Добірка наукової літератури з теми "530.155 7222"

ABSTRACT This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (C max), time to maximum concentration (T max), or area under the concentration-time curve from 0 h to infinity (AUC0–∞) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C maxwere 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC0–∞ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T max was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows:K a = 0.37 to 0.48 h−1,V/F = 2.0 to 2.8 liters/kg, CL/F = 56.5 to 72.2 liters/h, and terminal half-life = 1.7 to 2.1 h, where Ka is the absorption rate constant,V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.

FLASH radiotherapy is a new irradiation method in which large doses of ionizing radiation are delivered to tumors almost instantly (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. Although this technique is primarily studied in the context of electron and photon therapies, proton delivery at high dose rates can also reduce the adverse side effects on normal cells. So far, no definitive mechanism has been proposed to explain the differences in the responses to radiation between tumor and normal tissues. Given that living cells and tissues consist mainly of water, we set out to study the effects of high dose rates on the radiolysis of water by protons in the energy range of 150 keV – 500 MeV (i.e., for linear energy transfer (LET) values between ∼72.2 and 0.23 keV/μm, respectively) using Monte Carlo simulations. To validate our methodology, however, we, first, report here the results of our calculations of the yields (G values) of the radiolytically produced species, namely the hydrated electron ([Formula: see text]), •OH, H•, H2, and H2O2, for low dose rates. Overall, our simulations agree very well with the experiment. In the presence of oxygen, [Formula: see text] and H• atoms are rapidly converted into superoxide anion or hydroperoxyl radicals, with a well-defined maximum of [Formula: see text] at ∼1 μs. This maximum decreases substantially when going from low-LET 500 MeV to high-LET 150 keV irradiating protons. Differences in the geometry of the proton track structure with increasing LET readily explain this diminution in [Formula: see text] radicals.

Abstract Introduction During the pandemic, healthcare workers have shared their stresses on social media, including regarding sleep disturbances. However, an assessment of sleep using validated measures among healthcare workers on social media is lacking. Methods A restricted, self-selection survey was distributed on Facebook, Twitter, and Instagram for 16 days targeting healthcare workers who were clinically active during COVID-19. In addition to demographics and career information, participants completed the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index. Poor sleep quality was defined as PSQI > 5. Moderate-to-severe insomnia was defined as an ISI > 14. Multivariate logistic regression tested the association between demographics and career characteristics and sleep outcomes. Results Of the 983 who clicked our link, 906 completed the survey. Participants were mostly white (70%), female (75%), physicians (64%). Mean sleep duration was 6.1 (SD1.2) hours. Nearly 90% experienced poor sleep (PSQI). One third reported moderate or severe insomnia. Many (60%) reported sleep disruptions due to device usage or due to bad dreams at least once per week (45%). In multivariable regression, non-physicians (OR 3.5, CI: 2.5, 5.0), Hispanic ethnicity (OR 2.2; CI: 1.44, 3.45), being single (1.5, CI: 1.03, 2.21), and youngest age group (18–24) (OR 9.9; CI: 1.44, 68.09) had increased odds of insomnia. In open-ended comments, sleep disruptions mapped to 5 categories: (1) Work demands (“The volume of calls and messages from my patient and caregiver population is through the roof”); (2) Pandemic related (“I never had sleep issues prior to the COVID-19 pandemic. Suddenly I had issues with sleep initiation.”; (3) Children and family (“COVID plus home stress plus stress over my kids, my job, my marriage.”); (4) Personal health (“Insomnia predating COVID, but worsened with COVID.”); (5) Responses to the pandemic (“I worry about how COVID is being managed by the President...This does keep me awake at night.”). Conclusion During the COVID-19 pandemic, 90% of healthcare workers surveyed on social media reported poor sleep, with over one-third of participants reporting moderate-severe insomnia. Online sleep interventions for healthcare workers are urgently needed. Support (if any):

