Increased Risk of Transient Cerebral Ischemia After Subarachnoid Hemorrhage in Patients with Premorbid Opioid Use Disorders: A Nationwide Analysis of Outcomes

Abstract Introduction In the current epidemic of opioid-related deaths, and widespread use of opioids to treat chronic pain, there is a pressing need to understand the underlying risk factors that contribute to such devastating conditions. Shiftwork has been associated with adverse health outcomes. We tested whether shiftwork during middle age is linked to the development of chronic pain and opioid misuse. Methods We studied 116,474 participants in active employment between 2006–2010 (mean age 57±8; range 37–71) from the UK Biobank, who have been followed for up to 10 years until 2017. We included participants who were free from all forms of self-reported pain, and were not taking opioid medications at baseline. Chronic pain and opioid use disorder diagnoses were determined using hospitalization records and diagnostic coding from ICD-10. Multivariate logistic regression models were performed to examine the associations of shiftwork status (yes/no) and nightshift frequency (none/occasional/permanent) and with incident chronic pain and/or opioid use disorder during follow-up. Models were adjusted for demographics, education, Townsend deprivation index, major confounders (BMI, diabetes, bone fractures/injuries, operations, peripheral vascular disease, joint/inflammatory diseases, cancer, standing/manual labor at work) and covariates (smoking, alcohol, high cholesterol, depression/anxiety, and cardiovascular diseases). Results In total, 190 (1.6/1,000) developed chronic pain or opioid use disorders. Shiftworkers (n=17,673) saw a 1.5-fold increased risk (OR 1.56, 95% CI: 1.08–2.24, p=0.01) relative to day workers. Within shiftworkers, those who reported occasional nightshift work (n=3,966) were most vulnerable (OR 1.57, 95% CI: 1.06–2.34, p=0.02). Results remained similar after adjusting for baseline sleep duration, chronotype and insomnia. Conclusion Shiftwork, and in particular rotating nightshift work is associated with increased risk for developing chronic pain and opioid use disorders. Replication is required to confirm the findings and to examine underlying mechanisms. Support This work was supported by NIH grants T32GM007592, RF1AG064312, and RF1AG059867.

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Predictors for readmission within one year after discharge from an alcohol rehabilitation program

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.121 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S115-S115 ◽

Cited By ~ 1

Author(s):

M. Müller ◽

G. Weniger ◽

S. Prinz ◽

S. Vetter ◽

S. Egger

Keyword(s):

Alcohol Use ◽

Rehabilitation Program ◽

Primary Diagnosis ◽

Index Hospitalization ◽

Opioid Use ◽

Increased Risk ◽

Alcohol Rehabilitation ◽

Opioid Use Disorders ◽

One Year ◽

Time Of Admission

IntroductionAlcohol use disorders have been associated with an increased risk of frequent readmissions. This study aimed to examine factors that contribute to the risk for readmission within one year after discharge from an alcohol rehabilitation program.MethodsRehospitalization status was assessed for all patients with an alcohol use disorder as primary diagnosis (n = 468) admitted to our inpatient unit between July 1, 2012, and June 30, 2014. All patients were followed up for one year after their first hospitalization (index hospitalization) within this period. Time to readmission within one year after discharge was measured using the Kaplan–Meier method. Risk factors for readmission were examined using Cox proportional hazard regression models. Three set of variables were selected to be included in the analyses:– demographic features at time of admission of index hospitalization;– comorbid conditions at time of admission of index hospitalization;– treatment-related variables in relation to the index hospitalization including observer-rated outcome measures.ResultsReadmissions within one year after discharge from an alcohol rehabilitation program as well as the corresponding time to readmission were linked to higher numbers of previous hospitalizations and the presence of comorbid opioid use disorders.ConclusionHigher numbers of past treatments for AUD are indicators for a chronic course of the disorder, which, in turn, increase the risk of further relapses. Our findings further confirmed previous findings suggesting high rates of comorbidity among alcohol and opioid use disorders, and their link with poorer clinical outcomes.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Commentary on Post, et al. Ultra-early tranexamic acid after subarachnoid hemorrhage: A randomized controlled trial. Lancet 2021

