Early Clinical Disease Research Articles

Investigation of the Use of Environmental Samples for the Detection of EHV-1 in the Stalls of Subclinical Shedders.

In populations of healthy show horses, the subclinical transmission and circulation of respiratory pathogens can lead to disease outbreaks. Due to recent outbreaks of equine herpesvirus-1 myeloencephalopathy (EHM) in the USA and Europe, many show organizers have instituted various biosecurity protocols such as individual horse testing, monitoring for early clinical disease and increasing hygiene and cleanliness protocols. The aim of this study was to determine the accuracy of detecting EHV-1 in the various environmental samples collected from the stalls of subclinical shedders. Four healthy adult horses were vaccinated intranasally with a modified-live EHV-1 vaccine in order to mimic subclinical shedding. Three additional horses served as non-vaccinated controls. All the horses were stabled in the same barn in individual stalls. Each vaccinated horse had nose-to-nose contact with at least one other horse. Prior to the vaccine administration, and daily thereafter for 10 days, various samples were collected, including a 6" rayon-tipped nasal swab, an environmental sponge, a cloth strip placed above the automatic waterer and an air sample. The various samples were processed for nucleic acid purification and analyzed for the presence of EHV-1 via quantitative PCR (qPCR). EHV-1 in nasal secretions was only detected in the vaccinated horses for 1-2 days post-vaccine administration. The environmental sponges tested EHV-1 qPCR-positive for 2-5 days (median 3.5 days) in the vaccinated horses and 1 day for a single control horse. EHV-1 was detected by qPCR in stall strips from three out of four vaccinated horses and from two out of three controls for only one day. EHV-1 qPCR-positive air samples were only detected in three out of four vaccinated horses for one single day. For the vaccinated horses, a total of 25% of the nasal swabs, 35% of the environmental stall sponges, 7.5% of the strips and 7.5% of the air samples tested qPCR positive for EHV-1 during the 10 study days. When monitoring the subclinical EHV-1 shedders, the collection and testing of the environmental sponges were able to detect EHV-1 in the environment with greater frequency as compared to nasal swabs, stationary strips and air samples.

The Value of Serum Procalcitonin, Thromboelastography Combined with Platelet Count in Predicting the Short-Term Progression of Septic Shock in the Intensive Care Unit.

By evaluating the level of serum procalcitonin (PCT), thromboelastography (TEG) and platelet count (PLT) of patients with septic shock in intensive care unit (ICU), the predictive value of the combination of the three indicators on the short-term progression was discussed, which provided a new basis for early clinical diagnosis and disease evaluation. The clinical data of 130 patients with septic shock admitted to the IUC of our hospital from December 2021 to December 2023 were analyzed retrospectively. These subjects were divided into good prognosis group (n=78) and poor prognosis group (n=52) according to the 28 d deaths. The influencing factors were explored using the Multivariate logistic regression analysis. The value of single or combined PCT, PLT and TEG in predicting poor short-term prognosis was assessed using the receiver operating characteristic (ROC) curve. The patients in poor prognosis group had higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, serum PCT level, coagulation reaction time (R value) and coagulation formation time (K value), but lower PLT levels, final strength of coagulation (MA value) and coagulation formation rate (α angle) than those in good prognosis group (P<0.001). PCT, R value and K value were risk factors (P<0.001), while PLT, MA value and α angle were protective factors (P<0.001). The area under the curve (AUC) of PCT, PLT and TEG predicting poor short-term progression was 0.813, 0.658 and 0.752, respectively. The AUC of combined three indicators was 0.905, which had the highest predictive value. Serum levels of PCT, PLT and TEG had certain value in predicting poor short-term progression of septic shock patients, and their combined diagnostic value was higher. Therefore, regular monitoring of these three indicators could provide certain guiding significance for the prevention and treatment of poor short-term prognosis in patients with septic shock.

