PURPOSE
The aim of this study was to compare, through scanning electron microscope (SEM), the ability of four Ni-Ti rotary instrument systems in shaping root canal walls and their ability in removing smear layer and dentin debris.

METHODS
Forty-six extracted single-rooted human teeth were divided into four groups and prepared to size 35 (Alpha System, FlexMaster, MFile) or 30 (NRT files). Irrigation was carried out with NaOCl and EDTA. Three parameters were evaluated in the coronal, middle, and apical thirds of the root canals: smear layer morphology, pulpal-inorganic debris presence and surface profile morphology. Data were statistically analyzed using the Kruskal-Wallis test (ANOVA).

RESULTS
None of the Ni-Ti rotary instrument systems resulted in being able to obtain constantly regular shaped surfaces in apical thirds, where smear layer, pulpal and inorganic debris were often present.

CONCLUSIONS
NRT file specimens resulted in being relatively free from debris and smear layer and gained better results and scores at any canal level.


Laparoscopy is a relatively safe invasive procedure. However, the rate of bleeding complications during this procedure is still debatable. Moreover, it is not clear whether portal hypertension may increase the risk of this event. The authors analyzed retrospectively the records of 1,000 consecutive patients with chronic liver disease undergoing laparoscopy and guided direct-vision hepatic biopsy, and they examined the rate of bleeding complications from the trocar site after insertion of the Veress needle or after liver biopsy. A total of 400 of 1,000 patients had liver cirrhosis. Of these, 22.7% had splenomegaly, 13.0% had laparoscopic signs of portal hypertension, and 8.2% had esophageal varices. Bleeding occurred in 0.9% of patients from the trocar site, in 0.2% from the biopsy site, and in 0% from the Veress needle site. These figures were independent of the presence of advanced liver disease, with or without portal hypertension. Bleeding complications occur rarely during laparoscopy with guided liver biopsy and do not seem to be related per se to the presence of liver cirrhosis and portal hypertension. If anything, bleeding complications represent an unpredictable event in most cases.


The tumor suppressor gene p53 has been implicated in the loss of neuronal viability, but the signaling events associated with p53-mediated cell death in cortical and hippocampal neurons are not understood. Previous work has shown that adenovirus-mediated delivery of the p53 gene causes cortical and hippocampal neuronal cell death with some features typical of apoptosis. In the present study we determined whether p53-initiated changes in neuronal viability were dependent on members of the Bcl-2 family of cell death regulators. Primary cultures of cortical neurons were derived from animals containing Bax (+/+ and +/−) or those deficient in Bax (−/−). Cell damage was assessed by direct cell counting and by measurements of MTT activity. Neurons containing at least one copy of the Bax gene were damaged severely by exposure to excitotoxins or by the induction of DNA damage. In contrast, Bax-deficient neurons (−/−) exhibited significant protection from both types of injury. Bax protein expression was elevated significantly by glutamate exposure, but not by camptothecin-induced DNA damage in wild-type neurons. The glutamate-induced increase in Bax protein was dependent on the presence of the p53 gene. However, increased p53 expression, using adenovirus-mediated transduction, was not sufficient by itself to elevate Bax protein levels. These results demonstrate that Bax is required for neuronal cell death in response to some forms of cytotoxic injury and further support the key role for p53 activation in response to excitotoxic and genotoxic injury.


The Mancos Shale of the San Juan Basin has been an important resource for the exploration and development of oil and gas. However, as with most unconventional plays, the shales have low porosity and extremely low permeability with predominantly nanometer-sized pores. Thus, it is critical to understand the nanopetrophysical properties of the reservoir so a proper assessment of the reservoir quality can be made. Working with three as-received core samples from three different wells of the Tacito Marine Bar and Offshore Mancos play types, we have developed an initial understanding of the nanopetrophysical properties of the pore structure as well as fluid-rock interactions in these tight reservoirs. We have performed a suite of integrated tests, such as mercury intrusion porosimetry (MIP), low-pressure nitrogen physisorption, core plug porosity and permeability, scanning electron microscopy imaging, water immersion porosimetry after vacuum pulling, contact angle, and fluid imbibition. In addition, we obtained supplementary data for total organic carbon, X-ray diffraction, and pyrolysis to further evaluate reservoir quality. The Mancos Shale samples exhibit petrophysical characteristics that are controlled by a predominant presence of nanometer-sized pore space, with 56%–96% pore volumes present as 3.4–50 nm in pore-throat sizes, as shown by the MIP approach. Contact angle and fluid imbibition tests demonstrate that samples are oil wet to mixed wet, with a tendency of pore networks to imbibe oil over water. The findings from integrated pore structure and wettability studies provide a database and some insights, from the perspectives of nanopetrophysical characterization, into the reservoir quality of the Mancos Shale.


Abstract. An analysis of altimeter significant wave height data of May 2007 revealed the occurrence of an extreme weather event off southern tip of South Africa in the Atlantic Ocean, and generation of a series of very high swells at 40° S. These swells propagated towards northeast and broke over La Reunion island in the Indian Ocean on 12 May 2007. The wave model WAVEWATCH III was used to study the propagation of these swells in the Indian Ocean. The model was validated for the Indian Ocean using moored buoy data at 12 locations and merged altimeter wave data. The wave model accurately reproduced the event of May 2007. Swell heights, of the order of 15.0 m, at the generation area reduced to 6.0 m near La Reunion island. This study shows that the swells generated in the Roaring Forties of the Atlantic Ocean (between 15° to 80° E longitude) propagate in the NE/NNE direction towards the north Indian Ocean, and wave characteristics of the Arabian Sea are least influenced compared to that of Bay of Bengal, when swells from the Atlantic Ocean enter the Indian Ocean. The double peak spectrum extracted for the Bay of Bengal indicates that one of the peaks is due to swells generated off southern tip of South Africa.


Intestinal parasitic organisms are common pathogens among HIV patients worldwide and have been known to cause severe and life-threatening diarrhea in such subjects. In the present study, the prevalence of Cryptosporidium spp and other intestinal parasites in stool samples from 151 HIV/AIDS patients attending a HIV treatment center in South Africa was determined using' standard parasitological methods, as well as molecular methods including PCR and quantitative PCR for confirmation of Cryptosporidium spp. In addition, the loop-mediated isothermal amplification (LAMP) method was evaluated for detection of Cryptosporidium spp in 24 stool samples. Standard parasitological methods indicated that Cryptospo- ridium spp (26.5%), Entamoeba spp (26.5%) and Giardia lamblia (13%) were the most common protozoan parasites, while Ascaris lumbricoides (8%), Schistosoma mansoni (6%) and Trichuris trichiura (4.6%) were the most commonly found helminths. PCR, quantitative PCR and LAMP methods identified Cryptosporidium spp in 28% (30/106), 35% (53/151) and 58% (14/24) of the stool samples, respectively. Multiple infections (34%) were commonly found in the study population. Females above 45 years had the highest Cryptosporidium prevalence (58%). Prevention measures must be implemented in order to curb the negative impact of Cryptosporidium-causing diarrhea among HIV/AIDS patients in this region as well as other parasitic infections identified in this study.


Objectives As new medical technology develops, medical costs increase. When high medical costs affect the patient as a toxicity, it is called financial toxicity (FT). In Japan, all patients are covered by the public health insurance system, which may alleviate FT. However, previous research using the Japanese version of the '''''COmprehensive Score for financial Toxicity (COST)''''' tool, whose score quantifies FT, showed that Japanese patients with cancer had FT. Our objective is to analyze its internal validity and the relationship between the COST score and patient information particularly for patients with ovarian, cervical, or endometrial cancer during chemotherapy. Furthermore, this study aims to clarify the correlation between COST and QOL scores. Methods We will enroll 147 patients, including 49 patients each with ovarian, cervical, and endometrial cancers, from April 2019 to April 2020. Each patient will have been receiving chemotherapy for more than 2 months at enrollment. Each participant will answer the COST tool, EORTC-QLQ-C30, OV28/CX24/EN24, and EQ-5D-5L at baseline and at the end of chemotherapy. The patients will also complete a questionnaire about employment, assets, income, private insurance, medical payments in the last 2 months, presence of children or family members who need a caregiver, and consultation for medical payment before chemotherapy. Results This research will clarify the characteristics and longitudinal changes in the COST score in gynecologic cancer patients. The impact of FT on the clinical situation will also be determined. Conclusions We expect to find that the COST score can be used prospectively to improve QOL in patients with gynecologic cancer.


As a result of the widespread use of the landslide classifications of Varnes (1978), and Hutchinson (1988), certain terms describing common types of flow-like mass movements have become entrenched in the language of engineering geology. Example terms include debris flow, debris avalanche and mudslide. Here, more precise definitions of the terms are proposed, which would allow the terms to be retained with their original meanings while making their application less ambiguous. A new division of landslide materials is proposed, based on genetic and morphological aspects rather than arbitrary grain-size limits. The basic material groups include sorted materials: gravel, sand, silt, and clay, unsorted materials: debris, earth and mud, peat and rock. Definitions are proposed for relatively slow non-liquefied sand or gravel flows, extremely rapid sand, silt or debris flow slides accompanied by liquefaction, clay flow slides involving extra-sensitive clays, peat flows, slow to rapid earth flows in nonsensitive plastic clays, debris flows which occur in steep established channels or gullies, mud flows considered as cohesive debris flows, debris floods involving massive sediment transport at limited discharges, debris avalanches which occur on open hill slopes and rock avalanches formed by large scale failures of bedrock.


