Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite pulmonary impairments being the most prevalent, extra-pulmonary ...manifestations of COVID-19 are abundant. Confirmed COVID-19 cases have now surpassed 57.8 million worldwide as of 22 November 2020. With estimated case fatality rates (number of deaths from COVID-19 divided by number of confirmed COVID-19 cases) varying between 1 and 7%, there will be a large population of recovered COVID-19 patients that may acquire a multitude of long-term health consequences. While the multi-organ manifestations of COVID-19 are now well-documented, the potential long-term implications of these manifestations remain to be uncovered. In this review, we turn to previous similar coronaviruses (i.e. SARS-CoV-1 and Middle East respiratory syndrome coronavirus MERS-CoV) in combination with known health implications of SARS-CoV-2 infection to predict potential long-term effects of COVID-19, including pulmonary, cardiovascular, hematologic, renal, central nervous system, gastrointestinal, and psychosocial manifestations, in addition to the well-known post-intensive care syndrome. It is necessary to monitor COVID-19 patients after discharge to understand the breadth and severity of long-term effects. This can be accomplished by repurposing or initiating large cohort studies to not only focus on the long-term consequences of SARS-CoV-2 infection, but also on acquired immune function as well as ethno-racial group and household income disparities in COVID-19 cases and hospitalizations. The future for COVID-19 survivors remains uncertain, and if this virus circulates among us for years to come, long-term effects may accumulate exponentially.
The amyloid hypothesis has so far been at the forefront of explaining the pathogenesis of Alzheimer's Disease (AD), a progressive neurodegenerative disorder that leads to cognitive decline and ...eventual death. Recent evidence, however, points to additional factors that contribute to the pathogenesis of this disease. These include the neurovascular hypothesis, the mitochondrial cascade hypothesis, the inflammatory hypothesis, the prion hypothesis, the mutational accumulation hypothesis, and the autoimmunity hypothesis. The purpose of this review was to briefly discuss the factors that are associated with autoimmunity in humans, including sex, the gut and lung microbiomes, age, genetics, and environmental factors. Subsequently, it was to examine the rise of autoimmune phenomena in AD, which can be instigated by a blood-brain barrier breakdown, pathogen infections, and dysfunction of the glymphatic system. Lastly, it was to discuss the various ways by which immune system dysregulation leads to AD, immunomodulating therapies, and future directions in the field of autoimmunity and neurodegeneration. A comprehensive account of the recent research done in the field was extracted from PubMed on 31 January 2022, with the keywords "Alzheimer's disease" and "autoantibodies" for the first search input, and "Alzheimer's disease" with "IgG" for the second. From the first search, 19 papers were selected, because they contained recent research on the autoantibodies found in the biofluids of patients with AD. From the second search, four papers were selected. The analysis of the literature has led to support the autoimmune hypothesis in AD. Autoantibodies were found in biofluids (serum/plasma, cerebrospinal fluid) of patients with AD with multiple methods, including ELISA, Mass Spectrometry, and microarray analysis. Through continuous research, the understanding of the synergistic effects of the various components that lead to AD will pave the way for better therapeutic methods and a deeper understanding of the disease.
While coronavirus disease 2019 (COVID-19) begins as a respiratory infection, it progresses as a systemic disease involving multiorgan microthromboses that underly the pathology. SARS-CoV-2 enters ...host cells via attachment to the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is widely expressed in a multitude of tissues, including the lung (alveolar cells), heart, intestine, kidney, testis, gallbladder, vasculature (endothelial cells), and immune cells. Interference in ACE2 signaling could drive the aforementioned systemic pathologies, such as endothelial dysfunction, microthromboses, and systemic inflammation, that are typically seen in patients with severe COVID-19. ACE2 is a component of the renin-angiotensin system (RAS) and is intimately associated with the plasma kallikrein-kinin system (KKS). As many papers are published on the role of ACE and ACE2 in COVID-19, we will review the role of bradykinin, and more broadly the KSS, in SARS-CoV-2-induced vascular dysfunction. Furthermore, we will discuss the possible therapeutic interventions that are approved and in development for the following targets: coagulation factor XII (FXII), tissue kallikrein (KLK1), plasma kallikrein (KLKB1), bradykinin (BK), plasminogen activator inhibitor (PAI-1), bradykinin B1 receptor (BKB1R), bradykinin B2 receptor (BKB2R), ACE, furin, and the NLRP3 inflammasome. Understanding these targets may prove of value in the treatment of COVID-19 as well as in other virus-induced coagulopathies in the future.
