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Purpose of the study was to identify and describe the Hope Family Optimization Program (PKH) in community development efforts in Kotamenara Village. The problem in the research was how to optimize the Family Hope Program (PKH) in community development efforts in Kotamenara Village. The research method used is qualitative. Qualitative research method aims to provide a systematic, factual and accurate description. Data collection techniques are observation, interviews and documentation. The results in the field research show that the Family Hope Program (PKH) really helps poor families in accessing education, health and social welfare services. Prior to this program, it was difficult for the poor in Kotamenara Village to access these three things. Where in the field of education, most of the people in the Kotamenara village are only elementary and junior high schools, now with the PKH program, many people have graduated from high school / vocational school, or 12 years of compulsory education. In the health sector, it was difficult for people to get proper and modern health services, now people can access proper health services. In the welfare sector, now the elderly and people with disabilities can get social protection through the Family Hope Program (PKH).

The future of nuclear medicine would appear to be the paradigm of personalized medicine — targeted radionuclide therapy to spare healthy tissue, and theranostic medicine, which pairs an imaging isotope with a therapeutic isotope to provide simultaneous, real-time dose delivery and verification, leading to drastic reductions in prescribed patient dose. Candidate isotopes to meet these needs have been identified based on their chemical and radioactive decay properties. This dissertation represents two extremes of cross section measurement for isotope production, as part of a larger campaign to address deficiencies in cross-cutting nuclear data needs. These studies will serve to facilitate the production of pre-clinical quantities of radioactivity for emerging and novel medical radionuclides. This dissertation details two experiments, focusing on production pathways for the radionuclides 90Mo, 64Cu, and 47Sc. Each of these experiments has been designed as part of efforts to measure production cross sections for emerging medical radionuclides and develop new methods for the monitoring of charged-particle beams. The discussion focuses on describing the experimental methods and analysis used for this measurement, and illustrates the importance of accurate knowledge of target composition. The experimental measurement of the 93Nb(p,4n) 90Mo reaction was motivated by its use as an intermediate-energy proton monitor, and was carried out through a stacked-target irradiation of thin niobium, copper, and aluminum foils at LANSCE-IPF. The work described herein is the first step in an effort to characterize this reaction as a robust and reliable, contamination-free monitor reaction channel for 40–200 MeV protons. In addition, it illustrates the potential for this 100 MeV proton beam as a production pathway for multiple novel radionuclides. The measurement of the 64Zn, 47Ti(n,p) cross sections was carried out at the recently-commissioned UC Berkeley High Flux Neutron Generator, a compact DD neutron generator designed originally for geochronology measurements. This work was motivated by the production of 64Cu and 47Sc, a pair of emerging medical radionuclides prized in particular for their capacity for theranostic applications. This measurement additionally provides context for the utility of neutron generators for isotope production, as well as introducing an efficiency quantification metric. Based on experience garnered from the LANSCE-IPF experiment, we have established a sister facility for measurements at the Lawrence Berkeley National Laboratory’s 88-Inch Cyclotron. First experiments have already been performed, and one such measurement is briefly described here. The work described here may help to enable exciting new campaigns of investigation in basic science, disease biology research, and nuclear medicine. This dissertation serves as a pedagogical example to those who follow of how the assort- ment of unexpected difficulties in precision nuclear data measurements can make “simple” experiments not so simple, after all. One significant issue that was uncovered as a result of this work was the production of 22,24Na as the proton beam traversed the acrylic adhesive on the Kapton tape used to contain the individual stacked targets in these measurements. Reactions on the silicone adhesive would occur in any stacked-target activation experiments where adhesive-backed Kapton is used, and has the potential to systematically dampen the magnitude of reported cross sections by as much as 50%. This issue is discussed as a caution- ary note to future stacked-target cross section measurements. In addition, contributions to the slowing of charged particle beams due to the adhesive have often been neglected in much work performed to date. While this plays a limited role at high beam energies, it becomes increasingly important for proton energies below 25 MeV.

