius. The angular subtense of the partial anulus with respect to the disk depended on where (along its tectal course) the fascicle had been labeled; the more rostral the label site, the longer was the angular subtense. These results were interpreted in the context of retinotectal growth, and it was inferred that the axons followed two rules: (1) grow in along the edge of the tectum and (2) exit and terminate in order, axons from temporal retina first, nasal retina last. These rules would produce a retinotopic projection in peripheral tectum, but they require that some of the terminals already in place must shift as the tectum grows.


[Use of thiamine for correcting the immune response during physical loading].
A study was made of the effect of thiamine on the development of the immune response under exercise. It was established that the 4-hour swimming inhibited the development of the immune response to sheep red blood cells in Wistar rats fed about 40 g thiamine per day with the diet. Additional administration of 100 g vitamin increased the intensity of the immune response after exercise. The serum from the swimming rats suppressed the development of the immune response in intact animals. Thiamine did not produce any effect on the exercise-induced synthesis and release of immunosuppressant factors but reduced the sensitivity of effector cells of the humoral immune response to the action of those factors.


Formation of Pentylpyridines in an Oil Medium.
The effects of an oil medium on the release of free ammonia from each of five amino acids (glycine, L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine) and the formation of pentylpyridines were studied. Among the five amino acids, only asparagine and glutamine generated ammonia readily by deamidation of amide side chains at 180 degrees C under oil conditions, even though both of them produced less ammonia than under aqueous conditions. However, the difference in the relative amounts of ammonia released between asparagine and glutamine was larger under oil conditions and much more free ammonia was liberated from glutamine than from asparagine. On the other hand, when each of the five amino acids was reacted with 2,4-decadienal under oil conditions, an increased amount of 2-pentylpyridine could be produced from asparagine and glutamine compared to aqueous conditions. Specifically, >10 times the amount of 2-pentylpyridine was found in the reaction of glutamine and 2,4-decadienal under oil conditions than under aqueous conditions despite the fact that both asparagine and glutamine could liberate less ammonia in oil systems. However, only a small amount of 3-pentylpyridine was formed in the asparagine and glutamine that produced a large amount of 2-pentylpyridine under oil conditions.


Measuring hospital performance in congenital heart surgery: administrative versus clinical registry data.
In congenital heart surgery, hospital performance has historically been assessed using widely available administrative data sets. Recent studies have demonstrated inaccuracies in case ascertainment (coding and inclusion of eligible cases) in administrative versus clinical registry data; however, it is unclear whether this impacts assessment of performance on a hospital level. Merged data from The Society of Thoracic Surgeons (STS) database (clinical registry) and the Pediatric Health Information Systems (PHIS) database (administrative data set) for 46,056 children undergoing cardiac operations (2006-2010) were used to evaluate in-hospital mortality for 33 hospitals based on their administrative versus registry data. Standard methods to identify/classify cases were used: Risk Adjustment in Congenital Heart Surgery, version 1 (RACHS-1) in the administrative data and STS-European Association for Cardiothoracic Surgery (STAT) methodology in the registry. Median hospital surgical volume based on the registry data was 269 cases per year; mortality was 2.9%. Hospital volumes and mortality rates based on the administrative data were on average 10.7% and 4.7% lower, respectively, although this varied widely across hospitals. Hospital rankings for mortality based on the administrative versus registry data differed by 5 or more rank positions for 24% of hospitals, with a change in mortality tertile classification (high, middle, or low mortality) for 18% and a change in statistical outlier classification for 12%. Higher volume/complexity hospitals were most impacted. Agency for Healthcare Quality and Research (AHRQ) methods in the administrative data yielded similar results. Inaccuracies in case ascertainment in administrative versus clinical registry data can lead to important differences in assessment of hospital mortality rates for congenital heart surgery.


