scholarly journals Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Lacey W. Heinsberg ◽  
Daniel E. Weeks ◽  
Sheila A. Alexander ◽  
Ryan L. Minster ◽  
Paula R. Sherwood ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Patient Outcomes ◽  
Iron Homeostasis ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Long Term Outcomes ◽  
Cpg Sites ◽  
Significance Threshold ◽  
Empirical Significance ◽  
Trajectory Group

Abstract Background Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1–3] and death) patient outcomes after aSAH. Results Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (n = 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (STEAP3) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based on p-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (OR = 11.7, p = 0.0006 and OR = 15.6, p = 0.0018, respectively) and death at 3 and 12 months (OR = 19.1, p = 0.0093 and OR = 12.8, p = 0.0041, respectively). These results were replicated in an independent sample (n = 100 participants) observing significant associations with GOS at 3 and 12 months (OR = 8.2, p = 0.001 and OR = 6.3, p = 0.0.0047, respectively) and death at 3 months (OR = 2.3, p = 0.008) and a suggestive association (i.e., p-value < 0.05 not meeting an empirical significance threshold) with death at 12 months (OR = 2.0, p = 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups. Conclusion Our results support a role for DNAm of cg25713625/STEAP3 in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/STEAP3 as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.

scholarly journals ANGPT1 methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Dongjing Liu ◽  
Annie I. Arockiaraj ◽  
John R. Shaffer ◽  
Samuel M. Poloyac ◽  
Paula R. Sherwood ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Pooled Analysis ◽  
Aneurysm Rupture ◽  
Cpg Sites ◽  
Significance Threshold ◽  
Post Hoc

Abstract Background Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. Results EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. Conclusions We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

scholarly journals Improving patients’ experience and outcome of total joint replacement: the RESTORE programme

2016 ◽  
Vol 4 (12) ◽  
pp. 1-508 ◽  
Author(s):  
Ashley W Blom ◽  
Neil Artz ◽  
Andrew D Beswick ◽  
Amanda Burston ◽  
Paul Dieppe ◽  
...  
Keyword(s):  
Systematic Review ◽  
Patient Outcomes ◽  
Joint Replacement ◽  
Applied Research ◽  
Feasibility Studies ◽  
Controlled Trials ◽  
Long Term Outcomes ◽  
Surgical Interventions ◽  
Research Studies

BackgroundTotal hip replacements (THRs) and total knee replacements (TKRs) are common elective procedures. In the REsearch STudies into the ORthopaedic Experience (RESTORE) programme, we explored the care and experiences of patients with osteoarthritis after being listed for THR and TKR up to the time when an optimal outcome should be expected.ObjectiveTo undertake a programme of research studies to work towards improving patient outcomes after THR and TKR.MethodsWe used methodologies appropriate to research questions: systematic reviews, qualitative studies, randomised controlled trials (RCTs), feasibility studies, cohort studies and a survey. Research was supported by patient and public involvement.ResultsSystematic review of longitudinal studies showed that moderate to severe long-term pain affects about 7–23% of patients after THR and 10–34% after TKR. In our cohort study, 10% of patients with hip replacement and 30% with knee replacement showed no clinically or statistically significant functional improvement. In our review of pain assessment few research studies used measures to capture the incidence, character and impact of long-term pain. Qualitative studies highlighted the importance of support by health and social professionals for patients at different stages of the joint replacement pathway. Our review of longitudinal studies suggested that patients with poorer psychological health, physical function or pain before surgery had poorer long-term outcomes and may benefit from pre-surgical interventions. However, uptake of a pre-operative pain management intervention was low. Although evidence relating to patient outcomes was limited, comorbidities are common and may lead to an increased risk of adverse events, suggesting the possible value of optimising pre-operative management. The evidence base on clinical effectiveness of pre-surgical interventions, occupational therapy and physiotherapy-based rehabilitation relied on small RCTs but suggested short-term benefit. Our feasibility studies showed that definitive trials of occupational therapy before surgery and post-discharge group-based physiotherapy exercise are feasible and acceptable to patients. Randomised trial results and systematic review suggest that patients with THR should receive local anaesthetic infiltration for the management of long-term pain, but in patients receiving TKR it may not provide additional benefit to femoral nerve block. From a NHS and Personal Social Services perspective, local anaesthetic infiltration was a cost-effective treatment in primary THR. In qualitative interviews, patients and health-care professionals recognised the importance of participating in the RCTs. To support future interventions and their evaluation, we conducted a study comparing outcome measures and analysed the RCTs as cohort studies. Analyses highlighted the importance of different methods in treating and assessing hip and knee osteoarthritis. There was an inverse association between radiographic severity of osteoarthritis and pain and function in patients waiting for TKR but no association in THR. Different pain characteristics predicted long-term pain in THR and TKR. Outcomes after joint replacement should be assessed with a patient-reported outcome and a functional test.ConclusionsThe RESTORE programme provides important information to guide the development of interventions to improve long-term outcomes for patients with osteoarthritis receiving THR and TKR. Issues relating to their evaluation and the assessment of patient outcomes are highlighted. Potential interventions at key times in the patient pathway were identified and deserve further study, ultimately in the context of a complex intervention.Study registrationCurrent Controlled Trials ISRCTN52305381.FundingThis project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 4, No. 12. See the NIHR Journals Library website for further project information.

