ResearchPad - prognosis https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Prognostic value of ATN Alzheimer biomarkers: 60‐month follow‐up results from the Argentine Alzheimer's Disease Neuroimaging Initiative]]> https://www.researchpad.co/article/elastic_article_15241 To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine‐Alzheimer's Disease Neuroimaging Initiative (arg‐ADNI) cohort.MethodsTwenty‐three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aβ; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aβ42), tau (T: CSF phosphorylated‐tau), and neurodegeneration (N: CSF total‐tau, fluorodeoxyglucose [FDG]‐PET scan, or structural magnetic resonance imaging [MRI] scan).ResultsA+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non‐AD pathophysiology (SNAP, A‐T‐N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5‐year follow‐up were 85% in A+T+N+ MCI patients and 50% in A‐T‐N+ patients.ConclusionsWe present initial 5‐year follow‐up results of a regional ADNI based on AD biomarkers and the ATN classification. ]]> <![CDATA[Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome]]> https://www.researchpad.co/article/elastic_article_15108 We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS).MethodsIn a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non‐demented and without MCI or AD at baseline and throughout follow‐up; n = 103 had incident MCI and n = 81 had incident AD. Proteomics were conducted on banked plasma samples from a previously generated algorithm.ResultsThe proteomic profile was highly accurate in predicting incident MCI (area under the curve [AUC] = 0.92) and incident AD (AUC = 0.88). For MCI risk, the support vector machine (SVM)‐based high/low cut‐point yielded an adjusted hazard ratio (HR) = 6.46 (P < .001). For AD risk, the SVM‐based high/low cut‐point score yielded an adjusted HR = 8.4 (P < .001).DiscussionThe current results provide support for our blood‐based proteomic profile for predicting risk for MCI and AD among adults with DS. ]]> <![CDATA[The precise long-term outcomes of adult IgA nephropathy by mail questionnaires: Better renal survival compared to earlier cohort studies]]> https://www.researchpad.co/article/elastic_article_14721 The estimated 20-year renal survival rate of immunoglobulin A (IgA) nephropathy is approx. 60%, but it is difficult to determine the 'big picture' for IgA nephropathy because a biopsy is essential for its diagnosis. Here we attempted to determine the longer and more precise renal prognosis of IgA nephropathy. We examined 310 patients with primary IgA nephropathy. Using the patients' clinical records and histological reports from our hospital and other clinics, we surveyed their renal prognoses and treatments within 1 year post-biopsy, and we sent questionnaires to the patients who had stopped visiting any hospital. We set renal death as the primary endpoint and analyzed factors related to renal death. The total patient cohort was 267: 159 males, 108 females; average age at biopsy, 37.7 years; average estimated glomerular filtration rate (eGFR), 69.7 mL/min/1.73m2; urinary protein, 1.3 g/day. The mean follow-up duration was prolonged to 13.8±8.9 years (vs. 9.2±8.5 years using only medical records). The 10- and 20-year follow-up rates were 61.7% and 27.3%. The 10-, 20-year renal survival rates were 83.6% and 72.5%. Lower eGFR, hypertension, and smoking were revealed as factors independently related to renal death. To study survival of relatively benign diseases such as IgA nephropathy, longer survival rate was affected by many censoring cases. The results regarding the long-term renal prognoses of IgA nephropathy patients (including those with a mild phenotype) obtained by our analysis of a questionnaire sent to the patients provided more precise and longer-term prognoses compared to earlier studies.

