Citations

Background: Urine mast cell mediator levels have found significant clinical utility in supporting the diagnosis of various allergic disorders in the adult population. There are few studies on the range of these mediator levels in the children and its clinical utility. Objectives: We determined the range of the urine mast cell mediator levels in children. Methods: Pediatric allergy and community-based pediatric clinics including children with and without an allergic disorder, respectively, served as the source of the study. Baseline urine mast cell mediator levels were obtained for all children. Demographics, atopic disorders, clinical symptoms and response to medication were documented. Results: Urine 2,3-Dinor-11Beta-Prostaglandin F2 Alpha (BPG) values were significantly higher in children with an underlying allergic disorder when compared to those without. Stratification based on age, sex and allergic disorder was performed in patients with an allergic disorder. Urine Leukotriene E 4 (LTE 4 ) and n-Methylhistamine (NMH) were significantly correlated with age (Spearman’s rho -0.4874 and -0.6902 respectively). With every year of age, the level of the urine NMH decreased by 18 units and urine LTE 4 by 3 units approximately. Urine LTE 4 and NMH levels were significantly higher in males when compared to females. Urine BPG levels were not significantly affected by age or sex. Conclusion: Distribution of urine mast cell mediator levels are slightly different from the values derived from studies in the adult population. Urine mast cell mediators may provide clinical utility in the diagnosis and management of allergic disorders. Further large-scale studies are warranted to validate clinical utility.

ABSTRACTBackgroundIn sinonasal cancer (SNC), treatment with proton therapy (PT) provides excellent local control, especially after gross total resection. Because of the heterogeneity and rarity of this disease site, a comprehensive assessment of toxicity, survival, and control rates is lacking. Our primary objective was to assess the toxicity outcomes of PT in SNC patients, with a secondary aim of assessing survival and tumor control after PT.MethodsPubMed, Embase, EBSCO, Scopus, Science Direct, Web of Science, Ovid, Proquest, and Cochrane Library were searched from inception to August 2024 reporting PT acute and late toxicity, survival, and tumor control outcomes in SNC patients. A random‐effect meta‐analysis was used to assess the pooled safety, survival, and tumor control outcomes. The primary analysis was to report acute and late toxicity. The secondary aims included overall survival (OS), disease‐free survival (DFS), local control (LC), regional control (RC), and distant metastasis control (DMC) rate.ResultsFourteen studies were included for qualitative analysis. We pooled data from 756 patients who received PT for SNC. Among acute toxicity (AT), there was a 31.9% occurrence rate of grade ≥ 3 events, whereas within late toxicity (LT), grade ≥ 3 events occurred at a rate of 35.3%. Most LT (62.1%) were classified as grade 2, with the most frequent being ocular (24.8%) or neurological (18.4%) toxicities. The most common grade ≥ 3 toxicities were mucositis (15.3%) in AT and ocular toxicity (9.6%) in LT. The pooled 5‐year OS, DFS, LC, RC, and DMC were 36.8%, 34.2%, 35.6%, 28.6%, and 54.3%, respectively.ConclusionOur analysis demonstrates that PT‐treated SNC patients experience acceptable rates of acute and LT consistent with other published outcomes with highly conformal radiation techniques. PT demonstrates favorable OS and DFS. Further prospective and comparative effectiveness research is needed to better quantify the magnitude of the benefit of PT or other forms of radiation modalities.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