Surgical Neurology International ◽

10.25259/sni_242_2021 ◽

2021 ◽

Vol 12 ◽

pp. 156

Author(s):

Benjamin W. Y. Lo ◽

Hitoshi Fukuda ◽

Anderson C. O. Tsang ◽

David J. Langer ◽

Satoru Miyawaki ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Tranexamic Acid ◽

Controlled Trial ◽

Delayed Cerebral Ischemia ◽

Control Group ◽

Early Administration ◽

Randomized Controlled ◽

Increased Risk

Background: Tranexamic acid (TA) administration in aneurysmal subarachnoid hemorrhage (SAH) within the first 24 hours may reduce the incidence of early aneurysmal rebleeding. However, this is also the potential for an increased risk of delayed cerebral ischemia if TA is administered for more than 72 hours following the initial aneurysmal rupture. Methods: In the ultra-early tranexamic acid after subarachnoid hemorrhage randomized controlled trial by Post et al., patients were randomized to receive TA within the first 24 hours, or until start of aneurysm treatment. These results were compared to a matched control group. Results: Ultra-early administration (≤24 h) of TA reduced the incidence of rebleeding, and did not alter the incidence of delayed cerebral ischemia and/or extracranial thrombosis. Further, no significant differences were noted between the TA group and control arm in the incidence of good (modified Rankin scores 0-3) clinical outcomes at 6 months. Conclusion: Ultra-early administration of TA (≤24 h) resulted in a lower rate of recurrent hemorrhage, without increasing the incidence of delayed cerebral ischemia in SAH patients.

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Increased risk of delayed cerebral ischemia in subarachnoid hemorrhage patients with additional intracerebral hematoma

Journal of Neurosurgery ◽

10.3171/2015.12.jns151563 ◽

2017 ◽

Vol 126 (2) ◽

pp. 504-510 ◽

Cited By ~ 17

Author(s):

Johannes Platz ◽

Erdem Güresir ◽

Marlies Wagner ◽

Volker Seifert ◽

Juergen Konczalla

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Intracerebral Hematoma ◽

World Federation ◽

Single Center ◽

New Classification ◽

Increased Risk ◽

The Impact

OBJECTIVE Delayed cerebral ischemia (DCI) has a major impact on the outcome of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to assess the influence of an additional intracerebral hematoma (ICH) on the occurrence of DCI. METHODS The authors conducted a single-center retrospective analysis of cases of SAH involving patients treated between 2006 and 2011. Patients who died or were transferred to another institution within 10 days after SAH without the occurrence of DCI were excluded from the analysis. RESULTS Additional ICH was present in 123 (24.4%) of 504 included patients (66.7% female). ICH was classified as frontal in 72 patients, temporal in 24, and perisylvian in 27. DCI occurred in 183 patients (36.3%). A total of 59 (32.2%) of these 183 patients presented with additional ICH, compared with 64 (19.9%) of the 321 without DCI (p = 0.002). In addition, DCI was detected significantly more frequently in patients with higher World Federation of Neurosurgical Societies (WFNS) grades. The authors compared the original and modified Fisher Scales with respect to the occurrence of DCI. The modified Fisher Scale (mFS) was superior to the original Fisher Scale (oFS) in predicting DCI. Furthermore, they suggest a new classification based on the mFS, which demonstrates the impact of additional ICH on the occurrence of DCI. After the different scales were corrected for age, sex, WFNS score, and aneurysm site, the oFS no longer was predictive for the occurrence of DCI, while the new scale demonstrated a superior capacity for prediction as compared with the mFS. CONCLUSIONS Additional ICH was associated with an increased risk of DCI in this study. Furthermore, adding the presence or absence of ICH to the mFS improved the identification of patients at the highest risk for the development of DCI. Thus, a simple adjustment of the mFS might help to identify patients at high risk for DCI.