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<![CDATA[Predictive powers of the Modified Early Warning Score and the National Early Warning Score in general ward patients who activated the medical emergency team]]> https://www.researchpad.co/article/elastic_article_14562 The current early warning scores may be insufficient for medical emergency teams (METs) to use in assessing the severity and the prognosis of activated patients. We evaluated the predictive powers of the Modified Early Warning Score (MEWS) and the National Early Warning Score (NEWS) for 28-day mortality and to analyze predictors of 28-day mortality in general ward patients who activate the MET.MethodsAdult general ward inpatients who activated the MET in a tertiary referral teaching hospital between March 2009 and December 2016 were included. The demographic and clinical characteristics and physiologic parameters at the time of MET activation were collected, and MEWS and NEWS were calculated.ResultsA total of 6,729 MET activation events were analyzed. Patients who died within 28 days were younger (mean age 60 vs 62 years), were more likely to have malignancy (72% vs 53%), were more likely to be admitted to the medical department rather than the surgical department (93% vs 80%), had longer intervals from admission to MET activation (median, 7 vs 5 days), and were less likely to activate the MET during nighttime hours (5 PM to 8 AM) (61% vs 66%) compared with those who did not die within 28 days (P < 0.001 for all comparisons). The areas under the receiver operating characteristic curves of MEWS and NEWS for 28-day mortality were 0.58 (95% CI, 0.56–0.59) and 0.60 (95% CI, 0.59–0.62), which were inferior to that of the logistics regression model (0.73; 95% CI, 0.72–0.74; P < 0.001 for both comparisons).ConclusionsBoth the MEWS and NEWS had poor predictive powers for 28-day mortality in patients who activated the MET. A new scoring system is needed to stratify the severity and prognosis of patients who activated the MET. ]]> <![CDATA[<i>In silico</i> analyses identify lncRNAs: WDFY3-AS2, BDNF-AS and AFAP1-AS1 as potential prognostic factors for patients with triple-negative breast tumors]]> https://www.researchpad.co/article/elastic_article_13870 Long non-coding RNAs (lncRNAs) are characterized as having 200 nucleotides or more and not coding any protein, and several been identified as differentially expressed in several human malignancies, including breast cancer.MethodsHere, we evaluated lncRNAs differentially expressed in triple-negative breast cancer (TNBC) from a cDNA microarray data set obtained in a previous study from our group. Using in silico analyses in combination with a review of the current literature, we identify three lncRNAs as potential prognostic factors for TNBC patients.ResultsWe found that the expression of WDFY3-AS2, BDNF-AS, and AFAP1-AS1 was associated with poor survival in patients with TNBCs. WDFY3-AS2 and BDNF-AS are lncRNAs known to play an important role in tumor suppression of different types of cancer, while AFAP1-AS1 exerts oncogenic activity.ConclusionOur findings provided evidence that WDFY3-AS2, BDNF-AS, and AFAP1-AS1 may be potential prognostic factors in TNBC development. ]]> <![CDATA[Proenkephalin A Adds No Incremental Prognostic Value After Acute Ischemic Stroke]]> https://www.researchpad.co/article/Nb42a9d58-70ec-4363-8ab0-eda7cb7c696a

Objective:

The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort.

Methods:

The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures.

Results:

After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33).

Conclusion:

Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.

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<![CDATA[Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Predict All-Cause Mortality in Acute Pulmonary Embolism]]> https://www.researchpad.co/article/N7351fb3a-ec25-48dc-bcb8-e0d04a90c0cb

The aim of this study was to investigate the utility of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to predict all-cause mortality in patients presenting with acute pulmonary embolism (PE). Three hundred consecutive patients with acute PE between March 2016 and December 2018 were retrospectively analyzed. We identified 191 patients who met the study inclusion criteria. Twenty-eight patients died during the study period. There was a significant difference in PLR, but not NLR, between patients with low risk, submassive, and massive risk PE (P = .02 and P = .58, respectively, by the Kruskal-Wallis test). Elevated NLR and PLR were associated with all-cause mortality (P < .01 and P < .01, respectively). Neutrophil-to-lymphocyte ratio of 5.46 was associated with all-cause mortality with sensitivity of 75.0% and specificity of 66.9% (area under the curve [AUC]: 0.692 [95% confidence interval, CI]: 0.568-0.816); P < .01). Platelet-to-lymphocyte ratio of 256.6 was associated with all-cause mortality with sensitivity of 53.6% and specificity of 82.2% (AUC: 0.693 [95% CI: 0.580-0.805]; P < .01). Neutrophil-to-lymphocyte ratio and PLR are simple biomarkers that are readily available from routine laboratory values and may be useful components of PE risk prediction models.

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<![CDATA[The Consortium for the early identification of Alzheimer's disease–Quebec (CIMA‐Q)]]> https://www.researchpad.co/article/N62b2e4b7-3537-44f4-ab74-38a07ad2ec51

Introduction

The Consortium for the early identification of Alzheimer's disease–Quebec (CIMA-Q) created a research infrastructure to recruit, characterize, and track disease progression in individuals at risk of dementia.