Background Epidural clonidine produces analgesia without motor impairment, and is associated with a local anesthetic-sparing effect during labor. The authors have recently demonstrated that epidural neostigmine initiates selective labor analgesia devoid of adverse effects. Both drugs possess common analgesic mechanisms mediated through spinal acetylcholine release. This study evaluates their epidural combination in parturients. Methods At the beginning of labor, parturients were randomly allocated to one of five groups to receive one of the following after a test dose: 150 microg epidural clonidine, 750 microg neostigmine, or 75 microg clonidine combined with 250, 500, or 750 microg neostigmine. A pain score (visual analog scale, 0-100) was recorded before administration and at regular intervals until request for a supplemental injection. Subsequent analgesia was provided by continuous epidural infusion of ropivacaine. Results Parturients did not differ regarding demographic data and initial pain score. Clonidine 150 microg , neostigmine 750 microg , and 75 microg clonidine plus 250 microg neostigmine produced ineffective and short-lasting effects. Clonidine 75 microg plus 500 microg neostigmine and 75 microg clonidine plus 750 microg neostigmine presented comparable durations of 90 +/- 32 and 108 +/- 38 min (mean +/- SD), respectively, and final analgesic efficacies, with 72.2% and 84%, respectively, of the parturients reporting a visual analog scale score of less than 30 out of 100 after 30 min. Ropivacaine use was significantly reduced in all clonidine groups (average, 9.5 mg/h) in comparison with neostigmine alone (17 +/- 3 mg/h). No adverse effects were observed for 75 mug clonidine combined with any dose of neostigmine while maternal sedation (20%) and hypotension (33%) occurred with 150 microg clonidine alone. Conclusions Epidural clonidine, 75 microg , with 750 microg neostigmine is an effective combination to initiate selective labor analgesia without adverse effects. Clonidine use further reduces local anesthetic consumption throughout the course of labor.

Human inborn immune-related errors comprise a heterogeneous group of rare genetically determined diseases of the immune system caused by loss or gain of function mutations altering relevant protein functions. The 2019 International Union of Immunological Societies recently proposed the classification for such pathologies now comprising 406 distinct disorders with 430 different gene defects. Predominantly antibody deficiencies represent most common group of human inborn immune-related errors, which diagnostics poses uneasy challenge for general practitioner due to a broad range of their clinical manifestations, such as infection, allergy, autoimmunity and malignancy. In addition, patients with human immune-related inborn errors may develop a vaccine-associated disease after administering live vaccines in accordance with the Russia-wide National Vaccine Schedule. Most common among vaccine-associated diseases are vaccine-associated paralytic poliomyelitis, vaccine-associated encephalitis (1 case per 1 000 000 doses of measles, rubella, varicella vaccine), vaccine-associated meningitis (1 case per 250 000 – 500 000 doses of mumps vaccine) as well as adverse effects related to BCG immunization: local (infiltration, cold abscess – 8.6 case per 100,000 vaccinated patients) and disseminated complications (BCG lymphadenitis – 15.5 case per 100 000 vaccinated patients, BCG osteitis – 3.5 case per 100 000 vaccinated patients). Vaccine-associated paralytic poliomyelitis in vaccinated patients occurs after the first, second and rarely third oral polio vaccine dose inoculation. Incidence rate for vaccineassociated paralytic polio after 1 and 3 oral vaccine inoculation ranges from 1 case per 700 000 vaccine doses to 1 case per 3 500 000, respectively. Vaccine-associated paralytic poliomyelitis mainly emerges due to inborn mutations related to humoral immunity after primary vaccination with oral polio vaccine or close contact of unvaccinated patients with subjects vaccinated with oral polio vaccine. Here, we describe a clinical case of vaccine-associated paralytic poliomyelitis in patient with primary immunodeficiency. Our is aimed at emphasizing importance of immunological alertness with regard to detecting primary immunodeficiencies and timely apply a replacement therapy prior to verifying type of immunodeficiency.

Разработан способ определения ртути(II) с использованием пенополиуретана, модифицированного на поверхности треугольными нанопластинками серебра со средней длиной ребра 52 нм и толщиной 4 нм. Способ основан на окислении нанопластинок серебра ртутью(II). Оно сопровождается уменьшением полосы поверхностного плазмонного резонанса наночастиц, что позволяет рассматривать полученный нанокомпозитный материал в качестве твердофазного аналитического реагента для определения ртути(II). Исследовано влияние времени взаимодействия и pH раствора на чувствительность определения ртути. Предел обнаружения ртути в выбранных условиях равен 50 мкг/л, диапазон определяемых содержаний составляет 150–1000 мкг/л. Увеличение объема анализируемого раствора с 5.0 до 100.0 мл за счет концентрирования позволяет снизить предел обнаружения ртути до 5 мкг/л.

