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OBJECTIVE: Use of colour duplex ultrasound (CDUS) and computed tomography angiography (CTA) for infrarenal endovascular aortic aneurysm repair (EVAR) surveillance differs in internationally published guidelines. This study aimed firstly to compare CDUS detection of significant sac abnormalities with CTA. Secondly, a sensitivity analysis was conducted to compare financial estimates of the, predominantly CDUS based, local and Society of Vascular Surgery (SVS) protocols, the risk stratified European Society of Vascular Surgery (ESVS) protocol, and the CTA based National Institute of Health and Care Excellence (NICE) protocol. METHODS: Agreement between CDUS and CTA was assessed for detection of significant sac abnormalities. Surveillance protocols were extrapolated from published guidelines and applied to infrarenal EVAR patients active on local surveillance at a large, single centre. Surveillance intensity was dependent on presence of endoleak and subsequent risk of treatment failure in accordance with surveillance recommendations. Estimates for each surveillance protocol were inclusive of a range of published incidences of endoleak, contrast associated acute kidney injury (AKI), and excess hospital bed days, and estimated for a hypothetical five year surveillance period. RESULTS: The kappa coefficient between CDUS and CTA for detecting sac abnormalities was 0.68. Maximum five year surveillance cost estimates for the 289 active EVAR patients were £272 359 for SVS, £230 708 for ESVS, £643 802 for NICE, and £266 777 for local protocols, or £1 270, £1 076, £3 003, and £1 244 per patient. Differences in endoleak incidence accounted for a 1.1 to 1.4 fold increase in costs. AKI incidence accounted for a 3.3 to 6.2 fold increase in costs. CONCLUSION: A combined CTA and CDUS EVAR surveillance protocol, with CTA reserved for early seal assessment and confirmatory purposes, provides an economical approach without compromising detection of sac abnormalities. AKI, as opposed to direct imaging costs, accounted for the largest differences in surveillance cost estimates.
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Aneurisma da Aorta Abdominal/cirurgia , Angiografia por Tomografia Computadorizada/economia , Endoleak/diagnóstico por imagem , Vigilância da População/métodos , Ultrassonografia Doppler em Cores/economia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/economia , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste/efeitos adversos , Endoleak/economia , Endoleak/etiologia , Endoleak/cirurgia , Procedimentos Endovasculares/efeitos adversos , Feminino , Seguimentos , Fidelidade a Diretrizes/economia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Guias de Prática Clínica como Assunto , Reoperação , Estudos RetrospectivosRESUMO
Over the past decade, the field of two-dimensional (2D) layered materials has surged, promising a new platform for studying diverse physical phenomena that are scientifically intriguing and technologically relevant. Contacts are the communication links between these 2D materials and the three-dimensional world for probing and harnessing their exquisite electronic properties. However, fundamental challenges related to contacts often limit the ultimate performance and potential of 2D materials and devices. This article provides a comprehensive overview of the basic understanding and importance of contacts to 2D materials and various strategies for engineering and improving them. In particular, we elucidate the phenomenon of Fermi level pinning at the metal/2D contact interface, the Schottky versus Ohmic nature of the contacts and various contact engineering approaches including interlayer contacts, phase engineered contacts, and basal versus edge plane contacts, among others. Finally, we also discuss some of the relatively under-addressed and unresolved issues, such as contact scaling, and conclude with a future outlook.
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Emerging two-dimensional (2-D) materials such as transition-metal dichalcogenides show great promise as viable alternatives for semiconductor and optoelectronic devices that progress beyond silicon. Performance variability, reliability, and stochasticity in the measured transport properties represent some of the major challenges in such devices. Native strain arising from interfacial effects due to the presence of a substrate is believed to be a major contributing factor. A full three-dimensional (3-D) mapping of such native nanoscopic strain over micron length scales is highly desirable for gaining a fundamental understanding of interfacial effects but has largely remained elusive. Here, we employ coherent X-ray diffraction imaging to directly image and visualize in 3-D the native strain along the (002) direction in a typical multilayered (â¼100-350 layers) 2-D dichalcogenide material (WSe2) on silicon substrate. We observe significant localized strains of â¼0.2% along the out-of-plane direction. Experimentally informed continuum models built from X-ray reconstructions trace the origin of these strains to localized nonuniform contact with the substrate (accentuated by nanometer scale asperities, i.e., surface roughness or contaminants); the mechanically exfoliated stresses and strains are localized to the contact region with the maximum strain near surface asperities being more or less independent of the number of layers. Machine-learned multimillion atomistic models show that the strain effects gain in prominence as we approach a few- to single-monolayer limit. First-principles calculations show a significant band gap shift of up to 125 meV per percent of strain. Finally, we measure the performance of multiple WSe2 transistors fabricated on the same flake; a significant variability in threshold voltage and the "off" current setting is observed among the various devices, which is attributed in part to substrate-induced localized strain. Our integrated approach has broad implications for the direct imaging and quantification of interfacial effects in devices based on layered materials or heterostructures.
