Miracle-dz/UniFAR-FTUs huggingface dataset:
Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinoma and Urothelial Carcinoma: Rationale and Clinical Evidence

The treatment landscape for metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) has evolved rapidly in recent years with the approval of several checkpoint inhibitors. Despite these advances, survival rates for metastatic disease remain poor, and additional strategies will be needed to improve the efficacy of checkpoint inhibitors. Combining anti-VEGF/VEGFR agents with checkpoint inhibitors has emerged as a potential strategy to advance the immunotherapy paradigm, because VEGF inhibitors have immunomodulatory potential. Cabozantinib is a tyrosine kinase inhibitor (TKI) whose targets include MET, AXL, and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical efficacy as a monotherapy in mRCC and mUC, making it a potentially suitable partner for checkpoint inhibitor therapy. In this review, we summarize the current status of immunotherapy for mRCC and mUC and discuss the development of immunotherapy–TKI combinations, with a focus on cabozantinib. We discuss the rationale for such combinations based on our growing understanding of the tumor microenvironment, and we review in detail the preclinical and clinical studies supporting their use.
Percutaneous Ultrasound-Guided Core Needle Biopsy: Comparison of 16-Gauge versus 14-Gauge Needle and the Effect of Coaxial Guidance in 1065 Breast Biopsies – A Prospective Randomized Clinical Noninferiority Trial

Abstract Purpose Ultrasound-guided core needle biopsy (CNB) is considered the standard assessment to diagnose sonographically visible suspicious breast mass lesions. Based on nonrandomized trials, the current German guidelines recommend at least three cylinders with ≤ 14-gauge needle biopsy. However, no recommendation is made as to how many specimens are needed with a smaller needle size, such as 16-gauge, or if biopsy with coaxial guidance improves diagnostic accuracy and quality. Therefore, in a prospective monocentric unblinded randomized controlled clinical noninferiority trial, the diagnostic accuracy of 16-gauge versus 14-gauge core needle biopsy, with and without coaxial guidance, was evaluated. Materials and Methods 1065 breast biopsies were included in order to analyze the number of core samples necessary to obtain an appropriate rate of diagnostic quality adequate for histological evaluation, and to achieve high diagnostic accuracy and diagnostic yield. Histological results were verified by surgery or long-term follow-up of at least two years up to five years. Results In order to obtain an additive diagnostic accuracy of > 99 %, a minimum of two cylinders with 14-gauge biopsy were required. The diagnostic accuracy and the diagnostic quality of 14-gauge biopsy were not affected by the coaxial technique. When performing a 16-gauge biopsy, five cylinders were required to achieve an additive diagnostic accuracy of > 99 %. Without coaxial guidance, 16-gauge CNB required at least three samples, whereas five needle passes with coaxial-guided 16-gauge biopsy were needed. Conclusion The diagnostic accuracy and quality of ultrasound-guided 16-gauge core needle biopsy were inferior to the 14-gauge needle size, regardless of the use of a coaxial technique.
Abaloparatide at the Same Dose Has the Same Effects on Bone as PTH (1‐34) in Mice