Formation of DNA adducts of chemical carcinogens is a trigger for carcinogenesis. Adducts of benzo[a]pyrene metabolites and estradiol metabolites with DNA have been found in normal and tumor cells in healthy women and patients with breast and colorectal cancer. These low-weight compounds in macromolecular complexes induce the synthesis of specific antibodies. Previously, the presence of specific antibodies against benzo[a]pyrene (IgA-Bp), estradiol (IgA-Es) and progesterone (IgA-Pg) was revealed in breast cancer patients. The aim of this study is to identify the putative features of the IgA-Bp, IgA-Es, and IgA-Pg formation in postmenopausal women with colorectal cancer, in comparison with healthy and breast cancer patients. Using a noncompetitive enzyme-linked immunosorbent assay, the content of these antibodies was studied in the blood serum of healthy women (n = 401), patients with colorectal cancer (n = 219) and breast cancer (n = 1469) using conjugates of Bp, Es, and Pg with bovine serum albumin as adsorbed antigens. When compared with healthy people, the patients with colorectal cancer exhibited higher incidence of IgA-Bp 3 (75% vs 37%, p 0.0001, OR = 5.0), as well as more common levels of individual antibody ratios: IgA-Bp/IgA-Es 1 (82% vs 41%, p 0.0001, OR = 6.5); IgA-Bp/IgA-Pg 1.5 (77% vs 20%, p 0.0001, OR = 13.4); IgA-Es/IgA-Pg 1 (89% vs 48%, p 0.0001, OR = 8.7). In breast cancer patients, compared with healthy people, high IgA-Bp values ( 3) were more common (45% vs 37%, p 0.004, OR = 1.4), as well as increased IgA-Bp/IgA-Es ratio 1 (57% vs 41%, p 0.0001, OR = 1.9), IgA-Bp/IgA-Pg 1.1 (71% vs 36%, p 0.0001, OR = 4.4) and IgA-Es/IgA-Pg 1.1 (71% vs 41%, p 0.0001, OR = 3.5). In patients with colorectal cancer, compared with patients with breast cancer we have found higher incidence of increased IgA-Bp values ( 3) (75% vs 45%, p 0.0001), IgA-Es 3 (53% vs 39%, p 0, 0001), and of IgA-Pg 2 (52% vs 44%, p = 0.025), as well as IgA-Bp/IgA- Es 1 (82% vs 57%, p 0.0001, OR = 50.8 ); IgA-Bp/IgA-Pg 1.5 (77% vs 49%, p 0.0001); IgA-Es/IgA-Pg 1.1 (85% vs 71%, p 0.0001). The apparently high serum IgA-Bp levels reflect the formation of DNA-Bp adducts at large scale in target cells in colorectal cancer compared with healthy women and breast cancer patients, due to direct exposure of colon epithelium to Bp from food. Immunoassay for IgA-Bp, IgA-Es and IgA-Pg is proposed for assessing individual risk of colorectal cancer in postmenopausal women. The ratios of IgA Bp/IgA-Pg levels 1.5 represent the most informative marker of individual risk for colorectal cancer.

90 Background: Treatment-related infertility is an important cause of distress in young women with breast cancer (YWBC) that is preventable by fertility preservation (FP) prior to initiating therapy. This study assesses FP service use by YWBC in Quebec (Canada). Methods: Administrative claims for women ≤ 40 diagnosed between 01-04-2012 and 31-03-2018 were identified using Quebec’s universal health services database (RAMQ). Access to and use of FP services were ascertained by identifying claims for a visit with an obstetrician/gynecologist (OB/GYN) ≤ 90 days of diagnosis, followed by claims for ovarian stimulation, ovule harvesting or artificial insemination. Patient, disease and treatment-related predictors were estimated using logistic regression. Results: 1 616 YWBC were treated. Mean age was 36 (SD 4.1), 72.1% had a CCI = 0, 84.5% were urban residents, and 72.2% experienced some form of socioeconomical disadvantages. Stage distribution was: 0.93%, 68.8, and 30.3% for stages 0, 1-2, and 3 respectively. 53.0% had a mastectomy, 40.8% received chemotherapy (CT), 70.7% received radiotherapy, 20.9% initiated anti-estrogen therapy. 387 YWBC consulted an OB/GYN within 90 days of diagnosis and 155 subsequently received FP services. Predictors associated with FP use included: decreased age (OR= 0.82, 95CI = 0.79-0.86), type of surgery (OR = 0.46, CI = 0.22-0.97), social isolation (OR =1.39, 95CI = 0.99-1.96) and receipt of chemotherapy (OR = 1.74, 95CI = 1.10-2.76). Conclusions: Only 23.9% of eligible YWBC in Quebec accessed FP specialists. Of these, 40.1% chose to move forward with FP. These findings raise important questions on how to optimize access to FP expertise. [Table: see text]

