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BACKGROUND AND OBJECTIVES: Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown. DESIGN AND INTERVENTION: Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment. RESULTS: When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213. CONCLUSION: In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.
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Disfunción Cognitiva , Diabetes Mellitus Experimental , Ratas Zucker , Animales , Ratas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Masculino , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Resistencia a la Insulina , Glucemia/efectos de los fármacos , Glucemia/metabolismoRESUMEN
New astronomical observations point to a nucleosynthesis picture that goes beyond what was accepted until recently. The intermediate "i" process was proposed as a plausible scenario to explain some of the unusual abundance patterns observed in metal-poor stars. The most important nuclear physics properties entering i-process calculations are the neutron-capture cross sections and they are almost exclusively not known experimentally. Here we provide the first experimental constraints on the ^{139}Ba(n,γ)^{140}Ba reaction rate, which is the dominant source of uncertainty for the production of lanthanum, a key indicator of i-process conditions. This is an important step towards identifying the exact astrophysical site of stars carrying the i-process signature.
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Los paradigmas de tratamiento para pacientes con metástasis de columna vertebral han evolucionado significativamente en las últimas dos décadas. El cambio más transformador de estos paradigmas ha sido la integración de la radiocirugía estereotáctica espinal (sSRS). La sSRS permite la administración de dosis de radiación lítica con preservación de los órganos cercanos en riesgo, particularmente la médula espinal. La evidencia apoya la seguridad y la eficacia de la radiocirugía, ya que actualmente ofrece un control tumoral local duradero con bajas tasas de complicaciones, incluso para tumores que anteriormente se consideraban radiorresistentes a la radioterapia convencional de haz externo. El papel de la intervención quirúrgica sigue siendo consistente, pero se ha observado una tendencia hacia técnicas menos agresivas, a menudo mínimamente invasivas. Utilizando tecnologías modernas e instrumentación mejorada, los resultados quirúrgicos continúan mejorando con una morbilidad reducida. Además, los agentes dirigidos, como los productos biológicos y los inhibidores de puntos de control, han revolucionado la atención del cáncer al mejorar tanto el control local como la supervivencia del paciente. Estos avances han dado lugar a la necesidad de nuevas herramientas de pronóstico y a una revisión más crítica de los resultados a largo plazo. La naturaleza compleja de los esquemas de tratamiento actuales requiere un enfoque multidisciplinario que incluya cirujanos, oncólogos médicos, oncólogos radioterápicos, intervencionistas y especialistas en dolor. Esta revisión recapitula los datos actuales basados en la evidencia sobre el tratamiento de las metástasis espinales e integra estos datos en un marco de decisión, NOMS, que se basa en cuatro pilares centinela de la toma de decisiones en tumores metastásicos de la columna vertebral: estado neurológico, comportamiento oncológico del tumor, estabilidad mecánica, y carga sistémica de la enfermedad y comorbilidades médicas.(AU)
Spinal metastases are a common oncologic challenge as 2040% of cancer patients are affected during the course of their illness and up to 20% of those will become symptomatic from spinal cord compression.15 The magnitude of this problem is expected to grow commensurate with the exponential rise in the use of targeted therapies which have demonstrated markedly improved survivals for virtually all malignant tumors. Additionally, the increased availability of advanced diagnostic imaging such as magnetic resonance imaging and 18-FDG PET scans will also serve to increase detection of spine metastatic disease. Despite extended survivals conveyed by biologics and checkpoint inhibitors, the treatment goals for patients with spine metastases remain palliative and focused on the preservation or restoration of neurological function and spinal stability, improved pain control and health related quality of life (HRQOL), and durable tumor control. Scoring systems such as the Tomita score6 and Tokuhashi revised score7 historically have been used to estimate survival and dictate treatment but increasingly have become obsolete due to their inability to incorporate and account for advances in all domains of cancer treatment.(AU)
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Humanos , Médula Espinal , Neoplasias de la Médula Espinal/tratamiento farmacológico , Metástasis de la Neoplasia/terapia , Radiocirugia , Neoplasias/tratamiento farmacológico , Traumatología , Procedimientos Ortopédicos , OrtopediaRESUMEN
