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1.
Artigo em Inglês | MEDLINE | ID: mdl-33833508

RESUMO

Background: Penehyclidine hydrochloride is a selective antagonist of M1 and M3 receptors. Clinical studies suggest that it is a potential drug for the treatment of chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate the effect of penehyclidine hydrochloride on the inflammatory response of lung tissue during mechanical ventilation in rats with COPD and explore the role of the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathway. Methods: Eight-week-old male Sprague Dawley rats were exposed to cigarette smoke for 30 minutes every day for two months, and on the first and thirtieth days, 200 ug of lipopolysaccharide was injected into the trachea. Two months later, the rats were randomly divided into the control group (C), model group (M), model + normal saline group (N), and penehyclidine hydrochloride group (H) to undergo anesthesia and mechanical ventilation. In group H, 1 mg/kg of penehyclidine hydrochloride was injected intravenously. Results: The results showed that: ① Compared with group C, the other groups all showed typical chronic obstructive pathological changes in the lung tissue; their wet/dry weight ratio (W/D), TNF-α, JNK, and p-JNK levels increased (P < 0.05), and their interleukin (IL)-10 levels decreased (P < 0.05). ② Compared with group M, there was no significant change in the lung tissue indexes in group N (P > 0.05). ③ Compared with group N, the W/D, TNF-α, JNK, and p-JNK levels in group H decreased (P < 0.05), while the levels of IL-10 increased (P < 0.05). Conclusion: Penehyclidine hydrochloride can alleviate the pulmonary inflammatory response in rats with COPD undergoing mechanical ventilation. The JNK/SAPK signaling pathway may be involved in this process.

2.
Life Sci ; 277: 119505, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33872662

RESUMO

PURPOSE: We aimed to investigate the patterns and prognostic roles of tumor mutation burden and immune microenvironment in pancreatic cancer. METHODS: The somatic mutation data, transcriptome profiles and clinical information were downloaded from the Cancer Genome Atlas database. Gene expression difference, Gene ontology, KEGG, gene set enrichment analyses and "CIBERSORT" algorithm were performed to screen differentially expressed genes, enriched functions or pathways and immune infiltrates differences between high and low TMB groups. Single sample gene set enrichment and unsupervised consensus clustering analyses were used for immunity grouping. Immune cell infiltration and expressions of HLA and checkpoint genes were investigated. Finally, a nomogram model integrating TMB and immune infiltration was established. RESULTS: A total of 608 differentially expressed genes were identified between high and low TMB groups, KEGG base excision repair and DNA replication pathways were enriched in high TMB group. Infiltration levels of M0 macrophages were higher and dendritic resting cells were lower in high TMB group. The risk model based on TMB-related immune genes, FAM19A2 and SLC22A17 was established and high risk scores indicated poorer prognosis. The expressions of HLA genes and immune checkpoint genes were higher in high immunity group. The nomogram showed remarkable ability for individualized survival estimation with good AUC values (0.794 and 0.800, respectively) for 3- and 5-year survival rates prediction. CONCLUSIONS: The characteristics of tumor mutation burden and immune infiltration in pancreatic cancer provide new insights into the tumor microenvironment, immunotherapies and a novel prognostic nomogram model for pancreatic cancer patients.

3.
Biomater Sci ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908463

RESUMO

Anti-tumor treatment based on free radicals is often inefficient in hypoxic tumors, mainly because of the oxygen-dependent generation mechanism of reactive oxygen species (ROS). Herein, we report an NIR laser-controlled nano-system that is capable of generating alkyl radicals in situ in an oxygen-independent approach. Hollow mesoporous Prussian blue nanoparticles (HPB NPs) were developed to co-encapsulate the azo initiator (AIBI) and 1-tetradecanol as the phase change material (PCM, melting point of ∼39 °C), obtaining the AP@HPB NPs. At normal body temperature, the PCM remained in the solid state to prevent the pre-leakage of AIBI. Upon NIR laser irradiation (808 nm) at the tumor site, AP@HPB NPs generated heat upon photothermal conversion, which melted the PCM to release AIBI and decomposed AIBI to produce toxicity free alkyl radicals under both normoxic and hypoxic conditions. The alkyl free radicals efficiently killed tumor cells by causing oxidative stress and damaging DNA. Meanwhile, NIR light-induced hyperthermia cooperated with free radicals to efficiently eradicate tumors. This study therefore provides a promising strategy toward oxygen-independent free radical therapy, especially for the treatment of hypoxic tumors.