AbstractBackgroundImaging and plasma markers are used as key indicators of disease for Alzheimer’s disease (AD) but their usefulness in predicting regional tau pathology is relatively understudied. Our objective was to construct predictive models for regional tau pathology measured on postmortem brain tissue using multiple ante‐mortem AD biomarkers. We focused on hippocampal and parietal regions that were immunostained with AT8 and 2E9 that reflect early and advanced aspects of tangle maturity, respectively.MethodsUsing autopsy data from 63 participants enrolled in the Mayo Clinic Study of Aging (MCSA) where the last clinical visit is within three years of death, we analyzed three ante‐mortem plasma markers ‐ phosphorylated tau protein at the threonine 181 residue, glial fibrillary acidic protein, total β‐amyloid Aβ42 relative to Aβ40 ratio (Quanterix Simoa HD‐X Analyzer), and three regional MRI markers computed using SPM12 ‐ parietal thickness, parietal volume relative to total intracranial volume ratio, and hippocampal volume adjusted for total intracranial volume. Based on eight separate cross‐sectional linear regression models weighted by the inverse of time from last visit to death, we estimated the multiple and partial R2 predicting post‐mortem pathology measures, including AT8 and 2E9 in both the hippocampal and parietal regions. All models were adjusted for age, sex, and cardiovascular and metabolic conditions score.ResultsThe MRI models (R2 of 0.26‐0.53) had greater predictive power compared to the plasma models (R2 of 0.17‐0.26). The best multiple R2 was 0.53 for prediction of hippocampal AT8 using antemortem hippocampal volume adjusted for total intracranial volume followed by R2 of 0.43 for prediction of hippocampal 2E9 using hippocampal volume adjusted for total intracranial volume. Though the model prediction of parietal AT8 and 2E9 measurements was low (R2 of 0.21‐0.26), parietal thickness exhibited better predictive performance than parietal volume relative to total intracranial volume ratio.ConclusionsThe data we presented here may be utilized to validate biomarkers using regional pathology. Our results support that regional MRI is sensitive to tau pathology. Newer MRI methods should be tested to examine the specificity of newer quantitative measurements to tau pathology.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n=71; hospitalized, n=9, non‐hospitalized, n=62 during the acute infection) and controls (n=50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p=0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) are often comorbid with Alzheimer’s disease and increase the risk of dementia. Blood‐based biomarkers may be promising for identifying individuals at high risk for VCID due to small vessel disease (SVD).MethodWe included 1709 participants from the Mayo Clinic Study of Aging who had concurrent MRI, plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) measured on the HD‐X Simoa Quanterix platform, and clinical dementia rating scale (CDR). We categorized participants into SVD vs. not using WMH/TIV≥1.3% which corresponds to Fazekas>=2 cutoff and cognitively impaired (CI) vs. not using CDR≥0.5. We obtained four groups using SVD and cognitively normal and impaired classifications: cognitively unimpaired without SVD (CU), CU with SVD (Vas‐CU), CI with SVD (VCI), and CI without SVD (Non‐vas‐CI). Univariate and multivariable logistic regression models were used to obtain odds ratios, confidence intervals and ROC curves to evaluate the association between plasma markers and each disease group compared to CU. We also evaluated these analyses in amyloid positive and negative participants.ResultThere was a high proportion of CU (Vas‐CU/(CU+Vas‐CU)=18%) and CI (VCI/(VCI+ Non‐vas‐CI)=47%) participants with SVD in the population‐based sample. Higher plasma levels were associated with greater vascular burden and differed by amyloid status (Figure 1). ROC analyses showed that both NfL and GFAP provided discrimination between Vas‐CU and CU groups (AUC=0.83) as well as VCI and CU groups (AUC=0.88) (Figure 2, Table 1). Though GFAP and NfL are non‐specific and may also reflect non‐vascular damage, we found that these plasma markers did not clearly separate NonVas‐CI from the CU group in the overall cohort (AUC=0.69). When amyloid status was available, the discriminative power of NfL and GFAP in separating the 4 groups was very low in amyloid positive participants. On the other hand, NfL and GFAP separated Vas‐CU and VCI groups from CI reasonably well in the amyloid negative group.ConclusionPlasma biomarkers associated with SVD‐burden provided reliable discriminative power in predicting VCID, particularly in the absence of amyloid, suggesting their utility in the prognosis and stratification for clinical trials.