Isophorone-based crystallization-induced-emission sensors detect proteome aggregation in live cells and tissues with breast cancer

BackgroundProtein misfolding and aggregation can lead to various diseases. Recent studies have shed light on the aggregated protein in breast cancer pathology, which suggests that it is crucial to design chemical sensors that visualize protein aggregates in breast cancer, especially in clinical patient-derived samples. However, most reported sensors are constrained in cultured cell lines. ResultsIn this work, we present the development of two isophorone-based crystallization-induced-emission fluorophores for detecting proteome aggregation in breast cancer cell line and tissues biopsied from diseased patients, designated as A1 and A2. These probes exhibited viscosity sensitivity and recovered their fluorescence strongly at crystalline state. Moreover, A1 and A2 exhibit selective binding capacity and strong fluorescence for various aggregated proteins. Utilizing these probes, we detect protein aggregation in stressed breast cancer cells, xenograft mouse model of human breast cancer and clinical patient-derived samples. Notably, the fluorescence intensity of both probes light up in tumor tissues. SignificanceThe synthesized isophorone-based crystallization-induced-emission fluorophores, A1 and A2, enable sensitive detection of protein aggregation in breast cancer cells and tissues. In the future, aggregated proteins are expected to become indicators for early diagnosis and clinical disease monitoring of breast cancer.

Assessment of Early Glaucomatous Optic Neuropathy in the Dog by Spectral Domain Optical Coherence Tomography (SD-OCT).

Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the ADAMTS10 gene. Using this model, the study describes early clinical disease markers for canine glaucoma. Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, ADAMTS10-mutant (median age 45.6 months, range 28.8-52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/- SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/- SEM 0.53 mmHg). Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/- SEM 38.4 μm to 9.3 +/- SEM 22.1 μm; p < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: -0.78; p < 0.003). There were no significant differences in the thickness of any retinal layers evaluated. SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin.

Organic polymer/inorganic heterostructure coupled with efficient allosteric bicycle strand displacement for photochemical sensing

In this work, a high-performance conjugated microporous polymer (CMP) decorated with BiOBr (Tr(PhXOD)3-CMP/BiOBr) is synthesized to application in construction of ultrasensitive photoelectrochemical (PEC) biosensor for sensing miRNA-122, by firstly coupling with efficient clip toehold-mediated allosteric bicycle strand displacement (ABSD). Notably, the Tr(PhXOD)3-CMP/BiOBr not only owns self-enhanced D-A-D structure that extremely shortens migration distance of photo-generated electron, but also forms Z-type heterostructure for accelerating electron-hole separation, thereby significantly enhancing the photocurrent with 10-fold higher than commonly used methods. Meanwhile, the clip toehold-mediated ABSD based on ternary linkage structure transformation avoids the attrition of invading strand, endowing the conservation of high concentration for undergoing rapid reaction with high-efficiency DNA amplification, which dramatically improves reaction time and superior target conversion. The experimental results indicate that proposed PEC biosensor had a high sensitivity to miRNA-122 with a detection limit of 0.49 fM, which provides a newly organic/inorganic photosensitive nanomaterials and efficient DNA strand displacement in bioanalytical and early clinical disease diagnosis.

阿尔茨海默病和轻度认知障碍患者的外周免疫细胞与神经心理学量表、脑18 F‐FDG、18F‐AV45 PET‐CT 之间的相关性

AbstractBackgroundImmune dysfunction in Alzheimer’s disease (AD) was previously thought to be limited to the central nervous system, but recent studies suggest that the peripheral immune system also plays a key role. This study compared and analyzed the changes in peripheral immune cells in patients with AD and mild cognitive impairment (MCI) and their correlation with cognition, and combined 18F‐FDG PET and 18F‐AV45 PET to investigate the role of peripheral immune cells in AD pathology and the possibility as biomarkers for early clinical diagnosis and disease assessment.MethodsThe 146 participants included 70 AD patients, 26 MCI patients, and 50 controls. 34 AD patients tested with 18F‐AV45 (18F ‐Florbetapir) positron emission tomography (PET). 23 were Aβ‐positive (A+), and 11 were Aβ‐negative (A‐). All participants had a peripheral immune cell, cognitive evaluation, and detailed nervous system examination.Results(1) Significant differences in peripheral immune cells in AD compared with MCI and CG; (2) There was no significant correlation between NEU%, NLR, LY, and LY% and cognitive scale scores for patients in the AD and A+ groups, while there was a significant correlation with cognitive scale scores in the MCI and A‐ groups; and (3) Peripheral immune cells NEU%, NLR, LY, and LY% in A+ patients were correlated with FDG metabolism in several functional brain areas and Aβ load in some brain areas, but not with Aβ load in all functional brain areas in A‐ patients.ConclusionDifferences in peripheral immune cells help to distinguish AD from MCI, with NLR having better diagnostic efficacy. peripheral immune cells may have a greater impact on early cognitive dysfunction; NEU%, NLR, LY, and LY% may be associated with Aβ deposition and could serve as potential biomarkers for early clinical diagnosis and disease assessment in AD.