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Sample entropy (SE) has relative consistency using biologically-derived, discrete data >500 data points. For certain populations, collecting this quantity is not feasible and continuous data has been used. The effect of using continuous versus discrete data on SE is unknown, nor are the relative effects of sampling rate and input parameters m (comparison vector length) and r (tolerance). Eleven subjects walked for 10-minutes and continuous joint angles (480Hz) were calculated for each lower-extremity joint. Data were downsampled (240, 120, 60Hz) and discrete range-of-motion was calculated. SE was quantified for angles and range-of-motion at all sampling rates and multiple combinations of parameters. A differential relationship between joints was observed between range-of-motion and joint angles. Range-of-motion SE showed no difference; whereas, joint angle SE significantly decreased from ankle to knee to hip. To confirm findings from biological data, continuous signals with manipulations to frequency, amplitude, and both were generated and underwent similar analysis to the biological data. In general, changes to m, r, and sampling rate had a greater effect on continuous compared to discrete data. Discrete data was robust to sampling rate and m. It is recommended that different data types not be compared and discrete data be used for SE.
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BACKGROUND: Arteriovenous fistula (AVF) formation for long-term haemodialysis in children is a niche discipline with little data for guidance. We developed a dedicated Vascular Access Clinic that is run jointly by a transplant surgeon, paediatric nephrologist, dialysis nurse and a clinical vascular scientist specialised in vascular sonography for the assessment and surveillance of AVFs. We report the experience and 2-year outcomes of this clinic. METHODS: Twelve new AVFs were formed and 11 existing AVFs were followed up for 2 years. All children were assessed by clinical and ultrasound examination. RESULTS: During the study period 12 brachiocephalic, nine basilic vein transpositions and two radiocephalic AVFs were followed up. The median age (interquartile range) and weight of those children undergoing new AVF creation were 9.4 (interquartile 3-17) years and 26.9 (14-67) kg, respectively. Pre-operative ultrasound vascular mapping showed maximum median vein and artery diameters of 3.0 (2-5) and 2.7 (2.0-5.3) mm, respectively. Maturation scans 6 weeks after AVF formation showed a median flow of 1277 (432-2880) ml/min. Primary maturation rate was 83 % (10/12). Assisted maturation was 100 %, with two patients requiring a single angioplasty. For the 11 children with an existing AVF the maximum median vein diameter was 14.0 (8.0-26.0) mm, and the median flow rate was 1781 (800-2971) ml/min at a median of 153 weeks after AVF formation. Twenty-two AVFs were used successfully for dialysis, a median kt/V of 1.97 (1.8-2.9), and urea reduction ratio of 80.7 % (79.3-86 %) was observed. One child was transplanted before the AVF was used. CONCLUSIONS: A multidisciplinary vascular clinic incorporating ultrasound assessment is key to maintaining young children on chronic haemodialysis via an AVF.
