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Annals of Emergency Medicine Jun 2024Acute aortic syndrome is a life-threatening emergency condition. Previous systematic reviews of D-dimer diagnostic accuracy for acute aortic syndrome have been...
STUDY OBJECTIVE
Acute aortic syndrome is a life-threatening emergency condition. Previous systematic reviews of D-dimer diagnostic accuracy for acute aortic syndrome have been contradictory and based on limited data, but recently published studies offer potential for a more definitive overview. We aimed to perform a systematic review and meta-analysis to determine the diagnostic accuracy of D-dimer for diagnosing acute aortic syndrome.
METHODS
We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic cohort studies (prospective or retrospective) that assessed the use of D-dimer for diagnosing acute aortic syndrome compared with a reference standard test (eg, computed tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two independent reviewers completed study selection, data extractions and quality assessment using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Data were synthesized using a bivariate meta-analysis model.
RESULTS
Of 2017 potentially relevant citations, 25 cohort studies met the inclusion criteria, and 18 reporting the 500 ng/mL threshold were included in the primary meta-analysis. Risk of bias domains were mostly unclear due to limited study reporting. The summary sensitivity was 96.5% (95% credible interval [CrI] 94.8% to 98%) and summary specificity was 56.2% (95% CrI, 48.3% to 63.9%). Study specificity varied markedly from 33% to 86%, indicating substantial heterogeneity. Sensitivity analysis including the 7 studies reporting other thresholds showed summary sensitivity of 95.7% (95% CrI, 93.2% to 97.5%) and summary specificity of 57.5% (95% CrI, 50.1% to 64.6%).
CONCLUSION
D-dimer concentration has high sensitivity (96.5%) and moderate specificity (56.2%) for acute aortic syndrome, with some uncertainty around estimates due to risk of bias and heterogeneity. Previous meta-analysis reporting higher specificity may be explained by inclusion of case-control studies that may overestimate accuracy.
PubMed: 38888529
DOI: 10.1016/j.annemergmed.2024.05.001 -
Alzheimer's Research & Therapy Jun 2024Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a...
BACKGROUND
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
METHODS
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
RESULTS
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
CONCLUSIONS
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Topics: Humans; Locus Coeruleus; Female; Alzheimer Disease; Male; Aged; Magnetic Resonance Imaging; tau Proteins; Aged, 80 and over; Cohort Studies; Amyloid beta-Peptides; Positron-Emission Tomography; Cerebral Cortex; Carbolines; Thiazoles; Aniline Compounds; Brain Cortical Thickness
PubMed: 38886798
DOI: 10.1186/s13195-024-01500-0 -
Heliyon Jun 2024The molecular pathology of lung injury in patients with Corona Virus Disease 2019 (COVID-19) remain unclear. In this study, we performed a proteomic study of lung...
The molecular pathology of lung injury in patients with Corona Virus Disease 2019 (COVID-19) remain unclear. In this study, we performed a proteomic study of lung tissues from seven patients with COVID-19, and eight without. Lung parenchymal tissues with COVID-19 were obtained from autopsy samples, while control samples were obtained from paracancerous tissues. Proteins were extracted using phenol extraction. A tandem mass tag-based quantitative proteomic approach combined with bioinformatic analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. A total of 6,602, and 6,549 proteins were identified in replicates 1 and 2, respectively. Of these, 307, and 278, respectively, were identified as differentially expressed proteins (DEPs). In total, 216 DEPs were identified in this study. These proteins were enriched in 189 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The downregulated proteins are mainly involved in focal adhesion (n = 5), and the PI3K-Akt signaling pathway (n = 4). The upregulated proteins were related to neutrophil extracellular trap (NET) formation (n = 16), and the phagosome pathway (n = 11). The upregulated proteins in these two pathways interact with one another. Further immunohistochemistry verified NET enrichment in the tissues with COVID-19 compared to the controls. Our results systematically outlined the proteomic profiles of the lung's response to SARS-CoV-2 infection and indicated that NET formation was hyper-activated. These results will hopefully provide new evidence for understanding the mechanism behind fatal COVID-19.
PubMed: 38882332
DOI: 10.1016/j.heliyon.2024.e31878 -
Cureus Jun 2024Background Inborn errors of metabolism (IEM) are collectively rare but potentially preventable causes of sudden unexpected death (SUD) in infancy or childhood, and...
Background Inborn errors of metabolism (IEM) are collectively rare but potentially preventable causes of sudden unexpected death (SUD) in infancy or childhood, and metabolic autopsy serves as the final tool for establishing the diagnosis. We conducted a retrospective review of the metabolic and molecular autopsy on SUD and characterized the biochemical and genetic findings. Methodology A retrospective review of postmortem metabolic investigations (dried blood spot acylcarnitines and amino acid analysis, urine metabolic profiling where available, and next-generation sequencing on a panel of 75 IEM genes) performed for infants and children who presented with SUD between October 2016 and December 2021 with inconclusive autopsy findings or autopsy features suspicious of underlying IEM in our locality was conducted. Clinical and autopsy findings were reviewed for each case. Results A total of 43 infants and children aged between zero days to 10 years at the time of death were referred to the authors' laboratories throughout the study period. One positive case of multiple acyl-CoA dehydrogenase deficiency was diagnosed. Postmortem reference intervals for dried blood spot amino acids and acylcarnitines profile were established based on the results from the remaining patients. Conclusions Our study confirmed the importance of metabolic autopsy and the advantages of incorporating biochemical and genetic testing in this setting.