Methods

CIMA-Q established standardized clinical, neuropsychological, neuroimaging, blood (plasma, serum, RNA, genomic DNA), cryopreserved peripheral blood mononuclear cells, and cerebrospinal fluid collection protocols. These data and biological materials are available to the research community.

Results

In phase 1, 115 persons with subjective cognitive decline, 88 with mild cognitive impairment, 31 with early probable Alzheimer's disease, and 56 older adults with no worries nor impairments received detailed clinical and cognitive evaluations as well as blood and peripheral blood mononuclear cells collections. Among them, 142 underwent magnetic resonance imaging, 29 a 18fluorodeoxyglucose positron emission tomography, and 60 a lumbar puncture.

Discussion

CIMA-Q provides procedures and resources to identify early biomarkers and novel therapeutic targets, and holds promise for detecting cognitive decline in Alzheimer's disease.

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<![CDATA[What outcomes are important to patients with mild cognitive impairment or Alzheimer's disease, their caregivers, and health-care professionals? A systematic review]]> https://www.researchpad.co/article/5ca25d22d5eed0c4846d4c94

Introduction

Clinical trials involving patients with Alzheimer's disease (AD) continue to try to identify disease-modifying treatments. Although trials are designed to meet regulatory and registration requirements, many do not measure outcomes of the disease most relevant to key stakeholders.

Methods

A systematic review sought research that elicited information from people with AD, their caregivers, and health-care professionals on which outcomes of the disease were important. Studies published in any language between 2008 and 2017 were included.

Results

Participants in 34 studies described 32 outcomes of AD. These included clinical (memory, mental health), practical (ability to undertake activities of daily living, access to health information), and personal (desire for patient autonomy, maintenance of identity) outcomes of the disease.

Discussion

Evidence elicited directly from the people most affected by AD reveals a range of disease outcomes that are relevant to them but are not commonly captured in clinical trials of new treatments.

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<![CDATA[Subjective cognitive decline, APOE ε4, and incident mild cognitive impairment in men and women]]> https://www.researchpad.co/article/5c9d2972d5eed0c4840ae935

Introduction

Possible joint effects of subjective cognitive decline (SCD) and apolipoprotein E (APOE) ε4 genotype on incident mild cognitive impairment (MCI) were examined for men and women separately.

Methods

Cognitively normal participants with and without SCD were included from the first follow-up examination of the population-based Heinz Nixdorf Recall study. Sex-stratified logistic regression models estimated main effects and interactions (additive, multiplicative) of SCD at the first follow-up (yes+/no−) and APOE ε4 (positive+/negative−) groups for MCI 5 years later.

Results

Odds for MCI 5 years later were higher in SCD/APOE ε4 group +/+ than the sum of groups +/− and −/+ in women, with a trend for positive interaction. Odds for incident MCI in men was highest in group +/−, with no interaction effect.

Discussion

Our findings indicate that APOE ε4 may play an important role in the association of SCD and incident MCI, especially considering sex. Further studies need to examine these associations with larger sample sizes.

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<![CDATA[Long-term visual acuity in patients with optic pathway glioma treated during childhood with up-front BB-SFOP chemotherapy—Analysis of a French pediatric historical cohort]]> https://www.researchpad.co/article/5c8c1959d5eed0c484b4d486

Background

Visual outcome is one of the main issues in the treatment of optic pathway glioma in childhood. Although the prognostic factors of low vision have been discussed extensively, no reliable indicators for visual loss exist. Therefore, we aimed to define initial and evolving factors associated with long-term vision loss.

Methods

We conducted a multicenter historical cohort study of children treated in France with up-front BB-SFOP chemotherapy between 1990 and 2004. Visual acuity performed at the long-term follow-up visit or within 6 months prior was analyzed. Logistic regression analysis was used to estimate the effects of clinical and radiological factors on long-term visual outcome.