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Abstract W MP39: SSRI/SNRI Use Is Not Associated With Increased Risk Of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Stroke ◽

10.1161/str.46.suppl_1.wmp39 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Jimmy Young ◽

Tarun Singh ◽

Jennifer Fugate ◽

Alejandro Rabinstein

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Reuptake Inhibitor ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Multivariate Logistic Regression Analysis ◽

Fisher Score ◽

Symptomatic Vasospasm ◽

Increased Risk ◽

Norepinephrine Reuptake Inhibitor

Objective: To determine the effect of Selective Serotonin Reuptake Inhibitor (SSRI)/Selective Norepinephrine Reuptake Inhibitor (SNRI) use prior to or during admission for aneurysmal subarachnoid hemorrhage (aSAH) on the risk of symptomatic vasospasm and diffuse cerebral ischemia (DCI). Methods: Review of electronic records at Mayo Clinic, Rochester from Jan. 2001 to Dec. 2013 of consecutive patients with aSAH. The variables collected and analyzed were: age, sex, active smoking, transfusion, modified Fisher score, WFNS grade, and outcome at discharge. Multivariate logistic regression analysis was used to evaluate factors associated with DCI, symptomatic vasospasm, and poor outcome (modified Rankin score 3-6) within 1 year. Results: 583 [females 367 (63%)] patients with a median age of 55 (47-65) years were admitted with aSAH during the study period. WFNS at nadir was IV-V in 243 (41.6%) and modified Fisher score was 3-4 in 438 (75.2%). Eighty one (14.6%) patients were taking SSRI or SNRI prior to admission and these medications were continued in all of them. Symptomatic vasospasm was present in 154 (27.7%), radiological infarction in 172(29.5%), and DCI in 250(42.9%) patients. SSRI/SNRI use was not associated with the occurrence of DCI (p=0.458), symptomatic vasospasm (p=0.097), radiological infarction (p=0.972), or poor functional outcome (p=0.376). Conclusions: The use of SSRI/SNRI prior to admission and/or during hospitalization in patients with aSAH was not associated with symptomatic vasospasm or DCI.

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Source and cause of endothelin-1 release into cerebrospinal fluid after subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1997.87.2.0287 ◽

1997 ◽

Vol 87 (2) ◽

pp. 287-293 ◽

Cited By ~ 110

Author(s):

Ryszard M. Pluta ◽

Robert J. Boock ◽

John K. Afshar ◽

Kathleen Clouse ◽

Mima Bacic ◽

...

Keyword(s):

Endothelial Cells ◽

Cerebrospinal Fluid ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Vasospasm ◽

Plasma Levels ◽

Transient Cerebral Ischemia ◽

Content Type ◽

Endothelin 1 ◽

Fine Print

✓ Despite years of research, delayed cerebral vasospasm remains a serious complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors examined this hypothesis in a series of experiments. In a primate model of SAH, serial ET-1 levels were measured in samples from the perivascular space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vasospasm. To determine whether elevated ET-1 production was a direct cause of vasospasm or acted secondary to ischemia, the authors also measured ET-1 levels in plasma and CSF after transient cerebral ischemia. To elucidate the source of ET-1, they measured its production in cultures of endothelial cells and astrocytes exposed to oxyhemoglobin (10 µM), methemoglobin (10 µM), or hypoxia (11% oxygen). There was no correlation between the perivascular levels of ET-1 and the development of vasospasm or its resolution. Cerebrospinal fluid and plasma levels of ET-1 were not affected by vasospasm (CSF ET-1 levels were 9.3 ± 2.2 pg/ml and ET-1 plasma levels were 1.2 ± 0.6 pg/ml) before SAH and remained unchanged when vasospasm developed (7.1 ± 1.7 pg/ml in CSF and 2.7 ± 1.5 pg/ml in plasma). Transient cerebral ischemia evoked an increase of ET-1 levels in CSF (1 ± 0.4 pg/ml at the occlusion vs. 3.1 ± 0.6 pg/ml 4 hours after reperfusion; p < 0.05), which returned to normal (0.7 ± 0.3 pg/ml) after 24 hours. Endothelial cells and astrocytes in culture showed inhibition of ET-1 production 6 hours after exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothelial cells at 24 hours (6.4 ± 0.8 pg/ml vs. 0.1 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05) and at 48 hours (6.4 ± 0.6 pg/ml vs. 0 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05), but in astrocytes hypoxia induced an increase of ET-1 at 6 hours (1.5 ± 0.6 vs. 6.4 ± 1.1 pg/ml, control vs. hypoxic astrocytes; p < 0.05). Endothelin-1 is released from astrocytes, but not endothelial cells, during hypoxia and is released from the brain after transient ischemia. There is no relationship between ET-1 and vasospasm in vivo or between ET-1 and oxyhemoglobin, a putative agent of vasospasm, in vitro. The increase in ET-1 levels in CSF after SAH from a ruptured intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.

