Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, ...death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.
Background
Most published minimally invasive esophagectomy techniques involve a multiple field approach, including laparoscopic and thoracoscopic esophageal mobilization. Laparoscopic transhiatal ...esophagectomy (LTE) should potentially reduce the complications associated with thoracotomy. This study aims to compare outcomes of LTE with open transhiatal esophagectomy (OTE) and en-bloc esophagectomy (EBE).
Methods
Retrospective chart review was performed on all patients who had an LTE for cancer between July 2008 and July 2012 at our institution. Data was compared with an historic cohort of patients who underwent OTE and EBE at the same institution from July 2002 to July 2008.
Results
There were 33 patients with LTE, compared with 60 patients with OTE and 139 with EBE. The presence of minor operative complications was similar (
p
= 0.36), but major complications were significantly less common in the LTE group (12, 23 and 33 %, respectively;
p
= 0.04). The median number of blood transfusions during hospitalization was significantly lower in the LTE group (0, 2.5 and 3, respectively;
p
= 0.005). Median tumor size was significantly smaller (1.5, 2.2, and 3 cm, respectively;
p
= 0.03), but the LTE group had a significantly higher percentage of patients with neoadjuvant treatment (39, 14 and 29 %, respectively;
p
= 0.008). Median lymph node yield for LTE was lower (24, 36 and 48, respectively;
p
< 0.0001), but the percentage of patients with positive nodes was similar (33, 33 and 39 %, respectively;
p
= 0.69). Mortality was equivalent among the groups (0, 2 and 4 %, respectively;
p
= 0.38). The median LOS for the LTE group was significantly lower (10, 13 and 15 days, respectively;
p
< 0.0001). Overall survival was not different between the three groups (
p
= 0.65), with median survival at 24 months of 70, 65 and 65 %, respectively.
Conclusion
LTE can be performed safely with less major complications and shorter hospital stay than open esophagectomy. The reduced lymph-node harvest did not impact overall survival.
Models of Alzheimer's disease propose a sequence of amyloid β (Aβ) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features ...evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal.
Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817)
11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years SD 3·3 before expected onset), followed by hypometabolism (14·1 years 5·1 before expected onset), and lastly structural decline (4·7 years 4·2 before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aβ accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning).
Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.
US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.
Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR ...images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐σ and FLAIR‐σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐μ decreased and T1‐σ and FLAIR‐σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.
Orange and blue brain regions respectively show regions with a significant increase or decrease in our new MR intensity‐based biomarkers (T1 Mu, T1 sigma, FLAIR mu and FLAIR sigma) or the conventional PET imaging biomarkers (Tau PET and Amyloid PET), when compared between mutation carriers versus non‐carriers of dominantly‐inherited Alzheimer disease. Great intensity of color corresponds to a smaller p‐value of the tested model, while EYO corresponds to accumulation of pathology over the years prior to symptom onset. Note that the temporal and regional distribution of abnormalities in FLAIR Mu, our most important intensity‐based biomarker, closely resemble those of tau PET.
Vital signs are frequently used in pediatric prehospital assessments and guide protocol utilization. Common pediatric vital sign classification criteria identify >80% of children in the prehospital ...setting as having abnormal vital signs, though few receive lifesaving interventions (LSIs). We sought to identify data-driven thresholds for abnormal vital signs by evaluating their association with prehospital LSIs.
We evaluated prehospital care records for children (<18 years) transported to the hospital during 2022 from a large, national repository of emergency medical services (EMS) patient encounters. Predictors of interest were heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), and pulse oximetry. HR, RR, and SBP were converted to Z-scores using age-based distributional models. Our outcome was potential LSIs, defined as performance of selected respiratory procedures, resuscitative interventions, or medication administrations. Using cut point analysis, we identified higher specificity (maximal specificity with a minimum of 25% sensitivity) and higher sensitivity (maximal sensitivity with a minimum of 25% specificity) ranges for each vital sign and evaluated measures of diagnostic accuracy.
We included 987,515 children (median age 10 years, IQR 2-15 years). An LSI occurred in 4.3% (2.1% with respiratory procedures, 1.2% with resuscitative interventions, and 2.0% with medication administration). HR, RR, and SBP demonstrated a U-shaped association with LSIs. Specificities ranged from 84.1% to 93.7% for higher specificity criteria, with RR demonstrating the best performance (sensitivity 84.6%, specificity 27.0%). Sensitivities ranged from 62.3% to 84.4% for higher sensitivity criteria.
Cut points for pediatric vital signs were associated with LSIs. Specific age-adjusted ranges can identify children at higher and lower risk for receipt of LSI. These ranges may be combined with other objective measures to improve the assessment of children in the prehospital setting, assist in optimizing protocol utilization, improve transport decision making, and guide destination selection.
INTRODUCTION
Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin‐1 (PSEN1) mutation ...carriers. We investigated how mutation position relative to codon 200 (pre‐/postcodon 200) influences these pathologic features and dementia at different stages.
METHODS
Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross‐sectionally evaluated regional Pittsburgh compound B‐positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging‐based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.