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Derivação Arteriovenosa Cirúrgica/métodos , Ambulatório Hospitalar/organização & administração , Diálise Renal/instrumentação , Diálise Renal/métodos , Dispositivos de Acesso Vascular , Adolescente , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Vasos Sanguíneos/diagnóstico por imagem , Veias Braquiocefálicas/diagnóstico por imagem , Veias Braquiocefálicas/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Cultura Organizacional , Resultado do Tratamento , Ultrassonografia , Ultrassonografia Doppler , Dispositivos de Acesso Vascular/efeitos adversos , Recursos HumanosRESUMO
Primary hyperparathyroidism is primarily due to a solitary parathyroid adenoma but multi-gland disease, parathyroid carcinoma, and ectopic parathyroid hormone production can occur. Although primary hyperparathyroidism mostly presents sporadically, strong familial predispositions also exist. Much is known about heritable genetic mutations responsible for these syndromes, including multiple endocrine neoplasia types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, and familial hypocalciuric hypercalcemia. Acquired mutations in common sporadic hyperparathyroidism have also been discovered. Here we focus on the most common and well-established genetic drivers: 1) involvement of the oncogene cyclin D1 in human neoplasia was first established in parathyroid adenomas, followed by recognition of its importance in other tumor types including breast cancer and B-lymphoid malignancy; and 2) somatic mutation of the MEN1 gene, first identified as the source of pathogenic germline mutations in patients with familial endocrinopathies, is found in a substantial fraction of non-familial parathyroid adenomas.
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Ciclina D1/genética , Hiperparatireoidismo Primário/genética , Neoplasias das Paratireoides/genética , Proteínas Proto-Oncogênicas/genética , Adenoma/genética , Fibroma/genética , Humanos , Hiperparatireoidismo/genética , Hiperparatireoidismo Primário/etiologia , Neoplasias Maxilomandibulares/genética , Neoplasias das Paratireoides/complicaçõesRESUMO
Both Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD.
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Transtorno do Espectro Autista/psicologia , Sistema Nervoso Autônomo/fisiopatologia , Emoções/fisiologia , Música , Ajustamento Social , Síndrome de Williams/psicologia , Estimulação Acústica , Adolescente , Nível de Alerta/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Criança , Expressão Facial , Feminino , Humanos , Masculino , Percepção Social , Fala/fisiologia , Síndrome de Williams/fisiopatologiaRESUMO
PURPOSE: We sought to develop and characterize a model of human vitamin D nutritional insufficiency/deficiency in the adult mouse, which could have broad utility in examining health consequences of this common condition. METHODS: Adult mice were fed diets containing cholecalciferol contents of 0.05 IU/g, 0.25 IU/g, 0.5 IU/g or 1.5 IU/g for four months. We studied induction of steady-state vitamin D insufficiency, and its consequences on primary cholecalciferol metabolite levels, calcium homeostasis, parathyroid physiology, and bone morphology. RESULTS: All diets were well tolerated, without adverse effects on body weight. Diets containing 0.05 IU/g and 0.25 IU/g cholecalciferol significantly lowered serum 25-hydroxyvitamin D levels (median 25OHD, 10.5 ng/ml, and 21.6 ng/ml, respectively), starting as early as one month following initiation of the diets, maintained through the four-month experimental period. The 0.05 IU/g diet significantly decreased 1,25-dihydroxyvitamin D (1,25OH2D) levels (median, 78 pg/ml). Despite these decreased 25OHD and 1,25OH2D levels, the diets did not alter parathyroid gland morphology or parathyroid cell proliferation. There were no statistical differences in the serum total calcium and serum PTH levels among the various dietary groups. Furthermore, the 0.05 IU/g diet did not cause any alterations in the cortical and trabecular bone morphology, as determined by microCT. CONCLUSIONS: The dietary manipulations yielded states of vitamin D insufficiency or modest deficiency in adult mice, with no overtly detectable impact on parathyroid and bone physiology, and calcium homeostasis. This model system may be of value to study health effects of vitamin D insufficiency/deficiency especially on extraskeletal phenotypes such as cancer susceptibility or immune function.