In recent years, the phenomenon of trouping investors, both individual and institutional, has become more frequent and common in China and the U.S., especially under the circumstance of COVID 19, which has wreaked havoc in all sectors including the financial market. The market has witnessed increased volatility caused by herd behavior among retail investors and institutional investors. This article will focus on the interaction between retailer and institutional investors and the herd behavior within institutional investors. The battle between individual investors and institutional investors can be studied from the GameStop context. Individual investors have banded together from Reddit to push up GME's stock price in an attempt to hurt the Wall Street established big institutional investors who are shorting GME. This demonstrated the rising power of individual investors and the influence of social media. This herd behavior indicates a change in power dynamics in the financial market. The second manifestation of heightened herd behavior would be seen in the banding together among institutional investors in Nasdaq and in China's financial market. In Nasdaq, investors have come together to invest in technology stocks, whereas in China's financial market, big institutions focused on buying A-shares heavily. This coordination and focus have also increased volatility. Thus, the heightened herd behavior under Covid-19 has indicated a change in the power dynamic between individual investors and institutional investors, which caused the increased volatility in the financial market. Individual investors, institutional investors, and the government should take note of such heightened herd behavior and take appropriate actions to guard themselves against this heightened herd behavior.


Background. Cardiovascular disease is a global emerging problem and its risk starts in children and adolescents. Adolescents have modifiable cardiovascular risk factors that have been found globally, and nationally, and early intervention programs may be able to lower these risks for both individuals and populations. Accurate risk factor evaluation at the individual level is crucial in this situation for the prevention of cardiovascular disease. Objective. The study aimed to investigate cardiovascular disease knowledge and to determine physical activity, and dietary patterns among school-going adolescents in Arakkonam, Tamil Nadu, India. Methods. A school-based cross-sectional survey was conducted to assess cardiovascular disease knowledge among 500 adolescents aged 10-18 from public schools. The study period was from September 2021 to February 2022. The measurement taken on anthropometrics such as height, weight, body mass index, and bio-physiological measurement as blood pressure, structured questionnaire assessed for knowledge, dietary questionnaire assessed previous week food consumption which the investigator developed, and physical activity standard questionnaire assessed the past week's exercise level. Data were analyzed using IBM Statistical Package for Social Sciences version 20. Results. The mean study population age was 13.7±1.7, 53% were boys, and 47% were girls. Factors like age 16-18 years (p=0.01), site of residence from urban (p=0.001), education of teenagers (p=0.01), and family history of cardiovascular disease (p=0.001) are significantly correlated with the level of knowledge score, with better-educated adolescents having fair knowledge score than others. Level of knowledge score and demographic traits are associated with physical activity, such as 16 to 18 years (p=0.03), living in an urban region (p=0.03), being in a joint household (p=0.001), adolescents who are at higher secondary (p=0.02), and having a family history contribute more to cardiovascular disease (p=0.001) than other variables. Mean days eating diets were egg (4.18±2.27), vegetables (3.92±0.93), milk products (3.85±1.87), fried foods (3.75±1.25), toffees, and chocolates (3.35±1.81) all had higher percentages of consumed foods than others. Conclusion: There is a risk of cardiovascular disease higher among adolescents. Still a need for school-based primordial preventive educational approaches needed to improve to curb this burden.


: derealization is mental disorder, manifested in a feeling of unreality and strangeness of the surrounding real world, a form of impairment of consciousness. The most common and recognizable such disorder is the phenomenon of «d é j à vu» – deja vu (DV). Objective: to study the clinical and diagnostic value derealization disorders (DD) in epilepsy. Materials and Methods: the total study group was 152 persons (mean age 25,17±9,19; 63,2% of women). The phenomena of derealization were compared in groups of healthy subjects (n = 139) and patients with epilepsy (n = 23). Patients were interviewed on the DV characteristics and long-term (12-16 hours) ambulatory EEG monitoring was conducted. Results: the same frequency of DV in patients with cryptogenic and symptomatic focal epilepsy was demonstrated. DV could be combined with any types of seizures, it could be aura of a seizure or own seizure. The main clinical characteristics that differentiate DV in healthy from DV in patients with epilepsy are: frequency, fear of the onset DV and emotional coloring. The most important criterion is the dynamic characteristics of the DV: elongation increased the appearance of negative emotions. The DV phenomenon characterized in EEG by start with polyspiking activity in the right temporal leads and, in some cases, ended by slow wave, theta-delta activity in the right hemisphere.


European competition law is predominantly focused on maximizing consumer welfare. This overarching purpose (which is supported by economic theory) leaves little place for safeguarding non-economic values, such as sustainability. This makes it difficult to allow cooperation between companies to contribute to such non-economic goals. In this article we explore whether it is possible to establish a different normative framework, in which such goals can be taken into account and can be balanced against the economic goal of consumer welfare. To answer this question, we take four steps. First, we discuss current EU competition law and the difficulty of fitting non-economic goals into the dominant interpretation of that law. Second, we propose a different normative framework, based on the capability approach advanced by philosopher Martha Nussbaum and economist Amartya Sen. Third, we argue that there are good principled reasons to incorporate non-economic goals into competition law. Fourth, we apply both the capability approach and the consumer welfare approach to three (illustrative) cases in which non-economic goals are at stake. Overall, we argue that the capability framework, although not without difficulties of its own, may provide a more legitimate theory for the interpretation of European competition law.


The growth of children undergoing continuous ambulatory peritoneal dialysis (CAPD) therapy for end-stage renal disease (ESRD) was compared with the growth of children undergoing hemodialysis and that of children after successful kidney transplantation. The bone ages of the children were used to predict expected growth velocities. The actual growth velocities observed were then expressed as percentages of the predicted rates. Children receiving CAPD therapy grew better than those treated by hemodialysis and as well as the children who received a kidney transplant. There was some correlation between growth and allograft function in the transplant recipients. Children receiving CAPD were less acidotic and were more likely to exhibit improvement in renal osteodystrophy than children treated by ongoing hemodialysis. There were no significant differences in reported caloric intake between the two groups.


State-sponsored projects in the transition economies often lack reliable finance sources as governments deal with orthodox policy limitations. At the same time reliance on relatively inconsistent natural resources export revenues, migrant remittances or conditional loans and foreign aid may not be adequate for long run development projects. One alternative is a Diaspora-sovereign bond program with a patriotic discount. Implied independent decision-making and fiscal responsibility will allow for strategic funds allocation, with an incentive for infrastructure and social initiatives investment with strong feedback into a productive economy stimulating effective demand. Ultimately these components define modern fiscal policy and are fundamental to economic growth and development. Regulated via ―State–Diaspora Supervisory Board,‖ a Diaspora bond may also serve as the initial or renewed access to the international capital markets, especially for smaller economies and those with low sovereign ratings.


In 1798, after Congress had passed its first direct tax on houses, the government cooked up a scheme to count and measure the windows on every taxpayer's house, in order to calculate how much to charge. But German settlers in eastern Pennsylvania would have none of it. They organized into small bands, armed themselves, and scoured the countryside for assessors who were seized, assaulted, and driven across county lines. When some of the rebels were arrested, an auctioneer named John Fries marched on the courthouse and freed them. President John Adams called out the militia. Fries was arrested, tried for treason, and sentenced to be hanged. It was hardly the first tax revolt in American history. From the Boston Tea Party to the Whiskey Rebellion to the Fries Rebellion, the late eighteenth century in America was full of armed violence in response to hated taxes. Yet, as Charles Adams recounts in this remarkable book, the Fries Rebellion was also far from the last of its kind. Throughout its history America has been home to a series of little-known tax rebellions. These rebellions have played major roles in the presidencies of George Washington, John Adams, Thomas Jefferson, and many of their successors. They have helped bring about the Civil war, the birth of the Ku Klux Klan, and, ironically, the birth of the Internal Revenue Service. When the old Internal Revenue Bureau was strengthened to control moonshiner tax rebels in the Appalachias, it started a "Second Whiskey Rebellion" that continues even today. Country singer George Jones' popular ballad recalls: "G-Men, T-Men, Revenuers too, looking for the place where my pappy made his brew." Today, as long-overdue calls for abolishing or overhauling the IRS are finally being heard in the halls of Congress, "Those Dirty Rotten Taxes" teaches us that we are continuing a long and vitally important American tradition. We have overthrown the tyranny of British taxes, Federalists' taxes, the Tariff, and the Revenuers' system. Has the tyranny of the Income Tax finally had its day?


In this paper, the impacts of environmental vibration on precision instruments as well as the vibration allowances of precision instruments are introduced firstly. Then the integrated model of a high-rise building is established, and the vibration responses of the floor where a precise instrument is fixed are calculated by inputting micro-vibration loads. The passive control method is used by putting several lead rubber bearings at the bottom of instrument and at the bottom of building separately, and the isolated vibration responses are calculated and analyzed. Some valuable conclusions are obtained by comparing the vibration responses of isolation system and non-isolation system with acceptable values according to the environmental vibration codes for precise instruments.


Abstract The thyroid functions as a regulator of cardiac function and rhythm through genomic and nongenomic actions of triiodothyronine (T3) in cardiac myocytes. Atrial fibrillation is a common complication of thyrotoxicosis. Hypothyroidism is not considered a risk factor for arrhythmias despite well-known EKG changes in this condition. This case control study was conducted to analyze the differences, if any, in the prevalence of cardiac arrhythmias between hypothyroid patients and euthyroid controls. Three hundred and four consecutive patients admitted at our medical center for a period of one year were included in the study. The study population was divided into 2 groups (age, gender and race matched): patients with hypothyroidism and euthyroid subjects as a control group. Major arrhythmia data were obtained from telemetry recordings and from known past medical history. There were 152 subjects in each arm of the study. The mean age was 61.9 years. Mean TSH in hypothyroid group was 40.4 mIU/l (95% CI 33.3–47.5) (range 10.09–304, SE 3.62) and in euthyroid group was 0.89 mIU/l (95% CI 0.82–0.96). Chi-square analysis revealed a higher prevalence of ventricular tachycardia (p=0.04) and any ventricular arrhythmia in the hypothyroid group (p=0.007). This relatively large case control study revealed a statistically higher prevalence of ventricular arrhythmias in hypothyroidism. Our study has thrown light on the prevalence of arrhythmias in hypothyroidism and the observation of increased ventricular arrhythmias necessitates future large scale prospective studies to better define the risk of such ventricular arrhythmias and the effects of thyroid supplementation on this risk.