Widespread SARS-CoV-2 testing is invaluable for identifying asymptomatic/pre-symptomatic individuals. There remains a technological gap for highly reliable, easy, and quick SARS-CoV-2 diagnostic ...tests suitable for frequent mass testing. Compared to nasopharyngeal (NP) swab-based tests, saliva-based methods are attractive due to easier and safer sampling. Current saliva-based SARS-CoV-2 rapid antigen tests (RATs) are hindered by limited analytical sensitivity. Here, we report one of the first ultrasensitive, saliva-based SARS-CoV-2 antigen assays with an analytical sensitivity of <0.32 pg/mL, corresponding to four viral RNA copies/µL, which is comparable to that of PCR-based tests.
Using the novel electrochemiluminescence (ECL)-based immunoassay, we measured the SARS-CoV-2 nucleocapsid (N) antigen concentration in 105 salivas, obtained from non-COVID-19 and COVID-19 patients. We then verified the results with a second, independent cohort of 689 patients (3.8% SARS-CoV-2 positivity rate). We also compared our method with a widely used point-of-care rapid test.
In the first cohort, at 100% specificity, the sensitivity was 92%. Our assay correctly identified samples with viral loads up to 35 CT cycles by saliva-based PCR. Paired NP swab-based PCR results were obtained for 86 cases. Our assay showed high concordance with saliva-based and NP swab-based PCR in samples with negative (<0.32 pg/mL) and strongly positive (>2 pg/mL) N antigen concentrations. In the second cohort, at 100% specificity, sensitivity was also 92%. Our assay is about 700-fold more sensitive than the Abbott Panbio Rapid Test.
We demonstrated the ultrasensitivity and specificity assay and its concordance with PCR. This novel assay is especially valuable when compliance to frequent swabbing may be problematic.
Gliomas are among the most malignant tumors, with a very poor prognosis. Early diagnosis is highly desirable since it can help implement more effective treatments for smaller tumors, which have not ...yet extensively metastasized. Improving early diagnosis may facilitate access of patients to clinical trials and prepare them for the future availability of new disease-modifying treatments.
We analyzed retrospective samples collected at diagnosis (before therapy initiation), with PEA (Olink Proteomics), quantifying about 3000 proteins. We utilized 30 plasmas from gliomas (20 glioblastomas, 5 anaplastic astrocytomas, 5 anaplastic oligodendrogliomas) and 20 meningiomas (as controls). We then analyzed the data to identify proteins which either alone, or in combination, could discriminate gliomas from meningiomas, or correlate with clinical and molecular alterations.
We identified 8 plasma proteins which were increased in gliomas vs. meningiomas (GFAP, NEFL, EDDM3B, PROK1, MMP3, CTRL, GP2, SPINT3) and 4 proteins which were decreased in gliomas vs. meningiomas (FABP4, ALDH3A1, IL-12B and OXT). Partition algorithms and logistic regression algorithms with two biomarkers (GFAP and FABP4) achieved sensitivity of 83% and 93% at 100% and 90% specificity, respectively. The strongest single marker was GFAP with an area under the ROC curve (AUC) of 0.86. The AUC for the GFAP-FABP4 combination was 0.98.
PEA is a powerful new proteomic technology for biomarker discovery. GFAP and a handful of other plasma biomarkers may be useful for early glioma detection and probably, prognosis.