scholarly journals P-P19 Incidentally detected Double Duct Sign (InDDuS): a study on the long-term outcomes

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
Lu Yao ◽  
Somaiah Aroori
Keyword(s):  
Patient Outcomes ◽  
Elevated Serum ◽  
Magnetic Resonance Cholangiopancreatography ◽  
Ampullary Cancer ◽  
Radiology Department ◽  
Minimal Risk ◽  
Long Term Outcomes ◽  
Tertiary Referral

Abstract Background The long-term outcomes of patients with biliary and pancreatic ductal dilatation (double duct sign-DDS), without a detectable underlying cause, is unclear in the current literature. This study aims to review the five-year outcomes of patients with incidentally detected double duct sign. Methods This is a retrospective study of patients that were found to have DDS between January 2010 to December 2015 at a tertiary referral Hepato-Pancreatico-Biliary unit. Patients were identified from the departmental performance team and cross-checked with the Radiology department. Patients who had malignancy and benign causes of DDS (such as pancreatitis and gallstones) were excluded. Five-year patient outcomes were collected from subsequent MDT outcomes and clinic letters. Results Initial screen identified 108 patients with DDS. Of these, 37 patients (81% female, median age 69 years, range 26-94 years) had no identifiable cause and were analysed. Main presenting complaints were abdominal pain (n = 22), weight loss (n = 9), and asymptomatic (n = 3). Twelve had anaemia, 14 had derange LFTs and 2 patients had elevated serum CA19-9. A median of two (range 0-9) further investigations were performed to determine the underlying cause of DDS (US = 6, CT = 24, MRCP=17, endoscopy=16). Median follow up of 7.2 (range 5-11) years detected no pancreatic or ampullary cancer amongst all patients. Conclusions Results from this study suggests DDS without evidence of malignancy on Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) have minimal risk of developing pancreatic or ampullary cancer in the next five years. Thus, they can be safely discharged from follow up.

scholarly journals Long-term consequences of acute kidney injury: a narrative review

2020 ◽  
Author(s):  
Joana Gameiro ◽  
Filipe Marques ◽  
José António Lopes
Keyword(s):  
Acute Kidney Injury ◽  
Patient Outcomes ◽  
Kidney Injury ◽  
Current Evidence ◽  
Long Term Outcomes ◽  
Increased Risk ◽  
Follow Up Care ◽  
Risk Of Progression