Recent research progress of surface enhanced Raman scattering dominated analysis strategy in early diagnosis of diseases.

Timely and powerful diagnostic means can achieve better therapeutic effects, reduce disease torment, and improve survival rate. As a powerful non-invasive spectroscopy technology, surface-enhanced Raman scattering (SERS) have testified to be a great potential candidate for extensive early clinical disease diagnosis. In recent years, the introduction of SERS label, combined with other analysis modes or artificial intelligence, and the emergence of miniaturized devices have made SERS technology more advantageous in early diagnosis of diseases. This review focuses on the research progress of SERS dominated analytical strategies in the field of early disease diagnosis in the past five years. The main content includes the application of label-free SERS detection; the construction of label SERS methodologies for various disease markers; SERS dominated multimode early disease diagnosis strategies; integration of SERS and artificial intelligence; portable Raman equipment and SERS imaging; opportunities and trends for SERS diagnostic technology in the future.

Histological prognosticators in neoadjuvant naive oesophageal cancer patients.

Prognosis of oesophageal cancer is primarily based upon the TNM stage of the disease. However, even in those with similar TNM staging, survival can be varied. Additional histopathological factors including venous invasion (VI), lymphatic invasion (LI) and perineural invasion (PNI) have been identified as prognostic markers yet are not part of TNM classification. The aim of this study is to determine the prognostic importance of these factors and overall survival in patients with oesophageal or junctional cancer who underwent transthoracic oesophagectomy as the unimodality treatment. Data from patients who underwent transthoracic oesophagectomy for adenocarcinoma without neoadjuvant treatment were reviewed. Patients were treated with radical resection, with a curative intent using a transthoracic Ivor Lewis or three staged McKeown approach. A total of 172 patients were included. Survival was poorer when VI, LI and PNI were present (p<0.001), with the estimated survival being significantly worse (p<0.001) when patients were stratified according to the number of factors present. Univariable analysis of factors revealed VI, LI and PNI were all associated with survival. Presence of LI was independently predictive of incorrect staging/upstaging in multivariable logistic regression analysis (OR 12.9 95% CI 3.6-46.6, p<0.001). Histological factors of VI, LI and PNI are markers of aggressive disease and may have a role in prognostication and decision-making prior to treatment. The presence of LI as an independent marker of upstaging could be a potential indication for the use of neoadjuvant treatment in patients with early clinical disease.

Enzyme‐Free Fluorescent Detection of MicroRNA in Clinical Samples by Catalytic Hairpin Assembly Coupled with Magnetic Bead‐Confined 3D DNA Walking

AbstractCatalytic hairpin assembly (CHA), as an enzyme‐free isotheral nucleic acid amplification method, can easily cooperate with other amplification procedures to improve the sensitivity and accuracy of detection. Herein, we constructed a cascaded CHA sensing platform for breast cancer biomarker detection. Introducing a short double nucleic acid stand avoids the product of CHA1 to directly trigger the CHA2 reaction, which simplifies the design of the CHA hairpins. Compared with the single CHA2 reaction, the cascaded CHA biosensor activated by microRNA‐155 holds nearly 10 times the amplification efficiency with detection limit down to 47.4 pM and quantifies the target in the range from 50 pM to 200 nM. Besides, the magnetic bead‐confined CHA2 taking 3D DNA walking as the display form contributes to decreasing the environmental interference. As expected, the strategy sensitively distinguishes expression levels of microRNA‐155 in different cell lines and cancer patients, which are consistent with the results of traditional qRT‐PCR method. More importantly, simply adjusting the microRNA recognition sequence of CHA1 can extend the cascaded CHA platform to a wider detection range. Therefore, the robustness and efficiency of the approach enable the potential applications for detection of microRNA and early clinical disease diagnosis.