One of the goals of theoretical galaxy formation is to use simulations combined with observations in order to constrain the fundamental physics that govern the formation of galaxies. Of particular interest are physical processes that can impact the formation of small-scale structures. Among the things we can potentially constrain with a combination of observations and simulations of small-scale structures are stellar feedback, reionization, and dark matter particle physics. We investigate several promising avenues to constrain fundamental physics with simulations of galaxy formation. First, we use the star formation histories (SFH) for Local Group dwarf galaxies in order to constrain high-redshift stellar mass functions (SMFs). Second, we look at the destruction of substructure around large galaxies, and how it may impact the detection of substructure via subhalo lensing. Finally, we use full hydrodynamics simulations of Local Volume dwarf galaxies in order to investigate the impact of stellar feedback on the age distributions of stars within these galaxies.

Lymphatic filariasis and onchocerciasis are major neglected tropical diseases affecting over 90 million people worldwide with painful and profoundly disfiguring pathologies (such as lymphoedema or blindness). Type 2 inflammation is a hallmark of filarial nematode tissue infection and is implicated both in eosinophil dependent immunity and lymphatic or ocular immunopathologies. Type-2 innate lymphoid cells (ILC2) are known to play an important role in the initiation of type 2 inflammation in helminth infection. We therefore tracked comparative IL-12Rβ2

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.

The Virgin Suicides (1999) USA Director Sofia Coppola Runtime 97 minutes Blu-ray USA, 2018 Produced and Distributed by The Criterion Collection (region A/1)

The precise environmental mechanisms controlling Quaternary glacial cycles remain ambiguous. To address this problem, it is critical to better comprehend the drivers of spatio-temporal variability in ice-sheet evolution by establishing reliable chronologies of former outlet-glacier advances. When spanning multiple glacial cycles, such chronologies have the capacity to resolve conundrums on interhemispheric phasing of glaciations and climate events. In southern Argentina, reconstructions of this kind are achievable, as Quaternary expansions of the Patagonian Ice Sheet have emplaced a well-preserved geomorphological record covering several glacial cycles. Moreover, robust ice-sheet reconstructions from Patagonia are powerful barometers of former climate change, as Patagonian glaciers are influenced by the Southern Westerly Winds and its coupled Antarctic Circumpolar Current. Former shifts in these circulation mechanisms are essential to better constrain, as they may have played a critical role in pacing regional and possibly global Quaternary climate change. Here, we present a new set of cosmogenic 10Be and 26Al exposure ages from pre-Last Glacial Cycle moraine boulder, glaciofluvial outwash cobble and bedrock samples. This dataset constitutes the first direct chronology dating pre-LGM glacier advances in northern Patagonia, and completes our effort to date the entire preserved moraine record of the Río Corcovado valley system (43° S, 71° W). We find the outermost margins of the study site depict at least three distinct pre-Last Glacial Cycle glaciations occurring at 284 ± 7 ka, 257 ± 7 ka, and 147 ± 4 ka. Combined with the local LGM chronology, we discover that a minimum of four distinct Pleistocene glaciations occurred during Marine Isotope Stages eight, six, and two in northern Patagonia. Evidence for stage four and three deposits were not found at the study site, which illustrates former longitudinal and latitudinal asynchronies in Patagonian Ice Sheet mass balance during these stages. We find the most extensive middle-to-late Pleistocene expansions of the Patagonian Ice Sheet appear to be out-of-phase with local summer insolation intensity, but synchronous with orbitally-controlled periods of longer and colder winters. Our findings thus enable to explore the potential roles of seasonality and seasonal duration in driving southern mid-latitude ice-sheet mass balance and facilitate novel glacio-geomorphological interpretations for the study region. They also provide empirical constraints of former ice-sheet extent and dynamics that are essential to calibrating numerical ice-sheet and glacial isostatic adjustment models.