• Was aspiration a cause of lung metastases from basal cell carcinoma? We compared our case to prior reported cases with metastases to the lung attributable to aspiration and considered a prior experimental model. We are convinced we have another case of aspiration metastases from basal cell carcinoma, and hereby report "the 92nd known case." ( Arch Dermatol 114:589-590, 1978)


Mutations of the Doa locus of Drosophila melanogaster darken the eye color of the copia-induced white(apricot) (wa) allele and increase the accumulation of white promoter-initiated transcripts encoding functional mRNA. We show here that quantities of transcripts initiated in both long terminal repeats (LTRs) of the specific wa-copia element are increased, and those initiating in the 5' LTR of the element are structurally altered, yielding a slightly shortened transcript. Accumulation of host-initiated transcripts of a copia-induced mutation within the achaete-scute complex, Hairy-wing Ua (HwUa), are reduced by Doa mutations. Finally, we show that homozygosity for Doa mutations increases the accumulation of copia transcripts from the population of elements in the genome. These results suggest that Doa modulates the severity of copia-induced mutations while functioning as a dosage-sensitive modulator of copia transcription.


This paper aims at designing a differential pressure sensor. The objective of the work is to design and fabricate the electrodes of a capacitive pressure sensor, so as to measure absolute and differential pressure accurately with improved sensitivity. In place of conventional parallel plate diaphragm, S-type electrodes are proposed in the present work. The work comprises of study of the proposed design in terms of a mathematical model, input-output behavior along with detailed analysis of pressure distribution pattern. Output capacitance obtained for changes in pressure is converted to voltage with the suitable signal conditioning circuit and data acquisition system to acquire the signal on to a PC. A neural network model is designed to compensate the nonlinearities present in the sensor output. Input-output characteristics of the designed sensor shows an improved response as compared with existing pressure sensors.


Ultra filtration (UF) is increasingly used as a complete- or intermediate surface water purification technique. Ultra filtration membranes have a high selectivity, are easy to scale-up and have become economically attractive during the last 15 years. However, the buildup of fouling during filtration severely influences the performance of a UF membrane. For this reason frequent cleaning of the UF membrane is required. In the short term, the membrane is cleaned by means of backwashing, and in the long term the membrane is cleaned with cleaning chemicals. Although backwashing and chemical cleaning are useful methods to prevent fouling, the execution of such procedures are still based on pilot plant studies and rules of thumb. The expectation is that systematic modeling; optimization and control will significantly reduce operational costs and increase overall controllability of the UF process. In this contribution the formulation of a hierarchical modeling, optimization and control framework will be discussed that can be used to optimize the overall UF process. There will be special attention for mathematical modeling and optimization of membrane filtration, backwashing and chemical cleaning. Noted is further that the proposed models, optimization routines and control algorithm were tested and validated experimentally, on lab scale as well as pilot scale.


Corporate investigators provide investigative services to organisations faced with internal norm violations. Four main professional groups of corporate investigators can be identified in the Netherlands – private investigation firms, in-house security departments, forensic accountants and forensic legal investigators. These corporate investigators move in a semi-autonomous social field with a high level of discretion and autonomy. Extensive access to sources of information and settlement options, together with a context of highly fragmented legal frameworks, produce a corporate security sector that can provide its clients with a choice of solutions for norm violations. Corporate investigators are highly flexible in their investigatory work and in relation to the settlements that they recommend to their clients. Corporate investigators incorporate normative and reputational considerations, such as due process and fair play, into their day-to-day business. They largely work autonomously, engaging the criminal justice system only when this is considered desirable in the light of pragmatic or normative considerations. Other settlement options involve engaging civil and labour courts, arranging matters through out-of-court settlement agreements and making use of internal (labour) regulations of the organisation. Cooperation between law enforcement agencies and corporate investigators is fairly rare – public/private relationships are better conceptualised as coexistence, with public and private actors meeting only on an ad hoc basis. This means that the state has little insight into what happens in the corporate security sector. While this has the benefit for society that the criminal justice system is spared the trouble and costs of investigating and prosecuting these matters, it also means there is effectively no democratic control over the corporate security sector. For reasons of transparency and control, it may be wise to make the private investigation permit – now only obligatory for private investigation firms – a prerequisite for all corporate investigators, regardless of their professional or institutional background. As a result of the empirical work reported upon, it is proposed that control over such a permit system should be placed with the Dutch Data Protection Authority, rather than the police.


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Background The unique signature of a patient's tumor mandates the need to rationally design personalized therapies employing N=1 segmentation conceptually. Repurposing of existing drug agents with validated clinical safety and pharmacokinetics data provides a rapid translational path to clinic which otherwise would require years of development time and associated new chemical risks. By focusing on rationally designed personalized treatment mechanisms, our strategy targets multiple key pathways to address the clinical problem of emergence of single therapy resistance. In order to overcome MM resistance, we have (1) employed predictive simulation modeling based upon patient genetic and environment profiling to design patient context specific combinatorial therapeutic regimens using library of drug agents from across indications with prior clinical data and (2) validating designed therapy ex-vivo in patient derived cell lines.

Methods Clinical patient samples were analyzed for chromosome evaluation and molecular cytogenetic analysis by NYU. Using this information, an in silico simulation avatar of the patient was created. To identify effective personalized therapeutics, we focused our study on compounds from the National Center for Advanced Translational Science (NCATS) and other molecularly targeted agents. The predictive simulation based approach from Cellworks provides a comprehensive representation of MM disease physiology incorporating signaling and metabolic networks with an integrated phenotype view. This extensively validated simulation model predicts clinical outcomes with phenotype and bio-marker assays.

Hits were shortlisted from over thousand pharmacodynamic dose-response simulation studies using criteria of efficacy and synergy. Computer modeling predicted that therapeutic combination mechanistically targets apoptotic pathways and the combination of the agents provides greater than additive activity. These predictive findings are in the process of being assessed ex vivo and retrospectively validated.

Results The analysis detected loss of chromosome 13 signal consistent with monosomy 13 and loss of TP53 signal consistent with deletion of TP53; all other probes contained normal signal patterns. The shortlisted therapeutic combination identified from predictive simulation-based screening was BEZ235 (PI3K/mTOR inhibitor) and ABT-199 (BCL2 inhibitor). IC30 concentrations of the single agents resulted in a 56% inhibition of proliferation and 49% inhibition of viability in predictive simulations. The apoptotic markers CASP3, CASP9, Cleaved-PARP1 and BAK1 increased by 74% (1.75 fold), 132% (2.32 fold), 81% (1.8 fold), 217% (3.17 fold), respectively. The proposed mechanism of action using simulation model identified the p53 deletion as responsible for increased BCL2 activity and levels of activated AKT. Deletion of p53 increased levels of activated AKT via decreases in PTEN and IGFBP3. Hence, a mechanism that targets the PI3K/AKT/mTOR and BCL2 family showed efficacy in the simulation avatar of the patient and are currently being validated ex-vivo in patient cells.

Conclusions This study demonstrates and validates simulation approaches and technologies to leverage big data from patient genomic analysis to create a simulation avatar for rational design of personalized therapeutics. This level of personalization, beyond linking point mutations to associated drugs targeting the same mutations, truly incorporates the broad patient tumor signature in translational path forward.

Disclosures: No relevant conflicts of interest to declare.

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The majority of the UWB radars available on the market today are expensive and often closed forfurther development due to proprietary rights. Therefore it is difficult to fully understand and adaptthe functionality of an available UWB system to fit one's needs. The consulting-firm Addiva purchasedan UWB radar to be used in a safety system. However, the radar had limitations and the functionalityof it was partly unknown. This master thesis was inspired from this issue to examine the possibilitiesof developing a low-cost UWB radar, with main focus on research of human detection. The systemshould be easy to understand and modify, as well as reporting reliable data from the scanning. Theresults indicate that such a system can be developed. However, further development to the UWB radarneeds to be made in order to have a complete system.


In this study, neodymia doped poly(vinyl) alcohol/zirconium–cerium acetate (PVA/Zr-Ce) nanofibers were prepared using the electrospinning technique, and then calcined at 800°C for 2 hours. For this purpose, PVA/Zr-Ce polymer solutions doped with different concentrations of neodymia were prepared using electrospinning technique, and then calcined and sintered at 800°C for 2 hours. The effect of neodymia doping was investigated in terms of solution properties, morphological changes and thermal characteristics. The fibers were characterized by Fourier transform infrared (FT-IR), X-ray diffraction (XRD), and scanning electron microscope (SEM). The measurements showed that the conductivity, pH, viscosity, and surface tension of the hybrid polymer solutions have decreased with increasing Nd acetate content. The FT-IR spectra of the fibers were in good accordance with the literature. The average crystal size values for calcined and sintered samples which were obtained from precursor solutions were calculated. XRD analysis showed that the crystallite size was decreased with increasing Nd content. This result is verified by the calculation of the total areas of the peaks appeared in the XRD spectra. The very sharp and high intense peaks found in the diffraction patterns revealed the crystalline nature of the product. Moreover, the SEM micrograph of the fibers showed that the average fiber diameters decreased with increasing Nd content.