Assessment of the Impact of Early Diagnosis and Early Treatment in the Integrated Control of East Coast Fever (ECF) Involving Acquired Immunity Induced by Natural Infection in Ankole Cattle.

The integrated control of East Coast fever (ECF) by early diagnosis and treatment involving acquired immunity induced by natural infection in Ankole cattle was assessed. A longitudinal study was carried out in Kiruhura district, southwestern Uganda for six months on 244 Ankole breed of cattle from 18 herds under natural tick challenge and relaxed tick control measures. Calves aged three to six months old were recruited and monitored daily by farmers for detection of ECF clinical symptoms. The reported sick animals were treated using Buparvaquone and treatment outcome determined. Monthly follow-ups and blood collections were done to monitor ECF status. Blood was analyzed for Theileria parva parasites by microscopy, DNA by polymerase chain reaction (PCR) and antibodies by enzyme-linked immunosorbent assay (ELISA). The overall prevalence of ECF clinical disease within six months period was 30.3% (74). The major symptoms of early clinical ECF disease were fever and enlarged parotid or prescapular lymph nodes. Clinical cases were categorized as mild, 24% (18) or moderate, 76% (56). There was an overall recovery rate of 100% (74) of the ECF cases whereby 94.6% (70) recovered promptly and 5.4% (4) recovered slowly. Based on blood analysis, prevalence of ECF at baseline was 3.7% (9) by microscopy, 31.1% (76) by PCR and 38.1% (93) by ELISA. A significant increase (p < 0.05) was shown by the increased number of calves with T. parva specific antibodies in the sera from 38.1% at baseline to 68.8% after six months. High antibody levels (positive percentage ≥ 50%) were detected in all ECF-treated and recovered calves at the end of six months. The acquired immunity to ECF was high in treated and recovered cattle, indicating that natural exposure to infection, accurate early diagnosis and effective treatment enhance development of immune-protection in indigenous cattle in an endemic area. The prominent early clinical symptoms for ECF could be exploited in the development of decision support tools for chemotherapy and other integrated control measures.

Fluorine-nitrogen co-doped carbon dots with stable and strong electrochemiluminescence as an emitter for ultrasensitive detection of HIV-DNA fragment

Herein, the fluorine-nitrogen co-doped carbon dots (FNCDs) with stable and strong electrochemiluminescence (ECL) was used as a novel ECL emitter for constructing an ultrasensitive biosensor to detect human immunodeficiency virus (HIV) DNA fragment. The doping of fluorine and nitrogen in the carbon dots (CDs) not only effectively formed hydrogen bonds to hinder the free rotation of CDs for increasing the radiation transition probability, but also changed the charge distribution of CDs leading to a narrower energy gap, which improved the ECL intensity and stability of FNCDs. Moreover, exonuclease III (Exo III) -assisted multiple recycling amplification could convert the trace HIV-DNA fragment into a large amount of output DNA to trigger horizontal hybridization chain reaction (H-HCR) to form Y-supported three-dimensional (3D) network DNA nanostructure for immobilizing a lot of doxorubicin-ferrocenecarboxylic acid (Dox-FcCOOH) as ECL quencher, which significantly improved the sensitivity of the proposed biosensor. Thus, the fabricated ECL biosensor realized ultrasensitive detection of HIV-DNA fragment in the concentration range of 10 aM to 10 pM with a detection limit as low as 6.34 aM. This strategy provided a novel ECL emitter to construct biosensors for detection of biomolecule and early clinical disease diagnosis.

Magnetic resonance imaging-based scoring of the diseased lung in the preterm infant with bronchopulmonary dysplasia: UNiforme Scoring of the disEAsed Lung in BPD (UNSEAL BPD).

Neonatal chronic lung disease lacks standardized assessment of lung structural changes. We addressed this clinical need by the development of a novel scoring system [UNSEAL BPD (UNiforme Scoring of the disEAsed Lung in BPD)] using T2-weighted single-shot fast-spin-echo sequences from 3 T MRI in very premature infants with and without bronchopulmonary dysplasia (BPD). Quantification of interstitial and airway remodeling, emphysematous changes, and ventilation inhomogeneity was achieved by consensus scoring on a five-point Likert scale. We successfully identified moderate and severe disease by logistic regression [area under the curve (AUC), 0.89] complemented by classification tree analysis revealing gestational age-specific structural changes. We demonstrated substantial interreader reproducibility (weighted Cohen's κ 0.69) and disease specificity (AUC = 0.91). Our novel MRI score enables the standardized assessment of disease-characteristic structural changes in the preterm lung exhibiting significant potential as a quantifiable endpoint in early intervention clinical trials and long-term disease monitoring.