The impact of gut bacteria on the brain and behavior has become the subject of intense research. The brain is sensitive to biochemical and physiologic changes in the body, for example, changes in blood oxygenation or nutritional status. The collection of microorganisms residing within the digestive tract (the gut microbiome) is increasingly considered a major contributor to human physiology. These 2 considerations have led to the hypothesis that human psychology, including complex constructs like emotion and mental illness, could be influenced by the composition or function of gut bacteria. Five lines of evidence have been used to support the concept, including human correlational research, probiotic supplementation, antibiotic use, germ-free animal research, and fecal transplantation. Results from these experiments do not provide substantial support for the theory that complex human psychology is under the influence of gut bacteria. Placebo-controlled interventional research in humans, in particular fecal microbiota transplantation, will be required before a stronger conclusion can be reached.

Hirayama disease, also known as monomelic amyotrophy[1][1] or juvenile muscular atrophy of the upper extremity,[2][2],[3][3] is a rare neurologic condition that involves the inferior motor neurons[1][1] and commonly affects the C7 to T1 spinal nerves and their myotomes.[4][4] Hirayama first

Background: Diffusion tensor imaging (DTI) is a magnetic resonance–based imaging technique that can provide important information about the underlying structure and integrity of the white matter in the brain. Tractography, a DTI postprocessing technique, can provide a detailed model of individual white matter fiber tracts. Knowledge of these tracts may be beneficial in the surgical planning and execution for neurosurgical patients. Case Report: We review the basic principles behind DTI and present an illustrative case in which DTI was used to delineate the relationship of eloquent white matter tracts to a cavernous malformation in a patient undergoing resection. Conclusion: The use of DTI during preoperative planning allows the neurosurgeon to understand if a lesion is disrupting, infiltrating, or altering the course of local white matter tracts. With the combined use of DTI and intraoperative neuronavigation, the neurosurgeon can better identify and avoid white matter tracts, not only in the local area of resection but also during approach to the lesion, thereby reducing the risk of damage to vital cortical pathways and subsequent functional impairment.

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16−18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10–14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days., Graphical abstract Image 1, Highlights • CBR417 and CBR490 provide long-term effects in 2 chronic filaria jird models. • CBR417 and CBR490 deplete >99% Wolbachia in B. pahangi and L. sigmodontis filariae. • CBR417 and CBR490 clear L. sigmodontis microfilariae after 10–14 weeks. • CBR417 and CBR490 inhibit filarial embryogenesis in both models. • Suboptimal doses do not maintain reduction of microfilariae and Wolbachia.

The sequence diversity of natural and laboratory populations of Brugia pahangi and Brugia malayi was assessed with Illumina resequencing followed by mapping in order to identify single nucleotide variants and insertions/deletions. In natural and laboratory Brugia populations, there is a lack of sequence diversity on chromosome X relative to the autosomes (πX/πA = 0.2), which is lower than the expected (πX/πA = 0.75). A reduction in diversity is also observed in other filarial nematodes with neo-X chromosome fusions in the genera Onchocerca and Wuchereria, but not those without neo-X chromosome fusions in the genera Loa and Dirofilaria. In the species with neo-X chromosome fusions, chromosome X is abnormally large, containing a third of the genetic material such that a sizable portion of the genome is lacking sequence diversity. Such profound differences in genetic diversity can be consequential, having been associated with drug resistance and adaptability, with the potential to affect filarial eradication., Author summary Almost a billion people receive >7.7 billion doses of treatment aimed at eliminating lymphatic filariasis, which is caused by three filarial nematodes: Wuchereria bancrofti, Brugia malayi, and Brugia timori. Drug resistance and adaptation are both associated with pathogen success as well as higher levels of genetic diversity. In an examination of genetic diversity in Brugia malayi and Brugia pahangi, we observed a lack of genetic diversity over a third of the genome that is found on chromosome X. These species have neo-X chromosomes where a chromosome X fused with an autosome. Using publicly-available published data, the other filarial nematodes of greatest human significance are also found to have a similar lack of genetic diversity on their neo-X chromosomes. The two filarial nematodes with publicly-available data that lack neo-X chromosomes did not have this lack of genetic diversity. This lack of sequence diversity in B. malayi, W. bancrofti, and O. volvulus could have profound effects on all traits encoded on chromosome X.

