bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study
Authors: Khot Amit , Brajanovski Natalie , Cameron Donald P. , Hein Nadine , Maclachlan Kylee H. , Sanij Elaine , Lim John , Soong John , Link Emma , Blombery Piers , Thompson Ella R. , Fellowes Andrew , Sheppard Karen E. , McArthur Grant A. , Pearson Richard B. , Hannan Ross D. , Poortinga Gretchen , Harrison Simon J. 
Published: May 2019

Abstract

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.

Significance:
CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.
This article is highlighted in the In This Issue feature, p. 983
ДИНАМІКА ЗАХВОРЮВАНОСТІ Й ПОШИРЕНОСТІ ПАТОЛОГІЇ ЩИТОПОДІБНОЇ ЗАЛОЗИ СЕРЕД ДОРОСЛОГО НАСЕЛЕННЯ УКРАЇНИ
Authors: Chukur O. O. 
Published: May 2019

Мета: оцінити стан захворюваності та динаміку поширеності захворювань щитоподібної залози серед дорослого населення України протягом 2013–2017 рр.
Матеріали і методи. Проведено порівняльний аналіз офіційних обліково-звітних статистичних даних МОЗ України та Інституту ендокринології та обміну речовин ім. В. П. Комісаренка АМН України «Основні показники діяльності ендокринологічної служби України».
Результати. В Україні зріс обсяг тиреоїдної патології і становить 46 % від загальної ендокринологічної захворюваності. Найпоширенішою патологією є дифузний та вузловий зоб. Їх рівень в західному регіоні вищий за середньодержавні показники та показники північно-східних областей. За 5 років зросла на 28,4 % захворюваність на гіпотиреоз. Приріст тиреотоксикозу становив 8 %, а поширеність тиреоїдитів зросла на 12,7 %.
Висока частота тиреоїдної патології залежить від недостатності йоду в харчуванні населення, незбалансованості мікроелементного і вітамінного складу в раціоні харчування на тлі погіршення екологічної ситуації та недостатньо ефективних профілактичних заходів.
Висновки. Проведений аналіз свідчить про необхідність диференційованого підходу до проведення діагностики, лікування та профілактики хворих із різною патологією щитоподібної залози в окремих регіонах України.
Vertical Modes and Effective Stability of Quasi-2-Day Waves
Authors: Sumi Yukari , Masunaga Hirohiko 
Published: May 2019

Abstract
A quasi-2-day wave is known as a convectively coupled westward inertia–gravity (WIG) wave with a shallower equivalent depth (or slower phase speed) than the dry counterpart. This study investigates the relationship between the phase speed of quasi-2-day waves and effective static stability in terms of a vertical mode perspective. By using WIG filters with different equivalent depths, different phases of the 2-day wave are identified by filtering brightness temperature data obtained from geostationary satellites. The composite time series and the vertical modes in the tropical atmosphere are calculated from reanalysis data. The large-scale dynamical fields of the composite WIG waves are explained by the superposition of the first four baroclinic modes. Phase speed of the moist vertical mode is computed by applying the Radon transform to the mode transform coefficient. Different vertical modes share a common phase speed, which is slower than its dry counterpart, implying that the wave is not dispersive. To address the question of what slows the vertical modes, the effective static stability is evaluated by defining the degree of cancellation between diabatic heating and adiabatic cooling due to the ascent. This cancellation is confirmed to be almost complete for the first baroclinic mode as expected theoretically. The effective static stability is found to be higher for a higher vertical mode, but this change over different vertical modes is not as rapid as predicted from nondispersiveness. Possible reasons for this disagreement are discussed herein.
Effect of Evaporating Sea Spray on Heat Fluxes in a Marine Atmospheric Boundary Layer
Authors: Rastigejev Yevgenii , Suslov Sergey A. 
Published: May 2019