Background:Upadacitinib (UPA), an oral Janus kinase inhibitor (JAKi), has demonstrated efficacy in the phase 3 SELECT clinical program, conducted across a range of patients (pts) with rheumatoid arthritis (RA).1–6 Real-world data for UPA, including in pts previously treated with a JAKi, have not yet been reported since global approvals beginning in 2019.Objectives:To assess the characteristics of US-based pts receiving UPA and its effectiveness in clinical practice at 3 months.Methods:This observational study included US-based pts from the United Rheumatology Normalized Integrated Community Evidence (UR-NICE) database who initiated UPA 15 mg once daily from FDA approval (August 2019) to July 31, 2020 and had ≥6-month pre-baseline data available. Effectiveness was assessed in pts with a reported Clinical Disease Activity Index (CDAI) score at 3 months after UPA initiation and included proportions of pts achieving CDAI remission (≤2.8), CDAI low disease activity (≤10), other disease activity measures, and pt-reported outcomes. A subgroup analysis assessed UPA effectiveness in pts with or without prior tofacitinib (TOFA) treatment.Results:This analysis included 252 pts treated with UPA 15 mg, of whom 98 (38.9%) received UPA monotherapy and 154 (61.1%) received UPA combined with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs). 64.3% of pts were from the Southern region of the USA. 86.1%, 72.2%, and 47.6% of pts had been previously treated with csDMARDs, biologic DMARDs, and JAKis, respectively. Baseline characteristics were largely similar between UPA monotherapy and combination therapy groups and those with or without prior TOFA treatment (Table 1). Pts with prior TOFA treatment had a longer duration of RA since diagnosis and higher steroid use versus those without. UPA 15 mg improved disease activity scores (including CDAI) and pt-reported outcomes (including physical function and pain) after 3 months of treatment (Figure 1). Similar effectiveness was observed with UPA 15 mg in pts with or without prior TOFA treatment.Conclusion:In the UR-NICE real-world database of US-based pts, improvements in clinical and pt-reported outcomes were observed at 3 months in UPA-treated pts with RA, including those with or without prior TOFA treatment, despite the treatment-refractory population included in this dataset.References:[1]Burmester GR, et al. Lancet 2018;391:2503–12.[2]Smolen JS, et al. Lancet 2019;393:2303–11.[3]Fleischmann R, et al. Arthritis Rheumatol 2019;71:1788–800.[4]Genovese MC, et al. Lancet 2018;391:2513–24.[5]van Vollenhoven R, et al. Arthritis Rheumatol 2020;72:1607–20.[6]Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Table 1.Baseline characteristicsn (%), unless otherwise statedFull analysis set(n=252)Pts with prior TOFA treatment(n=113)Pts without prior TOFA treatment (n=139)Mean (SD) exposure, days219.7 (112.1)215.7 (116.7)222.9 (108.5)Female199 (79.0)85 (75.2)114 (82.0)Age ≥65 years75 (29.8)34 (30.1)41 (29.5)Oral steroid use140 (55.6)70 (61.9)70 (50.4)Prior csDMARDs217 (86.1)102 (90.3)115 (82.7)Prior TOFA113 (44.8)113 (100.0)0Prior biologic DMARDs182 (72.2)86 (76.1)96 (69.1)Tumor necrosis factor inhibitor147 (58.3)66 (58.4)81 (58.3)Interleukin-6 receptor inhibitor87 (34.5)47 (41.6)40 (28.8)nMean (SD)nMean (SD)nMean (SD)Duration of RA diagnosis, years1884.0 (3.0)895.1 (2.9)993.1 (2.8)Methotrexate dose, mg/week8817.0 (5.1)2817.8 (5.0)6016.6 (5.2)SJC282394.8 (5.7)1084.5 (5.0)1315.0 (6.2)TJC282376.5 (6.7)1076.5 (6.8)1306.5 (6.6)CDAI22520.4 (13.4)10520.2 (13.5)12020.6 (13.3)Routine assessment of patient index data 31654.2 (2.3)724.2 (2.4)934.3 (2.2)Disease Activity Score in 28 joints based on C-reactive protein1673.9 (1.5)833.9 (1.5)843.9 (1.5)Health Assessment Questionnaire-Disability Index1702.5 (2.1)742.4 (2.2)962.5 (2.1)Pain(0–10)22956.5 (28.5)10456.9 (29.3)12556.1 (28.0)SD, standard deviation; S/TJC, swollen/tender joint countAcknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Hilary Wong, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Allan Gibofsky Shareholder of: AbbVie, Amgen, Johnson & Johnson, and Pfizer, Consultant of: AbbVie, Celgene, Eli Lilly, Flexion, Pfizer, Relburn Pharma, and Samumed. Paid consultant with investment analysts on behalf of the Gerson Lehrman Group, Bhavna Dhillon Shareholder of: May own stock or options in United Rheumatology, Employee of: United Rheumatology, Mark E. Pearson Shareholder of: May own AbbVie stock or options, Namita Tundia Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Kendall Dunlap Shareholder of: May own stocks or shares in AbbVie, Employee of: AbbVie, Grace Wright Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Exagen, Myriad Autoimmune, Novartis, Sanofi/Regeneron, UCB, and Vindico, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Exagen, Gilead, Janssen, Myriad Autoimmune, Novartis, Pfizer, Sanofi/Regeneron, and UCB, Employee of: President and Founder of the Association of Women in Rheumatology

Abstract Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-01.