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Ultra-early angiographic vasospasm associated with delayed cerebral ischemia and infarction following aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2016.2.jns151939 ◽

2017 ◽

Vol 126 (5) ◽

pp. 1545-1551 ◽

Cited By ~ 8

Author(s):

Fawaz Al-Mufti ◽

David Roh ◽

Shouri Lahiri ◽

Emma Meyers ◽

Jens Witsch ◽

...

Keyword(s):

Logistic Regression ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Infarction ◽

Functional Outcome ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Angiographic Vasospasm ◽

Increased Risk ◽

Address Data

OBJECTIVEThe clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome.METHODSThe authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up.RESULTSThe cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4–3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0–3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4–1.6, p = 0.5).CONCLUSIONSUEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV.

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Source and cause of endothelin-1 release to cerebrospinal fluid after subarachnoid hemorrhage

Neurosurgical FOCUS ◽

10.3171/foc.1997.3.4.10 ◽

1997 ◽

Vol 3 (4) ◽

pp. E9

Author(s):

Ryszard M. Pluta ◽

Robert J. Boock ◽

John K. Afshar ◽

Kathleen Clouse ◽

Mima Bacic ◽

...

Keyword(s):

Endothelial Cells ◽

Cerebrospinal Fluid ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Vasospasm ◽

Plasma Levels ◽

Transient Cerebral Ischemia ◽

Endothelin 1 ◽

Delayed Cerebral Vasospasm ◽

Ruptured Intracranial Aneurysm

Despite years of research, delayed cerebral vasospasm remains a serious complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors examined this hypothesis in a series of experiments. In a primate model of SAH, serial ET-1 levels were measured in samples from the perivascular space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vasospasm. To determine whether elevated ET-1 production was a direct cause of vasospasm or acted secondary to ischemia, the authors also measured ET-1 levels in plasma and CSF after transient cerebral ischemia. To elucidate the source of ET-1, they measured its production in cultures of endothelial cells and astrocytes exposed to oxyhemoglobin (10 μM), methemoglobin (10 μM), or hypoxia (11% oxygen). There was no correlation between the perivascular levels of ET-1 and the development of vasospasm or its resolution. Cerebrospinal fluid and plasma levels of ET-1 were not affected by vasospasm (CSF ET-1 levels were 9.3 ± 2.2 pg/ml and ET-1 plasma levels were 1.2 ± 0.6 pg/ml) before SAH and remained unchanged when vasospasm developed (7.1 ± 1.7 pg/ml in CSF and 2.7 ± 1.5 pg/ml in plasma). Transient cerebral ischemia evoked an increase of ET-1 levels in CSF (1 ± 0.4 pg/ml at the occlusion vs. 3.1 ± 0.6 pg/ml 4 hours after reperfusion; p < 0.05), which returned to normal (0.7 ± 0.3 pg/ml) after 24 hours. Endothelial cells and astrocytes in culture showed inhibition of ET-1 production 6 hours after exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothelial cells at 24 hours (6.4 ± 0.8 pg/ml vs. 0.1 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05) and at 48 hours (6.4 ± 0.6 pg/ml vs. 0 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05), but in astrocytes hypoxia induced an increase of ET-1 at 6 hours (1.5 ± 0.6 vs. 6.4 ± 1.1 pg/ml, control vs. hypoxic astrocytes; p < 0.05). Endothelin-1 is released from astrocytes, but not endothelial cells, during hypoxia and is released from the brain after transient ischemia. There is no relationship between ET-1 and vasospasm in vivo or between ET-1 and oxyhemoglobin, a putative agent of vasospasm, in vitro. The increase in ET-1 levels in CSF after SAH from a ruptured intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.