Findings

Of the 180 patients in the cohort, long-term visual acuity data were available for 132 (73.3%) patients (median follow-up: 14.2 years; range: 6.1–25.6). At the last follow-up, 61/132 patients (46.2%) had impaired vision, and 35 of these patients (57.3%) were partially sighted or blind. Multivariate analysis showed that factors associated with a worse prognosis for long-term visual acuity were an age at diagnosis of < 1 year (OR 3.5 [95% CI: 1.1–11.2], p = 0.04), tumor extent (OR 4.7 [95% CI: 1.2–19.9], p = 0.03), intracranial hypertension requiring one or more surgical procedures (OR 5.6 [95% CI: 1.8–18.4], p = 0.003), and the need for additional treatment after initial BB-SFOP chemotherapy (OR 3.5 [95% CI: 1.1–11.9], p = 0.04). NF1 status did not appear as a prognostic factor, but in non-NF1 patients, a decrease in tumor volume with contrast enhancement after BB-SFOP chemotherapy was directly associated with a better visual prognosis (OR 0.8 [95% CI: 0.8–0.9], p = 0.04).

Interpretation

Our study confirms that a large proportion of children with optic pathway glioma have poor long-term outcomes of visual acuity. These data suggest new prognostic factors for visual acuity, but these results need to be confirmed further by large- and international-scale studies.

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<![CDATA[Hepatocellular carcinoma with extrahepatic metastasis: Are there still candidates for transarterial chemoembolization as an initial treatment?]]> https://www.researchpad.co/article/5c99029ed5eed0c484b98241

Background and aim

Currently, sorafenib is indicated for hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM), and many other systemic agents are becoming available. However, a few HCC patients with EHM still undergo transarterial chemoembolization (TACE) for intrahepatic tumor control. We aimed to investigate whether TACE is appropriate for patients with EHM, and if so, which subgroup may benefit from TACE.

Methods

A total of 186 consecutive HCC patients (median: 55 years, male: 86.0%, hepatitis B virus: 81.7%, Child-Pugh Class A: 83.3%) with EHM (nodal metastasis: 60.8%, distant metastasis: 39.2%) between 2010 and 2014 were analyzed. Initial treatment included sorafenib in 69 patients, and TACE in 117 patients.

Results

During a median follow-up of 6.6 months (range: 0.2–94.6 months), mortality was observed in 90.3% (168/186). The median survival was better for patients who received TACE than those treated with sorafenib (8.2 months vs. 4.6 months, p < 0.001). However, baseline characteristics varied between patients initially treated with TACE and sorafenib, and the treatment modality was not an independent factor associated with overall survival (hazard ratio: 1.19, 95% confidence interval: 0.81–1.75, p = 0.36). In sub-group analysis, TACE was associated with better survival only among younger patients and those with segmental/lobar portal vein invasion.

Conclusion

In HCC patients with EHM, TACE was not an independent favorable prognostic factor compared to sorafenib. The concept of intrahepatic control in HCC patients with EHM may need to be reevaluated in the era of promising systemic therapies, although there can be specific subgroups who still benefit from TACE.

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<![CDATA[Pretreatment neutrophil-to-lymphocyte ratio predicts clinical relapse of ulcerative colitis after tacrolimus induction]]> https://www.researchpad.co/article/5c8acc85d5eed0c48498f939

Objectives

Although tacrolimus is useful as an induction therapy in patients with ulcerative colitis (UC), information regarding the long-term outcome after tacrolimus therapy is insufficient. The aim of this study was to evaluate the clinical significance of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor in patients with UC receiving tacrolimus, to aid treatment selection.

Materials and methods

Patients with moderate-to-severe active UC who received oral tacrolimus induction therapy and subsequent immunomodulatory maintenance therapy at our hospital between 2009 and 2017 and who showed clinical response at week 12, were retrospectively enrolled. Cox regression analysis was conducted to study the prognostic role of the pretreatment NLR. The combined impact of the NLR and other known prognostic factors was investigated with multivariate regression.

Results

Among 45 patients included in this study, 21 patients experienced relapse during a median follow-up period of 16.6 months. Multivariate Cox regression analysis identified the pretreatment NLR (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.72–0.94, P < 0.01) and the use of immunomodulators at the start of tacrolimus treatment (HR: 0.18, 95% CI: 0.05–0.66, P = 0.01) as independent predictors of clinical relapse.

Conclusions

The pretreatment NLR is an independent prognostic factor in patients with UC treated with tacrolimus.