AbstractA detailed analysis of the evaporating ocean spray effect on the vertical latent and sensible heat fluxes in a marine atmospheric boundary layer (MABL) for different droplet sizes, vertical distributions of air temperature, humidity, and turbulent intensity is presented. For our analysis we have employed a two-temperature nonequilibrium MABL model developed in our previous work. The obtained analytical and numerical solutions show that the latent and total heat fluxes are significantly enhanced by large droplets because these droplets produce steep vertical gradients of moisture and air temperature in a MABL. Small droplets, however, do not noticeably change the total heat flux but rather redistribute the energy between its sensible and latent components. It has been shown that evaporating spray affects the turbulent kinetic energy (thus the intensity of the vertical turbulent transport) mostly mechanically by altering the vertical distribution of the mass density of the air–spray mixture rather than thermodynamically by changing vertical profiles of the air temperature and moisture. Furthermore, we have found that the vertical profiles of heat fluxes are approximately self-similar for a wide range of defining parameters, that is, can be approximately scaled to a reference heat profile for a wide range of vertical distributions of the temperature, humidity, and turbulence intensity. The obtained analytical expressions for the vertical heat fluxes affected by the spray presence enable their quick and efficient calculations. This will allow for the future construction of a computationally efficient spray and accurate parameterization to be used in global weather prediction models.
Trajectories of antipsychotic use before and during pregnancy and associated maternal and birth characteristics
Authors: Schaffer Andrea L , Zoega Helga , Tran Duong T , Buckley Nicholas A , Pearson Sallie , Havard Alys 
Published: May 2019

Objective: To identify distinct trajectories of antipsychotic use prior to and during pregnancy and describe the associated maternal and birth characteristics. Methods: We conducted a population-based cohort study of births (2005–2012) using linked administrative data in New South Wales, Australia. We used group-based trajectory modelling to classify trajectories of antipsychotic use in the 450 days prior to pregnancy and during pregnancy. We characterised women with different trajectories according to maternal sociodemographic characteristics, mental health diagnoses and hospitalisations, use of psychotropic medicines and birth outcomes. Results: Of 137,993 women who gave birth, 2741 (2.0%) were exposed to antipsychotics prior to or during pregnancy. We identified six trajectories of antipsychotic use: two involved short-term use of low daily doses prior to pregnancy (51.1%), while three involved long-term use of low (20.9%), moderate (11.0%) and high (2.0%) daily doses throughout pregnancy. One trajectory (15.0%) involved increasing use during pregnancy. Women with long-term use were more likely to have a schizophrenia or bipolar disorder diagnosis, to have used multiple psychotropics and to have a mental health hospitalisation during pregnancy. Overall, women using antipsychotics had elevated rates of adverse birth outcomes compared to unexposed women. Women with the greatest antipsychotic exposure had the highest rates of gestational diabetes and gestational hypertension. Conclusion: Women using antipsychotics around pregnancy are heterogeneous, with varying patterns of use and associated birth outcomes, reflecting underlying differences in the indications for treatment and/or severity of illness. This diversity should be considered when developing clinical guidelines and designing safety studies.
Associations between non-anaemic iron deficiency and outcomes following surgery for colorectal cancer: An exploratory study of outcomes relevant to prospective observational studies
Authors: Miles Lachlan F , Sandhu Ravinder NS , Grobler Anneke C , Heritier Stephane , Burgess Adele , Burbury Kate L , Story David A 
Published: May 2019

Iron deficiency is common in colorectal cancer. Despite perioperative guidelines advocating for the correction of non-anaemic iron deficiency prior to major surgery, the impact of this pathology on postoperative outcome is unclear. We conducted a single-centre, historical cohort study of 141 elective resections for colorectal cancer. We stratified non-anaemic patients into iron deficient and iron replete groups, and collected data on baseline characteristics, preoperative laboratory results, intraoperative events and postoperative outcomes. As this study was an exploratory work for future research, a P-value of 0.25 was considered relevant. Patients in the deficient group demonstrated lower baseline ferritin (median (interquartile range, IQR) 76 (41–141) µg/L versus 207 (140–334) µg/L, P < 0.001) and transferrin saturation (mean (standard deviation, SD) 18% (8%) versus 32% (12%), P < 0.001) than those in the replete group, and lower starting haemoglobin (mean (SD) 138 (10) g/L versus 144 (12) g/L, P = 0.01). The deficient group had increased re-admission (25% (24%) versus 4% (11%), P = 0.15) and all-cause infection (25% (24%) versus 5% (14%), P = 0.24). A decrease of two days in days alive and out of hospital at postoperative day 90 was seen in the deficient group on univariate analysis (median (IQR) 81 (75–84) versus 83 (78–84), P = 0.25). This reduced to 1.24 days in multivariate adjusted quantile regression analysis ( P = 0.22). Days alive and out of hospital at day 90, postoperative re-admission and postoperative infection may be meaningful outcome measures for future prospective observational work examining non-anaemic iron deficiency in patients undergoing major surgery for colorectal cancer.
Liquid-type non-thermal atmospheric plasma ameliorates vocal fold scarring by modulating vocal fold fibroblast
Authors: Won Ho-Ryun , Song Eun Hye , Won Jong Eun , Lee Hye Young , Kang Sung Un , Shin Yoo Seob , Kim Chul-Ho 
Published: May 2019