DR4/DQ2 haplotype confers susceptibility to T1DM with early clinical disease onset: A retrospective analysis in a tertiary-care hospital in Italy.

T1DM is the most frequent form of diabetes in children. It has a multifactorial pathogenesis in which genetic, environmental and immunological factors are involved. Among genetic explanations a major role is attributed to second class HLA genes, with the greatest risk associated with the simultaneous presence of the haplotypes DR3DQ2 and DR4DQ8. Based on results obtained in other countries, the aim of this research is to verify a possible association between the haplotype DRB1 * 04: 05-DQA1 * 03-DQB1 * 02 and the onset of T1DM among Italian children with possible genotype-phenotype correlations. Greater knowledge of genes which increase or decrease susceptibility is important for genome analysis. 165 patients with type 1 diabetes treated at the Diabetology Unit of the Meyer Children's University Hospital, were clinically analyzed. Data relating to age at diagnosis, pancreatic anti-beta cell autoimmunity, comorbidities with date of diagnosis and family history were retrospectively collected from medical data. A case-control study was conducted to investigate the HLA types of the patients compared to a control group of 819 Tuscan donors enrolled in the National Bone Marrow Donor Register. Typing was carried out using the Eurospital "DIABEGEN" kit, currently in use at the immunology laboratory of the Meyer Children's University Hospital. Mean age at diagnosis was 9.3 years; most children (97%) had anti-pancreatic beta cell autoimmunity; the anti-insulin antibody (IAA) was more frequent among children with early clinical disease onset (0-5 years of age). From the case control comparison performed on HLA typing, it emerged that the greatest risk for the development of type 1 diabetes is conferred by the haplotypes DR3DQ2 and DR4DQ8, but in addition to these haplotypes, already known in other countries, we identified another haplotype, DR4DQ2 (DRB1 * 04: 05-DQA1 * 03-DQB1 * 02) which appears to predispose children to type 1 diabetes (p value 2.80E-08) and it is associated with early clinical disease onset (p-value = 0.002). We report a new haplotype which increases susceptibility to type 1 diabetes among Italian children and which is associated with early clinical disease onset. Given the central role attributed to genetic factors in the pathogenesis of T1DM and to the II class HLA genes, this new haplotype ought to be recognized as a risk factor and included in tests routinely carried out to identify patients with a genetic predisposition to type I diabetes in Italy. These findings could have practical implications in research and prevention programs.

Molecular Monitoring of EHV-1 in Silently Infected Performance Horses through Nasal and Environmental Sample Testing.

While the main goal in the management of an EHM outbreak focuses on identifying early clinical disease in order to physically separate infected horses, little effort is placed towards monitoring healthy horses. The assumption that EHV-1 shedding parallels clinical disease is erroneous, as subclinical shedders have been shown to be actively involved in viral spread. In an attempt to document the frequency of EHV-1 shedders and their impact on environmental contamination, we collected nasal swabs from 231 healthy horses and 203 environmental samples for the testing of EHV-1 by qPCR. Six horses and 28 stalls tested qPCR-positive for EHV-1. There was no association in the EHV-1 qPCR-positive status between nasal and stall swabs. While testing nasal secretions of healthy at-risk horses can detect active shedding at a specific time point, the testing of stall swabs allows to assess the temporal EHV-1 shedding status of a horse. The study results highlight the risk of subclinical EHV-1 shedders and stalls occupied by these horses as sources of infection for susceptible horses. The testing of individual stalls for the presence of EHV-1 may be a more practical approach than the collection of individual nasal swabs for the monitoring and early detection of the circulating virus. The results also highlight the need to improve the cleanliness and disinfection of stalls utilized by performance horses during show events.

Tumor-related Molecular Regulatory Mechanisms of Long Non-coding RNA RMST: Recent Evidence.