Los paradigmas de tratamiento para pacientes con metástasis de columna vertebral han evolucionado significativamente en las últimas dos décadas. El cambio más transformador de estos paradigmas ha sido la integración de la radiocirugía estereotáctica espinal (sSRS). La sSRS permite la administración de dosis de radiación lítica con preservación de los órganos cercanos en riesgo, particularmente la médula espinal. La evidencia apoya la seguridad y la eficacia de la radiocirugía, ya que actualmente ofrece un control tumoral local duradero con bajas tasas de complicaciones, incluso para tumores que anteriormente se consideraban radiorresistentes a la radioterapia convencional de haz externo. El papel de la intervención quirúrgica sigue siendo consistente, pero se ha observado una tendencia hacia técnicas menos agresivas, a menudo mínimamente invasivas. Utilizando tecnologías modernas e instrumentación mejorada, los resultados quirúrgicos continúan mejorando con una morbilidad reducida. Además, los agentes dirigidos, como los productos biológicos y los inhibidores de puntos de control, han revolucionado la atención del cáncer al mejorar tanto el control local como la supervivencia del paciente. Estos avances han dado lugar a la necesidad de nuevas herramientas de pronóstico y a una revisión más crítica de los resultados a largo plazo. La naturaleza compleja de los esquemas de tratamiento actuales requiere un enfoque multidisciplinario que incluya cirujanos, oncólogos médicos, oncólogos radioterápicos, intervencionistas y especialistas en dolor. Esta revisión recapitula los datos actuales basados en la evidencia sobre el tratamiento de las metástasis espinales e integra estos datos en un marco de decisión, NOMS, que se basa en cuatro pilares centinela de la toma de decisiones en tumores metastásicos de la columna vertebral: estado neurológico, comportamiento oncológico del tumor, estabilidad mecánica, y carga sistémica de la enfermedad y comorbilidades médicas.(AU)
Spinal metastases are a common oncologic challenge as 2040% of cancer patients are affected during the course of their illness and up to 20% of those will become symptomatic from spinal cord compression.15 The magnitude of this problem is expected to grow commensurate with the exponential rise in the use of targeted therapies which have demonstrated markedly improved survivals for virtually all malignant tumors. Additionally, the increased availability of advanced diagnostic imaging such as magnetic resonance imaging and 18-FDG PET scans will also serve to increase detection of spine metastatic disease. Despite extended survivals conveyed by biologics and checkpoint inhibitors, the treatment goals for patients with spine metastases remain palliative and focused on the preservation or restoration of neurological function and spinal stability, improved pain control and health related quality of life (HRQOL), and durable tumor control. Scoring systems such as the Tomita score6 and Tokuhashi revised score7 historically have been used to estimate survival and dictate treatment but increasingly have become obsolete due to their inability to incorporate and account for advances in all domains of cancer treatment.(AU)
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Humanos , Masculino , Femenino , Médula Espinal , Neoplasias de la Médula Espinal/tratamiento farmacológico , Metástasis de la Neoplasia/terapia , Radiocirugia , Neoplasias/tratamiento farmacológico , Traumatología , Procedimientos Ortopédicos , OrtopediaRESUMEN
Treatment paradigms for patients with spine metastases have evolved significantly over the past two decades. The most transformative change to these paradigms has been the integration of spinal stereotactic radiosurgery (sSRS). sSRS allows for the delivery of tumoricidal radiation doses with sparing of nearby organs at risk, particularly the spinal cord. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional external beam radiation therapy. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care by improving both local control and patient survival. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases and integrates these data into a decision framework, NOMS, which is based on four sentinel pillars of decision making in metastatic spine tumors: neurological status, Oocologic tumor behavior, mechanical stability and systemic disease burden and medical co-morbidities.
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BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict heart failure (HF) and mortality, but whether NT-proBNP predicts ventricular arrhythmias (VA) is not clear. HYPOTHESIS: We hypothesize that high NT-proBNP concentrations associate with the risk of incident VA, defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia. METHODS: In a prospective, observational study of patients treated with implantable cardioverter defibrillator (ICD), we analyzed NT-proBNP concentrations at baseline and after mean 1.4 years in association to incident VA. RESULTS: We included 490 patients (age 66 ± 12 years, 83% men) out of whom 51% had a primary prevention ICD indication. The median NT-proBNP concentration was 567 (25-75 percentile 203-1480) ng/L and patients with higher concentrations were older with more HF and ICD for primary prevention. During mean 3.1 ± 0.7 years, 137 patients (28%) had ≥1 VA. Baseline NT-proBNP concentrations were associated with the risk of incident VA (hazard ratio [HR]: 1.39, 95% confidence interval [95% CI]: 1.22-1.58, p < .001), HF hospitalizations (HR: 3.11, 95% CI: 2.53-3.82, p < .001), and all-cause mortality (HR: 2.49, 95% CI: 2.04-3.03, p < .001), which persisted after adjusting for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction. The association with VA was stronger in secondary versus primary prevention ICD indication: HR: 1.59 (95% CI: 1.34-1.88 C-statistics 0.71) versus HR: 1.24, 95% CI: 1.02-1.51, C-statistics 0.55), p-for-interaction = 0.06. Changes in NT-proBNP during the first 1.4 years did not associate with subsequent VA. CONCLUSIONS: NT-proBNP concentrations are associated with the risk of incident VA after adjustment for established risk factors, with the strongest association in patients with a secondary prevention ICD indication.