4.
Heart ; 107(9): 734-740, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33685933

RESUMO

OBJECTIVE: There are concerns that healthcare and outcomes of black, Asian and minority ethnic (BAME) communities are disproportionately impacted by the COVID-19 pandemic. We investigated admission rates, treatment and mortality of BAME with acute myocardial infarction (AMI) during COVID-19. METHODS: Using multisource national healthcare records, patients hospitalised with AMI in England during 1 February-27 May 2020 were included in the COVID-19 group, whereas patients admitted during the same period in the previous three consecutive years were included in a pre-COVID-19 group. Multilevel hierarchical regression analyses were used to quantify the changes in-hospital and 7-day mortality in BAME compared with whites. RESULTS: Of 73 746 patients, higher proportions of BAME patients (16.7% vs 10.1%) were hospitalised with AMI during the COVID-19 period compared with pre-COVID-19. BAME patients admitted during the COVID-19 period were younger, male and likely to present with ST-elevation acute myocardial infarction. COVID-19 BAME group admitted with non-ST-elevation acute myocardial infarction less frequently received coronary angiography (86.1% vs 90.0%, p<0.001) and had a longer median delay to reperfusion (4.1 hours vs 3.7 hours, p<0.001) compared with whites. BAME had higher in-hospital (OR 1.68, 95% CI 1.27 to 2.28) and 7-day mortality (OR 1.81 95% CI 1.31 to 2.19) during COVID-19 compared with pre-COVID-19 period. CONCLUSION: In this multisource linked cohort study, compared with whites, BAME patients had proportionally higher hospitalisation rates with AMI, less frequently received guidelines indicated care and had higher early mortality during COVID-19 period compared with pre-COVID-19 period. There is a need to develop clinical pathways to achieve equity in the management of these vulnerable populations.


Assuntos
Procedimentos Clínicos , Disparidades em Assistência à Saúde , Infarto do Miocárdio sem Supradesnível do Segmento ST , Infarto do Miocárdio com Supradesnível do Segmento ST , /mortalidade , Angiografia Coronária/métodos , Angiografia Coronária/estatística & dados numéricos , Procedimentos Clínicos/organização & administração , Procedimentos Clínicos/normas , Inglaterra/epidemiologia , Feminino , Necessidades e Demandas de Serviços de Saúde , Disparidades em Assistência à Saúde/normas , Disparidades em Assistência à Saúde/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/etnologia , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Avaliação de Processos e Resultados em Cuidados de Saúde , Fatores Raciais , Infarto do Miocárdio com Supradesnível do Segmento ST/etnologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia
5.
Mayo Clin Proc ; 96(4): 952-963, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33714592

RESUMO

OBJECTIVE: To describe the place and cause of death during the coronavirus disease 2019 (COVID-19) pandemic to assess its impact on excess mortality. METHODS: This national death registry included all adult (aged ≥18 years) deaths in England and Wales between January 1, 2014, and June 30, 2020. Daily deaths during the COVID-19 pandemic were compared against the expected daily deaths, estimated with use of the Farrington surveillance algorithm for daily historical data between 2014 and 2020 by place and cause of death. RESULTS: Between March 2 and June 30, 2020, there was an excess mortality of 57,860 (a proportional increase of 35%) compared with the expected deaths, of which 50,603 (87%) were COVID-19 related. At home, only 14% (2267) of the 16,190 excess deaths were related to COVID-19, with 5963 deaths due to cancer and 2485 deaths due to cardiac disease, few of which involved COVID-19. In care homes or hospices, 61% (15,623) of the 25,611 excess deaths were related to COVID-19, 5539 of which were due to respiratory disease, and most of these (4315 deaths) involved COVID-19. In the hospital, there were 16,174 fewer deaths than expected that did not involve COVID-19, with 4088 fewer deaths due to cancer and 1398 fewer deaths due to cardiac disease than expected. CONCLUSION: The COVID-19 pandemic has resulted in a large excess of deaths in care homes that were poorly characterized and likely to be the result of undiagnosed COVID-19. There was a smaller but important and ongoing excess in deaths at home, particularly from cancer and cardiac disease, suggesting public avoidance of hospital care for non-COVID-19 conditions.