En el presente documento se encontrará información acerca del proyecto Mountain Chocolat, realizado por el departamento de competitividad regional de la Cámara de Comercio Barrancabermeja. Se encontrarán descritas las actividades operativas y logísticas que se llevaron a cabo durante mi proceso de prácticas empresariales en esta institución, las funciones que me eran asignadas para cumplir con el buen desarrollo del proyecto, e información relacionada con el perfil y portafolio de servicios ofrecidos por la empresa. In this document you will find information about the Mountain Chocolat project, carried out by the regional competitiveness department of the Barrancabermeja Chamber of Commerce. The operational and logistical activities that were carried out during my business internship process in this institution, the functions that were assigned to me to comply with the good development of the project, and information related to the profile and portfolio of services offered by the company will be described. Profesional en Negocios Internacionales http://www.ustabuca.edu.co/ustabmanga/presentacion Pregrado

Introduction: Septic arthritis is a destructive form of acute arthritis that requires expeditious recognition. as delayed treatment yields significant morbidity and mortality. Case Report: A 40-year-old male presented to the emergency department with right elbow pain. Examination revealed tachycardia, swelling, redness, tenderness, and decreased range of motion of the right humeroulnar joint. Synovial fluid analysis was consistent with an inflammatory etiology, but blood and joint cultures ultimately revealed Haemophilus influenzae. Discussion: This case highlights the importance of trusting clinical findings over laboratory evidence in patients with suspected septic arthritis.

BACKGROUND Intestinal bacterial communities are not homogenous throughout the gastrointestinal tract. Human research on the gut microbiome often neglects intra-intestinal variability by relying on a single measurement from stool samples. One source of complexity is the adherence to undigested, residual fiber. Currently, no procedure exists to extract RNA from distinct bacterial subpopulations in stool samples. MATERIAL AND METHODS A serial centrifugation procedure was developed in which bacterial RNA could be extracted from distinct stool-fractions - fiber-adherent and non-fiber-adherent bacteria. To test whether the separation procedure yielded distinct bacterial subpopulations, a set of RT-qPCR assays were developed for a fiber-adherent bacterial species, Bifidobacterium adolescentis, then a within-subject repeated-measures study was conducted with 3 human subjects undergoing 4 dietary regimens. At each timepoint, between-fraction differences in gene expression were evaluated. RESULTS The RNA isolation procedure was able to isolate intact RNA in 20 of 24 samples in the fiber-adherent fraction. PurB and sdh were identified as suitable reference genes for B. adolescentis RT-qPCR assays. When subjects were provided a high resistant starch diet, bacterial fractions exhibited different expression of the trp operon (p=0.031). CONCLUSIONS Our study provides human gut microbiome researchers a novel tool for evaluating functional characteristics of bacterial subpopulations in human stool. Moreover, these experiments provide modest support for the existence of a functionally unique fiber-adherent subpopulation of B. adolescentis. Until a more thorough evaluation of the adherent and non-adherent fraction can be performed, researchers should be cautious when generalizing functional data derived solely from unfractionated stool samples.

Lymphatic filariasis is the major global cause of nonhereditary lymphedema. We demonstrate that the filarial nematode Brugia malayi induced lymphatic remodeling and impaired lymphatic drainage following parasitism of limb lymphatics in a mouse model. Lymphatic insufficiency was associated with elevated circulating lymphangiogenic mediators, including vascular endothelial growth factor C. Lymphatic insufficiency was dependent on type 2 adaptive immunity, the interleukin-4 receptor, and recruitment of C-C chemokine receptor-2-positive monocytes and alternatively activated macrophages with a prolymphangiogenic phenotype. Oral treatments with second-generation tetracyclines improved lymphatic function, while other classes of antibiotic had no significant effect. Second-generation tetracyclines directly targeted lymphatic endothelial cell proliferation and modified type 2 prolymphangiogenic macrophage development. Doxycycline treatment impeded monocyte recruitment, inhibited polarization of alternatively activated macrophages, and suppressed T cell adaptive immune responses following infection. Our results determine a mechanism of action for the antimorbidity effects of doxycycline in filariasis and support clinical evaluation of second-generation tetracyclines as affordable, safe therapeutics for lymphedemas of chronic inflammatory origin.