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<![CDATA[Pneumonia severity index in viral community acquired pneumonia in adults]]> https://www.researchpad.co/article/5c897759d5eed0c4847d2a8b

Pneumonia severity index (PSI) is an important scoring system that can assess the severity of community acquired pneumonia and determine admission status. However, there is a lack of research on whether this scoring system can be applied to viral community acquired pneumonia. The purpose of this study was to evaluate the usefulness of PSI in viral community acquired pneumonia. This retrospective cohort study included 1,434 adult patients (aged ≥18 years) who were admitted to the emergency department of a university hospital during 2013–2015 because of community-acquired pneumonia. Viral infections were diagnosed by multiplex PCR. Patients diagnosed with non-viral community-acquired pneumonia were included in the control group (N = 1,173). The main outcome was 30-day all-cause mortality. multivariate Cox regression analyses were performed to calculate the risk of death. Respiratory viruses were detected in 261 (18.2%) patients with community-acquired pneumonia. Two types of respiratory viruses were detected in 7 cases. Of the 254 cases detected with only one virus, 62 were influenza A, 18 were influenza B, 65 were rhinovirus, 35 were respiratory syncytial virus, 25 were metapneumovirus, 20 were parainfluenza, 17 were coronavirus, 7 were bocavirus, and 5 were adenovirus. Mortality was not significantly different between patients with respiratory virus and those without respiratory virus; the 30-day all-cause mortality rates were 20.3% and 22.4%, respectively (P = 0.45). Mortality rate increased with an increasing PSI score with or without respiratory viral infection. Pulmonary severity index was significantly associated with mortality adjusted for respiratory virus detection (hazard ratio = 1.024, 95% confidence interval = 1.020–1.028). Pneumonia severity index score is an important factor for assessing the prognosis of patients with community-acquired pneumonia, regardless of respiratory virus detection.

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<![CDATA[Previously-initiated hemodialysis as prognostic factor for in-hospital mortality in pneumonia patients with stage 5 chronic kidney disease: Retrospective database study of Japanese hospitals]]> https://www.researchpad.co/article/5c818e8bd5eed0c484cc24db

Background

Some clinicians keep patients in stage 5 chronic kidney disease (CKD) without hemodialysis for a while. This study investigated whether previously-initiated hemodialysis in stage 5 CKD patients may become a prognostic factor for in-hospital mortality due to pneumonia.

Methods

Patient data were obtained from the multi-institutional diagnosis procedure combination database between April 1, 2012 and March 31, 2016. The patients had records of pneumonia as both trigger and major diagnoses and records of end stage renal disease (ESRD) or stage 5 CKD as a comorbidity or other diagnoses on admission and aged 18 years or older. The following factors were adjusted: age, sex, body mass index, Barthel index, orientation disturbance, arterial oxygen saturation, systolic blood pressure, C-reactive protein level or the extent of consolidation on chest radiography, ambulance use, hospitalization within 90 days, and comorbidities upon admission. The primary outcome measure was all-cause in-hospital mortality obtained via multivariable logistic regression analysis using four Models. Model 1 involved complete case analysis with overlapping; one hospitalization per patient was counted as one. Model 2 involved a complete case analysis without overlapping; only the first hospitalization per patient was counted. Model 3 involved multilevel analysis clustered by hospital codes. Model 4 was created after multiple imputation for lacking adjusted factors.

Results

A total of 907 hospitals and 7,726 patients were identified. Hemodialysis was significantly associated with lower in-hospital mortality in all models (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.54–0.87 in Model 1; OR = 0.71, 95% CI: 0.55–0.91 in Model 2; OR = 0.67, 95% CI: 0.52–0.86 in Model 3; and OR = 0.68, 95% CI: 0.54–0.87 in Model 4).

Conclusion

Previously-initiated hemodialysis may be an independent prognostic factor for in-hospital mortality in pneumonia patients with end-stage renal disease. This should be borne in mind when considering the time of initiation of dialysis.

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<![CDATA[Towards a universal concept of vulnerability: Broadening the evidence from the elderly to perinatal health using a Delphi approach]]> https://www.researchpad.co/article/5c76fe2ed5eed0c484e5b68a

Background

The concept 'vulnerability' is prevalent in the public domain, health care, social institutions and multidisciplinary research. Conceptual heterogeneity is present, hampering the creation of a common evidence-base of research achievements and successful policies. Recently an international expert group combined a specific literature review with a 2-stage Delphi procedure, arriving at a seemingly universal concept of vulnerability for the elderly with applications for research instruments. We replicated and extended this study, to generalize this result to health in general, and perinatal health in particular.