A model that conserves charge, is valid in the strong inversion regime, and is based on the quasi-static approximation is presented. Major second-order effects such as carrier velocity saturation, mobility degradation, and channel-length modulation are included in the derivation of current and charges. The theoretical predictions of the model are compared to both experimental and numerically simulated data and are found to be in good agreement over a wide range of gate and drain voltages and to confirm many properties that have been observed or predicted. >


Abstract. We present detailed surface elevation measurements for the McMurdo Dry Valleys, Antarctica derived from aerial lidar surveys flown in the austral summer of 2014–2015 as part of an effort to understand geomorphic changes over the past decade. Lidar return density varied from 2 to > 10 returns m−2 with an average of about 5 returns m−2. Vertical and horizontal accuracies are estimated to be 7 and 3 cm, respectively. In addition to our intended targets, other ad hoc regions were also surveyed including the Pegasus flight facility and two regions on Ross Island, McMurdo Station, Scott Base (and surroundings), and the coastal margin between Cape Royds and Cape Evans. These data are included in this report and data release. The combined data are freely available at https://doi.org/10.5069/G9D50JX3 .


This project was concerned with the clinical knowledge reported by general practitioners in relation to the diagnosis and management of seven common clinical conditions: acute otitis media, jaundice, iron-deficiency anaemia, transient cerebral vascular insufficiency, infectious mononucleosis, pulmonary infarction, and carcinoma of the prostate. Postal questionnaires were sent to three groups of doctors: a constant group of experienced general practitioners who were or had been trainers, randomly selected groups of 200 general practitioners, and small groups of consultants who were specialists in each condition. The last two groups were changed for each of the chosen clinical conditions; the constant group remained the same throughout. The study was not concerned with the attitudes and skills of general practitioners or consultants, and no attempt has been made to analyse the process of clinical problem-solving. The differences between the constant group and random group of general practitioners were minor. Consultants received questionnaires identical to those sent to general practitioners and were asked to answer them as they would expect a competent general practitioner to do; their answers suggested a more direct approach to the problem concerned than those given by general practitioners. The information obtained has implications for education for general practice and educational audit programmes. Areas for further research are suggested.


The Web Mining arises like an appropriate tool to exploit the derived knowledge of the web-user interaction, describing models that use patterns and characterize the profiles of the different groups of users which use Internet. To achieve this, currently there are numerous techniques. Some of these techniques are integrated in this work to build a Hybrid System of Web Mining that allows to extract useful information of the web users. Specifically, three techniques of the area of Web Mining were used: Sequential Patterns, Path Analysis and Cubes. The System obtains a group of access patterns from the users to a website, to arrange them in a multidimensional structure, called Cube. Using that, the system can discover correlations between the web pages and users' groups, behaviors of the web users, among other things.


To the Editor: Patients with renal impairment have elevated homocysteine levels and are at high risk of cardiovascular complications [1]. Herein, we caution against the use of nitrous oxide (N2O) anesthesia for these patients. Under most conditions, N2O appears to be inert, but prolonged exposure to the gas leads to significant increases in plasma homocysteine levels in patients presenting for elective craniotomy [2]. N2O directly inhibits methionine synthase, which contains cobalamin as a prosthetic group and catalyzes a folate-dependent conversion of homocysteine to methionine. Recently, Selzer et al [3] have described the neurologic deterioration and death of a child anesthetized twice with N2O before the diagnosis of 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency was established. The N2O-induced defect of methionine synthase superimposed on an inherited defect of MTHFR caused the death of the reported patient. The adverse effects of N2O were reported in two other children with severe dietary cobalamin deficiency. One developed acute neurologic deficit six days after N2O anesthesia, and the other showed hypotonia, dehydration, and acidosis three weeks after N2O anesthesia. Acute rise in plasma homocysteine level causes substantial impairment of endothelial function in healthy volunteers [4]. It is likely that when such endothelial dysfunction occurs in patients with renal impairment, it exacerbates the vascular dysfunction. The above-mentioned catastrophic events may provide us a cautionary message; plasma homocysteine and methionine levels should be closely monitored in patients with renal impairment undergoing N2O anesthesia. Pretreatment with vitamins (folic acid, vitamin B6, and B12) may block the N2O-induced increase in homocysteine level in at-risk individuals.


When service design got its boost in 2003-2005, as design firms plunged into what seemed to be unchartered area, the possibilities and provisions for the design discipline was under explored. In this chapter we will trace one of the strands of development that have supported service design since then, and also point towards areas where service design might benefit from building on earlier developments. Digital interaction designers were starting to graduate in the 90's, from our and other universities. Since then quite a few students have gone into different business sectors and established for themselves specific roles. Meeting them and starting to talk to these professional designers about service design and what service design is, a typical comment was "sure, that's basically what we've been doing all along". Strange as their laid back reaction seemed, I tried to figure out what was behind this. The obvious was of course that they were designing online services, mobile services, etc. And even though these might be regarded as service channels, in some cases they were the only service channel. Another reason seemed to be that, because some of the basic qualities of the design object are so similar between services in general and digital interaction design, the design techniques and methods, and the focus on user centered design, give them a vantage point on the design object that allows them to think in terms of services. Yet another reason was that the Scandinavian design traditions, such as cooperative design, made it possible for them to work with inclusive processes with several stakeholders with varying objectives.


A new species of inarticulate brachiopods Discinisca polonica sp. n., is established for the specimens represented by isolated dorsal valves, and occurring in the littoral deposits developed along the shores of the Korytnica Basin (Middle Miocene, Badenian Holy Cross Mountains, Central Poland). The new species, the dorsal valves of which are characterized by their small size, low-conical to strongly and irregularly depressed shape, and by the distinct robbing, bears some similarities both to the species D. scutellum (DREGER) from the contemporaneous deposits of the Vienna Basin, and to some Recent species typical on the Indo-Pacific realm. The bearing of the new species on the content of littoral organic communities of the Korytnica Basin, and on the recognition of its tropical conditions and lndo-Pacific bioprovincial affinities are briefly discussed.


Motor development has all too often been considered as a set of milestones with little significance for the psychology of the child. Nothing could be more wrong. From an action perspective, motor development is at the heart of development and reflects all its different aspects, including perception, planning and motivation. Recent converging evidence demonstrates that, from birth onwards, children are agents who act on the world. Even in the newborn child, their movements are never just reflexes. On the contrary, they are purposeful goal-directed actions that foresee events in the world. Thus, motor development is not just a question of gaining control over muscles; equally important are questions such as why a particular movement is made, how the movements are planned, and how they anticipate what is going to happen next.


A simple, rapid, and sensitive HPLC is proposed to test six amino acids in plasma/serum. Deproteinization was carried out with acetonitrile; derivation was made with the orthophthalic aldehyde 2-mercaptoethanol. Separation was accompanied on a Chromolith (Merck), 4.6 mm in size, with monolytic reverse-phase silica gel in the isocratic mode with ultraviolet detection at 230 nm. The eluent contained a 50% mixture of methanol-acetonitrile-isopropanol (90:5:5, v/v/v) and 50% 0.01 M phosphate buffer (pH 6.7); flow rate 1000 ul/min; pressure 42 bars. Complete separation lasted at least 10 min. The detection limit was about 1 ng for phenylalanine, leucine, and isoleucine and less than 0.5 ng for tryptophan, valine, and methionine at a signal/noise ratio of 3.0. The simplicity, reproducibility, and sufficient sensitivity of the technique along with the feasibility of its application on standard chromatographic equipment (an isocratic pump and a ultraviolet detector) make it suitable for routine clinical application.


Intellectual property is briefly the knowledge of somebody owns that gained importance in today's business strategy. A patent is a license of exclusive rights granted by a state to the holder to an invention, design or process for a period of time.  Intellectual Property Rights (IPR) in the field of cosmetics are often; patents, trademarks and trade secrets include formulations and production techniques. Research & Development (R&D), innovation, technology transfer, patent, establishing quality systems, branding and benchmarking are the important factors that must be considered for sustainability of the cosmetic sector. In the scope of sustainable economy and thus economic growth of a country R&D, Research & Technological Development (RTD) and innovation activities need to be encouraged and supported by effectively protected IPR systems. Negative effects of infringements of IPR to consumers, right owners, legal businesses and states can be listed basically as health risks arising from using unsafe products, decreasing the encouragement of innovation, loss of jobs and money. Especially determining the critical steps in the life cycle of products and checking their legality is efficient at fighting with counterfeiting and IPR crimes. Cooperation of competent authorities and right owners has great importance of detecting infringements of intellectual property rights and counterfeit products and conducting an effective legal process.


Background: Youth citizenship is now on the international agenda with African countries increasingly interrogating their national perspectives on citizenship andcitizenship education. In this emergent field of research, African scholars arebeginning to challenge the prevailing (Western) theories of citizenship and democracy. Purpose: The aim of this paper is to contribute an African perspective to the study of citizenship education by exploring the political influences and meanings that shaped citizenship education in Kenya, and how these have evolved from independence to the present day. Data and Methods: This article is based on a documentary analysis of key policy-related documents, complemented by an analysis of some critical historical moments in the life of Kenya as a postcolonial nation. The policy-related documents include government policy documents, as well as political statements, speeches, development reports, technical commission reports, media articles, research publications and reports, education syllabi and curriculum documents. Main Findings: Post-independence, the Kenyan government focused on rethinking the colonial concept of citizenship in line with its political–cultural traditions, encouraging new notions of belonging, of civic virtues and of duties in relation to nation-building and economic development. Social Ethics and Education (SEE) programmes in schools were established and then later removed from the secondary school curriculum. Conclusions: This paper yields important insights into the international and national political agendas that shape Kenya's notions of active citizenship. It indicates the tensions which vulnerable and fragile states such as Kenya experience in negotiating their citizenship education agenda, whilst attempting to win foreign investment and aid for their economy, and whilst addressing regional and ethnic inequalities and high levels of poverty.