RESULTS
Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.
DISCUSSION
We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.
Highlights
Mutation position influences Aβ burden, SVD, and dementia.
PSEN1 pre‐200 group had stronger associations between Aβ burden and disease stage.
PSEN1 post‐200 group had stronger associations between SVD markers and disease stage.
PSEN1 post‐200 group had worse dementia score than pre‐200 in late disease stage.
Diffusion tensor imaging‐based SVD markers mediated mutation position effects on dementia in the late stage.
The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. ...Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.
The shock index (SI), the ratio of heart rate to systolic blood pressure, is a clinical tool for assessing injury severity. Age-adjusted SI models may improve predictive value for injured children in ...the out-of-hospital setting. We sought to characterize the proportion of children in the prehospital setting with an abnormal SI using established criteria, describe the age-based distribution of SI among injured children, and determine prehospital interventions by SI.
We performed a multi-agency retrospective cross-sectional study of children (<18 years) in the prehospital setting with a scene encounter for suspected trauma and transported to the hospital between 2018 and 2022 using the National Emergency Medical Services (EMS) Information System datasets. Our exposure of interest was the first calculated SI. We identified the proportion of children with an abnormal SI when using the SI, pediatric age-adjusted (SIPA); and the pediatric SI (PSI) criteria. We developed and internally validated an age-based distributional model for the SI using generalized additive models for location, scale, and shape to describe the age-based distribution of the SI as a centile or Z-score. We evaluated EMS interventions (basic airway interventions, advanced airway interventions, cardiac interventions, vascular access, intravenous fluids, and vasopressor use) in relation to both the SIPA, PSI, and distributional SI values.
We analyzed 1,007,863 pediatric EMS trauma encounters (55.0% male, median age 13 years IQR, 8–16 years). The most common dispatch complaint was for traffic/transport related injury (32.9%). When using the PSI and SIPA, 13.1% and 16.3% were classified as having an abnormal SI, respectively. There were broad differences in the percentage of encounters classified as having an abnormal SI across the age range, varying from 5.1 to 22.8% for SIPA and 3.7–20.1% for PSI. The SIPA values ranged from the 75th to 95th centiles, while the PSI corresponded to an SI greater than the 90th centile, except in older children. The centile distribution for SI declined during early childhood and stabilized during adolescence and demonstrated a difference of <0.1% at cutoff values. An abnormal PSI, SIPA and higher SI centiles (>90th centile and >95th centiles) were associated with interventions related to basic and advanced airway management, cardiac procedures, vascular access, and provision of intravenous fluids occurred with greater frequency at higher SI centiles. Some procedures, including airway management and vascular access, had a smaller peak at lower (<10th) centiles.
We describe the empiric distribution of the pediatric SI across the age range, which may overcome limitations of extant criteria in identifying patients with shock in the prehospital setting. Both high and low SI values were associated with important, potentially lifesaving EMS interventions. Future work may allow for more precise identification of children with significant injury using cutpoint analysis paired to outcome-based criteria. These may additionally be combined with other physiologic and mechanistic criteria to assist in triage decisions.
Purpose
To evaluate the accuracy of clinical parameters and established pre‐treatment risk stratification systems for prostate cancer (PCa) in predicting PSMA‐positive metastases in men undergoing ...Ga‐68‐PSMA PET/CT as initial staging examination.
Materials and Methods
A retrospective analysis in 108 consecutive treatment‐naïve patients with biopsy‐proven PCa undergoing Ga‐68‐PSMA PET/CT (median age, 72 years range, 49‐82 years) was performed. Prediction of PSMA‐positive metastases by serum PSA, clinical T stage (cT), ISUP group, percentage of positive biopsy cores, and derived risk scores (D'Amico risk classification system, Roach RF, Yale formula YF, and Briganti nomogram BN) was examined with ROC analysis.
Results
Any PSMA‐positive metastases were found in 36 of 108 patients, including LN metastases in 28 patients, extrapelvic LN metastases in 15 patients, and organ metastases in 19 patients (bone, 19; lung, 1). AUCs for PSA, cT, ISUP, and percentage of positive biopsy cores regarding PSMA‐positive metastases did not differ significantly (range, 0.6‐0.8; each P > 0.05). D'Amico (AUC, 0.61‐0.64) was inferior to RF (0.76‐0.83), YF (0.81‐0.86), and BN (0.73 to 0.88; each P < 0.05). Among the 89 high‐risk patients (D'Amico), decision for or against PET imaging based on RF (cut‐off, >18.0), YF (>10.8), or BN (>8.0) would have prevented PSMA PET/CT in 4 (5%), 15 (17%), or 18 patients (20%), respectively, while preserving a sensitivity ≥95% for PSMA‐positive metastases.
Conclusions
Clinical parameters and established risk stratification systems for PCa can predict Ga‐68‐PSMA PET‐positive metastases in treatment‐naïve patients. Especially YF and BN may improve identification of patients with the highest probability of metastatic disease detected by Ga‐68‐PSMA PET/CT.
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