Abaloparatide, a novel analog of parathyroid hormone‐related protein (PTHrP 1–34), became in 2017 the second osteoanabolic therapy for the treatment of osteoporosis. This study aims to compare the effects of PTH (1‐34), PTHrP (1‐36), and abaloparatide on bone remodeling in male mice. Intermittent daily subcutaneous injections of 80 μg/kg/d were administered to 4‐month‐old C57Bl/6J male mice for 6 weeks. During treatment, mice were followed by DXA‐Piximus to assess changes in bone mineral density (BMD) in the whole body, femur, and tibia. At either 4 or 18 hours after the final injection, femurs were harvested for μCT analyses and histomorphometry, sera were assayed for bone turnover marker levels, and tibias were separated into cortical, trabecular, and bone marrow fractions for gene expression analyses. Our results showed that, compared with PTH (1‐34), abaloparatide resulted in a similar increase in BMD at all sites, whereas no changes were found with PTHrP (1‐36). With both PTH (1‐34) and abaloparatide, μCT and histomorphometry analyses revealed similar increases in bone volume associated with an increased trabecular thickness, in bone formation rate as shown by P1NP serum level and in vivo double labeling, and in bone resorption as shown by CTX levels and osteoclast number. Gene expression analyses of trabecular and cortical bone showed that PTH (1‐34) and abaloparatide led to different actions in osteoblast differentiation and activity, with increased Runx2, Col1A1, Alpl, Bsp, Ocn, Sost, Rankl/Opg, and c‐fos at different time points. Abaloparatide seems to generate a faster response on osteoblastic gene expression than PTH (1‐34). Taken together, abaloparatide at the same dose is as effective as PTH (1‐34) as an osteoanabolic, with an increase in bone formation but also an increase in bone resorption in male mice. © 2019 American Society for Bone and Mineral Research.
Option introduction, short sale constraints and market efficiency: a new perspective

This article undertakes a new investigation of the effect of option introduction on short sale constraints. I find that post option improvement in stock price adjustment efficiency is isolated to short sale constrained stocks responding to negative information. No significant improvement in adjustment efficiency is found in response to positive information. The empirical results suggest that up to 76% of the disparity in stock price efficiency between stocks with high and low short sale constraint levels is eliminated by option introduction. Further, I find evidence that post option improvement in efficiency is similar in relation to market wide public and firm specific, jointly private and public information. Commonality in efficiency improvements in relation to private and public information suggests irrational, behavioral biases are a significant source of short sale constraint effects which options act to
Retinal defect in children with infantile spasms of varying etiologies

Objective To determine the prevalence of retinal defect in children with infantile spasms (IS) unrelated to treatment with vigabatrin and clarify if specific primary etiologies for IS are associated with retinal defect more than others. Methods This was an observational cohort study including 312 patients (176 male, 136 female) with IS who were vigabatrin-naive. Participants ranged from 1.7 to 34.7 months of age (mean 8.8 months). Electroretinograms (ERGs) were performed according to the International Society for Clinical Electrophysiology of Vision. Retinal defect was identified as abnormal if the 30-Hz flicker ERG amplitude was lower than the age-corrected normal 95% prediction interval. The primary etiology for IS, as determined by the treating pediatric neurologist(s), was obtained from patient health records and classified into 1 of 9 etiologic subgroups: (1) genetic disorders alone, (2) genetic-structural disorders, (3) structural-congenital, (4) structural-acquired (perinatal), (5) structural-acquired (postnatal), (6) metabolic disorders, (7) immunologic disorders, (8) infectious, and (9) unknown causes. Results Fifty-nine of the 312 vigabatrin-naive children (18.9%) showed retinal defect and the prevalence of retinal defect was highest (24.4%) in the structural-acquired (perinatal) subgroup, which included hypoxic-ischemic defect. Retinal function compared across subgroups showed no significant difference. Conclusions Care is required in diagnosing retinal toxicity, which would be enhanced by baseline flicker ERG in children with IS prior to starting vigabatrin.
The effect of a low‐dose naloxone infusion on the incidence of respiratory depression after intrathecal morphine administration for major open hepatobiliary surgery: a randomised controlled trial