Two hypotheses are available for the origin of the Zimbabwe culture. A religious hypothesis attributes its development to an African society in isolation, placing it in the class of a primary state. In contrast, the trade hypothesis maintains that it was a secondary state resulting from the gold trade. If the religious hypothesis is correct, then Zimbabwe would be an exception to all other known cases of primary state formation. The archaeological evidence points to a horticultural subsistence throughout the Iron Age sequence in the area and a small population until Period III/IV. On the other hand, all known primary states were based on large populations and intensive agriculture. It is more likely that Zimbabwe is a typical case of secondary state formation. The stratigraphy on the Acropolis indicates that a social transition from Period II to III probably occurred at Zimbabwe and was not the result of an immigrant group, and the short chronology places this transition around A.D. 1250. The evidence available from Arab documents, trade imports and ancient mining demonstrates that trade existed well before then. Consequently, the evolution of the Zimbabwe culture was almost certainly due to the Arab gold trade.


In this paper first the effect of new hardware and software technologies on threats to data integrity and usage integrity is considered. Next the potential is considered of new technical facilities for improving the protection. It is concluded that the increasing risks for data and usage integrity are not counter balanced at present by new protection measures. A concerted action is proposed to face this problem. Especially action is proposed to develop methods for quality assurance of software, for access control in networks and to improve data/usage integrity around PC's.


Social interaction can improve animal performance through the prevention of stress-related events, the provision of security, and the enhancement of reproductive output and survival. We investigated the effects of prolonged chronic social isolation stress on behavioral, cognitive, and physiological performance in the social, long-lived rodent Octodon degus. Degu pups were separated into two social stress treatments: control (CTRL) and chronically isolated (CI) individuals from post-natal and post-weaning until adulthood. We quantified anxiety-like behavior and cognitive performance with a battery of behavioral tests. Additionally, we measured their basal metabolic rate (BMR) and analyzed the multifractal properties of the oxygen consumption time series using Multifractal Detrended Fluctuation Analysis, a well-known method for assessing the fractal characteristics of biological signals. Our results showed that CI induced a significant increase in anxiety-like behaviors and led to a reduction in social and working memory in male degus. In addition, CI-treated degus reduced the multifractal complexity of BMR compared to CTRL, which implies a decrease in the ability to respond to environmental stressors and, as a result, an unhealthy state. In contrast, we did not observe significant effects of social stress on BMR. Multivariate analyses showed a clear separation of behavior and physiological variables into two clusters, corresponding to CI and CTRL degus. This study provides novel insights into the effects of prolonged chronic social isolation stress on behavior, cognitive performance, and metabolic complexity in this rodent animal model. To the best of our knowledge, it is the first study to integrate cognitive-behavioral performance and multifractal dynamics of a physiological signal in response to prolonged social isolation. These findings highlight the importance of social interactions for the well-being and overall performance of social animals.


Military and industry are moving toward every device being network enabled and connected for reliable availability of communication and information. To make this type of system a reality, the devices must be capable of forming a network topology on their own in a dynamic environment to ensure that the correct information reaches a desired location and on-time. This research presents three contributions for solving highly dynamic (i.e. drastic change within the network) Multi-commodity Capacitated Network Design Problems (MCNDPs) resulting in a distributed multi-agent network design algorithm. The first contribution incorporates an Ant Colony Optimization (ACO) algorithm Ant Colony System (ACS) to solve the static MCNDP with weak constraints. Second, a new algorithm is developed and has the capability to dynamically adjust its exploration parameter of the solution space. This enhanced algorithm converges quicker and automatically adjusts to the dynamically changing network environment. Third, a distributed approach is created replacing the previous centralized solver. The distributed algorithm produces comparable results, but more importantly calculates the network topology in less than 20 percent of the computation time.


PURPOSE
To describe the status of health care systems in five Central Asian Republics (CAR): Kyrgzstan, Kazakhstan, Uzbekistan, Turkmenistan, and Tajikistan, with particular attention to women's and children's health.

ORGANIZING CONSTRUCT
Changing mortality profiles are investigated using the "protracted-polarized" model of epidemiologic transition.

SOURCES
Empirical evidence was drawn from the World Health Organization (WHO) database for the region, along with additional evidence presented at a maternal-child health conference held in Bishkek, Kyrgyzstan, on November 11-14, 1998. The conference was sponsored by the Albert Schweitzer Institute and the Soros Foundation. This evidence is evaluated for completeness, validity, and reliability. Trends are identified using the 1998 and 1999 World Health Reports and 1999/2000 World Bank Development Report.

FINDINGS
Incomplete data prohibited comprehensive analysis. Available data indicated high but variable rates of maternal and child mortality and overall declines in health status and the health care infrastructure in the 1990s.

CONCLUSIONS
Data collection and analysis from this part of the world are often incomplete and unreliable. Future research should focus on improving maternal and child health indicators by enhancing resource sharing and opportunities for international collaboration.


The influence of direct current field (DCF) on powder-pack boriding has been investigated by applying DCF between boriding agent and specimen during the soaking. Experimental results show that DCF has the function of heating the agent and the specimen and thus enhancing boriding. It is shown that the specimen's side facing anode has the deepest boride case when the specimen is taken as cathode. It is proposed that DCF forces active boron-containing species to diffuse toward the specimen at the cathode. This makes boron concentration around the specimen as cathode higher than that at the anode or other position and that in the conventional powder-pack boriding (CPB), which relatively decreases boron's absorption by inner wall surface of the pack box and the non-working surface of the specimen. DCF's physical effect of enhancing chemical reaction in the agent increases the activity and concentration of active boron atoms and boron-containing species, which overcomes the shortcoming that CPB can not produce enough boron-containing species by conventional way of heating.


Introduction Symptoms of vocal cord dysfunction (VCD) are caused predominantly by vocal cord adduction during inspiration. It is commonly seen in the asthma clinic, both where asthma has been misdiagnosed and as an additional diagnosis. The current "gold standard" for diagnosis of VCD is direct visualisation of the vocal cords during laryngoscopy. A flow volume loop recorded whilst symptomatic may also demonstrate an abnormal pattern, and VCD may be induced in susceptible subjects—for example, by hypertonic saline (HS) challenge. Taramarcaz and colleagues (J Allergy Clin Immunol. 2004) have reported a decrease in forced inspiratory flow (FIF50) after HS challenge in a case series of three patients with postviral VCD. Methods We designed a prospective, controlled study to determine whether HS challenge testing provokes VCD, as evidenced by changes in FIF50 and visual analogue scores (VAS). Baseline questionnaires (Hospital Anxiety Depression Score (HAD), adapted John Hunter Cough Questionnaire (aJHCQ) and a VCD VAS) were completed, then HS challenge performed, with a shortened VAS and spirometry recorded after each dose interval. Results Twenty-seven subjects (mean (range) age 38 (21–62) years, 38% male) completed the study, seven subjects with VCD (6 with a previous diagnosis of asthma), six physician-confirmed asthma alone and 14 healthy controls (HCs). Subjects with VCD were older, with higher HAD, baseline VAS and aJHCQ scores than the other groups. As expected, HS induced a greater fall in forced expiratory volume in 1 s (FEV1) in the group with asthma than in the VCD or HC groups. However, change in FIF50 after the final dose of HS did not significantly differ between groups. The change in mean VAS score, and particularly items 1 and 2, discriminated between VCD and the other groups during HS challenge (table 1). Conclusion FIF50 may not be a useful dynamic marker of VCD during HS challenge, but our modified VCD VAS did show symptom changes in subjects with VCD compared with those with asthma and healthy controls. This tool could potentially be used in the diagnosis and treatment of VCD after further evaluation and validation.


We study physicians' incentives to use personalized medicine techniques, replicating the physician's trade-offs under the option of personalized medicine information. In a laboratory experiment where prospective physicians play a dual-agent real-effort game, we vary both the information structure (free access versus paid access to personalized medicine information) and the payment scheme (pay-for-performance (P4P), capitation (CAP) and fee-for-service (FFS)) by applying a within-subject design. Our results are threefold. i) Compared to FFS and CAP, the P4P payment scheme strongly impacts the decision to adopt personalized medicine. ii) Although expected to dominate the other schemes, P4P is not always efficient in transforming free access to personalized medicine into higher quality patient care. iii) When it has to be paid for, personalized medicine is positively associated with quality, suggesting that subjects tend to make better use of information that comes at a cost. We conclude that this last result can be considered a "commitment device". However, quantification of our results suggests that the positive impact of the commitment device observed is not strong enough to justify generalizing paid access to personalized medicine.


The Holy Quran is very important to the Muslims with respect to its authenticity. This paper studies and exploits the fragile watermarking method that works on block-wise in the wavelet domain and pixel-wise in the spatial domain. The input image is transformed into wavelet domain using discrete wavelet transform. Then, using block-wise based approach the coefficients matrix of wavelet-transformed image is divided into several blocks for further watermark the authentication bits. The authentication bits are embedded into a block with 2n elements by modifying only one original element with ±1. Afterward, the modified coefficients matrix is inverted back to the spatial domain. The difference of coefficients matrix of the modified and the inverse is embedded on the pixel by changing one insignificant bit. Obviously, it ensures imperceptible watermark on the host image. Public-key cryptography is utilized to encrypt the authentication bits. The authentication bits are derived from input image using well-known hash function. The experimental result shows proposed method is able to detect any manipulation on the content of digital Holy Quran and thus preserves its content's integrity.