Abstract The incidence of acute kidney injury (AKI) has increased in the past decades. AKI complicates up to 15% of hospitalizations and can reach up to 50–60% in critically ill patients. Besides the short-term impact of AKI in patient outcomes, several studies report the association between AKI and adverse long-term outcomes, such as recurrent AKI episodes in 25–30% of cases, hospital re-admissions in up to 40% of patients, an increased risk of cardiovascular events, an increased risk of progression of chronic kidney disease (CKD) after AKI and a significantly increased long-term mortality. Despite the long-term impact of AKI, there are neither established guidelines on the follow-up care of AKI patients, nor treatment strategies to reduce the incidence of sequelae after AKI. Only a minority of patients have been referred to nephrology post-discharge care, despite the evidence of improved outcomes associated with nephrology referral by addressing cardiovascular risk and risk of progression to CKD. Indeed, AKI survivors should have specialized nephrology follow-up to assess kidney function after AKI, perform medication reconciliation, educate patients on nephrotoxic avoidance and implement strategies to prevent CKD progression. The authors provide a comprehensive review of the transition from AKI to CKD, analyse the current evidence on the long-term outcomes of AKI and describe predisposing risk factors, highlight the importance of follow-up care in these patients and describe the current therapeutic strategies which are being investigated on their impact in improving patient outcomes.

scholarly journals Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage

2020 ◽  
Vol 33 (3) ◽  
pp. 749-758
Author(s):  
Lacey W. Heinsberg ◽  
Sheila A. Alexander ◽  
Elizabeth A. Crago ◽  
Ryan L. Minster ◽  
Samuel M. Poloyac ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Genetic Variability ◽  
Patient Outcomes ◽  
Iron Homeostasis ◽  
Aneurysmal Subarachnoid Hemorrhage

The effectiveness of ventriculocystocisternostomy for suprasellar arachnoid cysts

2011 ◽  
Vol 7 (1) ◽  
pp. 64-72 ◽  
Author(s):  
Cormac O. Maher ◽  
Liliana Goumnerova
Keyword(s):  
Treatment Failure ◽  
Patient Outcomes ◽  
Arachnoid Cysts ◽  
Imaging Data ◽  
Long Term Outcomes ◽  
Clinical Imaging ◽  
The Difference ◽  
Reoperation Rates

Object The aim of this study was to report the long-term outcomes of patients receiving endoscopic ventriculocystocisternostomy (VCC) for suprasellar arachnoid cysts (SACs), and to analyze all published reports on outcomes of ventriculocystostomy (VC) versus VCC to compare the effectiveness of the 2 techniques. Methods Eleven consecutive patients with previously untreated SACs were surgically treated using endoscopic VCC. Another 2 patients were treated with VCC following ventriculoperitoneal shunt placement. Clinical imaging data were recorded. An analysis was performed of all published patient outcomes following endoscopic VC or VCC for an SAC. Results Developmental delay and progressive macrocephaly were the most common preoperative symptoms. At a mean clinical follow-up interval of 63 months, 10 of 11 patients undergoing primary VCC did not require reoperation. An analysis of the literature suggests that VCC may be more effective than VC. Of the 44 reported patients that underwent VC as a first treatment, 7 (16%) required reoperation, and 7 (8%) of 86 patients who underwent VCC as a first treatment required reoperation. When VC or VCC was performed following a prior surgical procedure, 4 of 11 patients undergoing VC had a treatment failure requiring reoperation. In contrast, only 2 of the 17 reported cases of VCC following a prior procedure required further treatment. The difference in reoperation rates following either primary or secondary VC was significantly higher than following primary or secondary VCC (p = 0.04). Conclusions The authors conclude that VCC is an effective and durable treatment for symptomatic SACs in most cases.

scholarly journals Differential DNA methylation by early versus late parenteral nutrition in the PICU: a biological basis for its impact on emotional and behavioral problems documented 4 years later

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
An Jacobs ◽  
Fabian Güiza ◽  
Ines Verlinden ◽  
Karolijn Dulfer ◽  
Gonzalo Garcia Guerra ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Parenteral Nutrition ◽  
Critically Ill ◽  
Behavioral Problems ◽  
Methylation Status ◽  
Critically Ill Children ◽  
Biological Basis ◽  
Cpg Sites ◽  
The Impact