Methods

Two independent expert panels (general health, perinatal health) repeated the Delphi-procedure, using an extended and updated literature review to derive statements on the concept and defining pathways of vulnerability. Additional views were collected on research tools. Consensus-by-design was explicitly avoided. Data collection and processing was independent.

Results

Both panels showed surprising convergence on the pathways of vulnerability to health/ill-health, and their interaction. The agreed conceptual model describes a dynamic relation between health and ill-health and vulnerability. The 2 key pathways that link to vulnerability, are complementary, but not symmetrical as biological processes of maintaining health or obtaining better health are not reciprocal to recovery, so also not in terms of vulnerability impacts. An individual's degree of vulnerability is the net balance of risk effects and protective and healing factors (socially, biologically and in terms of health literacy and health care access). These factors can for measurement purposes (according to the panels: interview for exploration, checklists for population research) be grouped into ‘material resources’, ‘taking responsibility for one’s own health’, ‘risky activities and behaviors’, and ‘social support’.

Supportive and transforming action can thus be undertaken.

Conclusion

A universal concept of vulnerability in the context of health was successfully derived after careful replication and extension of an international Delphi study on vulnerability among the elderly.

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<![CDATA[Liver metastasis and Heng risk are prognostic factors in patients with non-nephrectomized synchronous metastatic renal cell carcinoma treated with systemic therapy]]> https://www.researchpad.co/article/5c76fe33d5eed0c484e5b6ea

Objective

This study aimed to determine the prognostic factors of progression-free survival (PFS) and overall survival (OS) in non-nephrectomized patients with synchronous metastatic renal cell carcinoma (mRCC) receiving first-line vascular endothelial growth factor (VEGF)-targeted therapy or immunotherapy.

Methods

Of 70 patients, 57 (81.4%) were treated with targeted therapy, including 5 (7.1%) with previous immunotherapy and 13 (18.6%) with immunotherapy only. The medical records of patients were retrospectively reviewed and analyzed to determine factors of PFS and OS using the Cox proportional hazards model with a statistical significance p-value <0.05.

Results

The median treatment and follow-up periods were 3.9 and 30.9 months, respectively. Disease progression was reported in 90.0% of patients, with an objective response rate and clinical benefit rate of 26.1% and 76.8%, respectively. The lung (77.1%) was the most common site of metastasis. Multivariable analysis showed that poor Heng risk (hazard ratio [HR]: 2.37) and liver metastasis (HR: 2.34) were significant prognostic factors for PFS, and female sex (HR: 2.13), poor Heng risk (HR: 3.14), and liver metastasis (HR: 2.78) were significant prognostic factors for OS (p < 0.05). A subset analysis of risk factors among patients without previous history of immunotherapy also showed poor Heng risk (HR 2.92 and HR 4.24 for PFS) and liver metastasis (HR 2.87 and HR 4.81 for OS) as significant factors for both PFS and OS (p<0.05).

Conclusion

Poor Heng risk, sex, and liver metastasis were associated with survival outcomes after first-line systemic therapy in patients with non-nephrectomized synchronous mRCC.

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<![CDATA[Ornithine decarboxylase antizyme inhibitor 2 (AZIN2) is a signature of secretory phenotype and independent predictor of adverse prognosis in colorectal cancer]]> https://www.researchpad.co/article/5c70673fd5eed0c4847c6c9d