Worldwide utilities and industries have seen various technological advancements in circuit breaker (CB) testing and analysing. Yet most of the owners underperform the maintenance activity when it comes to circuit breaker maintenance and many limit themselves to an operating time test or a static contact resistance test using inappropriate test equipment. The reasons cited for this were 'complicated test procedures which involve longer outage time on the feeder', 'lack of availability of the feeder for maintenance' and 'lack of permission to remove the earth rod or earth switch while the breaker was in shutdown condition'. Also the decision making process and pin pointing the fault in a breaker after performing a basic circuit breaker test will often be a challenge. Though the basic tests like timing test on a circuit breaker provides preliminary information about the breaker condition, actual condition of a deteriorating breaker becomes obvious in a well matured state and often revealed only by a catastrophic failure while in service. Different utilities, switch gear manufacturers, researchers and test equipment manufacturers have stressed the importance of various advanced test methodologies to save time and money. Those tests include coil current analysis, dynamic resistance measurement, testing on dual ground conditions, vibration testing, first trip analysis, online testing and so on. These circuit breaker testing technologies often provide critical information of the circuit breaker and make the decision making process simple. Pinpointing the fault in a circuit breaker and attempting the maintenance activity in a very short time will be complicated if the directions guided by the test methodologies or equipments are not clear enough or easy enough. Also one particular method, tool or technology will never provide a complete solution on the circuit breaker analysis. In this paper we would like to present a report on how some of the latest technologies in the testing industry with an integrated approach of different test methods have averted major catastrophes in substations and has made the CB testing and analysing processes simple, safe, effective and efficient. (6 pages)


SUMMARY
Within a period of one year two children were treated for a
transverse intraluminal chord of the esophagus, which
developed following repair of the esophageal atresia and
peripheral tracheo-esophageal fistula. The chord was
located at the level of the anastomosis in the upper third of
the esophagus. In the first child, the chord was partially
obstructing the esophageal lumen, causing severe dysphagia
and requiring dilatation. In the second child, the chord was
causing only mild stenosis and minimal symptoms. There
were no available instruments suitable for the transsection
of the chord and a special snare was improvised on site.
The etiology of this singular formation is unknown. A
possible explanation for this formation is discussed.
Key words: Esophageal atresia, stenosis, transverse chorde


: Insurance coverage denial and excessive premium rates have made the small employer health insurance market a popular target for sweeping reforms. Many proponents of small market insurance reform have advocated pure community rating by requiring carriers to charge the same rate to all of their customers as a solution. But legislating the use of pure community rating could do more harm than good in solving the problems of cost and access. A more sensible approach would limit rate differences through either rating bands or community rating by class.


The advances in mobile and wearable sensing have led to a myriad of approaches for stress detection in both laboratory and free-living settings. Most of these methods, however, rely on the usage of some combination of physiological signals measured by the sensors to detect stress. While these solutions work great in a lab or a controlled environment, the performance in free-living situations leaves much to be desired. In this work, we explore the role of context of the user in free-living conditions, and how that affects users' perceived stress levels. To this end, we conducted an 'in-the-wild' study with 23 participants, where we collected physiological data from the users, along with 'high-level' contextual labels, and perceived stress levels. Our analysis shows that context plays a significant role in the users' perceived stress levels, and when used in conjunction with physiological signals leads to much higher stress detection results, as compared to relying on just physiological data.


The molecular analysis of the genetic systems controlling the main stages of nodule bacteria (rhizobia) interaction with a legume host (signaling at early stages and symbiotic nitrogen fixation) has shown that the widespread recombination of genetic material in free-living ancestors of rhizobia was an important factor in the evolution of these systems. These recombinations could be conditioned by a high content of repeated DNA sequences and the IS elements in the rhizobial genome. A high recombination activity of rhizobia is manifested in the panmictic structure of their populations, which is associated with frequency-dependent selection favoring rare recombinants. This selection is realized through the competition of virulent strains for the nodule formation and can be controlled by the genes whose expression depends on population density (via the quorum sensing mechanism). A high degree of panmixia in rhizobial populations is associated with their ecotypic polymorphism, manifested as the coexistence of symbiotic and nonsymbiotic strains. This type of polymorphism is caused by individual selection during the periodic changes of ecological niches (soil-plant host) in the rhizobia life cycle. The rhizobia-plant interaction stimulates selection in bacterial populations, which results in the increased levels of their heterogeneity and panmixia. The combination of individual and frequency-dependent selection types resulted in the high rates of symbiosis evolution and polyphyletic origin of diverse rhizobial species.


This paper presents a computational efficient distributed circuit model for broadband power-line communications (PLC) in the frequency range of 1 to 30 MHz. The model is derived based on the full wave approach and it takes into account the mutual coupling between the power lines, the effect of the ground plane and the discontinuity along the lines (e.g., PLC line bent with an arbitrary angle and the terminations). To derive the distributed circuit model, the PLC lines were divided into many small elements with each element treated as a dipole antenna. The electromagnetic fields along the power lines were considered as the summation of the field of these elements solved by the boundary conditions at the air-conductor and the air-ground interfaces from which the explicit expressions of the per-unit-length circuit parameters were obtained. To check the accuracy of our proposed model, the current distributions along PLC lines excited by an external source were determined using the chain matrix approach. Common-mode current is calculated with the transmission line equations. The agreement between our theoretical calculations with the experimental data as well as with full wave approach shows the validity and applicability of our proposed model for such PLC applications.


Abstract: The cardiac sarcolemmal Na+/H+ exchanger (NHE) extrudes one H+ in exchange for one Na+ entering the myocyte, utilizing for its driving force the inwardly directed Na+ gradient that is maintained by the Na+/K+ ATPase. The exchanger is quiescent at physiological values of intracellular pH but becomes activated in response to intracellular acidosis. Recent evidence suggests that a variety of extracellular signals (e.g., adrenergic agonists, thrombin, and endothelin) also modulate sarcolemmal NHE activity by altering its sensitivity to intracellular H+. Since sarcolemmal NHE activity is believed to be an important determinant of the extent of myocardial injury during ischemia and reperfusion, regulation of exchanger activity by endogenous ligands associated with ischemia is likely to be of pathophysiological importance.


Background With the increasing shift to reusable shopping bags and the potential ban on plastic bags in Canada in the near future, the question arises as to whether consumers are aware of the proper practices to maintain a safe environment within the bags themselves. The reason for this study was to determine if people are aware of the need to keep specific bags for certain food groups and if they are aware of the need to wash and/or sanitize their reusable shopping bags due to the risk of cross-contamination. Usage of the same bag for various foods (e.g. lettuce and raw meat) without proper sanitation practices can lead to cross-contamination between the foods, and in turn, create a risk of food borne illness. Methods A survey created on Microsoft Office 365 Word was administered through Survey Monkey and distributed on Reddit, various social media, and by email. The survey collection ran for one week in the month of January 2020. The survey consisted of 14 questions and took approximately two to three minutes to complete. Results 225 respondents filled out the online survey. The majority of survey responses were from British Columbia (47%), were female (54%), attended post-secondary institutions (65%) and were between the ages of 20 to 30 (46%). Nearly half of reusable shopping bag users use the same bag to store their fruits/vegetables and their meats, 61% of users have never cleaned their shopping bags, 7% clean them weekly, and only 1% clean their bag after every use. Those who mix produce and meats in the same bag are less likely to wash their RSBs (p = 0.0006). Males are less likely to wash their shopping bags than females (P = 0.009). 97% of survey respondents were not provided with any cleaning instructions upon their purchase of a reusable shopping bag and 93% have never seen educational material presented on RSB cleaning and/or the risk of cross-contamination. 84% believe there is not appropriate awareness and knowledge among the general public on the cleaning requirements of reusable shopping bags and the potential risk of cross-contamination while 10% believe there is sufficient awareness. Not surprisingly, those who were not aware that shopping bags need to be cleaned between uses were less likely to wash them (p = 7.804 x10-19). Conclusion In conclusion: 1. people who are not aware that their RSBs need to be cleaned between uses are also less likely to clean them, 2. males are less likely to clean their reusable shopping bags, 3. bags that contain both fruits/vegetables and meats in the same bags are also less likely to be cleaned, and 4. bags that are used more frequently also cleaned more frequently. Further education on reusable shopping bags is needed along with the transition from plastic bags to reusable shopping bags. At the time of publication, the 2020 Covid-19 pandemic was rapidly spreading throughout the world. In order to prevent fomite spread of disease, British Columbia forbade the use of RSBs in grocery stores, resulting in a proliferation of plastic bags. Time will tell when, and if, RSBs will be permitted for grocery shopping.


This research by practice into the visual and aesthetic qualities of ceramic glaze investigates
its ability to create an impression of depth. Because perspectival depth alone can not fully
account for my artistic concerns, and the requirements of perspectival illusion are at odds
with some of my major artistic preoccupations, such as an interest in accidents and
imprecision in material rendering, I raised the hypothesis of a poetic dimension of depth,
posing the research question for this project:

"What is poetic depth in a ceramic glaze?"

Traditionally, research into glazes focuses on aspects of material science, craftsmanship,
archaeology or art history, and optical depth has been the subject of investigations into the
microstructure of glaze. By seeking to address the aesthetic dimension of glaze I am moving
away from such concerns. While the aesthetics of ceramic glaze is a new field of research,
with little existing material, I am seeking to find parallels with practice, theories and research
from the field of literary poetry, even though by 'poetic' I am referring to a quality that is not
only mediated by language and goes beyond the field of literature. Further, I am also
referring to Gaston Bachelard's approach to material imagination through his poetics of the
natural elements and to the concept of transitional space developed by psychoanalysts of the
British Independent Group, Donald Winnicott and Marion Milner.

