Citations

Abstract The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient. image

AbstractBackgroundOur study aimed to characterize kidney retransplant recipients using an unsupervised machine‐learning approach.MethodsWe performed consensus cluster analysis based on the recipient‐, donor‐, and transplant‐related characteristics in 17 443 kidney retransplant recipients in the OPTN/UNOS database from 2010 to 2019. We identified each cluster's key characteristics using the standardized mean difference of >.3. We compared the posttransplant outcomes, including death‐censored graft failure and patient death among the assigned clustersResultsConsensus cluster analysis identified three distinct clusters of kidney retransplant recipients. Cluster 1 recipients were predominantly white and were less sensitized. They were most likely to receive a living donor kidney transplant and more likely to be preemptive (30%) or need ≤1 year of dialysis (32%). In contrast, cluster 2 recipients were the most sensitized (median PRA 95%). They were more likely to have been on dialysis >1 year, and receive a nationally allocated, low HLA mismatch, standard KDPI deceased donor kidney. Recipients in cluster 3 were more likely to be minorities (37% Black; 15% Hispanic). They were moderately sensitized with a median PRA of 87% and were also most likely to have been on dialysis >1 year. They received locally allocated high HLA mismatch kidneys from standard KDPI deceased donors. Thymoglobulin was the most commonly used induction agent for all three clusters. Cluster 1 had the most favorable patient and graft survival, while cluster 3 had the worst patient and graft survival.ConclusionThe use of an unsupervised machine learning approach characterized kidney retransplant recipients into three clinically distinct clusters with differing posttransplant outcomes. Recipients with moderate allosensitization, such as those represented in cluster 3, are perhaps more disadvantaged in the kidney retransplantation process. Potential opportunities for improvement specific to these re‐transplant recipients include working to improve opportunities to improve access to living donor kidney transplantation, living donor paired exchange and identifying strategies for better HLA matching.

Patients with IgA nephropathy (IgAN), including Henoch-Schönlein purpura nephritis (HSP), who present with rapidly progressive glomerulonephritis (RPGN) have a poor prognosis despite aggressive immunosuppressive therapy. The utility of plasmapheresis/plasma exchange (PLEX) for IgAN/HSP is not well established. This systematic review aims to assess the efficacy of PLEX for IgAN and HSP patients with RPGN. A literature search was conducted using MEDLINE, EMBASE, and through Cochrane Database from inception through September 2022. Studies that reported outcomes of PLEX in IgAN or HSP patients with RPGN were enrolled. The protocol for this systematic review is registered with PROSPERO (no. CRD42022356411). The researchers systematically reviewed 38 articles (29 case reports and 9 case series articles) with a total of 102 RPGN patients (64 (62.8%) had IgAN and 38 (37.2%) had HSP). The mean age was 25 years and 69% were males. There was no specific PLEX regimen utilized in these studies, but most patients received at least 3 PLEX sessions that were titrated based on the patient’s response/kidney recovery. The number of PLEX sessions ranged from 3 to 18, and patients additionally received steroids and immunosuppressive treatment (61.6% of patients received cyclophosphamide). Follow-up time ranged from 1 to 120 months, with the majority being followed for at least 2 months after PLEX. Among IgAN patients treated with PLEX, 42.1% (n = 27/64) achieved remission; 20.3% (n = 13/64) achieved complete remission (CR) and 18.7% (n = 12/64) partial remission (PR). 60.9% (n = 39/64) progressed to end-stage kidney disease (ESKD). Among HSP patients treated with PLEX, 76.3% (n = 29/38) achieved remission; of these, 68.4% (n = 26/38) achieved CR and 7.8% achieved (n = 3/38) PR. 23.6% (n = 9/38) progressed to ESKD. Among kidney transplant patients, 20% (n = 1/5) achieved remission and 80% (n = 4/5) progressed to ESKD. Adjunctive plasmapheresis/plasma exchange with immunosuppressive therapy showed benefits in some HSP patients with RPGN and possible benefits in IgAN patients with RPGN. Future prospective, multi-center, randomized clinical studies are needed to corroborate this systematic review’s findings.

Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Methods: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Results: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Conclusion: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Abstract Background Small bowel fibrostenotic strictures are common in patients with Crohn’s disease (CD). No global consensus recommendations on definitions, diagnosis and clinical management are available. Methods Several systematic reviews followed by a RAND/University of California Los Angeles appropriateness study on the definitions, diagnosis and clinical management of fibrostenosing CD in clinical practice were performed. A panel of 28 global experts and a patient representative were convened. They assessed a total of 152 candidate items. The items were subsequently evaluated for appropriateness. Results No accurate predictive biomarkers are available for naïve or anastomotic fibrostenosing strictures. Accurate diagnosis of fibrostenosing CD requires cross-sectional imaging which should evaluate bowel wall thickness, luminal narrowing and prestenotic dilatation. A potential inflammatory component should be assessed. Abdominal cross-sectional imaging was considered necessary prior to any treatment decision. The panel proposed an approach to medical, endoscopic, and surgical therapies (Figure 1 and Table 1). Technical characteristics for endoscopic balloon dilation and follow up strategies after successful dilation therapy were identified. Appropriateness, types and performance of different surgical approaches in various settings were evaluated. Conclusion This global consensus provides clinical guidance for the diagnostic and therapeutic management of patients with fibrostenotic CD.

Background: The utilization of multi-dimensional patient data to subtype hepatorenal syndrome (HRS) can individualize patient care. Machine learning (ML) consensus clustering may identify HRS subgroups with unique clinical profiles. In this study, we aim to identify clinically meaningful clusters of hospitalized patients for HRS using an unsupervised ML clustering approach. Methods: Consensus clustering analysis was performed based on patient characteristics in 5564 patients primarily admitted for HRS in the National Inpatient Sample from 2003–2014 to identify clinically distinct HRS subgroups. We applied standardized mean difference to evaluate key subgroup features, and compared in-hospital mortality between assigned clusters. Results: The algorithm revealed four best distinct HRS subgroups based on patient characteristics. Cluster 1 patients (n = 1617) were older, and more likely to have non-alcoholic fatty liver disease, cardiovascular comorbidities, hypertension, and diabetes. Cluster 2 patients (n = 1577) were younger and more likely to have hepatitis C, and less likely to have acute liver failure. Cluster 3 patients (n = 642) were younger, and more likely to have non-elective admission, acetaminophen overdose, acute liver failure, to develop in-hospital medical complications and organ system failure, and to require supporting therapies, including renal replacement therapy, and mechanical ventilation. Cluster 4 patients (n = 1728) were younger, and more likely to have alcoholic cirrhosis and to smoke. Thirty-three percent of patients died in hospital. In-hospital mortality was higher in cluster 1 (OR 1.53; 95% CI 1.31–1.79) and cluster 3 (OR 7.03; 95% CI 5.73–8.62), compared to cluster 2, while cluster 4 had comparable in-hospital mortality (OR 1.13; 95% CI 0.97–1.32). Conclusions: Consensus clustering analysis provides the pattern of clinical characteristics and clinically distinct HRS phenotypes with different outcomes.

Abstract Objectives/Background Post‐traumatic headache (PTH) is a common symptom after mild traumatic brain injury (mTBI). Although there have been several studies that have used clinical features of PTH to attempt to predict headache recovery, currently no accurate methods exist for predicting individuals’ improvement from acute PTH. This study investigated the utility of clinical questionnaires for predicting (i) headache improvement at 3 and 6 months, and (ii) headache trajectories over the first 3 months. Methods We conducted a clinic‐based observational longitudinal study of patients with acute PTH who completed a battery of clinical questionnaires within 0–59 days post‐mTBI. The battery included headache history, symptom evaluation, cognitive tests, psychological tests, and scales assessing photosensitivity, hyperacusis, insomnia, cutaneous allodynia, and substance use. Each participant completed a web‐based headache diary, which was used to determine headache improvement. Results Thirty‐seven participants with acute PTH (mean age = 42.7, standard deviation [SD] = 12.0; 25 females/12 males) completed questionnaires at an average of 21.7 (SD = 13.1) days post‐mTBI. The classification of headache improvement or non‐improvement at 3 and 6 months achieved cross‐validation area under the curve (AUC) of 0.72 (95% confidence interval [CI] 0.55 to 0.89) and 0.84 (95% CI 0.66 to 1.00). Sub‐models trained using only the top five features still achieved 0.72 (95% CI 0.55 to 0.90) and 0.77 (95% CI 0.52 to 1.00) AUC. The top five contributing features were from three questionnaires: Pain Catastrophizing Scale total score and helplessness sub‐domain score; Sports Concussion Assessment Tool Symptom Evaluation total score and number of symptoms; and the State‐Trait Anxiety Inventory score. The functional regression model achieved for modeling headache trajectory over the first 3 months. Conclusion Questionnaires completed following mTBI have good utility for predicting headache improvement at 3 and 6 months in the future as well as the evolving headache trajectory. Reducing the battery to only three questionnaires, which assess post‐concussive symptom load and biopsychosocialecologic factors, was helpful to determine a reasonable prediction accuracy for headache improvement.