Assuntos
Causas de Morte/tendências , Cardiopatias/mortalidade , Serviços de Assistência Domiciliar/estatística & dados numéricos , Neoplasias/mortalidade , Casas de Saúde/estatística & dados numéricos , Adulto , Idoso de 80 Anos ou mais , /mortalidade , Erros de Diagnóstico/mortalidade , Erros de Diagnóstico/estatística & dados numéricos , Inglaterra/epidemiologia , Feminino , Cuidados Paliativos na Terminalidade da Vida/estatística & dados numéricos , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , País de Gales/epidemiologia
6.
Thromb Res ; 202: 17-23, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33711754

RESUMO

BACKGROUND: Evidence supports an excess of deaths during the COVID-19 pandemic. We report the incidence and mortality of thrombo-embolic events (TE) during the COVID-19 pandemic. METHODS: Multi-sourced nationwide cohort study of adults (age ≥18 years) admitted to hospital with TE and deaths from TE in England (hospital and community) between 1st February 2018 and 31st July 2020. Relative risks, adjusted for age, sex, atrial fibrillation, co-morbidities and time trend comparing before and during the COVID-19 pandemic were estimated using Poisson regression. FINDINGS: Of 272,423 patients admitted with TE to 195 hospitals, 86,577 (31.8%) were admitted after 2nd March 2020 (first COVID-19 death in the UK). The incidence of TE hospitalised increased during the COVID-19 pandemic from 1090 to 1590 per 100,000 (absolute risk change 45.9% [95% CI 45.1-46.6%], adjusted relative risk [ARR] 1.43 [95% CI 1.41-1.44]) driven particularly by pulmonary embolism; 1.49, 95% CI 1.46-1.52. TE were more frequent among those with COVID-19; 1.9% vs. 1.6%, absolute risk change 21.7%, 95% CI 21.0-22.4%, ARR 1.20, 95% CI 1.18-1.22. There was an increase in the overall mortality from TE during the pandemic (617, 6.7% proportional increase compared with the historical baseline), with more TE deaths occurring in the community compared with the historical rate (44% vs. 33%). INTERPRETATION: The COVID-19 pandemic has resulted in an increase in the incidence of hospitalised TE. There were more deaths from TE in the community highlighting a number of mechanisms including the hypercoagulable state associated with COVID-19 infection and potential impact of delays in seeking help. RESEARCH IN CONTEXT: Evidence before this study We searched PubMed on 16 November 2020 for articles that documented the incidence and mortality of thrombo-embolic events (TE) during the COVID-19 pandemic using the search terms "COVID-19" OR "Coronavirus*" OR "2019-nCOV" OR "SARS-CoV" AND ("Thromboembolism" OR "Venous Thromboembolism" OR "thromboembol*") with no language or time restrictions. The majority of data on TE in COVID-19 pertains to hospitalised patients from retrospective cohort studies. One study found that TE in hospitalised patients was associated with an increased mortality rate (adjusted hazard ratio 1.82; 95% CI 1.54-2.15). A systematic review and meta-analysis of 35 studies in 9249 hospitalised patients calculated an overall pooled incidence of TE of 17.8% (95% CI: 9.9-27.4%), rising to 22.9% (95% CI: 14.5-32.4%) in patients admitted to intensive care (ICU). The most contemporary data are from a cohort of 1114 patients (715 outpatient, 399 hospitalised, 170 admitted to ICU). With robust COVID-19-specific therapies and widespread thromboprophylaxis the prevalence of venous TE in ICU patients was reported as 7% (n = 12) when catheter-/device-related events were excluded, and among the outpatients there was no TE reported. No published studies have used nationwide data to investigate TE during the pandemic or the effect of the pandemic on outcomes of patients with TE but without Covid-19. Added value of this study This retrospective multi-sourced nationwide unlinked cohort study compares the overall incidence and mortality of TE prior to and during the COVID-19 pandemic. We found an increased incidence of TE despite only a small proportion having a diagnosis of COVID-19. This may highlight the lack of testing, particularly in the community during the initial phase of the pandemic, and the possibility of other factors contributing to TE risk, such as decreased daily activity mandated by home quarantine and alterations in medication concordance. Mortality from TE was higher in the community during the pandemic and this highlights that adverse societal effects of the pandemic, such as aversion to seeking medical assessment, may precipitate worse outcomes related to TE. Implications of all the available evidence Evidence suggests that COVID-19 produces a hypercoagulable state and thromboprophylaxis is recommended in hospitalised patients to prevent excess mortality from TE. Whether to anticoagulate non-hospitalised ambulatory patients with COVID-19 will be answered by ongoing trials. Clinicians should consider the risks posed by decreased daily activity and fear of medical contact, and provide appropriate advice to patients.