Injection laryngoplasty is a widely used therapeutic option for drug delivery into vocal folds (VFs). Efficient injectable materials are urgently needed for treating intractable VF disease. Liquid-type non-thermal atmospheric plasma (LTP) has been found to be useful for various biological applications, including in regenerative medicine. We evaluated the effects of LTP on VF regeneration. Migration and matrix metalloproteinase-2 expression of lipopolysaccharide (LPS)-treated human vocal fold-derived mesenchymal stem cells (VF-MSCs) were enhanced by LTP treatment. LTP treatment not only ameliorated nuclear factor-κB and interleukin-6 activation, induced by LPS treatment, but also the increased manifestation of α-smooth muscle actin and fibronectin, induced by transforming growth factor-ß. In a rabbit VF scarring animal model, histological analyses showed increased hyaluronic acid deposition and decreased collagen accumulation after LTP injection. Videokymographic analysis showed more improved vibrations in LTP-treated VF mucosa compared to those in non-treated group. In conclusion, LTP treatment enhanced the recruitment and activation of VF-MSCs. Regulated extracellular matrix (ECM) synthesis and eventual functional improvement of scarred VFs were observed upon LTP treatment. The results of this study suggest that LTP injection can enhance wound healing and improve functional remodeling following VF injury.Impact statementVoice disorder has a significant impact on life quality, and one of the major causes of this voice disorder is vocal fold scarring. Therefore, various approaches have been tried to treat for voice disorder. However, no method has satisfied all requirements until now. Plasma medicine, which involves the medical application of plasma, is a rapidly developing field. We have confirmed that liquid-type plasma improved vocal fold scarring by mobilizing and activating vocal fold fibroblast. In conclusion, liquid-type plasma is a potential therapeutic agent for promoting vocal fold scarring through simple injection and it may be an alternative therapeutic agent for the current situation to treat voice disorder.
Renal impairment induced by prenatal exposure to angiotensin II in male rat offspring
Authors: Svitok Pavel , Okuliarova Monika , Varga Ivan , Zeman Michal 
Published: May 2019