AbstractBackgroundThere has been a recent proliferation of various quantities based on single shell Diffusion Tensor Imaging (DTI) for capturing overall cerebrovascular health, especially Small Vessel Disease (SVD) as a single number. The existing literature has gaps in the comparison of these measures, so we evaluated them as predictors of both current and future White Matter Hyperintensity (WMH) as a proxy of SVD.MethodUsing baseline 3T MRI examinations (T1, DTI, FLAIR scans) of 598 participants (>60 years, amyloid negative, to limit to those on the SVD pathway) from the Mayo Clinic Study of Aging, we calculated five summary DTI quantities with varying degree of complexity. We estimated their partial R2 from cross‐sectional linear regression models and computed semi‐partial R2 from mixed models predicting WMH volume as a percentage of Total Intracranial Volume (TIV). All models were adjusted for age, sex, and scanner model, and the WMH and based were log‐transformed before fitting. We also conducted subset analyses with high (WMH+) vs. low (WMH‐) baseline WMH load (cut at 1.62%) to compare the performance of the measures in early vs. widespread WMH.ResultAll MD‐based quantities computed on the whole brain, including FWF, performed similarly to each other, but Genu FA underperformed at explaining WMH variance (Table 1). PSMD (skeletonized or atlas based) was more sensitive in WMH+ but dramatically less so in WMH‐. In WMH‐ and overall cohort, FWF and JHU MD (which is a simple averaging of MD in the JHU atlas) performed well.ConclusionAll MD‐based measures performed similarly to each other in the whole dataset but dichotomizing by WMH load showed interesting differences. PSMD measurements are driven by the extreme end (95th percentile) of the MD distribution and therefore more sensitive in WMH+. Genu FA, a regional measure, was not useful for predicting whole brain WMH change. We noticed some variation in how the quantities are affected by scanner model (GE Signa HDxt and Discovery 750) which needs broader investigation. Simply averaging MD over WM avoids additional processing and is more sensitive to WM degeneration that is not (yet) severe.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n = 71; hospitalized,n = 9,non‐hospitalized,n = 62 during the acute infection) and controls(n = 50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p = 0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

AbstractBackgroundImaging and plasma markers are used as key indicators of disease for Alzheimer’s disease (AD) but their usefulness in predicting regional tau pathology is relatively understudied. Our objective was to construct predictive models for regional tau pathology measured on postmortem brain tissue using multiple ante‐mortem AD biomarkers. We focused on hippocampal and parietal regions that were immunostained with AT8 and 2E9 that reflect early and advanced aspects of tangle maturity, respectively.MethodsUsing autopsy data from 63 participants enrolled in the Mayo Clinic Study of Aging (MCSA) where the last clinical visit is within three years of death, we analyzed three ante‐mortem plasma markers ‐ phosphorylated tau protein at the threonine 181 residue, glial fibrillary acidic protein, total ß‐amyloid Aß42 relative to Aß40 ratio (Quanterix Simoa HD‐X Analyzer), and three regional MRI markers computed using SPM12 ‐ parietal thickness, parietal volume relative to total intracranial volume ratio, and hippocampal volume adjusted for total intracranial volume. Based on eight separate cross‐sectional linear regression models weighted by the inverse of time from last visit to death, we estimated the multiple and partial R2 predicting post‐mortem pathology measures, including AT8 and 2E9 in both the hippocampal and parietal regions. All models were adjusted for age, sex, and cardiovascular and metabolic conditions score.ResultsThe MRI models (R2 of 0.26‐0.53) had greater predictive power compared to the plasma models (R2 of 0.17‐0.26). The best multiple R2 was 0.53 for prediction of hippocampal AT8 using antemortem hippocampal volume adjusted for total intracranial volume followed by R2 of 0.43 for prediction of hippocampal 2E9 using hippocampal volume adjusted for total intracranial volume. Though the model prediction of parietal AT8 and 2E9 measurements was low (R2 of 0.21‐0.26), parietal thickness exhibited better predictive performance than parietal volume relative to total intracranial volume ratio.ConclusionsThe data we presented here may be utilized to validate biomarkers using regional pathology. Our results support that regional MRI is sensitive to tau pathology. Newer MRI methods should be tested to examine the specificity of newer quantitative measurements to tau pathology.