7.
Autophagy ; : 1-19, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33764843

RESUMO

Chemotherapy is currently the main treatment for unresectable or advanced postoperative gastric cancers. However, its efficacy is negatively affected by the occurrence of chemoresistance, which severely affects patient prognosis. Recently, dysregulation in autophagy has been suggested as a potential mechanism for chemoresistence, and long noncoding RNA (lncRNA) also shows its regulatory role in cancer drug resistance. Using RNA sequencing, we found that lncRNA EIF3J-DT was highly expressed in drug-resistant gastric cancer cells. In-vitro and in-vivo experiments showed that EIF3J-DT activated autophagy and induced drug resistance in gastric cancer cells by targeting ATG14. Bioinformatics and experimental results showed that EIF3J-DT regulated the expression of ATG14 through direct binding to enhance stabilization of ATG14 mRNA and via blocking the degradation of ATG14 mRNA through competitively binding with microRNA (miRNA) MIR188-3p. Therefore, EIF3J-DT increased the expression of ATG14, contributing to activation of autophagy and chemoresistance. Furthermore, it was confirmed that EIF3J-DT and ATG14 were highly expressed in gastric cancer patients resistant to chemotherapy, and this was closely associated with patient prognosis. In conclusion, EIF3J-DT is involved in the regulation of autophagy and chemoresistance in gastric cancer cells by targeting ATG14. It may be a suitable new target for enhancing chemosensitivity and improving prognosis.Abbreviations: 3-MA: 3-methyladenine; 5-Fu: 5-fluorouracil; ATG: autophagy related; C-CASP3: cleaved caspase 3; C-CASP7: cleaved caspase 7; C-PARP: cleaved PARP; CQ: chloroquine; CR: complete response; DIG: digoxigenin; ESR1: estrogen receptor 1; FBS: fetal bovine serum; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; ISH: in situ hybridization; lncRNA: long noncoding RNA; miRNA: microRNA; MUT: mutant; NC: negative control; OXA: oxaliplatin; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TEM: transmission electron microscopy; WT: wild type.

8.
Sci Rep ; 11(1): 6993, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772068

RESUMO

The low proportion of gastric cancer (GC) patients with high HER2 expression limits the clinical application of trastuzumab, a humanized epidermal growth factor receptor 2 (HER2) antibody targeting for GC treatment. We found that Dicer was positively correlated with HER2 expression in GC tissue by immunostaining as well as induce HER2 overexpression without increasing invasiveness of GC cell. In addition, both the growth of GC referring to cell proliferation, invasion, migration and apoptosis was inhibited by Dicer overexpression. Moreover, the HER2 overexpression induced by Dicer provided more effective and additive target for trastuzumab to amplify the inhibition effect for GC cells in vitro and in vivo. Furthermore, as assessed in a subsequent experiment, calcitriol induced HER2 overexpression and amplified the inhibition effect of trastuzumab in GC cells referring to proliferation. Our finding demonstrated the calcitriol might increase indication of trastuzumab by inducing HER2 overexpression in GC patients. Dicer would be a potential target that extend the clinical indications of HER2 antibody in patients with low or negative HER2, who were not fit for HER2 antibody treatment before.