Suboptimal conditions during prenatal ontogeny can impair development of several physiological systems and result in cardiometabolic diseases in adulthood. The kidney has been identified as one of the most sensitive organs for developmental programming, but underlying mechanisms are not fully understood. Therefore, in our study we explored the consequences of prenatally increased angiotensin II (Ang II) on the structural development of the kidney and its damage by infiltrated immune cells under normal diet and after an increased salt intake, as a second insult representing a lifestyle factor in humans. Female rats were implanted with osmotic mini-pumps continuously releasing Ang II of dose 2 µg/kg/h during last two weeks of pregnancy, whereas control females were sham operated. Immunohistological and ultrastructural evaluations of the kidneys and their infiltration with immune cells were performed in mature male progeny kept either on a standard or increased salt (2% NaCl) diet. Glomerular volume decreased and the cortical tubulointerstitial injury increased in the offspring prenatally exposed to Ang II with no additional effect of increased salt. Ultrastructural examination demonstrated degenerative changes in proximal tubules, mainly fewer and shorter microvilli in the brush border, enlarged mitochondria, and an increased number of lysosomes in the epithelial cells in the progeny prenatally exposed to Ang II. Moreover, the treatment resulted in increased infiltration of T-cells and macrophages in the renal cortex compared to controls. These changes paralleled with reduced numbers of cytotoxic T-cells in circulation and higher oxidative burst of neutrophils in the progeny of Ang II-treated mothers compared to controls. Altogether, results suggest that prenatally increased Ang II promoted infiltration of immune cells in the kidney and subsequent oxidative stress, which induced a damage of renal glomerular and tubular system entailing negative consequences on the cardiovascular system.Impact statementSuboptimal prenatal conditions can contribute to development of cardiovascular diseases and an altered renin-angiotensin-aldosterone system (RAAS) can be involved in the process. In our study, increased angiotensin II in pregnant female rats resulted in renal cortical interstitial damage, and renal ultrastructural changes in the glomeruli, the brush border of proximal tubules and mitochondria in mature male offspring. The treatment promoted infiltration of T cells and macrophages in the kidneys and primed an oxidative burst of circulating neutrophils, indicating a pro-inflammatory state in the progeny of angiotensin II-treated mothers. Deregulated RAAS of mothers is involved in developmental programming of hypertension in adult male offspring via damaging kidney morphology and function. These findings suggest that preventing the activation of RAAS and oxidative stress during perinatal development might protect against hypertension development in adult male progeny.
Endovascular reconstructive treatment using a fill-and-tunnel technique for a fusiform vertebral artery dissecting aneurysm with ipsilateral dominance
Authors: Kyeung Ko Jun , Weon Lee Sang , Hwa Choi Chang , Lee Tae Hong 
Published: May 2019

Background Fusiform dissecting aneurysms involving the dominant vertebral artery with poor collaterals are challenging to treat. The purpose of this study was to present an initial experience with a fill and tunnel technique for reconstructive endovascular treatment of these conditions. Methods A total of 13 patients, 11 men and 2 women, each with a fusiform vertebral artery dissecting aneurysm not amenable to internal trapping of the parent artery, underwent reconstructive endovascular treatment using a fill and tunnel technique between January 2012 and December 2015. The safety, feasibility, and clinical and angiographic outcomes of these procedures were retrospectively evaluated. Results The average maximum diameter of the fusiform aneurysms was 12.1 mm. Five were ruptured. Three aneurysms were treated with a single stent and the remaining 10 aneurysms required double-stent placement. Treatment was technically successful in all 13 patients, achieving complete occlusion ( n = 10, 76.9%) and near-complete occlusion ( n = 3, 23.1%). No procedure-related complications occurred in any patient. There were no delayed thromboembolic or hemorrhagic complications during the follow-up period (mean, 19.0 months). Angiographic follow-ups (mean, 9.1 months) showed stable occlusion in 90.9% (10/11) and asymptomatic in-stent occlusion in one patient (9.1%, 1/11). At the end of the observation period (mean, 19.0 months), all patients had excellent clinical outcomes (modified Rankin Scale (mRS) 0, 92.3%, 12/13), except one (mRS 4), resulting from poor preoperative status. Conclusions This retrospective study demonstrated that endovascular reconstruction using a fill-and-tunnel technique was a technically safe, feasible, and clinically effective treatment method for fusiform vertebral artery dissecting aneurysms with ipsilateral dominance.
Symptom Chronicity and Tobacco Use: Differences in Athletic and Nonathletic Candidates for Cartilage Surgery
Authors: Everhart Joshua S. , Vajapey Sravya , Kirven James C. , Abouljoud Moneer M. , DiBartola Alex C. , Wright Brennan , Flanigan David C. 
Published: May 2019