[Combination of Libman-Sacks endocarditis with infectious endocarditis].
Out of 242 patients treated for systemic lupus erythematosus (SLE) in Novosibirsk for 15 years, valvular lesions and endocarditis were diagnosed in 41(16.9%) patients. Combination of Libman-Sax endocarditis (LSE) with infectious endocarditis (IE) was observed in three patients (two women, one man, age 18-40 year). SLE ran a subacute course in one woman, an acute one--in the other. LSE emerged early in SLE in two patients. All the patients had polyorganic lupus pathology, lupus nephritis with nephrotic syndrome (morphological class IV). Two patients had mitral valve disease, one patient--mitral-aortic disease. The rise of secondary IE was seen after massive immunosuppressive therapy. The diagnosis of secondary IE was made after SLE duration for 10-36 months. At IE diagnosis, all the patients had high titers of blood antiphospholipid antibodies. IE was of staphylococcal origin in two patients and candidosis-induced in one patient. In SLE with IE there was thromboembolic syndrome. LSE and IE have related aspects which should be regarded in clinical practice: possible "IE mask" in LSE, risk of secondary IE in about 10% of LSE patients, prophylactic measures necessary to prevent IE in hemodynamically prominent forms of LSE.


Empowerment Through Feminist Self-Defense: The IMPACT Lasts.
What do women learn in feminist self-defense that is empowering? This study examined the skills women used months and years after completing an IMPACT self-defense course. Ninety-seven survey participants described skills they had used and incorporated into their lives. The major themes that emerged through a classic grounded theory analysis were awareness, boundary setting, assertive body language, and managing adrenaline to prevent, interrupt, or stop uncomfortable, intrusive, or hostile behaviors. IMPACT-trained women did not engage in self-blaming or risky behavior and used their skills to prevent and interrupt aggressive behavior.


Robust and Accurate Features for Detecting and Diagnosing Autism Spectrum Disorders.
In this paper, we report experiments on the Interspeech 2013 Autism Challenge, which comprises of two subtasks - detecting children with ASD and classifying them into four subtypes. We apply our recently developed algorithm to extract speech features that overcomes certain weaknesses of other currently available algorithms [1, 2]. From the input speech signal, we estimate the parameters of a harmonic model of the voiced speech for each frame including the fundamental frequency (f 0). From the fundamental frequencies and the reconstructed noise-free signal, we compute other derived features such as Harmonic-to-Noise Ratio (HNR), shimmer, and jitter. In previous work, we found that these features detect voiced segments and speech more accurately than other algorithms and that they are useful in rating the severity of a subject's Parkinson's disease [3]. Here, we employ these features, along with standard features such as energy, cepstral, and spectral features. With these features, we detect ASD using a regression and identify the sub-type using a classifier. We find that our features improve the performance, measured in terms of unweighted average recall (UAR), of detecting autism spectrum disorder by 2.3% and classifying the disorder into four categories by 2.8% over the baseline results.


Newborn Safety Bundle to Prevent Falls and Promote Safe Sleep.
At our Baby-Friendly USA hospital, with at least 80% of mothers breastfeeding and rooming-in, it is not uncommon for mothers to fall asleep in their hospital bed while feeding. The aim of this study was to develop a newborn infant safety bundle and evaluate its efficacy in helping reduce unsafe sleep situations while simultaneously preventing newborn falls. Data were collected in March 2015 using an infant at risk-to-fall instrument prior to nurses initiating the newborn infant safety bundle. The bundle included: (a) a parent safety agreement; (b) education, teach-back, and role modeling of safe sleep practices; and (c) implementation of a reporting and debriefing system for infant falls. All new mothers were eligible for inclusion. Data were collected over a random month every quarter for four quarters (through June 2016). Fourteen percent (n = 23) of babies born at the hospital in March 2015 were found to be exposed to risk-to-fall situations; over half of their mothers were found asleep and still holding the baby. Following bundle implementation, identified unsafe sleep situations during June 2015 to June 2016 have trended down with no reports of an infant fall through May 2017. Increasing parental awareness, understanding, and participation in safe sleep practice creates and maintains a safer infant environment in the hospital setting.