9.
Clin Breast Cancer ; 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33637448

RESUMO

BACKGROUND: Accumulating studies have demonstrated that microRNAs (miRNAs) are involved in the progression of various cancers. This study aimed to investigate the potential clinical and functional role of miR-432 in breast cancer. MATERIALS AND METHODS: We evaluated the expression of miR-432 in 117 breast cancer samples and paired nontumor tissue samples, as well as 4 breast cancer cell lines using RT-qPCR analysis. Kaplan-Meier survival curve and multivariate Cox regression analysis were used to evaluate the prognostic significance of miR-432 in breast cancer patients. CCK-8 assay and Transwell assays were used to evaluate the biological function of miR-432 in the progression of breast cancer. RESULTS: miR-432 was downregulated in breast cancer tissues and cell lines, and its exotic expression was associated with tumor size, lymph node metastasis, and TNM stage. In addition, breast cancer patients with low miR-432 expression exhibited a shorter overall survival outcome. Further experiments revealed that overexpression of miR-432 inhibited the cell proliferation, migration, and invasion of breast cancer cells, while knockdown of miR-432 promoted these cellular activities. AXL was a direct target of miR-432 in breast cancer cells. CONCLUSION: The present study suggested that miR-432 may be a tumor suppressor in the progression of breast cancer through inhibiting cell proliferation, migration, and invasion by targeting AXL. And miR-432 might be a prognostic biomarker and therapeutic target for the treatment of breast cancer. This study provided a novel insight into breast cancer prognosis and treatment.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33620199

RESUMO

Single-crystal LiNi1-x-yCoxMnyO2 cathode materials can effectively suppress intergranular cracks that usually is seen in commercial polycrystal LiNi1-x-yCoxMnyO2 cathode materials. However, the surface structure degradation for single-crystal LiNi1-x-yCoxMnyO2 cathode materials is still aggravated at a higher cutoff voltage (over 4.5 V). In this work, we prepare single-crystal LiNi0.6Co0.2Mn0.2O2 cathode materials via a solid-state method and then coat an ultrathin Li-Si-O layer on their surface by a wet coating method. The results show that the single-crystal LiNi0.6Co0.2Mn0.2O2 cathode materials with a Li-Si-O coating layer deliver excellent cycling performance even at a higher cutoff voltage of 4.5 V. The optimized Li-Si-O-modified sample displays a capacity retention of 90.6% after 100 cycles, whereas only 68.0% for unmodified single-crystal LiNi0.6Co0.2Mn0.2O2. Further analysis of the cycled electrodes reveals that the surface structure degradation is the main reason for the decrease of electrochemical performance of single-crystal LiNi0.6Co0.2Mn0.2O2 at a high voltage (4.5 V). In contrast, with Li-Si-O coating, this phenomenon can be suppressed effectively to maintain interfacial stability and prolong the cycling life.