Objective To determine whether there are differences in symptomatic knee cartilage defects and rates of tobacco use among age-matched athletes versus nonathletes undergoing initial arthroscopic knee surgery who meet demographic and radiographic criteria for cartilage restoration surgery. Design Age-matched athletes ( n = 186) and nonathletes ( n = 159) age 40 or less with a body mass index (BMI) of 35 kg/m2 or less (mean 26.8 SD 4.1) and <50% joint space narrowing on weight-bearing radiographs were included. All patients had a symptomatic Outerbridge grade 2 or higher cartilage defect visualized during knee arthroscopy. Relationship between athletic status and chronicity of knee symptoms prior to surgery and tobacco use status, cartilage defect Outerbridge grade, size, and location at time of surgery were characterized. Results Nonathletes were more likely to smoke ( P < 0.001) and had higher BMI ( P = 0.005). Duration of symptoms prior to surgery was shorter among athletes ( P < 0.001). Grade 4 defects were equally prevalent ( P = 0.96) as were multicompartment grade 3-4 lesions ( P = 0.12). Mean grade 3-4 defect size was similar in lateral ( P = 0.96) and medial compartments ( P = 0.82). There was a trend toward larger anterior compartment defects in nonathletes ( P = 0.07). Conclusions Among age-matched athletes and nonathletes with symptomatic cartilage defects who meet demographic criteria for cartilage restoration, nonathletes were more likely to smoke and have a longer duration of symptoms prior to treatment. Athletes tended to present earlier but with similar size defects compared to nonathletes, supporting accelerated treatment of defects in athletes and caution toward allowing continued athletic participation in patients with known cartilage defects.
PsA-Disk, a novel visual instrument to evaluate psoriatic arthritis in psoriatic patients: an Italian derma-rheuma multicentre study
Authors: Chimenti Maria Sole , Esposito Maria , Graceffa Dario , Teoli Miriam , Peluso Giusy , Birra Domenico , Moretta Gaia , Galossi Alessandra , Carboni Valentina , Sensi Felice , Mazzotta Annamaria , Caccavale Rosalba , Bernardini Nicoletta , Sessa Paola , Richetta Antonio , Del Duca Ester , Urbani Sara , Persechino Severino , De Simone Clara , Bonifati Claudio , Gremese Elisa , Peris Ketty , Perricone Roberto 
Published: May 2019

Background: Consensus among dermatologists and rheumatologists in the diagnosis and assessment of musculoskeletal diseases in psoriasis (PsO) patients is needed. This study assesses characteristics of musculoskeletal pain in patients with PsO for the presence of psoriatic arthritis (PsA) and evaluation of a novel 16-item visual instrument (PsA-Disk). Methods: Data were collected from eight dermatological/rheumatological centres across Italy. Patients with PsO completed PEST (Psoriasis Epidemiology Screening Tool) and PsA-Disk questionnaires during the first visit. A rheumatological visit was performed to confirm the presence of PsA. Both validity and reliability of PsA-Disk were assessed. Results: A total of 573 patients with PsO were examined at the first visit, and 120 (21%) were diagnosed with PsA. Patients with PsA compared with patients with PsO ( n = 119) presented statistically significant differences for: nail involvement, PEST score ⩾3, higher erythrocyte sedimentation rate (ESR), Nail Psoriasis Severity Index (NAPSI)-feet, NAPSI-(hands + feet) and PsA-Disk scores (73.9 ± 32.1 versus 58.1 ± 39.8, p < 0.001). Patients with PsA with knee arthritis had higher PsA-Disk scores (98.4 ± 26 versus 71.5 ± 31.9, p = 0.006) that were also correlated with number of swollen ( r = 0.2, p < 0.05) and tender joints ( r = 0.24, p = 0.021), patient ( r = 0.4, p < 0.001) and physician-pain-visual analogue scale (VAS; r = 0.33, p < 0.001), patient global assessment (PGA)-VAS ( r = 0.23, p = 0.025), physician-health assessment questionnaire (HAQ; r = 0.38, p = 0.011), Disease Activity Score (DAS)-44 ( r = 0.25, p = 0.023) and Disease Activity in Psoriatic Arthritis (DAPSA; r = 0.31, p = 0.005). The instrument had excellent reliability in terms of internal consistency (Cronbach’s alpha = 0.90) and stability (intraclass correlation = 0.98). Moderate agreement between PsA-Disk and PEST (Cohen’s kappa = 0.46) was observed, while construct validity appeared appropriate [PsA + patients: PsA-Disk score (interquartile range; IQR) =71 (50–96); PsA-patients: PsA-Disk score (IQR)=50 (20–90); p < 0.001]. Conclusion: PsA-Disk may be considered a valid novel instrument aiding both dermatologists and rheumatologists in the rapid detection and assessment of musculoskeletal disease characteristics.