Long non-coding RNA rhabdomyosarcoma 2-associated transcript (LncRNA RMST) can affect every aspect of tumor progressions, such as proliferation, translocation, and apoptosis. As a result, RMST can be used as an attractive biomarker for early diagnosis and clinical therapies of different disease states. This article aims to review pathophysiological functions, molecular mechanisms as well as promising biotherapies of RMST in multiple tumors. Through the systematic induction and summary of 46 papers published in PubMed concerning this study, the molecular mechanisms of RMST in all kinds of tumors have been reviewed. LncRNA RMST is a tumor-related regulatory mediator, aberrantly expressed in diverse tumors, including medullary thyroid cancer, hepatocellular carcinoma, endometrial carcinoma, colon cancer, pancreatic cancer, glioma, Wilm's tumor, and breast cancer. Furthermore, as a mechanismbased player, RMST probably guides the translation and post-translation modification, containing DNA methylation and SUMOylation. It is capable of regulating distinct tumor cells and stem cells of biological behaviors via various molecular pathways. LncRNA RMST, potentially as an original therapeutic target, is valuable in the occurrence, development, and apoptosis of different tumors.

Beyond Lassa Fever: Systemic and structural barriers to disease detection and response in Sierra Leone.

BackgroundLassa fever (LF) often presents clinically as undifferentiated febrile illness. Lassa Fever cases in Sierra Leone have been falling since the 2014–2016 Ebola epidemic. Data from other LF endemic countries suggest that this is not a true reflection of local epidemiological decline, but rather a function of either health seeking behaviour or the health/referral system. In Sierra Leone, many other diseases present with a similar early clinical picture, including COVID-19 and Marburg Disease (which has recently emerged in neighbouring Guinea). This empirical study explores the implementation of health system processes associated with International Health Regulations (IHR) requirements for early detection and timely and effective responses to the spread of febrile disease, through the case study of LF in Sierra Leone.Methodology/Principal findingsThis study used a qualitative approach to analyse local policy and guidance documents, key informant interviews with policy and practice actors, and focus group discussions and in-depth interviews with health care workers (HCWs) and community health workers (CHWs) in Kenema District to examine the ways in which undifferentiated fever surveillance and response policies and processes were implemented in the post-Ebola period. Multiple challenges were identified, including: issues with the LF case definition, approaches to differential diagnosis, specimen transport and the provision of results, and ownership of laboratory data. These issues lead to delays in diagnosis, and potentially worse outcomes for individual patients, as well as affecting the system’s ability to respond to outbreak-prone disease.Conclusions/SignificanceIdentification of ways to improve the system requires balancing vertical disease surveillance programmes against other population health needs. Therefore, health system challenges to early identification of LF specifically have implications for the effectiveness of the wider Integrated Disease Surveillance and Response (IDSR) system in Sierra Leone more generally. Sentinel surveillance or improved surveillance at maternity facilities would help improve viral haemorrhagic fever (VHF) surveillance, as well as knowledge of LF epidemiology. Strengthening surveillance for vertical disease programmes, if correctly targeted, could have downstream benefits for COVID-19 surveillance and response as well as the wider health system—and therefore patient outcomes more generally.

Sera Metabolomics Characterization of Patients at Different Stages in Wuhan Identifies Critical Biomarkers of COVID-19.

We have witnessed the 2-year-long global rampage of COVID-19 caused by the wide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, knowledge about biomarkers of the entire COVID-19 process is limited. Identification of the systemic features of COVID-19 will lead to critical biomarkers and therapeutic targets for early intervention and clinical disease course prediction. Here, we performed a comprehensive analysis of clinical measurements and serum metabolomics in 199 patients with different stages of COVID-19. In particular, our study is the first serum metabolomic analysis of critical rehabilitation patients and critical death patients. We found many differential metabolites in the comparison of metabolomic results between ordinary, severe, and critical patients and uninfected patients. Through the metabolomic results of COVID-19 patients in various stages, and critical rehabilitation patients and critical death patients, we identified a series of differential metabolites as biomarkers, a separate queue and precise distinction, and predicted COVID-19 verification. These differentially expressed metabolites, included 1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate, propylparaben, 20-hydroxyeicosatetraenoic acid, triethanolamine, chavicol, disialosyl galactosyl globoside, 1-arachidonoylglycerophosphoinositol, and alpha-methylstyrene, all of which have been identified for the first time as biomarkers in COVID-19 progression. These biomarkers are involved in many pathological and physiological pathways of COVID-19, for example, immune responses, platelet degranulation, and metabolism which might result in pathogenesis. Our results showed valuable information about metabolites obviously altered in COVID-19 patients with different stages, which could shed light on the pathogenesis as well as serve as potential therapeutic agents of COVID-19.