11.
J Intern Med ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33462815

RESUMO

BACKGROUND: Patients with underlying cardiovascular disease and coronavirus disease 2019 (COVID-19) infection are at increased risk of morbidity and mortality. OBJECTIVES: This study was designed to characterize the presenting profile and outcomes of patients hospitalized with acute coronary syndrome (ACS) and COVID-19 infection. METHODS: This observational cohort study was conducted using multisource data from all acute NHS hospitals in England. All consecutive patients hospitalized with diagnosis of ACS with or without COVID-19 infection between 1 March and 31 May 2020 were included. The primary outcome was in-hospital and 30-day mortality. RESULTS: A total of 12 958 patients were hospitalized with ACS during the study period, of which 517 (4.0%) were COVID-19-positive and were more likely to present with non-ST-elevation acute myocardial infarction. The COVID-19 ACS group were generally older, Black Asian and Minority ethnicity, more comorbid and had unfavourable presenting clinical characteristics such as elevated cardiac troponin, pulmonary oedema, cardiogenic shock and poor left ventricular systolic function compared with the non-COVID-19 ACS group. They were less likely to receive an invasive coronary angiography (67.7% vs 81.0%), percutaneous coronary intervention (PCI) (30.2% vs 53.9%) and dual antiplatelet medication (76.3% vs 88.0%). After adjusting for all the baseline differences, patients with COVID-19 ACS had higher in-hospital (adjusted odds ratio (aOR): 3.27; 95% confidence interval (CI): 2.41-4.42) and 30-day mortality (aOR: 6.53; 95% CI: 5.1-8.36) compared to patients with the non-COVID-19 ACS. CONCLUSION: COVID-19 infection was present in 4% of patients hospitalized with an ACS in England and is associated with lower rates of guideline-recommended treatment and significant mortality hazard.

12.
Oncol Rep ; 45(2): 791-792, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33416176

RESUMO

Subsequently to the publication of this paper, an interested reader drew to the authors' attention that two pairs of data panels containing strikingly similar data were featured in Fig. 4A and B. The authors have re­examined their data and realized that Fig. 4 was assembled incorrectly. The revised version of Fig. 4, containing the correct data for Fig. 4A and B, is shown on the next page. The authors regret the errors that were made in the preparation of the published figure, and confirm that these errors did not seriously affect the conclusions reported in the paper. The authors are grateful to the editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologise to the readership for any inconvenience caused. [the original article was published in Oncology Reports 39: 1356-1368, 2018; DOI: 10.3892/or.2017.6169].

13.
Heart ; 107(5): 389-395, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33452123

RESUMO

AIMS: ACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition in this population. METHODS: In 1993, the Acute Infarction Ramipril Efficacy (AIRE) study randomly allocated patients with AMI and clinical heart failure to ramipril or placebo. The duration of masked trial therapy in the UK cohort (603 patients, mean age=64.7 years, 455 male patients) was 12.4 and 13.4 months for ramipril (n=302) and placebo (n=301), respectively. We estimated life expectancy and extensions of life (difference in median survival times) according to duration of follow-up (range 0-29.6 years). RESULTS: By 9 April 2019, death from all causes occurred in 266 (88.4%) patients in placebo arm and 275 (91.1%) patients in ramipril arm. The extension of life between ramipril and placebo groups was 14.5 months (95% CI 13.2 to 15.8). Ramipril increased life expectancy more for patients with than without diabetes (life expectancy difference 32.1 vs 5.0 months), previous AMI (20.1 vs 4.9 months), previous heart failure (19.5 vs 4.9 months), hypertension (16.6 vs 8.3 months), angina (16.2 vs 5.0 months) and age >65 years (11.3 vs 5.7 months). Given potential treatment switching, the true absolute treatment effect could be underestimated by 28%. CONCLUSION: For patients with clinically defined heart failure following AMI, ramipril results in a sustained survival benefit, and is associated with an extension of life of up to 14.5 months for, on average, 13 months treatment duration.