Intrathecal morphine is an analgesic option for major hepatopancreaticobiliary procedures but is associated with a risk of respiratory depression. We hypothesised that a postoperative low‐dose naloxone infusion would reduce the incidence of respiratory depression without an increase in pain scores. Patients scheduled for major open hepatopancreaticobiliary surgery and who were receiving 10 μg. kg−1 intrathecal morphine were eligible for inclusion. Patients were allocated randomly to receive a postoperative infusion of naloxone 5 μg. kg−1.h−1 (naloxone group) or saline at an identical infusion rate (control group) until the morning after surgery. Clinicians, nursing staff and patients were blinded to group allocation. The primary outcome measure was the incidence of respiratory depression (respiratory rate < 10 breaths.min−1 and/or oxygen saturation < 90%). Secondary outcome measures included: arterial partial pressure of carbon dioxide; pain score; requirement for supplemental analgesic; and incidence of nausea and vomiting, pruritus and sedation. In total, data from 95 patients (48 in the naloxone group and 47 in the control group) were analysed. The incidence of respiratory depression was lower in the naloxone group compared with the control group (10/48 vs. 21/47 patients, respectively; p = 0.037, relative risk 0.47 (95%CI 0.25–0.87). Maximum pain scores were greater for patients allocated to the naloxone group compared with control (median 5 (95%CI 4–6) vs. 4 (95%CI 2–4), respectively; p < 0.001). A low‐dose naloxone infusion decreases the incidence of respiratory depression following intrathecal morphine administration in patients having major hepatopancreaticobiliary surgery at the expense of a small increase in postoperative pain.
Seasonal patterns of traumatic brain injury deaths due to traffic-related incidents in the Slovak Republic

Abstract Objective: Traumatic Brain Injuries (TBIs) are an important type of injury in terms of both morbidity and mortality. Road Traffic Incidents are one of the most frequent causes of TBI. This analysis seeks to quantify the number of such injuries occurring in the Slovak Republic, and examine patterns of TBI according to mode of transport and seasonality. Methods: Data concerning total numbers of TBIs occurring from the years 1996–2015 were obtained from the Statistical Office of the Slovak Republic. The events caused by road incidents were examined separately according the external cause stated on death certification. Events were classified into seasons according to the month of death. Summary statistics were produced concerning numbers of deaths according to sex, mode of transport and season. Analyses were performed to examine trends in TBI by season and type of road user. Results: During a period of 20 years from 1996, there were 17,047 recorded deaths involving TBI in the Slovak Republic. Of these, 5,370 were caused by road traffic incidents (RTIs). Age standardized rates tended to decrease from 8.3/100,000/year (1996) to 2.5/100,000/year (2015). Males made up approximately 79% of road traffic-caused TBIs. Summer and autumn showed significantly more events than any other season, with motorcyclists and cyclists in particular being more frequently injured at this time of year. Conclusions: The results show that Slovakia, like many countries, suffers a considerable burden of TBI and that RTIs are a major contributor to this, especially among young adults. Rates of TBI vary by season in Slovakia, and users of different modes of transport appear more or less likely to suffer such injury during different seasons. Considerable variability in rates of injury exists between road users and times of year. Improved understanding of the timing and sufferers of injuries may allow better planning of response and care services. Further research into transport modes and policies aimed at safer driving should be explored.
Effects of Eurycoma Longifolia Jack Supplementation on Recreational Athletes` Endurance Running Capacity and Physiological Responses in the Heat

This study investigated the effects of supplementation of the nutraceutical product Eurycoma longifolia Jack on recreational athletes` endurance running capacity and physiological responses in the heat. Twelve Malaysian healthy male recreational athletes (Age: 23.3 (3.7) years old; VO2max: 45.1 (8.1) ml.kg-1.min-1) were recruited in this double blind, placebo-controlled, cross-over study. Subjects completed two endurance running trials in the heat (31°C, 70% relative humidity), performed on separate days, after consuming either 2 capsules of Eurycoma longifolia Jack (75 mg per capsule) or a placebo per day for 7 days before and one hour prior to the experimental trial. On trial day, after 5 minutes of warm-up at 50 % VO2max, the subjects were requested to run on the treadmill at 60 % VO2max for 60 minutes. This was immediately followed by a 20-minute time trial for determining endurance running capacity. Blood samples were taken before warm up, after warm-up, and every 20 minutes during the trial. Statistical analysis was performed using one-way ANOVA with repeated measures. Results showed that the endurance running capacity of E. longifolia was not significantly different from that of the placebo trial. Similarly, oxygen uptake, heart rate, skin temperature, tympanic temperature, ratings of perceived exertion, haemoglobin concentration, haematocrit level, plasma glucose concentration, and plasma free fatty acid concentration were not significantly different between the trials. These findings suggested that supplementation of the E. longifolia product at a dosage of 150 mg.day-1 for 7 days has not provided beneficial effects on endurance running capacity and physiological responses of recreational athletes in the heat. Higher dosage and longer duration of supplementation of the product may be warranted to evaluate further its endurance capacity during exercise.
THE HEARING RESULTS IN OTOSCLEROSIS AFTER STAPEDOTOMY