Associations between muscle strength, spirometric pulmonary function and mobility in healthy older adults.
Pathological obstruction in lungs leads to severe decreases in muscle strength and mobility in patients suffering from chronic obstructive pulmonary disease. The purpose of this study was to investigate the interdependency between muscle strength, spirometric pulmonary functions and mobility outcomes in healthy older men and women, where skeletal muscle and pulmonary function decline without interference of overt disease. A total of 135 69- to 81-year-old participants were recruited into the cross-sectional study, which was performed as a part of European study MyoAge. Full, partial and no mediation models were constructed to assess the interdependency between muscle strength (handgrip strength, knee extension torque, lower extremity muscle power), spirometric pulmonary function (FVC, FEV1 and FEF50) and mobility (6-min walk and Timed Up and Go tests). The models were adjusted for age, sex, total fat mass, body height and site of enrolment. Partial mediation models, indicating both direct and pulmonary function mediated associations between muscle strength and mobility, fitted best to the data. Greater handgrip strength was significantly associated with higher FVC, FEV1 and FEF50 (p < 0.05). Greater muscle power was significantly associated with better performance in mobility tests. Results suggest that decline in mobility with aging may be caused by decreases in both muscle strength and power but also mediated through decreases in spirometric pulmonary function. Future longitudinal studies are warranted to better understand how loss of function and mass of the respiratory muscles will affect pulmonary function among older people and how these changes are linked to mobility decline.


Pencil Beam Scanning Proton Therapy for Adolescents and Young Adults with Head and Neck Sarcomas.
To assess clinical outcomes of adolescents and young adults (AYAs) with head and neck sarcomas (HNSs) treated with pencil beam scanning proton therapy (PBSPT) and to report quality of life (QoL). Twenty-eight AYAs (aged 15 to 39 years) with HNS treated between January 2001 and July 2022 at our institution were included. The median age was 21.6 years. Rhabdomyosarcoma (39.3%), Ewing sarcoma (17.9%), chondrosarcoma (14.3%), and osteosarcoma (14.3%) were the most frequent diagnoses. Three (10.7%) patients were metastatic before PBSPT and 13 (46.4%) patients had a tumor with intracranial extension. The median total radiation dose was 63 GyRBE (range, 45 to 74 GyRBE). Thirteen (46.4%) patients received concomitant chemotherapy. Toxicity was reported according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US National Institutes of Health, Bethesda, Maryland). Survival was estimated using the Kaplan-Meier method. QoL was assessed using a PEDQOL (Pediatric Quality of Life Questionnaire) questionnaire. Self-reported outcomes were assessed using institutional questionnaires. With a median follow-up of 57 months (range, 3.7 to 243 months), 5 patients (17.8%) had local failure (LF) only, 2 (7.1%) experienced distant failure (DF) only, and 2 (7.1%) had LF and DF. The estimated 5-year local control (LC) and distant control (DC) rates were 71.8% and 80.5%, respectively. The median times to LF and DF were 13.4 and 22.2 months, respectively. Four (14.3%) patients died, all but one from their HNS. Estimated 5-year overall survival was 90.7%. Six (21.4%) patients developed nonocular grade ≥3 toxicity, which consisted of otitis media (n = 2), hearing impairment (n = 2), osteoradionecrosis (n = 1), and sinusitis (n = 1). Four (14.3%) patients developed cataracts that required surgery. The 5-year freedom from nonocular grade 3 toxicity was 91.1%. No grade 4 or higher toxicity was observed. Adolescents rated their quality of life before treatment worse than their parents did. Excellent outcomes with acceptable late-toxicity rates were observed for AYAs with HNS after PBSPT.