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Insuficiencia Cardíaca , Taquicardia Ventricular , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Péptido Natriurético Encefálico , Volumen Sistólico , Función Ventricular Izquierda , Biomarcadores , Estudios Prospectivos , Fragmentos de Péptidos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/epidemiología , PronósticoRESUMEN
Treatment paradigms for patients with spine metastases have evolved significantly over the past two decades. The most transformative change to these paradigms has been the integration of spinal stereotactic radiosurgery (sSRS). sSRS allows for the delivery of tumoricidal radiation doses with sparing of nearby organs at risk, particularly the spinal cord. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional external beam radiation therapy. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care by improving both local control and patient survival. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases and integrates these data into a decision framework, NOMS, which is based on four sentinel pillars of decision making in metastatic spine tumors: Neurological status, Oncologic tumor behavior, Mechanical stability, and Systemic disease burden and medical co-morbidities.
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Neutron-capture cross sections of neutron-rich nuclei are calculated using a Hauser-Feshbach model when direct experimental cross sections cannot be obtained. A number of codes to perform these calculations exist, and each makes different assumptions about the underlying nuclear physics. We investigated the systematic uncertainty associated with the choice of Hauser-Feshbach code used to calculate the neutron-capture cross section of a short-lived nucleus. The neutron-capture cross section for 73 Zn (n, γ ) 74 Zn was calculated using three Hauser-Feshbach statistical model codes: TALYS, CoH, and EMPIRE. The calculation was first performed without any changes to the default settings in each code. Then an experimentally obtained nuclear level density (NLD) and γ -ray strength function ( γ SF ) were included. Finally, the nuclear structure information was made consistent across the codes. The neutron-capture cross sections obtained from the three codes are in good agreement after including the experimentally obtained NLD and γ SF , accounting for differences in the underlying nuclear reaction models, and enforcing consistent approximations for unknown nuclear data. It is possible to use consistent inputs and nuclear physics to reduce the differences in the calculated neutron-capture cross section from different Hauser-Feshbach codes. However, ensuring the treatment of the input of experimental data and other nuclear physics are similar across multiple codes requires a careful investigation. For this reason, more complete documentation of the inputs and physics chosen is important. Supplementary Information: The online version contains supplementary material available at 10.1140/epja/s10050-023-00920-0.
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The ITER Collective Thomson scattering (CTS) diagnostic will measure the dynamics of fusion-born alpha particles in the burning ITER plasma by scattering a 1 MW 60 GHz gyrotron beam off fast-ion induced fluctuations in the plasma. The diagnostic will have seven measurement volumes across the ITER cross section and will resolve the alpha particle energies in the range from 300 keV to 3.5 MeV; importantly, the CTS diagnostic is the only diagnostic capable of measuring confined alpha particles for energies below â¼1.7 MeV and will also be sensitive to the other fast-ion populations. The temporal resolution is 100 ms, allowing the capture of dynamics on that timescale, and the typical spatial resolution is 10-50 cm. The development and design of the in-vessel and primary parts of the CTS diagnostic has been completed. This marks the beginning of a new phase of preparation to maximize the scientific benefit of the diagnostic, e.g., by investigating the capability to contribute to the determination of the fuel-ion ratio and the bulk ion temperature as well as integrating data analysis with other fast-ion and bulk-ion diagnostics.