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Microthrombosis after Aneurysmal Subarachnoid Hemorrhage: An Additional Explanation for Delayed Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.74 ◽

2008 ◽

Vol 28 (11) ◽

pp. 1761-1770 ◽

Cited By ~ 176

Author(s):

Mervyn DI Vergouwen ◽

Marinus Vermeulen ◽

Bert A Coert ◽

Erik SG Stroes ◽

Yvo BWEM Roos

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Time Window ◽

Clinical Symptoms ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Coagulation Cascade ◽

Future Research ◽

Increased Risk ◽

Depth Analysis

Patients with aneurysmal subarachnoid hemorrhage (SAH) who experience delayed cerebral ischemia (DCI) have an increased risk of poor outcome. Delayed cerebral ischemia is considered to be caused by vasospasm. However, not all patients with DCI have vasospasm. Inversely, not all patients with vasospasm develop clinical symptoms and signs of DCI. In the past, treatments aiming at vasospasm were not successful in preventing ischemia. The purpose of this review is to give an overview of clinical data showing that DCI cannot always be attributed to vasospasm, and to present an in-depth analysis of clinical and autopsy studies on the role of microthrombosis in the pathogenesis of DCI. Clinical studies show that DCI is associated with an activation of the coagulation cascade within a few days after SAH, preceding the time window during which vasospasm occurs. Furthermore, impaired fibrinolytic activity, and inflammatory and endothelium-related processes, lead to the formation of microthrombi, which ultimately result in DCI. The presence of microthrombi is confirmed by autopsy studies. Insight in the pathophysiology of DCI is crucial for the development of effective therapies against this complication. Because multiple pathways are involved, future research should focus on drugs with pleiotropic effects.

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Dual antiplatelet therapy in aneurysmal subarachnoid hemorrhage: association with reduced risk of clinical vasospasm and delayed cerebral ischemia

Journal of Neurosurgery ◽

10.3171/2017.5.jns17831 ◽

2018 ◽

Vol 129 (3) ◽

pp. 702-710 ◽

Cited By ~ 22

Author(s):

Yasunori Nagahama ◽

Lauren Allan ◽

Daichi Nakagawa ◽

Mario Zanaty ◽

Robert M. Starke ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Antiplatelet Therapy ◽

Dual Antiplatelet Therapy ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Control Group ◽

Increased Risk ◽

Hemorrhagic Complications ◽

Flow Diverters

OBJECTIVEClinical vasospasm and delayed cerebral ischemia (DCI) are devastating complications of aneurysmal subarachnoid hemorrhage (aSAH). Several theories involving platelet activation have been postulated as potential explanations of the development of clinical vasospasm and DCI. However, the effects of dual antiplatelet therapy (DAPT; aspirin and clopidogrel) on clinical vasospasm and DCI have not been previously investigated. The objective of this study was to evaluate the effects of DAPT on clinical vasospasm and DCI in aSAH patients.METHODSAnalysis of patients treated for aSAH during the period from July 2009 to April 2014 was performed in a single-institution retrospective study. Patients were divided into 2 groups: patients who underwent stent-assisted coiling or placement of flow diverters requiring DAPT (DAPT group) and patients who underwent coiling only without DAPT (control group). The frequency of symptomatic clinical vasospasm and DCI and of hemorrhagic complications was compared between the 2 groups, utilizing univariate and multivariate logistic regression.RESULTSOf 312 aSAH patients considered for this study, 161 met the criteria for inclusion and were included in the analysis (85 patients in the DAPT group and 76 patients in the control group). The risks of clinical vasospasm (OR 0.244, CI 95% 0.097–0.615, p = 0.003) and DCI (OR 0.056, CI 95% 0.01–0.318, p = 0.001) were significantly lower in patients receiving DAPT. The rates of hemorrhagic complications associated with placement of external ventricular drains and ventriculoperitoneal shunts were similar in both groups (4% vs 2%, p = 0.9).CONCLUSIONSThe use of DAPT was associated with a lower risk of clinical vasospasm and DCI in patients treated for aSAH, without an increased risk of hemorrhagic complications.

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