Importance of the C-terminal alpha-helical structure for glucagon's biological activity.
The synthetic glucagon analogues [Glu21]glucagon, 2, and [Lys17,18,Glu21]glucagon, 3, were designed using Chou-Fasman calculations for the purpose of enhancing the probability for the formation of a C-terminal amphipathic alpha-helical conformation. Circular dichroism indicates increased alpha-helical content for these analogues in solution relative to glucagon. Analogues 2 and 3 also exhibit a 3-fold and 5-fold increase in receptor binding potency, respectively. The adenylate cyclase stimulating potencies of 2 and 3 relative to glucagon are 2.1 and 7 times greater, respectively. Attempts were made at further alpha-helical enhancement by further substitutions in the 10-13 region of glucagon, as represented by the glucagon analogues [Phe13,Lys17,18 Glu21]glucagon, 4, and [Phe10,13,Lys17,18,Glu21]glucagon, 5. These latter substitutions resulted in lowered receptor binding and adenylate cyclase potencies for 4 and 5 relative to 3 despite increased alpha-helical content in solution as observed by circular dichroism spectroscopy.


Randomised trial of general practitioner online education for prescribing and test ordering.
Potentially inappropriate medicine prescriptions and low-value diagnostic testing pose risks to patient safety and increases in health system costs. The aim of the Clinical and Healthcare Improvement through My Health Record usage and Education in General Practice study was to evaluate a scalable online quality improvement intervention, integrating online education regarding a national shared electronic health record and rational prescribing, pathology and imaging ordering by Australian general practitioners (GPs). The study was a parallel three-arm randomised trial comprising a prescribing education arm, a pathology education arm and an imaging education arm. Currently practising GPs in Australia were eligible to participate and randomised on a 1:1:1 basis to the study arms after consenting. The response to the intervention in reducing potentially unnecessary medicine prescriptions and tests in each arm was assessed using the other two arms as controls. The primary outcome was the cost per 100 consultations of predefined medication prescriptions, pathology and radiology test ordering 6 months following the intervention, compared with 6 months prior. Outcomes were assessed on intention-to-treat and post hoc per-protocol bases using multilevel regression models, with the analysts blinded to allocation. In total, 106 GPs were enrolled and randomised (prescribing n=35, pathology n=36, imaging n=35). Data were available for 97 GPs at the end of trial (prescribing n=33, pathology n=32, imaging n=32) with 44 fully completing the intervention. In intention-to-treat analysis, there were no significant differences in the rates of change in costs across the three arms. Per protocol, there was a statistically significant difference in the rate of change in pathology costs (p=0.03). In the pathology arm, the rate of increase in pathology costs was significantly lower by $A187 (95% CI -$A340, -$A33) than the prescribing arm, and non-significantly $A9 (95% CI -$A128, $A110) lower than the imaging arm. This study provides some evidence for reductions in costs for low-value pathology test ordering in those that completed the relevant online education. The study experienced slow uptake and low completion of the education intervention during the COVID-19 pandemic. Changes were not significant for the primary endpoint, which included all participants. Improving completion rates and combining real-time feedback on prescribing or test ordering may increase the overall effectiveness of the intervention. Given the purely online delivery of the education, there is scope for upscaling the intervention, which may provide cost-effectiveness benefits. ACTRN12620000010998.


Effect of olfactory bulb pathology on olfactory function in normal aging.
Decline of olfactory function is frequently observed in aging and is an early symptom of neurodegenerative diseases. As the olfactory bulb (OB) is one of the first regions involved by pathology and may represent an early disease stage, we specifically aimed to evaluate the contribution of OB pathology to olfactory decline in cognitively normal aged individuals without parkinsonism or dementia. This clinicopathological study correlates OB tau, amyloid β (Aβ) and α-synuclein (αSyn) pathology densities and whole brain pathology load to olfactory identification function as measured with the University of Pennsylvania Smell Identification Test (UPSIT) and clinical data measured proximate to death in a large autopsy study including 138 cases considered non-demented controls during life. Tau pathology was frequently observed in the OB (95% of cases), while both Aβ (27% of cases) and αSyn (20% of cases) OB pathologies were less commonly observed. A weak correlation was only observed between OB tau and olfactory performance, but when controlled for age, neither OB tau, Aβ or αSyn significantly predict olfactory performance. Moreover, whole brain tau and αSyn pathology loads predicted olfactory performance; however, only αSyn pathology loads survived age correction. In conclusion, OB tau pathology is frequently observed in normally aging individuals and increases with age but does not appear to independently contribute to age-related olfactory impairment suggesting that further involvement of the brain seems necessary to contribute to age-related olfactory decline.