Background: The Mediterranean, Dietary Approach to Stop Hypertension (DASH), and plant-based diets may provide cardiovascular benefit to the general population. However, data on their effect on end stage kidney disease (ESKD) patients are limited. This systematic review aims to assess the impact of Mediterranean, DASH, and plant-based diets on outcomes among ESKD patients. Methods: A literature review was conducted in EMBASE, MEDLINE, and Cochrane databases from inception through September 2022 to identify studies that assess the clinical outcomes of Mediterranean, DASH, or plant-based diets on ESKD patients on hemodialysis (HD) or peritoneal dialysis (PD). Effect estimates from the individual studies were derived utilizing the random-effect, generic inverse variance approach of DerSimonian and Laird. Results: Seven studies with 9400 ESKD patients (8395 HD and 1005 PD) met the eligibility criteria and were included in the data analysis. Pooled odds ratios (ORs) of mortality for ESKD patients who adhered to the Mediterranean versus plant-based diet were 0.49 (95% CI: 0.07–3.54; two studies, I2 = 67%) and 0.87 (95% CI: 0.75–1.01; two studies, I2 = 0%), respectively. Data on mortality for ESKD patients on a DASH diet were limited to one study with an OR of 1.00 (95% CI: 0.89–1.12). The pooled OR of cardiovascular mortality among ESKD patients who adhered to a plant-based diet was 0.86 (95% CI: 0.68–1.08; two studies, I2 = 0%), compared to those who did not. Data on cardiovascular mortality among those with Mediterranean and DASH diet were limited to one study with ORs of 1.14 (95% CI: 0.90–1.43) and 1.19 (95% CI: 0.99–1.43), respectively. Mediterranean diet adherence was found to be associated with reduced risk of left ventricular hypertrophy (LVH) with an OR of 0.82 (95% CI: 0.68–0.99) in a study including 127 ESKD patients. The risk of hyperkalemia was not significant among those with a plant-based diet with an OR of 1.00 (95% CI: 0.94–1.07) in a study including 150 ESKD patients. Conclusions: While our systematic review demonstrated no significant associations of Mediterranean, DASH, and plant-based diets with reduced all-cause mortality or cardiovascular mortality, there was also no evidence that suggested harmful effects of these diets to ESKD patients.

OBJECTIVE Aneurysm occlusion has been used as surrogate marker of aneurysm treatment efficacy. Aneurysm occlusion scales are used to evaluate the outcome of endovascular aneurysm treatment and to monitor recurrence. These scales, however, require subjective interpretation of imaging data, which can reduce the utility and reliability of these scales and the validity of clinical studies regarding aneurysm occlusion rates. Use of a core lab with independent blinded reviewers has been implemented to enhance the validity of occlusion rate assessments in clinical trials. The degree of agreement between core labs and treating physicians has not been well studied with prospectively collected data. METHODS In this study, the authors analyzed data from the Hydrogel Endovascular Aneurysm Treatment (HEAT) trial to assess the interrater agreement between the treating physician and the blinded core lab. The HEAT trial included 600 patients across 46 sites with intracranial aneurysms treated with coiling. The treating site and the core lab independently reviewed immediate postoperative and follow-up imaging (3–12 and 18–24 months, respectively) using the Raymond-Roy occlusion classification (RROC) scale, Meyer scale, and recanalization survey. A post hoc analysis was performed to calculate interrater reliability using Cohen’s kappa. Further analysis was performed to assess whether degree of agreement varied on the basis of various factors, including scale used, timing of imaging, size of the aneurysm, imaging modality, location of the aneurysm, dome-to-neck ratio, and rupture status. RESULTS Minimal interrater agreement was noted between the core lab reviewers and the treating physicians for assessing aneurysm occlusion using the RROC grading scale (k = 0.39, 95% CI 0.38–0.40) and Meyer scale (k = 0.23, 95% CI 0.14–0.38). The degree of agreement between groups was slightly better but still weak for assessing recanalization (k = 0.45, 95% CI 0.38–0.52). Factors that significantly improved degree of agreement were scales with fewer variables, greater time to follow-up, imaging modality (digital subtraction angiography), and wide-neck aneurysms. CONCLUSIONS Assessment of aneurysm treatment outcome with commonly used aneurysm occlusion scales suffers from risk of poor interrater agreement. This supports the use of independent core labs for validation of outcome data to minimize reporting bias. Use of outcome tools with fewer point categories is likely to provide better interrater reliability. Therefore, the outcome assessment tools are ideal for clinical outcome assessment provided that they are sensitive enough to detect a clinically significant change.