15.
Radiat Oncol ; 16(1): 5, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407637

RESUMO

BACKGROUND: To investigate the potential benefit of cytoreductive radiotherapy (cRT) in metastatic castration-resistant prostate cancer (mCRPC) patients receiving abiraterone. METHODS: From February 2014 to February 2019, 149 mCRPC patients treated with abiraterone were identified. Patients receiving cRT before abiraterone failure (AbiRT group) were matched by one-to-two propensity score to patients without cRT before abiraterone failure (non-AbiRT group). RESULTS: The median follow-up was 23.5 months. Thirty patients (20.1%) were in the AbiRT group, whereas 119 patients (79.9%) were in the non-AbiRT group. The 2-year OS of patients managed by AbiRT and non-AbiRT were 89.5% and 73.5%, respectively (P = 0.0003). On multivariate analysis, only AbiRT (HR 0.17; 95% CI 0.05-0.58; P = 0.004) and prognostic index (HR 2.71; 95% CI 1.37-5.35; P = 0.004) were significant factors. After matching, AbiRT continued to be associated with improved OS (median OS not reached vs. 44.0 months, P = 0.009). Subgroup analysis revealed that patients aged ≤ 65 years (HR 0.09; 95% CI 0.01-0.65; P = 0.018), PSA ≤ 20 ng/mL (HR 0.29; 95% CI 0.09-0.99; P = 0.048), chemotherapy-naïve upon abiraterone treatment (HR 0.20; 95% CI 0.06-0.66; P = 0.008) and in intermediate prognosis groups by COU-AA-301 prognostic index (HR 0.13; 95% CI 0.03-0.57; P = 0.007) had improved OS with AbiRT. CONCLUSIONS: cRT before resistance to abiraterone may improve survival in selected mCRPC patients: age ≤ 65 years old, chemotherapy-naïve, with a relatively low PSA level at the diagnosis of mCRPC and intermediate prognosis.

16.
J Invasive Cardiol ; 33(3): E206-E219, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33348315

RESUMO

BACKGROUND: Public reporting of percutaneous coronary intervention (PCI) outcomes is a performance metric and a requirement in many healthcare systems. There are inconsistent data on the causes of death after PCI, and the proportion of these deaths that are attributable to cardiac causes. METHODS: All patients undergoing PCI in England between January 1, 2017 and May 10, 2020 (n = 273,141) were retrospectively analyzed according to their outcome from the date of PCI: no death, in-hospital death, postdischarge death, and total 30-day death. The present study examined short-term primary causes of death after PCI in a national cohort before and during COVID-19. RESULTS: The overall rates of in-hospital and 30-day death were 1.9% and 2.8%, respectively. The rate of 30-day death declined between 2017 (2.9%) and February 2020 (2.5%), mainly due to lower in-hospital death (2.1% vs 1.5%), before rising again from March 1, 2020 (3.2%) due to higher rates of postdischarge mortality. Only 59.6% of 30-day deaths were due to cardiac causes, with the most common causes being acute coronary syndrome, cardiogenic shock, and heart failure, and this persisted throughout the study period. In the 30-day death group, 10.4% after March 1, 2020 were due to confirmed COVID-19. CONCLUSIONS: In this nationwide study, we show that 40% of 30-day deaths are due to non-cardiac causes. Non-cardiac deaths have increased even more from the start of the COVID-19 pandemic, with 1 in 10 deaths from March 2020 being COVID-19 related. These findings raise a question of whether public reporting of PCI outcomes should be cause specific.


Assuntos
Síndrome Coronariana Aguda/cirurgia , Pandemias , Intervenção Coronária Percutânea/mortalidade , Síndrome Coronariana Aguda/epidemiologia , Idoso , Causas de Morte/tendências , Comorbidade , Inglaterra/epidemiologia , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências
17.
Gait Posture ; 84: 169-174, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341463

RESUMO

BACKGROUND: Backward walking and fast walking have distinctive gait patterns in adults; however, there is minimal literature describing these gait modifications in typically developing children. Additionally, most of previous research focused on overground backward walking, but not on a treadmill. RESEARCH QUESTION: How do typically developing children adapt their gait patterns, including spatiotemporal parameters, joint kinematics, and muscle activation, to changes in direction and speed during treadmill walking? METHODS: We recruited 19 children (10 M/9 F) aged 6-12 years. Treadmill conditions included forward and backward walking at three speeds: slow (75 % of normal speed), normal speed, and fast (125 % of normal speed). Subjects completed a 2-minute trial under each condition. Spatiotemporal, kinematic, kinetic and electromyography data were collected and analyzed. Correlations between forward and time-reversed backward walking were calculated for joint angles and vertical ground reaction force. RESULTS: During backward walking, children (a) decreased step lengths and increased step widths and foot clearance, (b) decreased peak hip and knee flexion and increased peak ankle dorsiflexion, and (c) increased muscle activity at the vastus lateralis, rectus femoris, and tibialis anterior. At faster speeds, children increased step lengths and inconsistently increased overall muscle activity. Both the hip and knee showed high correlation between forward and time-reversed backward walking, while correlation at the ankle was low. SIGNIFICANCE: Overall, children adapt their gait to changes in direction and speed of treadmill walking in similar ways to adults. However, notable differences emerged in that children limited their ankle range of motion. Our results suggest that, while many aspects of gait are mature enough by this age to adapt to backward walking on a treadmill, neuromuscular control at the ankle may still be lacking in children while walking backward on a treadmill.