Detecting gliomas as early as possible is highly desirable since it can significantly improve the chances of effective treatments. Reliable glioma biomarkers can timely inform glioma patients about the efficacy of their prescribed treatment. Our results reveal some novel putative glioma markers that may prove valuable, when used alone or in combination, towards improved clinical care of gliomas. In order to better appreciate the potential usefulness of these markers, their performance needs to be further validated in a larger cohort of samples.
Background Multiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of neurofilament as a ...cerebrospinal fluid (CSF) biomarker, there is reinvigorated interest in identifying other markers of or contributors to disease. The objective of this study is to probe the predictive potential of a panel of brain-enriched proteins on MS disease progression and subtype. Methods This study includes 40 individuals with MS and 14 headache controls. The MS cohort consists of 20 relapsing remitting (RR) and 20 primary progressive (PP) patients. The CSF of all individuals was analyzed for 63 brain enriched proteins using a method of liquid-chromatography tandem mass spectrometry. Wilcoxon rank sum test, Kruskal-Wallis one-way ANOVA, logistic regression, and Pearson correlation were used to refine the list of candidates by comparing relative protein concentrations as well as relation to known imaging and molecular biomarkers. Results We report 30 proteins with some relevance to disease, clinical subtype, or severity. Strikingly, we observed widespread protein depletion in the disease CSF as compared to control. We identified numerous markers of relapsing disease, including KLK6 (kallikrein 6, OR = 0.367, p < 0.05), which may be driven by active disease as defined by MRI enhancing lesions. Other oligodendrocyte-enriched proteins also appeared at reduced levels in relapsing disease, namely CNDP1 (carnosine dipeptidase 1), LINGO1 (leucine rich repeat and Immunoglobin-like domain-containing protein 1), MAG (myelin associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein). Finally, we identified three proteins--CNDP1, APLP1 (amyloid beta precursor like protein 1), and OLFM1 (olfactomedin 1)--that were statistically different in relapsing vs. progressive disease raising the potential for use as an early biomarker to discriminate clinical subtype. Conclusions We illustrate the utility of targeted mass spectrometry in generating potential targets for future biomarker studies and highlight reductions in brain-enriched proteins as markers of the relapsing remitting disease stage. Keywords: Multiple sclerosis, CSF, Biomarkers, Proteomics
Background Multiple sclerosis (MS) remains a highly unpredictable disease. Many hope that fluid biomarkers may contribute to better stratification of disease, aiding the personalisation of treatment ...decisions, ultimately improving patient outcomes. Objective The objective of this study was to evaluate the predictive value of CSF brain-specific proteins from early in the disease course of MS on long term clinical outcomes. Methods In this study, 34 MS patients had their CSF collected and stored within 5 years of disease onset and were then followed clinically for at least 15 years. CSF concentrations of 64 brain-specific proteins were analyzed in the 34 patient CSF, as well as 19 age and sex-matched controls, using a targeted liquid-chromatography tandem mass spectrometry approach. Results We identified six CSF brain-specific proteins that significantly differentiated MS from controls (p < 0.05) and nine proteins that could predict disease course over the next decade. CAMK2A emerged as a biomarker candidate that could discriminate between MS and controls and could predict long-term disease progression. Conclusion Targeted approaches to identify and quantify biomarkers associated with MS in the CSF may inform on long term MS outcomes. CAMK2A may be one of several candidates, warranting further exploration. Keywords: Multiple sclerosis, Brain-specific proteins, CSF, Biomarkers
Multiple sclerosis (MScl) remains a highly unpredictable disease. Many hope that fluid biomarkers may contribute to better stratification of disease, aiding the personalization of treatment ...decisions, ultimately improving patient outcomes. The objective of this study was to evaluate the predictive value of cerebrospinal fluid (CSF) brain-specific proteins from early in the disease course of MScl on long term clinical outcomes. In this prospective longitudinal study, 34 MScl patients had their CSF collected and stored within 5 years of disease onset and were then followed clinically for at least 15 years. CSF concentrations of 64 brain-specific proteins were analyzed in the 34 patient CSF, as well as 19 age and sex-matched controls, using a targeted liquid-chromatography tandem mass spectrometry approach. We identified six CSF brain-specific proteins that significantly differentiated MScl from controls (p < 0.05) and several proteins that could predict disease course over the next decade. Calcium/Calmodulin Dependent Protein Kinase II Alpha (CAMK2A) emerged as a biomarker candidate that could discriminate between MScl and controls and could predict long-term disease progression. Targeted approaches to identify and quantify biomarkers associated with MScl in the CSF may inform on long term MScl outcomes. CAMK2A may be one of several candidates, warranting further exploration.
Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) is a novel approach in gynecological surgery. This study was aimed at comparing perioperative and short-term postoperative outcomes of ...vNOTES versus laparoscopic approaches to uterosacral ligament suspension (USLS) for apical pelvic organ prolapse.INTRODUCTION AND HYPOTHESISVaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) is a novel approach in gynecological surgery. This study was aimed at comparing perioperative and short-term postoperative outcomes of vNOTES versus laparoscopic approaches to uterosacral ligament suspension (USLS) for apical pelvic organ prolapse.A retrospective cohort study included all women who underwent vNOTES versus laparoscopic USLS at two university-affiliated centers between 2017 and 2023. The relationships between variables were tested using Fisher's exact test or t test, including a sub-analysis comparing hysterectomy and hysteropexy outcomes within the groups. Logistic regression assessed the influence of baseline factors and operative factors on the primary and main secondary outcomes of interest.METHODSA retrospective cohort study included all women who underwent vNOTES versus laparoscopic USLS at two university-affiliated centers between 2017 and 2023. The relationships between variables were tested using Fisher's exact test or t test, including a sub-analysis comparing hysterectomy and hysteropexy outcomes within the groups. Logistic regression assessed the influence of baseline factors and operative factors on the primary and main secondary outcomes of interest.This study comprised 47 vNOTES and 54 laparoscopic USLS cases (including 11 and 15 hysteropexies respectively). Baseline demographics in the two groups were similar. There were no differences in operative outcomes and no instances of ureteral injury. The vNOTES technique allowed for the use of significantly more sutures per side (2.0 2.0-4.0 vs 1.0 1.0-1.0, p = 0.001). Postoperative complications within 6 weeks demonstrated no significant differences. Both groups exhibited comparable rates of baseline subjective POP symptoms (100% vs 96.2%, p = 1.00) which improved significantly at 6 weeks (4.3% vs 11.1%, p = 0.282). At 6 weeks, anatomical success was achieved by significantly more patients with vNOTES (93.5% vs 78.6%, p = 0.042). Baseline and 6-week POP symptoms in the hysterectomy and hysteropexy subgroups were similar.RESULTSThis study comprised 47 vNOTES and 54 laparoscopic USLS cases (including 11 and 15 hysteropexies respectively). Baseline demographics in the two groups were similar. There were no differences in operative outcomes and no instances of ureteral injury. The vNOTES technique allowed for the use of significantly more sutures per side (2.0 2.0-4.0 vs 1.0 1.0-1.0, p = 0.001). Postoperative complications within 6 weeks demonstrated no significant differences. Both groups exhibited comparable rates of baseline subjective POP symptoms (100% vs 96.2%, p = 1.00) which improved significantly at 6 weeks (4.3% vs 11.1%, p = 0.282). At 6 weeks, anatomical success was achieved by significantly more patients with vNOTES (93.5% vs 78.6%, p = 0.042). Baseline and 6-week POP symptoms in the hysterectomy and hysteropexy subgroups were similar.Both vNOTES and laparoscopic USLS demonstrated comparable subjective success rates at 6 weeks postoperatively. The vNOTES approach demonstrated improved anatomical success at 6 weeks, but the difference was not significant after adjusting for operative factors.CONCLUSIONBoth vNOTES and laparoscopic USLS demonstrated comparable subjective success rates at 6 weeks postoperatively. The vNOTES approach demonstrated improved anatomical success at 6 weeks, but the difference was not significant after adjusting for operative factors.
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