Otosclerosis is the most frequent cause of conductive hearing loss in patients with intact tympanic membrane. It can be treated by surgery with various techniques. Because of limited manipulation and comparably similar results, stapedotomy at present is preferred over other surgical techniques by most surgeons. Here we present the operative results of 114 otosclerotic patients who underwent stapedotomy between 1997-2002 in Rahnemoom hospital, Yazd and Amiralam hospital, Tehran. The aim of this study is to evaluate the efficacy and safety of stapedotomy in otosclerosis surgery. The average air-bone gaps of patients improved significantly from 41.82 db to 14.23 db after operation. Other hearing parameters of patients (including air conduction, bone conduction and speech discrimination score) also improved significantly. Permanent vertigo did not occur after operation and preoperative tinnitus resolved in 56 of 78 patients. Stapedotomy is a safe and effective modality for improving conductive hearing loss in otosclerotic patients. Acta Medica Iranica, 42(4): 277-280; 2004
In Vitro‐Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

Advanced glycation end‐products (AGEs) have been suggested to contribute to bone fragility in type 2 diabetes (T2D). AGEs can be induced through in vitro sugar incubations but there is limited data on the effect of total fluorescent AGEs on mechanical properties of human cortical bone, which may have altered characteristics in T2D. Thus, to examine the effect of AGEs on bone directly in T2D patients with uncontrolled sugar levels, it is essential to first understand the fundamental mechanisms by studying the effects of controlled in vitro‐induced AGEs on cortical bone mechanical behavior. Here, human cortical bone specimens from female cadaveric tibias (ages 57–87) were incubated in an in vitro 0.6 M ribose or vehicle solution (n = 20/group) for 10 days at 37°C, their mechanical properties were assessed by microindentation and fracture toughness tests, and induced AGE levels were quantified through a fluorometric assay. Results indicated that ribose‐incubated bone had significantly more AGEs (+81%, p ≤ 0.005), lower elastic modulus assessed by traditional microindentation, and lower fracture toughness compared with vehicle controls. Furthermore, based on pooled data, increased AGEs were significantly correlated with deteriorated mechanical properties. The findings presented here show that the accumulation of AGEs allows for lower stiffness and increased ability to initiate a crack in human cortical bone. Statement of clinical significance: High sugar levels as in T2D results in deteriorated bone quality via AGE accumulation with a consequent weakening in bone's mechanical integrity. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:972‐983, 2020
Maternal and newborn health indicators in Papua New Guinea – 2008–2018

Abstract Papua New Guinea (PNG) is the most populous country in the Pacific with more than 9 million people. Difficult terrain, poor roads and limited infrastructure mean providing effective health care – especially in rural areas, where most people live – is challenging. Women and newborns in PNG experience high rates of preventable morbidity and mortality; however, reliable data are often limited or unavailable. The aim of this paper is to provide an overview of research on key maternal and neonatal health (MNH) indicators conducted approximately over the past 11 years in PNG comparing research findings to global MNH estimates of the indicators. There was considerable variation in mortality indicators (maternal mortality ratio, neonatal mortality rate and stillbirth) reported across studies in PNG. Mortality was generally higher in rural areas. Rates of sexually transmitted infections (STIs) in pregnancy were consistently high, while anaemia in pregnancy, preterm birth and low birth weight varied widely between studies and settings. Breastfeeding seems to have been under-researched. There was a lack of data available on other indicators such as the adolescent birth rate, postnatal care provided to women and newborns, intermittent preventative treatment to prevent malaria in pregnancy and treatment to prevent mother-to-child transmission of HIV. Studies demonstrate the high burden of preventable maternal and newborn morbidity and mortality across PNG. Efforts to improve MNH outcomes need to be escalated.
Molecular Imaging with Reporter Genes: Has Its Promise Been Delivered?