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Calcifediol/sangue , Colecalciferol/farmacologia , Deficiência de Vitamina D/sangue , Vitaminas/metabolismo , Animais , Colecalciferol/administração & dosagem , Dieta , Modelos Animais de Doenças , Feminino , Masculino , CamundongosRESUMO
Hyperparathyroidism jaw-tumor syndrome is an autosomal dominant disorder caused by mutations in the CDC73/HRPT2 tumor suppressor gene, encoding parafibromin, and manifesting benign or malignant parathyroid tumors, ossifying jaw fibromas, uterine tumors, and kidney lesions. Sporadic parathyroid carcinomas also frequently exhibit inactivating CDC73 mutations and loss of parafibromin. To study the role of CDC73 in parathyroid cell proliferation in vivo, we generated mice with a parathyroid-specific deletion of Cdc73. Homozygous knockout mice on a mixed B6/129/CD1 background had decreased serum calcium and PTH and smaller parathyroid glands compared with heterozygous or wild-type littermates, whereas homozygous Cdc73-null mice on other backgrounds exhibited no abnormalities in parathyroid gland function or development. No hypercalcemia or parathyroid hypercellularity was observed in mice of any background examined at any age. Thus, although postnatally acquired complete loss of CDC73 causes parathyroid cell proliferation and hyperparathyroidism, such as seen in human hyperparathyroidism jaw-tumor syndrome, our results suggest that earlier, developmentally imposed complete loss of Cdc73 can cause a primary defect in parathyroid gland structure/function in a strain-dependent manner. This striking disparity in parathyroid phenotype related to genetic background offers a unique opportunity in an in vivo model system to precisely dissect and identify the responsible molecular mechanisms.
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Primary hyperparathyroidism (PHPT) is a common endocrinopathy for which several pathogenic mechanisms, including cyclin D1 overexpression, have been identified. Vitamin D nutritional status may influence parathyroid tumorigenesis, but evidence remains circumstantial. To assess the potential influence of vitamin D insufficiency/deficiency on initiation or progression of parathyroid tumorigenesis, we superimposed vitamin D insufficiency or deficiency on parathyroid tumor-prone parathyroid hormone-cyclin D1 transgenic mice. Mice were placed on diets containing either 2.75â IU/g, 0.25â IU/g, or 0.05â IU/g cholecalciferol, either prior to expected onset of PHPT or after onset of biochemical PHPT. When introduced early, superimposed vitamin D insufficiency/deficiency had no effect on serum calcium or on parathyroid gland growth. However, when introduced after the onset of biochemical PHPT, vitamin D deficiency led to larger parathyroid glands without differences in serum biochemical parameters. Our results suggest that low vitamin D status enhances proliferation of parathyroid cells whose growth is already being tumorigenically driven, in contrast to its apparent lack of direct proliferation-initiating action on normally growing parathyroid cells in this model. These results are consistent with the hypothesis that suboptimal vitamin D status may not increase incidence of de novo parathyroid tumorigenesis but may accelerate growth of a preexisting parathyroid tumor.
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Neoplasias das Paratireoides , Deficiência de Vitamina D , Animais , Camundongos , Glândulas Paratireoides , Neoplasias das Paratireoides/complicações , Ciclina D1/genética , Carcinogênese , Transformação Celular Neoplásica , Deficiência de Vitamina D/complicações , Vitamina D/farmacologia , Hormônio Paratireóideo , Vitaminas , Camundongos TransgênicosRESUMO
BACKGROUND: The Stroke Prevention Trial in Sickle Cell Anaemia (STOP) demonstrated the value of selective transfusion based on transcranial Doppler (TCD) US screening. This facilitated widespread surveillance, but due to reported differences with non-imaging TCD, imaging velocity thresholds have been reduced in some centres. OBJECTIVE: (1) Retrospectively review velocity measurements obtained by non-imaging and imaging TCD, using a standardised protocol. (2) Determine the impact on STOP classification of different velocity thresholds. MATERIALS AND METHODS: TCD data from 23 children (2-19 years of age) were reviewed. The TCD protocol focused on obtaining the velocity corresponding to the highest audible Doppler frequency. STOP velocity thresholds were the recommended for non-imaging TCD and values reduced by 5-15%. RESULTS: Non-imaging and imaging TCD velocities were correlated closely with little overall bias. Reducing imaging TCD velocity thresholds increased the number of abnormal and conditional classifications. Abnormal TCD imaging classifications ranged from 1.9% to 37% depending on the degree of correction applied to the velocity data. CONCLUSION: The current approach for applying STOP thresholds to imaging TCD data may not be required. Centres need to validate their imaging TCD practice to avoid inappropriate selection of patients for transfusion therapy.