Ornithine decarboxylase (ODC) is the rate-limiting enzyme of polyamine synthesis. The two ODC antizyme inhibitors (AZIN1) and (AZIN2) are regulators of the catalytic activity of ODC. While AZIN1 is a regulator of cell proliferation, AZIN2 is involved in intracellular vesicle transport and secretion. There are no previous reports on the impact of AZIN2 expression in human cancer. We applied immunohistochemistry with antibodies to human AZIN2 on tissue micro- arrays of colorectal cancers (CRC) from 840 patients with a median follow-up of 5.1 years (range 0–25.8). The 5-year disease-specific survival rate was 58.9% (95% Cl 55.0–62.8%). High AZIN2 expression was associated with mucinous histology (p = 0.002) and location in the right hemicolon (p = 0.021). We found no association with age, gender, stage, or histological tumor grade. High tumor expression of AZIN2 predicted an unfavorable prognosis (p<0.0001, log-rank test), compared to low AZIN2 expression. Cox multivariable analysis identified AZIN2 as an independent factor of an unfavorable prognosis in CRC. The strongest AZIN2 expression was seen in invasive tumor cells having morphological features of epithelial-mesenchymal transition (EMT). Induction of EMT in HT-29 CRC cells lead to upregulated expression of endogenous AZIN2. Given that AZIN2 is a regulator of vesicle transport and secretion, we overexpressed human AZIN2 cDNA in T84 CRC cells, and found strongly enhanced accumulation of CD63-positive exosomes in the culture medium. These findings indicate that AZIN2 expression is a signature of EMT-associated secretory phenotype that is linked to an adverse prognosis in CRC.

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<![CDATA[Efficient design and analysis of randomized controlled trials in rare neurological diseases: An example in Guillain-Barré syndrome]]> https://www.researchpad.co/article/5c76fe48d5eed0c484e5b7f7

Background

Randomized controlled trials (RCTs) pose specific challenges in rare and heterogeneous neurological diseases due to the small numbers of patients and heterogeneity in disease course. Two analytical approaches have been proposed to optimally handle these issues in RCTs: covariate adjustment and ordinal analysis. We investigated the potential gain in efficiency of these approaches in rare and heterogeneous neurological diseases, using Guillain-Barré syndrome (GBS) as an example.

Methods

We analyzed two published GBS trials with primary outcome ‘at least one grade improvement’ on the GBS disability scale. We estimated the treatment effect using logistic regression models with and without adjustment for prognostic factors. The difference between the unadjusted and adjusted estimates was disentangled in imbalance (random differences in baseline covariates between treatment arms) and stratification (change of the estimate due to covariate adjustment). Second, we applied proportional odds regression, which exploits the ordinal nature of the GBS disability score. The standard error of the estimated treatment effect indicated the statistical efficiency.

Results

Both trials were slightly imbalanced with respect to baseline characteristics, which was corrected in the adjusted analysis. Covariate adjustment increased the estimated treatment effect in the two trials by 8% and 18% respectively. Proportional odds analysis resulted in lower standard errors indicating more statistical power.

Conclusion

Covariate adjustment and proportional odds analysis most efficiently use the available data and ensure balance between the treatment arms to obtain reliable and valid treatment effect estimates. These approaches merit application in future trials in rare and heterogeneous neurological diseases like GBS.

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<![CDATA[A data-driven interactome of synergistic genes improves network-based cancer outcome prediction]]> https://www.researchpad.co/article/5c648d3fd5eed0c484c82364

Robustly predicting outcome for cancer patients from gene expression is an important challenge on the road to better personalized treatment. Network-based outcome predictors (NOPs), which considers the cellular wiring diagram in the classification, hold much promise to improve performance, stability and interpretability of identified marker genes. Problematically, reports on the efficacy of NOPs are conflicting and for instance suggest that utilizing random networks performs on par to networks that describe biologically relevant interactions. In this paper we turn the prediction problem around: instead of using a given biological network in the NOP, we aim to identify the network of genes that truly improves outcome prediction. To this end, we propose SyNet, a gene network constructed ab initio from synergistic gene pairs derived from survival-labelled gene expression data. To obtain SyNet, we evaluate synergy for all 69 million pairwise combinations of genes resulting in a network that is specific to the dataset and phenotype under study and can be used to in a NOP model. We evaluated SyNet and 11 other networks on a compendium dataset of >4000 survival-labelled breast cancer samples. For this purpose, we used cross-study validation which more closely emulates real world application of these outcome predictors. We find that SyNet is the only network that truly improves performance, stability and interpretability in several existing NOPs. We show that SyNet overlaps significantly with existing gene networks, and can be confidently predicted (~85% AUC) from graph-topological descriptions of these networks, in particular the breast tissue-specific network. Due to its data-driven nature, SyNet is not biased to well-studied genes and thus facilitates post-hoc interpretation. We find that SyNet is highly enriched for known breast cancer genes and genes related to e.g. histological grade and tamoxifen resistance, suggestive of a role in determining breast cancer outcome.

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