18.
Gait Posture ; 84: 175-181, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341464

RESUMO

BACKGROUND: While mini-trampolines have been used among a variety of groups including children as an intervention tool, the motor behavior children adopt while hopping on this soft, elastic surface is unknown. Identifying coordinative structures and their stability for hopping on a mini-trampoline is imperative for recommending future interventions and determining appropriateness to populations with motor dysfunctions. RESEARCH QUESTION: Do children demonstrate similar biomechanical and coordination patterns as adults while hopping on a mini-trampoline? METHODS: Fifteen adults aged 18-35 years and 14 children aged 7-12 years completed bouts of continuous two-legged hopping in-place on a stiff surface for 10 s at a time and on a mini-trampoline for 30 s at a time. 3-D motion capture tracked whole-body movement. We evaluated whole-body vertical stiffness as a ratio of peak vertical force and peak vertical displacement, as well as spatiotemporal parameters of hopping. Coordinative structures were evaluated as continuous relative phase angles of the foot, shank, thigh, and pelvis segments. RESULTS AND SIGNIFICANCE: Adults did not modify whole-body vertical stiffness on a mini-trampoline, while children increased whole-body vertical stiffness to compensate for the reduced surface stiffness. Both groups conserved the coordinative structure for hopping on a mini-trampoline by modulating hopping cycle timing. Moreover, children hopped with an adult-like coordinative structure, but required greater shank-thigh and thigh-pelvis out-of-phase motion. However, the consistency of their coordination was diminished compared to adults. Children aged 7-12 years old have formed a stable coordinative structure for spring-mass center-of-mass dynamics that is preserved on this soft, elastic surface. However, children might be developing control strategies for preferred whole-body vertical stiffness, particularly when required to dampen peak vertical forces. These results highlight the importance of evaluating the emerging motor behavior to manipulated environmental constraints, particularly when considering the utility and appropriateness of mini-trampoline interventions for children with motor dysfunctions.

19.
PLoS Med ; 17(12): e1003432, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33270649

RESUMO

BACKGROUND: Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. METHODS AND FINDINGS: We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998-2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person-years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0-14.9 mg, 1.6% for 15.0-24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54-1.85) for atrial fibrillation, 1.75 (95% CI 1.56-1.97) for heart failure, 1.76 (95% CI 1.51-2.05) for acute myocardial infarction, 1.78 (95% CI 1.53-2.07) for peripheral arterial disease, 1.32 (95% CI 1.15-1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47-2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose-response estimates. CONCLUSIONS: In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.

20.
BMC Med ; 18(1): 401, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33357217

RESUMO

BACKGROUND: Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status. METHODS: Post hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding. RESULTS: A fifth (19.6%) of the study population had frailty (fit: n = 4459, pre-frailty: n = 12,326, mild-moderate frailty: n = 3722, severe frailty: n = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19-1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27-1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty. CONCLUSIONS: Edoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00781391 . First registered on 28 October 2008.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fragilidade/diagnóstico , Fragilidade/tratamento farmacológico , Piridinas/administração & dosagem , Tiazóis/administração & dosagem , Varfarina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Coagulação Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Inibidores do Fator Xa/uso terapêutico , Feminino , Seguimentos , Fragilidade/complicações , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Prognóstico , Piridinas/efeitos adversos , Tiazóis/efeitos adversos , Resultado do Tratamento
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