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Anemia Falciforme/diagnóstico por imagem , Transfusão de Sangue , Programas de Rastreamento/normas , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/prevenção & controle , Ultrassonografia Doppler Transcraniana/instrumentação , Ultrassonografia Doppler Transcraniana/normas , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Criança , Pré-Escolar , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Guias de Prática Clínica como Assunto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento , Reino Unido , Adulto JovemRESUMO
Parathyroid hormone (PTH) increases fibroblast growth factor 23 (FGF23), mediated both by protein kinase A (PKA) and Wnt signaling, and decreases expression of sclerostin, a Wnt antagonist derived from osteocytes. Patients with primary hyperparathyroidism (PHPT) have lower serum sclerostin levels than healthy controls, consistent with the idea of SOST downregulation by PTH. Nevertheless, the relationship between FGF23 and sclerostin in PHPT is still unclear. We examined this issue in a mouse model of PHPT. PHPT mice had increased FGF23 and decreased sclerostin expression in calvaria and in their serum concentrations compared with wild-type (WT) mice. In UMR106 osteoblasts, PTH increased Fgf23 expression and decreased Sost expression, as well as forskolin, a PKA agonist, whereas inhibition of PKA reversed the changes in Fgf23 and Sost expression, stimulated by PTH. Sclerostin treatment had no effect on Fgf23 expression, but when it was added together with PTH, it statistically significantly abrogated the increase in Fgf23 expression. By contrast, there was no statistically significant correlation between serum FGF23 and sclerostin, whereas PTH was positively and negatively correlated with serum FGF23 and sclerostin, respectively. These results indicate that the high level of PTH in PHPT mice leads to increased FGF23 and decreased sclerostin expression in serum and calvaria. A decrease of sclerostin may further augment FGF23 in vitro; however, there was no statistically significant association between circulating FGF23 and sclerostin. It is suggested that the pathogenesis of increased FGF23 expression in PHPT mice may be modified by not only sclerostin, but also other regulatory factors modulated by PTH.
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In this narrative review, we present data gathered over four decades (1980-2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1-MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Hipercalcemia , Hiperparatireoidismo Primário , Recém-Nascido , Feminino , Humanos , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/genética , Cálcio , Hipercalcemia/genética , Receptores de Detecção de Cálcio/genética , Hormônio ParatireóideoRESUMO
CONTEXT: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. OBJECTIVE: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. DESIGN AND PATIENTS: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. RESULTS: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). CONCLUSIONS: Observed in vitro-activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.
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Hiperparatireoidismo Primário , Neoplasias das Paratireoides , Mutação em Linhagem Germinativa , Humanos , Hiperparatireoidismo Primário/diagnóstico , Proteínas Nucleares/genética , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/patologia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: In early phase oncology trials, novel targeted therapies are increasingly being tested in combination with traditional agents creating greater potential for enhanced and new toxicities. When a patient experiences a serious adverse event (SAE), investigators must determine whether the event is attributable to the investigational drug or not. This study seeks to understand the clinical reasoning, tools used and challenges faced by the researchers who assign causality to SAE's. METHODS: Thirty-two semi-structured interviews were conducted with medical oncologists and trial coordinators at six Canadian academic cancer centres. Interviews were recorded and transcribed verbatim. Individual interview content analysis was followed by thematic analysis across the interview set. FINDINGS: Our study found that causality assessment tends to be a rather complex process, often without complete clinical and investigational data at hand. Researchers described using a common processing strategy whereby they gather pertinent information, eliminate alternative explanations, and consider whether or not the study drug resulted in the SAE. Many of the interviewed participants voiced concern that causality assessments are often conducted quickly and tend to be highly subjective. Many participants were unable to identify any useful tools to help in assigning causality and welcomed more objectivity in the overall process. INTERPRETATION: Attributing causality to SAE's is a complex process. Clinical trial researchers apply a logical system of reasoning, but feel that the current method of assigning causality could be improved. Based on these findings, future research involving the development of a new causality assessment tool specifically for use in early phase oncology clinical trials may be useful.
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Antineoplásicos/efeitos adversos , Causalidade , Ensaios Clínicos como Assunto , Oncologia , Pesquisa Qualitativa , Feminino , Humanos , Entrevistas como Assunto , Masculino , MédicosRESUMO
Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclin D1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1 mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10 days before death. 5-Bromo-2'-deoxyuridine (BrdU, 6 mg/day) was infused by an osmotic pump for 5 days before death, followed by immunostaining of the thyroid-parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5 ± 3.1%) compared to wild-type mice (0.7 ± 0.1%) and was significantly suppressed by cinacalcet (1.2 ± 0.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT.