Minority stress theory posits that sexual minority people are regularly subjected to elevated levels of stress that ultimately contribute to health disparities within this population. Research suggests that this theoretical framework may further be useful in understanding the experiences of gay men with respect to family planning. As state-level legislation and child welfare policies continue to pose challenges for gay men seeking to form families, especially via adoption, attention must be directed towards ways in which such barriers to parenthood impact the wellness of this population, notably through involuntary childlessness. Informed by research on gay men’s parenting practices, child welfare policy, and sexual minority stress, the proposed study seeks to explore the effect of discriminatory legislation on gay men’s family planning decisions. Using minority stress theory as a framework, the present study aims to evaluate how proximal stress (fear associated with government intervention in gay men’s parenting status) and distal stress (perception of whether discriminatory state policies targeting gay parents exist) influence the relation between parenting desire and planned childlessness. These relations will be examined using a moderated multiple linear regression model with one predictor (parenting desire), two moderators (distal and proximal stress), and one outcome variable (planned childlessness). The proposed study has notable implications for clinical work with gay men, public policy reform, advocacy efforts, and education.

Segmental spinal dysgenesis (SSD) is a rare congenital deformity that occurs when portions of the spine and spinal cord fail to develop properly.[1][1] SSD was originally defined as agenesis or dysgenesis localized to the lumbar or thoracolumbar regions of the spine,[2][2] but the definition was

Basic and translational research on loiasis, a filarial nematode infection of medical importance, is impeded by a lack of suitable Loa loa infection models and techniques of obtaining and culturing life cycle stages. We describe the development of a new method for routine production of infective third-stage larvae (L3) of L. loa from the natural intermediate arthropod vector host, Chrysops silacea, following experimental infection with purified microfilariae. At 14-days post-infection of C. silacea, the fly survival rate was 43%. Survival was significantly higher in flies injected with 50 mf (55.2%) than those that received 100 mf (31.0%). However, yield per surviving fly and total yield of L3 was markedly higher in the group of flies inoculated with 100 mf (3474 vs 2462 L3 produced). The abdominal segment hosted the highest percentage recovery of L3 (47.7%) followed by head (34.5%) and thorax (17.9%). L. loa larval survival was higher than 90% after 30 days of in vitro culture. The in vitro moulting success rate to the L4 larval stage was 59.1%. After experimental infection of RAG2-/-IL-2γc-/—mice, the average L. loa juvenile adult worm recovery rate was 10.5% at 62 dpi. More than 87% of the worms were recovered from the muscles and subcutaneous tissues. Worms recovered measured an average 24.3 mm and 11.4 mm in length for females (n = 5) and males (n = 5), respectively. In conclusion, L. loa mf injected into C. silacea intrathoracically develop into infective larvae that remain viable and infective comparable to L3 obtained through natural feeding on the human host. This technique further advances the development of a full laboratory life cycle of L. loa where mf derived from experimentally-infected animals may be utilized to passage life cycle generations via intrathoracic injections of wild-caught vector hosts., Author summary The Neglected Tropical Disease, loiasis (tropical eye worm disease) affects 13–15 million individuals in Central Africa. Loiasis has recently been identified as a cause of premature mortality and is a barrier to ivermectin-based elimination of onchocerciasis or lymphatic filariasis where co-infections occur, due to the risk of serious adverse events. Loiasis lacks laboratory preclinical models for drug development, biomarker discovery and inflammatory pathology research. Here we detail the successful development of an experimental technique for the laboratory production of Loa loa infective larvae via injection of purified microfilariae into the thorax of wild-caught tabanid flies that are the natural transmission vector. The high yielding infective larvae produced in the laboratory were validated as biologically viable in culture and in a new mouse infection model whereby adult-stage parasites could be produced. The evidence reported herein is an important step to establishing a full laboratory life cycle of L. loa by passage between animal models and experimental injections of the wild-caught vector, Chrysops.