Applications of genomics in NSCLC.
Cisplatin-based chemotherapy has long been the cornerstone of non-small cell lung cancer (NSCLC) management. However, median survival rarely exceeds 1 year. The identification of molecular markers can help to predict response, leading to a broad implementation of the new concept of customized chemotherapy. ERCC1 is an excision nuclease within the nucleotide excision repair pathway that forms a heterodimer with XPE As a unit, they execute the 5' incision into the DNA strand relative to the site of DNA damage. The 5' excision is the last of several steps that are specific to excision of a platinum DNA lesion. In mouse models, normal ERCC1 function is critical to normal aging and brain development. Numerous studies indicate that ERCC1 influences the repair of platinum DNA damage. We report here our accumulated experience of ERCC1 mRNA expression and outcome in cisplatin-treated NSCLC patients and the preliminary confirmatory data on a prospective ERCC1 mRNA customized docetaxel-cisplatin trial, in which low ERCC1 mRNA levels in the tumor correlate with significantly better response. ERCC1 is one of several proteins involved in the repairosome, where other DNA repair genes, such as BRCA1, are also central to cisplatin resistance.


Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus.
Neuropeptide Y (NPY) inhibits seizures in experimental models and reduces excitability in human epileptic tissue. We studied the effect of long-lasting NPY overexpression in the rat hippocampus with local application of recombinant adeno-associated viral (AAV) vectors on acute kainate seizures and kindling epileptogenesis. Transgene expression was significantly increased by 7 d, reached maximal expression by 2 weeks, and persisted for at least 3 months. Serotype 2 AAV vector increased NPY expression in hilar interneurons, whereas the chimeric serotype 1/2 vector caused far more widespread expression, also including mossy fibers, pyramidal cells, and the subiculum. EEG seizures induced by intrahippocampal kainate were reduced by 50-75%, depending on the vector serotype, and seizure onset was markedly delayed. In rats injected with the chimeric serotype 1/2 vector, status epilepticus was abolished, and kindling acquisition was significantly delayed. Thus, targeted NPY gene transfer provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.


Residential exposures associated with asthma in US children.
Residential exposures are recognized risk factors for childhood asthma, but the relative contribution of specific risk factors and the overall contribution of housing to asthma in US children is unknown. The objective of this study was to identify risk factors and estimate the population attributable risk of residential exposures for doctor-diagnosed asthma for US children. A cross-sectional survey was conducted from 1988 to 1994. Survey participants were 8257 children who were <6 years old and who participated in the Third National Health and Nutrition Examination Survey, a survey of the health and nutritional status of children and adults in the United States. The main outcome measure was doctor-diagnosed asthma, as reported by the parent. Six percent of children had doctor-diagnosed asthma. The prevalence of asthma was higher among boys (6.7%) than girls (5.1%) and was higher among black children (8.9%) than white children (5.2%). Risk factors for doctor-diagnosed asthma included a family history of atopy (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.5, 3.1), child's history of allergy to a pet (OR: 24.2; 95% CI: 8.4, 69.5), exposure to environmental tobacco smoke (OR: 1.8; 95% CI: 1.2-2.6), use of a gas stove or oven for heat (OR: 1.8; 95% CI: 1.02-3.2), and presence of a dog in the household (OR: 1.6; 95% CI: 1.1, 2.3). The population attributable risk of >/=1 residential exposure for doctor-diagnosed asthma in US children <6 years old was 39.2%, or an estimated 533 000 excess cases, whereas having a family history of atopy accounted for 300 000. The attributable cost of asthma as a result of residential exposures for children <6 years old was $402 million (95% CI: $296-$507 million) annually. The elimination of identified residential risk factors, if causally associated with asthma, would result in a 39% decline in doctor-diagnosed asthma among US children <6 years old.