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Ciclina D1/antagonistas & inibidores , Hiperparatireoidismo Primário/tratamento farmacológico , Naftalenos/uso terapêutico , Glândulas Paratireoides/efeitos dos fármacos , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Cinacalcete , Ciclina D1/genética , Ciclina D1/metabolismo , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Animais , Oncogenes/genética , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/metabolismoRESUMO
As social beings, humans harbor an evolved capacity for loneliness - perceived social isolation. Loneliness is associated with atypical affective and social processing, as well as physiological dysregulation. We investigated how loneliness influences spontaneous facial mimicry (SFM), an interpersonal response involved in social connection and emotional contagion. We presented participants with emotional stimuli, such as video clips of actors expressing anger, fear, sadness, or joy, and emotional IAPS images. We measured participants' zygomaticus major ("smiling") muscle and their corrugator supercilii ("frowning") muscle with facial electromyography (fEMG). We also measured self-reported loneliness, depression, and extraversion levels. For socially connected individuals we found intact SFM, as reflected in greater fEMG activity of the zygomaticus and corrugator to positive and negative expressions, respectively. However, individuals reporting higher levels of loneliness lacked SFM for expressions of joy. Loneliness did not impair deliberate mimicry activity to the same expressions, or spontaneous reactions to positive, negative, or neutral IAPS images. Depression and extraversion did not predict any differences in fEMG responses. We suggest that impairments in spontaneous "smiling back" at another - a decreased interpersonal resonance - could contribute to negative social and emotional consequences of loneliness and may facilitate loneliness contagion.
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Solidão , Sorriso , Eletromiografia , Emoções/fisiologia , Expressão Facial , Músculos Faciais/fisiologia , HumanosRESUMO
Loneliness-perceived social isolation-is defined as a discrepancy between existing social relationships and desired quality of relationships. Whereas most research has focused on existing relationships, we consider the standards against which people compare them. Participants who made downward social or temporal comparisons that depicted their contact with others as better (compared to other people's contact or compared to the past) reported less loneliness than participants who made upward comparisons that depicted their contact with others as worse (Study 1-3). Extending these causal results, in a survey of British adults, upward social comparisons predicted current loneliness, even when controlling for loneliness at a previous point in time (Study 4). Finally, content analyses of interviews with American adults who lived alone showed that social and temporal comparisons about contact with others were both prevalent and linked to expressed loneliness (Study 5). These findings contribute to understanding the social cognition of loneliness, extend the effects of comparisons about social connection to the important public health problem of loneliness, and provide a novel tool for acutely manipulating loneliness.
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OBJECTIVE: Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation. METHODS: We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis. RESULTS: We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH. CONCLUSION: The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.
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INTRODUCTION: Classification of color deficiency has required substantial time and expense with the static Farnsworth-Munsell and Innova Rabin tests. Therefore, dynamic color tests were developed for the Nintendo 3DS. METHODS: Fifteen color deficient patients and 17 age-matched normals performed Rabin color test in addition to PDI Check dynamic color games resembling Farnsworth-Munsell presentation (version 0.2.8) and 3-color iso-luminance gray (version 0.2.13). RESULTS: Tests of red, green and blue cone-deficient with the v0.2.8 had sensitivity/specificity/PPV of 92%/86%/92% protanopes, 78%/90%/88% deutanopes and 87%/50%/93% tritanopes. Version 0.2.13 had sens/spec/PPV of 78%/83%/78% red-cone, 100%/85%/80% green cone and 67%/78%/33% blue cone. Corresponding IntraClass Correlation (ICC) utilizing v0.2.8 were red-cone 0.22 (-0.02-0.60), green-cone 0.34 (-0.10-0.67) and blue-cone 0.38 (0.12-0.75). ICC for v0.2.13 was higher with protanope 0.62 (-0.07-0.87), deuteranope 0.64 (-0.09-0.88) and tritanope 0.31 (-0.07-0.70). The PDI Check color game took 65 seconds compared to 197 seconds for Innova Rabin. CONCLUSION: The PDI Check color game quickly identifies patients with inherited color deficiencies.