The Overlap Index as a Means of Evaluating Early Tau PET Signal Reliability.

In tau PET, a reliable method to detect early tau accumulation in the brain is crucial. Noise, artifacts, and off-target uptake impede detection of subtle true-positive ligand binding. We hypothesize that identifying voxels with stable activity over time can enhance detection of true-positive tau. Methods: In total, 339 participants in the clinical spectrum ranging from clinically unimpaired to Alzheimer disease dementia underwent at least 2 serial tau PET scans with flortaucipir. The overlap index (OI) method was proposed to detect spatially identical, voxelwise SUV ratio (SUVR) elevation when seen sequentially in serial tau PET scans. The association of OI with tau accumulation, clinical diagnosis, and cognitive findings was evaluated. Results: OI showed good dynamic range in the low-SUVR window. Only OI was able to identify subgroups with increasing tau PET signal in low-SUVR meta-region-of-interest (ROI) groups. OI showed improved association with early clinical disease progression and cognitive scores versus meta-ROI SUVR measures. Conclusion: OI was more sensitive to tau signal elevation and longitudinal change than standard ROI measures, suggesting it is a more sensitive method for detecting early, subtle deposition of neurofibrillary tangles.

A benchmark for oncologic outcomes and model for lethal recurrence risk after transoral robotic resection of HPV-related oropharyngeal cancers

ObjectivesIncreasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm. Materials and methods634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts. Results5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P = .01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1–16.0, P = .001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3–28.5, P < .001). ConclusionsThis study sets a benchmark for oncologic outcomes from HPV+ OPSCC after TORS-based therapy. Under this treatment paradigm, margins are relevant for assessing lethal recurrence risk during clinical trial design and post-treatment surveillance.

The Overlap Index: A new means for early detection of serial tau PET signal change

AbstractBackgroundIn longitudinal tau (flortaucipir) positron emission tomography (PET), a reliable method to detect a tau accumulation while minimizing a random variability is crucial. Variability can be a problem especially in the early stages of tau pathology in which only small regions and low levels of accumulation may exist relative to the range of random noise fluctuation.MethodWe recruited 76 participants who had serial scans for a total of 234 tau PET scans. In this cohort we tested a PET signal measurement method we developed called the “overlap index” (OI). The OI was calculated by identifying voxels that have elevated tau PET signal that overlap on two successive tau PET scans in the same participant (Figure 1). This analysis procedure tests the hypothesis that voxel‐wise, elevated‐uptake consistency might be more sensitive for early detection of tau tangles than standard ROI based measures. We compared OI to ROI based measures for early detection of increasing tau PET signal and detection clinical progression. A meta ROI used in this analysis included the amygdala, entorhinal cortex, fusiform, parahippocampal, and inferior temporal and middle temporal gyri.ResultOI showed regional progression of tau in the temporal lobe followed by increases throughout the brain at relatively low standardized uptake value ratio (SUVr) levels (Figure 2A and B). The topographical pattern of OI was in agreement in some respects with the sequential appearance of tau aggregation (Figure 2B and C). The high‐OI group (OI&gt;0.5) had a significantly higher ΔSUVr compared to the low‐OI group (OI&lt;0.5) (Figure 3A and B). OI identified subjects that did or didn’t have tau accumulation within meta SUVr subgroups even when below the meta ROI SUVr threshold. OI was associated with early clinical disease stage progression vs meta‐ROI SUVr measures (Figure 3C‐E).ConclusionIn this study, we found that OI tau PET measurement was able to quantify voxel‐wise consistency using a set of serial scans. OI may detect earlier tau tangle accumulation and earlier disease progression than standard SUVr measurements in tau PET.