My thesis consists of a threefold dialogue between my artistic practice of glaze, theories and
practices of literary poetry and the concept of the transitional phenomenon.
My findings are at the intersection of those three elements, and they are the results of my
investigations through both making and writing:
• 'Poetic tension' is a paradoxical and conflicting process between authority – the ability
to control – and subjectivity on the one hand and factors of dissent, questioning the
very possibility of authorship, on the other: among these are the unconscious and the
materiality of the glaze.
• The concern for interiority is a central element of poetry, the transitional phenomenon
and my works.
• My practice of glaze is an attempt to re-enact and objectify the fusion between the
self and the world, addressing the issues of the illusion of all-encompassing
subjectivity and the disillusion of objectivity, both key elements of the transitional
phenomenon.
• Play has been a natural development of my practice of glaze and I further established
parallels with the literary poetic in a shared aspiration for subversion, dissent and
laughter.
• The concept of the formless permeates Bachelard's material imagination and my
practice of glaze. Moreover it is often a prerequisite for Winnicott's and Milner's
approach to creativity and play.
• Failure is the essence of a certain form of poetry, which Georges Bataille summed up
as the 'Impossible'. It is also a key aspect of my practice of glaze: an essence of flux
or a further element of play whose irresolution or unlikely balance can create yet
another dimension of the poetic.
• Flux is a necessary element of glazes but it also summarizes the dynamics and
dialectics of the transitional phenomenon and of the Bataillean 'Impossible' and the
playful poetic.

All three strands: my practice of glaze, the literary poetic and the transitional
phenomenon intertwine, cross-fertilize and develop in parallel. Together, they have
helped articulate the concepts and the artistic vocabulary through which the poetic and
the transitional phenomenon have become operative categories of aesthetics, artistic
practice, and of research processes.


Experimental and analytical investigations have been conducted on a new type of infilled frames with Frictional Sliding Fuses (FSF). The results show that these infilled frames have adjustable strength and high ductility similar to other structural elements. Furthermore, the ultimate strengths and deformation capacities of such infills are much more than regular similar fuse-less infilled frames. To study the behavior of such infilled frames in out of plane direction, a specimen was loaded transversally after being failed by in-plane loadings and having the experience of 6% drift in this direction. The results reveal that the infill has sufficient strength against out of plane components of regular earthquakes. The infill with the proposed configuration of this study is modeled by finite element method, in ABAQUS, to study the influence of the fuse sliding strength on its ultimate strength. It is shown that the ultimate strength is raised linearly by increasing the sliding strength of the fuse. In summary, the results confirms that such infilled frames can be regarded engineered for their high ductility as well as the capability of being adjusted for a desired strength.


This study was conducted to see how character branding of religious individual whose known as Ustaz Celebrity relates to the programs aired on TVAlhijrah, in accordance with its concept as an Islamic station which broadcast one hundred percent Islamic-oriented content. This study was conducted based on qualitative findings involving in-depth "face to face" interview and also through telephone conversations, used as a research instrument. The researcher also conducted a survey in which the questionnaires are distributed to tor TVAlhijrah's viewers. Respondents are divided into several categories such as age, gender and education level. Data from respondents, used to measure the characteristics of an ustaz which suits the title of ustaz celebrity and how their celebrities characteristic be able to used helping TVAlhijrah broadcasting their Islamic content. Transcripts, coding and data analysis was conducted using qualitative analysis. The results of this study can be used in helping TV Alhijrah to find more people to become Ustaz Celebrity in the future. It can also be used as a guideline for all TV station to choose Ustaz Celebrity to be anchoring their programmes. Character branding strategy through Ustaz Celebrity will attract more viewers to tune into TV stations as an alternative electronic medium that is capable of providing Islamic content in accordance with the requirements of syariah (Syariah Compliance)


The purpose of this study was to analyze the effect of the adaptive ability of customer relation officers in service recovery performance in the One Stop Integrated Services and Investment Office of the Special Capital Region of Jakarta (DKI). The method used in this research is quantitative. Sources of data were taken from informants, namely customer relation officers who were directly involved in the recommendation service for Building Use Rights over Land Management Rights, namely 50 respondents. The data collection technique was carried out by conducting initial interviews and distributing and filling out questionnaires. The results of the study found that culture competence, self management, social capacity, self-efficacy recovery and organizational system recovery, affect service recovery performance while informational fairness has no effect on service recovery performance of customer relation officers.


Preventing the decomposition reactions of electrolyte solutions is essential for extending the lifetime of lithium-ion batteries. However, the exact mechanism(s) for electrolyte decomposition at the positive electrode, and particularly the soluble decomposition products that form and initiate further reactions at the negative electrode, are still largely unknown. In this work, a combination of operando gas measurements and solution NMR was used to study decomposition reactions of the electrolyte solution at NMC (LiNixMnyCo1−x−yO2) and LCO (LiCoO2) electrodes. A partially delithiated LFP (LixFePO4) counter electrode was used to selectively identify the products formed through processes at the positive electrodes. Based on the detected soluble and gaseous products, two distinct routes with different onset potentials are proposed for the decomposition of the electrolyte solution at NMC electrodes. At low potentials (<80% state-of-charge, SOC), ethylene carbonate (EC) is dehydrogenated to form vinylene carbonate (VC) at the NMC surface, whereas at high potentials (>80% SOC), 1O2 released from the transition metal oxide chemically oxidises the electrolyte solvent (EC) to form CO2, CO and H2O. The formation of water via this mechanism was confirmed by reacting 17O-labelled 1O2 with EC and characterising the reaction products via1H and 17O NMR spectroscopy. The water that is produced initiates secondary reactions, leading to the formation of the various products identified by NMR spectroscopy. Noticeably fewer decomposition products were detected in NMC/graphite cells compared to NMC/LixFePO4 cells, which is ascribed to the consumption of water (from the reaction of 1O2 and EC) at the graphite electrode, preventing secondary decomposition reactions. The insights on electrolyte decomposition mechanisms at the positive electrode, and the consumption of decomposition products at the negative electrode contribute to understanding the origin of capacity loss in NMC/graphite cells, and are hoped to support the development of strategies to mitigate the degradation of NMC-based cells.


American translators, in collaboration with the Swiss authors, have expanded and edited this translation to produce an international review and compilation. It is pointed out that the German clinical studies have emphasized quantitative volumetric spirometry while Anglo-Americans have stressed alveolar air and blood chemical changes. An extensive bibliography is provided. The book is an analytic review, although much of the clinical experience of the translators has been incorporated. The high-tension mathematics involved takes this work out of the realm of everyday usage, but it should be a valuable reference for specialists in aerobiology, cardiopulmonary investigations, physiological fitness, pulmonary diffusion abnormalities, stress of metabolic origin, artificial respiration and oxygen therapy, high pressure submarine habitation, civil defense shelters, and gerontological adjustment. The subjects covered include ventilation function within physiological ranges, gaseous transfer between alveoli and blood, oxygen and carbon dioxide transport, respiratory regulation, tissue respiration, cyanosis, dyspnea, methods of clinical investigation, emphysema,


This work investigates model reduction techniques that are based on a quasi-continuum-like approach. These techniques reduce a large optimization problem to either a system of nonlinear equations or another optimization problem that are expressed in a smaller number of degrees of freedom. The reduction is based on the observation that many of the components of the solution of the original optimization problem are well approximated by certain interpolation operators with respect to a restricted set of representative components. Under certain assumptions, the "optimize and interpolate" and the "interpolate and optimize" approaches result in a regular nonlinear equation and an optimization problem whose solutions are close to the solution of the original problem, respectively. The validity these assumptions is investigated by using examples from potentialbased and electronic structure-based calculations in Materials Science models. A methodology is presented for using quasi-continuum -like model reduction for real-space DFT computations in the absence of periodic boundary conditions. The methodology is illustrated using a one-dimensional basic Thomas-Fermi-Dirac case study.


ABSTRACT The Pliocene Pleshet Formation was deposited in moderately high energy, nearshore environments dominated by upper shoreface and foreshore sediments, characterized by concentrations of heavy minerals and shell fragments, beach rock, shoreline conglomerates, and organic burrowing. The Pliocene marine transgression which prevailed during the deposition of the Pleshet Formation was offset by progradation related to infilling of the shallow marine basins by influxes of sand from both Negev and Mediterranean source areas. The sands are multi-component systems which contain up to 7 populations. The statistical parameters of the grain-size frequency distributions are directly related to the way in which these populations are mixed. The abrupt change in these parameters at the tops of the depositional sand units coincides with surfaces of erosion and suggests that one of the 2 source areas became a more active supplier of sand, thus changing the modal composition. Nearshore beach sedimentation ranging from current dominated to shallow water shoals with prevailing wave action is indicated by bivariate plots of grain-size parameters and the bimodality of the central parts of the frequency distributions. An upward improvement of sorting in several of the units reflects a shallowing of the environment with more influence of wave action.