PubMed: 38882225
DOI: 10.7759/cureus.62347 -
SAGE Open Medical Case Reports 2024Adrenal gland cysts are rare and uncommon manifestations. Mostly asymptomatic, discovered incidentally during radiological studies or at autopsy, or without...
Adrenal gland cysts are rare and uncommon manifestations. Mostly asymptomatic, discovered incidentally during radiological studies or at autopsy, or without characteristic symptoms. The spectrum of these entities may include benign cysts or malignant cystic neoplasms. They are classified into four types: pseudocysts, endothelial cysts, epithelial cysts, and parasitic cysts. Though pseudocysts are reported to be the most frequently clinically recognized adrenal cysts in surgical series, endothelial cysts are more frequent in autopsy series. Even with advanced imaging modalities, it is still difficult to differentiate a benign adrenal neoplasm from a malignant one. As a result, getting a definitive diagnosis and starting treatment is challenging. In both symptomatic and asymptomatic cases with a large diameter or increasing sizes during follow-up, or with any abnormality of adrenal hormones, surgery is the treatment of choice in symptomatic. Herein, we present a 47-year-old female with a nonfunctional left adrenal endothelial cyst, who was incidentally found during a computerized tomography scan. The patient presented with left-sided nephritic colic due to renal lithiasis. The objective of this paper is to recall the clinical characteristics and to specify the diagnostic contribution of imaging as well as the therapeutic modalities of this entity.
PubMed: 38881974
DOI: 10.1177/2050313X241261510 -
Forensic Science International Jun 2024Violence against women is a significant public health concern, with femicide as its most extreme manifestation. This crime is often perpetrated by current or former...
Violence against women is a significant public health concern, with femicide as its most extreme manifestation. This crime is often perpetrated by current or former intimate partners, thus taking the name of intimate partner femicide (IPF). Although international comparisons are essential for prevention policies, cross-country comparative studies are scarce in this context. The aim of this study was to evaluate and compare clinical, epidemiological and medico-legal characteristics of IPF autopsy cases investigated at the Institutes of Legal Medicine of two Western European cities, in order to identify a potential medico-legal pattern of IPF. Autopsy and police reports of IPF cases occurred in the judicial district of Freiburg (Germany) and Padova (Italy) from 2000 to 2022 were analyzed. Data relating to victims, perpetrators, relationship context, and circumstantial and pathological-forensic characteristics of the homicide were collected. Statistical analyses were performed to explore potential relationships between the data collected. Additionally, a review of the literature dealing with autopsy-based studies on IPF was performed. Overall, 82 cases of IPF were analyzed, 39 from Freiburg and 43 from Padova. A total of 6 papers fulfilled the review inclusion criteria. Our study identified a medico-legal pattern of IPF and demonstrated that it did not vary substantially between the two European Countries considered, suggesting that certain IPF characteristics are shared at the European level. However, a significant finding emerged regarding the higher prevalence of firearm-related IPFs in Italy compared to Germany. Forensic pathology research might contribute to developing targeted prevention policies to protect women from this lethal form of violence.
PubMed: 38879897
DOI: 10.1016/j.forsciint.2024.112084 -
Journal of Chromatography. B,... Jun 2024Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in...
Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.
PubMed: 38878710
DOI: 10.1016/j.jchromb.2024.124196 -
Frontiers in Pharmacology 2024Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart...
Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats. Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment. GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.
PubMed: 38873418
DOI: 10.3389/fphar.2024.1402138 -
Scientific Reports Jun 2024Traumatic brain injury (TBI) is a ubiquitous, common sequela of accidents with an annual prevalence of several million cases worldwide. In forensic pathology, structural...
Traumatic brain injury (TBI) is a ubiquitous, common sequela of accidents with an annual prevalence of several million cases worldwide. In forensic pathology, structural proteins of the cellular compartments of the CNS in serum and cerebrospinal fluid (CSF) have been predominantly used so far as markers of an acute trauma reaction for the biochemical assessment of neuropathological changes after TBI. The analysis of endogenous metabolites offers an innovative approach that has not yet been considered widely in the assessment of causes and circumstances of death, for example after TBI. The present study, therefore, addresses the question whether the detection of metabolites by liquid-chromatography-mass spectrometry (LC/MS) analysis in post mortem CSF is suitable to identify TBI and to distinguish it from acute cardiovascular control fatalities (CVF). Metabolite analysis of 60 CSF samples collected during autopsies was performed using high resolution (HR)-LC/MS. Subsequent statistical and graphical evaluation as well as the calculation of a TBI/CVF quotient yielded promising results: numerous metabolites were identified that showed significant concentration differences in the post mortem CSF for lethal acute TBI (survival times up to 90 min) compared to CVF. For the first time, this forensic study provides an evaluation of a new generation of biomarkers for diagnosing TBI in the differentiation to other causes of death, here CVF, as surrogate markers for the post mortem assessment of complex neuropathological processes in the CNS ("neuroforensomics").
Topics: Humans; Brain Injuries, Traumatic; Biomarkers; Male; Female; Middle Aged; Adult; Aged; Chromatography, Liquid; Metabolomics; Mass Spectrometry; Young Adult; Autopsy; Aged, 80 and over
PubMed: 38871842
DOI: 10.1038/s41598-024-64312-0 -
Scientific Reports Jun 2024Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and...
Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.
Topics: Animals; Hernias, Diaphragmatic, Congenital; Neurons; Oligodendroglia; Rats; Humans; Brain; Female; Stem Cells; Fetus; Disease Models, Animal; Pregnancy; Male
PubMed: 38871804
DOI: 10.1038/s41598-024-64412-x