Abstract Background The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. Early-PN was further shown to alter the methylation status of 37 CpG-sites in leukocyte DNA between admission and discharge from the pediatric intensive care unit (PICU). In a preplanned subanalysis of the PEPaNIC trial, we now investigated whether the altered methylation of these CpG-sites could statistically explain the negative impact of early-PN on emotion/behavior documented 4 years after PICU admission. Results The combination of DNA methylation data and data on behavior 4 years after PICU admission was available for 403 of the 1440 patients (aged 0–17 years at PICU admission) who were included in the PEPaNIC RCT (192 early-PN and 211 late-PN patients). Mediation analyses with use of bootstrapped multivariable non-linear regression analyses adjusted for baseline risk factors revealed that the adverse alterations by early-PN in methylation of the 37 CpG-sites together statistically explained its harmful impact on internalizing, externalizing and total emotional/behavioral problems. When adding the methylation status of the 37 CpG-sites to the models, the explanatory power improved with a 1.710 to 1.851-fold increase, and the impact of the altered methylation status of the CpG-sites explained the impact of the randomization to early-PN versus late-PN. Conclusions Abnormal DNA methylation induced by the early use of PN in the PICU provides a biological basis for its long-term harmful effect on emotion/behavior of critically ill children 4 years after PICU admission. Trial Registration ClinicalTrials.gov NCT01536275, registered February 17, 2012, https://clinicaltrials.gov/ct2/show/NCT01536275.

scholarly journals Long-term outcomes among octogenarians with aneurysmal subarachnoid hemorrhage

2019 ◽  
Vol 131 (2) ◽  
pp. 426-434 ◽  
Author(s):  
Hormuzdiyar Dasenbrock ◽  
William B. Gormley ◽  
Yoojin Lee ◽  
Vincent Mor ◽  
Susan L. Mitchell ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Treatment Modality ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Long Term Outcomes ◽  
Data Set ◽  
Term Survival ◽  
Microsurgical Clipping ◽  
Male Sex ◽  
National Analysis

OBJECTIVEData evaluating the long-term outcomes, particularly with regard to treatment modality, of aneurysmal subarachnoid hemorrhage (SAH) in octogenarians are limited. The primary objectives were to evaluate the disposition (living at home vs institutional settings) and analyze the predictors of long-term survival and return to home for octogenarians after SAH.METHODSData pertaining to patients age 80 and older who underwent microsurgical clipping or endovascular coiling for SAH were extracted from 100% nationwide Medicare inpatient claims and linked with the Minimum Data Set (2008–2011). Patient disposition was tracked for 2 years after index SAH admission. Multivariable logistic regression stratified by aneurysm treatment modality, and adjusted for patient factors including SAH severity, evaluated predictors of return to home at 60 and 365 days after SAH. Survival 365 days after SAH was analyzed with a multivariable Cox proportional hazards model.RESULTSA total of 1298 cases were included in the analysis. One year following SAH, 56% of the patients had died or were in hospice care, 8% were in an institutional post–acute care setting, and 36% had returned home. Open microsurgical clipping (adjusted hazard ratio [aHR] 0.67, 95% confidence interval [CI] 0.54–0.81), male sex (aHR 0.70, 95% CI 0.57–0.87), tracheostomy (aHR 0.63, 95% CI 0.47–0.85), gastrostomy (aHR 0.60, 95% CI 0.48–0.76), and worse SAH severity (aHR 0.94, 95% CI 0.92–0.97) were associated with reduced likelihood of patients ever returning home. Older age (aHR 1.09, 95% CI 1.05–1.13), tracheostomy (aHR 2.06, 95% CI 1.46–2.91), gastrostomy (aHR 1.55, 95% CI 1.14–2.10), male sex (aHR 1.66, 95% CI 1.20–2.23), and worse SAH severity 1.51 (95% CI 1.04–2.18) were associated with reduced survival.CONCLUSIONSIn this national analysis, 56% of octogenarians with SAH died, and 36% returned home within 1 year of SAH. Coil embolization predicted returning to home, which may suggest a benefit to endovascular treatment in this patient population.

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