The first reporter systems were developed in the early 1980s and were based on measuring the activity of an enzyme—as a surrogate measure of promoter-driven transcriptional activity—which is now known as a reporter gene system. The initial objective and application of reporter techniques was to analyze the activity of a specific promoter (namely, the expression of a gene that is under the regulation of the specific promoter that is linked to the reporter gene). This system allows visualization of specific promoter activity with great sensitivity. In general, there are 2 classes of reporter systems: constitutively expressed (always-on) reporter constructs used for cell tracking, and inducible reporter systems sensitive to endogenous signaling molecules and transcription factors that characterize specific tissues, tumors, or signaling pathways. This review traces the development of different reporter systems, using fluorescent and bioluminescent proteins as well as radionuclide-based reporter systems. The development and application of radionuclide-based reporter systems is the focus of this review. The question at the end of the review is whether the “promise” of reporter gene imaging has been realized. What is required for moving forward with radionuclide-based reporter systems, and what is required for successful translation to clinical applications?
Isometric handgrip exercise training attenuates blood pressure in prehypertensive subjects at 30% maximum voluntary contraction

Background: Prehypertension highlights a category of subjects who are at high risk of developing hypertension. Aim: This study assessed the blood pressure attenuating effect of isometric handgrip exercise in the management of prehypertension. Materials and Methods: A total of 400 prehypertensive subject with a mean age of 40 ± 10 years and recently diagnosed as prehypertension were recruited for the study. They were randomly distributed into exercise and control groups (n = 200). The control group was placed on lifestyle modification only, while the exercise group performed a 24 consecutive days isometric hand grip exercise training at 30% maximum voluntary contraction (MVC) for 2 min each day in combination with lifestyle modification protocol. Results: The results show a statistically significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP). The exercise group had a mean reduction of 7.48 ± 0.06 and 6.41 ± 1.01 mmHg of the SBP and DBP, respectively. It was further observed that both the SBP and DBP and pulse rate significantly increased acutely within 5 min post exercise at 30% MVC with a mean value of 8.60 ± 0.20 mmHg, 7.33 ± 0.03 mmHg, and 8.24 ± 0.20 beats/min of the SBP and DBP and pulse rate, respectively. However, this increase returned to pre-exercise value within 10 min post exercises to a mean value of −0.68 + 1.64 mmHg, 1.48 ± 1.02 mmHg, and 3.00 ± 0.11 beats/min, respectively. Conclusion: This study has shown that isometric handgrip exercise is effective in the attenuation of blood pressure in prehypertensive subjects especially when combined with the routinely recommended lifestyle modifications. However, caution should be taken when recommending it because of acute increase in blood pressure.
Quality of Life in Economic Evaluations of Health

markdownabstract__Abstract__ Health care expenditures have increased rapidly over the last decades in the Netherlands, in absolute terms and as percentage of gross domestic product. Curbing the rising health care costs has proven to be a very sensitive and complex societal issue. An important driver of rising costs is the availability and use of new and expensive medical technologies, causing a greater number of patients to be treated with more expensive interventions. Typically, these interventions do not only increase expenditures but also contribute to societal health and well-being. Since health care expenditures are high on the political agenda, policy makers are interested in the relative effectiveness and efficiency of new medical interventions: do they achieve larger health effects than other treatments, and if so, at what additional costs? Economic evaluations address this question. In economic evaluations, costs and effects of alternative medical interventions are compared, to see whether the new intervention offers good ‘value for money’. Researchers that which to apply economic evaluations to health care interventions face several methodological challenges. This thesis deals with one particular challenge: the measurement of the benefit of health care interventions in terms of quality of life.