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Objective: To investigate the relation between serum 25-hydroxyvitamin D (s-25(OH)D) and subjective sleep measures in an Arctic population (69°N). Methods: Cross-sectional data was collected from 21,083 individuals (aged ≥40 years) participating in the population based Tromsø Study: Tromsø7 (2015-2016). The present study included 20,438 participants, after having excluded respondents missing data on s-25(OH)D (n = 161) and/or subjective sleep measures (including sleep duration, insomnia, and daytime sleepiness)(n = 490). Based on s-25(OH)D (assessed using LC-MS/MS), participants were grouped as deficient (<30 nmol/L), insufficient (30-49.9 nmol/L), sufficient (50-75 nmol/L), or high (>75 nmol/L). Sleep duration was grouped as inadequate (ISD) if < 7 or ≥9 h. Linear and logistic regression were used to calculate unstandardized ß-values and odds ratios [95% confidence intervals]. The analyses were adjusted for season, age, BMI, lifestyle factors and relevant comorbidities. Results: In both men and women, s-25(OH)D was positively associated with sleep duration, and compared to the sufficient s-25(OH)D group, the insufficient s-25(OH)D group reported significantly shorter sleep duration in both sexes. There was an increased odds of ISD in both men and women but adjusted for confounding factors this was only significant in women (1.16 [1.03, 1.32], p = .017). In men, there were no significant associations between s-25(OH)D and the remaining sleep measures. Women in the high s-25(OH)D group had lower ESS-scores (-0.28 [-0.47, -0.08], p = .006), but higher odds of insomnia (1.16 [1.01, 1.33], p = .036) compared to women in the sufficient group. Conclusions: In this Arctic population, a tenuous association was found between s-25(OH)D and subjective sleep measures, predominantly in women.
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Cagrilintide is a novel long-acting amylin receptor agonist, which has shown a potent induction of weight loss. Interestingly, cagrilintide is a Dual Amylin and Calcitonin Receptor Agonist (DACRA) derived from an amylin backbone. Another class of long-acting DACRAs exists, namely the KBPs. These are salmon calcitonin-based and have shown preclinical potential; however, how and if they differentiate from amylin-derived molecules remain to be studied. Here, we compare cagrilintide to the DACRA KBP-336 with respect to receptor activation balance in vitro and using metabolic in vivo models. Peptide potencies were assessed using receptor-specific assays in vitro and in vivo. In vivo efficacies on body weight and glucose homeostasis were investigated head-to-head in high-fat diet (HFD) fed obese and T2D (ZDF) rat models. Both peptides activate the amylin and the calcitonin receptor in vitro and in vivo, with KBP-336 being more potent, and showing a CTR bias. KBP-336 and cagrilintide induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP-336 being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved fasting blood glucose, HbA1c levels, and insulin action, with KBP-336 being superior to cagrilintide in improving glucose control. In summary, both KBP-336 and cagrilintide are DACRAs, however with KBP-336 being biased towards the CTR resulting in a different receptor activation balance. Interestingly, KBP-336 showed superior long-term efficacy on both weight loss and glucose control, supporting relevance of the receptor balance, and highlighting KBP-336 as a promising agent for the treatment of obesity and T2D.
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Agonistas de los Receptores de Amilina , Diabetes Mellitus Tipo 2 , Animales , Ratas , Agonistas de los Receptores de Amilina/farmacología , Agonistas de los Receptores de Amilina/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Obesidad/tratamiento farmacológico , Ratas Sprague-Dawley , Receptores de Calcitonina/agonistas , Receptores de Calcitonina/uso terapéutico , Pérdida de PesoRESUMEN
INTRODUCTION: The prevalence of acetabular retroversion is sparsely investigated. It may be associated with increased anterior pelvic tilt. The purpose of this study was to investigate whether patients with symptomatic and radiographically verified acetabular retroversion demonstrated increased anterior pelvic tilt compared to a control group, and furthermore to evaluate the prevalence of acetabular retroversion in the general population. METHODS: Anteroposterior pelvic radiographs in standing position of 111 patients with acetabular retroversion prior to anteverting periacetabular osteotomy (PAO) and 132 matched controls from the general Danish population were assessed. Pelvic tilt was assessed by the sacrococcygeal joint-symphysis distance and pelvic-tilt-ratio. Acetabular retroversion was defined as positive cross-over sign and posterior wall sign. Prior to assessments, interrater reliability analysis was performed. Measurements were agreed by two independent assessors. A nonparametric regression model was used to test between-group differences in median pelvic tilt. The prevalence was calculated as the ratio of subjects and hips with acetabular retroversion, respectively. RESULTS: The patient group had significantly larger median anterior pelvic tilt of 14.3 mm in sacrococcygeal joint-symphysis distance and -0.08 in pelvic-tilt-ratio, compared to controls. The prevalence of subjects in the general population with either unilateral or bilateral acetabular retroversion was 24% and 18% for all hips. CONCLUSION: Our data demonstrated that patients with symptomatic acetabular retroversion have increased anterior pelvic tilt compared to the general population. Radiographic sign of acetabular retroversion was highly prevalent in the general population. IMPLICATION FOR PRACTICE: Increased anterior pelvic tilt should be considered when diagnosing and treating patients with hip pain, as symptoms may be related to the functional position of the pelvis and not necessarily solely come from the radiographic verified acetabular retroversion.