Near-shore marine sediments deposited along island arcs preserve evidence of past disaster events such as tsunamis. A tsunami occurred on 11 March 2011 off the Pacific coast of Tohoku, Japan, associated with the 2011 off the Pacific coast of Tohoku Earthquake. The event is likely preserved in marine sediments. This study aims to constrain the distribution of tsunami deposits and its preservation states in Sendai Bay, located west of the earthquake, by geochemical and rock magnetic analyses. Surface sediments on the seafloor were collected at four stations, the entrance (S-2) and outer sites (S-3, S-4, and S-5) in the Bay, between 2011 and 2014. Stations S-4 and S-5 are located under the axis of the storm wave base, which erode modern sediments (e.g., Saito, 1989). Results of low-temperature magnetometry indicate that transported magnetite by the tsunami is oxidized within a year at stations S-4 and S-5. Magnetic grain size parameters, Mr/Ms and Hcr/Hc, show that coarse grains are supplied at stations S-4 and S-5 in 2013-2014. Magnetic extracts observation with a scanning electron microscopy (SEM) and element identification by energy dispersive X-ray spectrometry (EDX) indicates that Ti-poor magnetite particles with less lamellae increase in the samples that collected after the 2011 Tohoku tsunami. Fe2O3 and Cr contents are high in the samples. While Cr content decreases from 2013 at all stations. Fe2O3 content also declines at station S-5 in 2014. It is implied that the 2011 Tohoku tsunami deposits are not preserved after 2013 at least.


Abstract Introduction: Infections due to carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CPCRE) are an emerging global public health threat. The purpose of this study was to investigate phenotypic and genotypic features of CP-CRE strains isolated from hospitalized patients. Material and methods: Between 1st of January - 1st of July 2017, in the Department of Microbiology, "Dr. Constantin Opriş" County Emergency Hospital Baia Mare, Romania, 1110 strains of Enterobacteriaceae were isolated from bronchial secretions, urine, wounds and blood cultures. Bacterial identification and antimicrobial susceptibility tests were performed by conventional methods, Vitek 2 Compact and M.I.C.E. strips. We analysed all Enterobacteriaceae strains non-susceptible to carbapenems according to CLSI 2017 criteria. The modified Hodge test (MHT), the modified carbapenem inactivation method (mCIM) and the combination disks test (KPC, MBL, OXA-48 Confirm kit, Rosco Diagnostica) were used for phenotypic confirmation, whereas a multiplex PCR assay for genes blaKPC, blaNDM and blaOXA-48 was used for genetic confirmation. Results: 19 non-duplicate strains isolated from 16 patients were phenotypically identified as CP-CRE: Klebsiella pneumoniae (n=14), Escherichia coli (n=2), Providencia stuartii (n=2) and Serratia marcescens (n=1). Most strains were isolated from bronchial secretions (n=9). The carbapenem-hydrolizing enzymes were identified by the combination disks test as: KPC (n=9), OXA-48-like (n=5) and MBL (n=5). Molecular confirmation was performed in 18 phenotypically positive isolates with 100% concordant results with mCIM and combination disks test. Discrepant results were noticed with the MHT in case of 4 NDM-producers confirmed by PCR. All CP-CRE strains were resistant to all tested cephems. Three out of 9 K. pneumoniae strains tested against colistin were found resistant. Conclusions: The most common carbapenemase detected was KPC. Therapeutic options were limited in all positive cases. Rapid and reliable detection of CP-CRE is critical for preventing the spread of these pathogens


Cellulose aerogels can be prepared via dissolution-coagulation-drying with supercritical CO2 (so-called "Aerocellulose"). They are ultra-light (apparent density 0.05-0.20 g/cm3), with rather high specific surface (200-300 m2/g) and pore sizes distribution ranging from a few tens of nanometers to few microns. In the view of Aerocellulose nanostructuring (for example, to achieve low thermal conductivity), two approaches were taken: i) cellulose chemical cross-linking and ii) preparation of cellulose-silica hybrid aerogels. Compared to pure Aerocellulose the thermal conductivity of such nanostructured Aerocellulose was found to be reduced and specific surface of organic-inorganic hybrids was increased up to 800 m2/g. Structure-properties relationships of these novel materials will be discussed.


Aims of our study were i) to compare in a large number of hypertensive subjects the relative effect of antihypertensive treatment on clinic (C) blood pressure (BP) and various ambulatory (A) BP components, and ii) to determine whether antihypertensive treatment affects BP variability. In 266 mild essential hypertensive outpatients (age: 18-78 years) CBP (trough measurements) and ABP (Spacelabs 90202 or 90207) were measured after 3 to 4 weeks of wash-out and after 4 to 8 weeks of treatment with an ACE-inhibitor (n = 135) or a calcium-antagonist (n = 131). ABP recordings were analyzed to obtain average 24 h, day-time (6 a.m. to midnight) and night-time (midnight to 6 a.m.) systolic and diastolic BP values and standard deviations (BP variabilities). Treatment reduced both CBP and ABP. Treatment-induced changes in CBP showed a poor correlation with those in 24h, day- and night-time BP (r never > 0.23) and the correlation was poor also when trough ABP (mean of last 2 h) was considered. Twenty-four hour, day- and night-time BP were similarly reduced by treatment with a direct relationship between the initial BP values and the subsequent BP falls. BP standard deviations were also reduced by treatment in relation to the pretreatment values but the overall reduction was small, limited to the day-time and proportional or less than proportional to the reduction in mean values, with no changes or an increase in variation coefficients. The effects of ACE-inhibitor and calcium-antagonist treatments were superimposable. Our results from a large data base show that antihypertensive treatment effectively reduces all ABP components. The reduction cannot be predicted by the concomitant fall in CBP but it relates to the initial ABP values. Treatment has a limited effect on BP variability, this being the case both for ACE-inhibitors and calcium-antagonists.


My central concern in this thesis is how science should be understood by the public. I argue that science should be understood, and valued for, the formative aspirations of the scientific community. The formative aspirations of the scientific community are the values members try to uphold as members of the group, even when this is not always possible. These aspirations are constitutive of the scientific 'form of life'. I argue that science and religion are distinct forms of life, and through their formative aspirations can be differentiated from one another. Drawing on the theory of Elective Modernism (Collins and Evans 2017), I argue that the formative aspirations of science overlap with democratic values.
Media representations of science shape public understanding. Non-fiction television is a ubiquitous and trusted medium for the communication of science. Non-fiction science television programme makers were interviewed to understand the process of science television production: the pressures, tensions and constraints inherent to this process.
I analyse representations of science in British non-fiction television programmes and argue that a 'religious' portrayal of science can be identified in some programmes. I identify a contrasting 'secular' portrayal of science in other programmes. The religious portrayal presents science as providing a definitive creation narrative. In this portrayal scientific knowledge is presented as a set of certain and immutable truths which are revealed by nature with little or no human intervention. In this portrayal science is presented as providing meaning. The secular portrayal's representation aligns more closely with a sociological understanding of science. In this portrayal scientific knowledge is represented as requiring human skill to produce and as being subject to change, revision and debate. Science in this portrayal is represented as producing both positive and negative outcomes for society.
From the perspective of Elective Modernism, if citizens are to properly understand, engage with and value science they need an understanding informed by sociological conceptions of science which emphasise science's formative aspirations as its defining characteristic. The requirements for the production of an 'elective modernist' portrayal of science, one which foregrounds the formative aspirations of science, are discussed. The problematic consequences of the religious portrayal of science are laid out. Presenting science as a religion disguises its formative aspirations. This provides an inaccurate picture of how science works and a widespread (mis)understanding of science as a religion would undermine democratic society.


Infant's gown of white cotton batiste. Round neckline trimmed with ruffle of broderie anglaise. Eleven horizontal bands of broderie anglaise separated with shirring down center front. Hemline trimmed with a 4" band of pin tucks, two band of broderie anglaise separated with shirring and scalloped hem of broderie anglaise. Sleeve hems trimmed with three rows of pin tucks and ruffle of broderie anglaise. Center back closure of 4 pearl buttons on rectangular panel of three vertical bands of broderie anglaise separated by two shirred sections; gathers at base of panel.


While photoperiod has been generally accepted as the primary if not the exclusive cue to stimulate reproduction in photoperiodic breeders such as the laying hen, current knowledge suggests that metabolism, and/or body composition can also play an influential role to control the hypothalamic-pituitary gonadal (HPG)-axis. This review thus intends to first describe how photoperiodic and metabolic cues can impact the HPG axis, then explore and propose potential common pathways and mechanisms through which both cues could be integrated. Photostimulation refers to a perceived increase in day-length resulting in the stimulation of the HPG. While photoreceptors are present in the retina of the eye and the pineal gland, it is the deep brain photoreceptors (DBPs) located in the hypothalamus that have been identified as the potential mediators of photostimulation, including melanopsin (OPN4), neuropsin (OPN5), and vertebrate-ancient opsin (VA-Opsin). Here, we present the current state of knowledge surrounding these DBPs, along with their individual and relative importance and, their possible downstream mechanisms of action to initiate the activation of the HPG axis. On the metabolic side, specific attention is placed on the hypothalamic integration of appetite control with the stimulatory (Gonadotropin Releasing Hormone; GnRH) and inhibitory (Gonadotropin Inhibitory Hormone; GnIH) neuropeptides involved in the control of the HPG axis. Specifically, the impact of orexigenic peptides agouti-related peptide (AgRP), and neuropeptide Y (NPY), as well as the anorexigenic peptides pro-opiomelanocortin (POMC), and cocaine-and amphetamine regulated transcript (CART) is reviewed. Furthermore, beyond hypothalamic control, several metabolic factors involved in the control of body weight and composition are also presented as possible modulators of reproduction at all three levels of the HPG axis. These include peroxisome proliferator-activated receptor gamma (PPAR-γ) for its impact in liver metabolism during the switch from growth to reproduction, adiponectin as a potential modulator of ovarian development and follicular maturation, as well as growth hormone (GH), and leptin (LEP).


Background: Three causative genes have been identified for autosomal dominant AD. Objective: To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes. Methods: A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years. Results: The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001). Conclusions: Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.