Key Points Immunity to chronic filarial worm infection is apparent in IL-4Rα–deficient mice. Delayed immunity in IL-4Rα−/− mice is due to suboptimal tissue eosinophilia. Eosinophil recruitment in the absence of IL-4R signaling requires CCR3 and IL-5., Helminth infections are accompanied by eosinophilia in parasitized tissues. Eosinophils are effectors of immunity to tissue helminths. We previously reported that in the context of experimental filarial nematode infection, optimum tissue eosinophil recruitment was coordinated by local macrophage populations following IL-4R–dependent in situ proliferation and alternative activation. However, in the current study, we identify that control of chronic adult filarial worm infection is evident in IL-4Rα–deficient (IL-4Rα−/−) mice, whereby the majority of infections do not achieve patency. An associated residual eosinophilia was apparent in infected IL-4Rα−/− mice. By treating IL-4Rα−/− mice serially with anti-CCR3 Ab or introducing a compound deficiency in CCR3 within IL-4Rα−/− mice, residual eosinophilia was ablated, and susceptibility to chronic adult Brugia malayi infection was established, promoting a functional role for CCR3-dependent eosinophil influx in immune control in the absence of IL-4/IL-13–dependent immune mechanisms. We investigated additional cytokine signals involved in residual eosinophilia in the absence IL-4Rα signaling and defined that IL-4Rα−/−/IL-5−/− double-knockout mice displayed significant eosinophil deficiency compared with IL-4Rα−/− mice and were susceptible to chronic fecund adult filarial infections. Contrastingly, there was no evidence that either IL-4R–dependent or IL-4R–independent/CCR3/IL-5–dependent immunity influenced B. malayi microfilarial loads in the blood. Our data demonstrate multiplicity of Th2-cytokine control of eosinophil tissue recruitment during chronic filarial infection and that IL-4R–independent/IL-5– and CCR3-dependent pathways are sufficient to control filarial adult infection via an eosinophil-dependent effector response prior to patency.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a delayed complication of brain irradiation.[1][1] Symptoms are varied but typically consist of recurrent migraines with subsequent stroke-like symptoms and seizures.[2][2]-[5][3] The associated imaging findings are unusual but

Las Normas Internacionales de Información Financiera (NIIF) o (IFRS por su sigla en inglés) surgen a partir de la globalización económica esta crea la necesidad de aplicar normas y, por ende, de hacer parte del proceso de armonización el cual era poder manejar la información financiera que cumpla con los caracteres de comparabilidad, transparencia y confiabilidad. Además, debido a que cada país implementaba su PUC, se vio la necesidad de implementar estas normas a las empresas y se ven reflejados en sus estados financieros, los flujos de efectivo, la operatividad de la empresa y las negociaciones equitativa generando varios impactos a nivel contable. The International Financial Reporting Standards (IFRS) emerge from economic globalization this creates the need to apply standards and, therefore, to be part of the harmonization process which was to be able to manage Financial information that complies with the characteristics of comparability, transparency and reliability. In addition, because each country implemented its PUC, it was necessary to implement these rules apply to the company and are reflected in its financial statements, cash flows, the operation of the company and fair negotiations, generating several impacts at the accounting level.

Review of: Writing for the Screen: Creative and Critical Approaches, 2nd ed., Craig Batty and Zara Waldeback (2019)London: Red Globe Press, 310pp.,ISBN: 9781352006087 (pbk), $27.99,ISBN: 9781352006025 (hbk), $84.99

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targetsWolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination ofWolbachiain the in vivoLitomosoides sigmodontisfilarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantifyWolbachiaelimination inBrugia pahangifilarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed inL. sigmodontis,Brugia malayi, andOnchocerca ochengiin vivo preclinical models of filarial disease and in vitro selectivity againstLoa loa(a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia. This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% Wolbachia depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.