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Acetábulo , Osteotomía , Acetábulo/diagnóstico por imagen , Estudios Transversales , Humanos , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND: Vitamin D has been linked to sleep health in observational studies. Data from randomized controlled trials (RCTs) with vitamin D is scarce. METHODS: This study presents the results of a secondary analysis of 189 vitamin D insufficient participants (47.1% women) in a previously performed RCT, of which 92 were randomized to vitamin D (100,000 IU (2500 µg) as a bolus dose followed by 20,000 IU (500 µg) per week), and 97 to placebo. At baseline and after 4 months at the end of the study serum 25-hydroxyvitamin D (s-25(OH)D) was measured, and the study questionnaire assessing sleep duration, daytime sleepiness, and symptoms of insomnia, was completed. RESULTS: At baseline, mean s-25(OH)D was 35.0 ± 11.8 and 35.5 ± 13.3 nmol/L in the vitamin D and placebo groups, respectively. After four months, we found no statistically significant differences between the intervention groups in any of the assessed sleep outcomes, neither when stratified by sex, nor when performed in subgroups based on baseline or end of study s-25(OH)D level or presence of sleep complaints at baseline. CONCLUSIONS: We were not able to demonstrate a significant effect of vitamin D supplementation on sleep in this vitamin D insufficient population.
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The validity of the Brink-Axel hypothesis, which is especially important for numerous astrophysical calculations, is addressed for ^{116,120,124}Sn below the neutron separation energy by means of three independent experimental methods. The γ-ray strength functions (GSFs) extracted from primary γ-decay spectra following charged-particle reactions with the Oslo method and with the shape method demonstrate excellent agreement with those deduced from forward-angle inelastic proton scattering at relativistic beam energies. In addition, the GSFs are shown to be independent of excitation energies and spins of the initial and final states. The results provide a critical test of the generalized Brink-Axel hypothesis in heavy nuclei, demonstrating its applicability in the energy region of the pygmy dipole resonance.
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BACKGROUND: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. OBJECTIVE: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. METHODS: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. RESULTS: The study is ongoing. Results will be published when the study is completed. CONCLUSION: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.
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OBJECTIVE: Dual amylin and calcitonin receptor agonists (DACRAs) are novel therapeutic agents that not only improve insulin sensitivity but also work as an adjunct to established T2DM therapies. DACRAs are currently administered once daily, though it is unknown whether DACRAs with increased plasma half-life can be developed as a once-weekly therapy. METHODS: The in vitro potencies of the KBP-066A and KBP-066 (non-acylated) were assessed using reporter assays. Acylation functionality was investigated by a combination of pharmacokinetics and acute food intake in rats. in vivo efficacies were investigated head-to-head in obese (HFD) and T2D (ZDF) models. RESULTS: In in vitro, KBP-066A activated the CTR and AMY-R potently, with no off-target activity. Acylation functionality was confirmed by acute tests, as KBP-066A demonstrated a prolonged PK and PD response compared to KBP-066. Both compounds induced potent and dose-dependent weight loss in the HFD rat model. In ZDF rats, fasting blood glucose/fasting insulin levels (tAUC) were reduced by 39%/50% and 36%/47% for KBP-066 and KBP-066A, respectively. This effect resulted in a 31% and 46% vehicle-corrected reduction in HbA1c at the end of the study for KBP-066 and KBP-066A, respectively. CONCLUSIONS: Here, we present pre-clinical data on an acylated DACRA, KBP-066A. The in vivo efficacy of KBP-066A is significantly improved compared to its non-acylated variant regarding weight loss and glycemic control in obese (HFD) and obese diabetic rats (ZDF). This compendium of pre-clinical studies highlights KBP-066A as a promising, once-weekly therapeutic agent for treating T2DM and obesity.
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Agonistas de los Receptores de Amilina/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Receptores de Calcitonina/agonistas , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/metabolismo , Agonistas de los Receptores de Amilina/química , Animales , Línea Celular , Dieta Alta en Grasa/efectos adversos , Control Glucémico , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Pérdida de Peso/efectos de los fármacosAsunto(s)
Humanos , Masculino , Anciano , Autoanticuerpos , Ataxia Cerebelosa/diagnóstico , Degeneraciones EspinocerebelosasRESUMEN
We present a novel method for efficient production of prototypes of microwave components by fused depositing modeling, also known as 3D plastic printing, and vapor deposition coating of a 1 µm copper layer. We demonstrate that the properties of the components follow the predicted performance for low power microwave propagation. The production method offers new opportunities for cheap and efficient production of mock-ups and prototypes of advanced-geometry components for tests with low-power microwaves.