Asymptomatic Individuals Research Articles

Feasibility and Colonoscopy Yield Using the Fecal Immunochemical Test (FIT)-Based Colorectal Cancer Screening in a Latin America Country

Background and aimsOrganized colorectal cancer (CRC) is not widely practiced in Latin America and the results of regional studies may help overcome barriers for implementation of national screening programs. We aimed to describe the implementation and findings of a fecal immunochemical test (FIT)-based program in Brazil. MethodsIn a prospective population-based study, asymptomatic individuals (50 to 75 years-old) from Sao Paulo city were invited to undergo FIT for CRC screening. Participants with positive FIT (>10 μg Hb/g feces) were referred for colonoscopy. Subjects were classified into groups according to the presence of CRC, precursor lesions, and other benign findings, possibly related to bleeding. ResultsOf a total of 9,881 subjects, 7.8% had positive FIT and colonoscopy compliance was 68.9% (n=535). Boston scale was considered adequate in 99% and cecal intubation rate was 99.4%. CRC was diagnosed in 5.9% of the cases, adenoma in 63.2%, advanced adenoma (AA) in 31.4%, and advanced neoplasia (AN) in 33.0%. Age was positively associated with CRC (p=0.03). Higher FIT concentrations were associated with increased detection of CRC (p<0.008), AA (p<0.001), and AN (p<0.001). ConclusionImplementation of a FIT-based CRC screening program was feasible in a low-resource setting, and there was a high yield for neoplasia in individuals with a positive FIT. This approach could be used as a model to plan and disseminate organized CRC screening more broadly in Brazil and Latin America.

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project

BackgroundTraumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals.MethodsOur cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES.ResultsCSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations.ConclusionSpecific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Diagnostic Value of Fasting and Bedtime Saliva Pepsin Measurements in Laryngopharyngeal Reflux.

The pepsin test is an emerging non-invasive diagnostic approach for laryngopharyngeal reflux (LPR). The aim of this study was to investigate the diagnostic value of multiple salivary pepsin tests for detecting LPR. Patients with suspected LPR and asymptomatic individuals were consecutively recruited from January 2020 to November 2022. Patients benefited from hypopharyngeal-esophageal impedance-pH monitoring (HEMII-pH) and fasting and bedtime saliva collections to measure oral pepsin. The sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were calculated considering fasting, bedtime, and the highest values of the pepsin tests at ≥16, ≥36, ≥45, and ≥100 ng/mL cutoffs. The pepsin test was adequately performed in 147 LPR patients and 32 controls. The pepsin tests were 81.6%, 74.8%, and 61.5% sensitive at cutoffs of ≥16, ≥45, and ≥100 ng/mL, respectively. The PPVs were 93.0%, 94.0%, and 94.8%, respectively. The highest specificity (81.8%) was found for the fasting pepsin test at a cutoff of 100 ng/mL. The highest sensitivity (81.6%) was found by considering the highest measured pepsin test at the ≥16 ng/mL threshold. The measurement of fasting saliva pepsin was associated with the highest sensitivity and specificity value. At ≥16 ng/mL, 27 patients had negative findings, indicating that 18.4% (27/147) of the true positive cases were missed by considering the highest pepsin test. The receiver operating characteristic curve reported that a cutoff of 21.5 was 76.9% sensitive and 62.5% specific, while the PPV and NPV were 91.1% and 38.2%, respectively. The consideration of the highest concentration of the fasting and bedtime saliva pepsin collections at a cutoff of 21.5 was associated with the best detection rate and sensitivity of the pepsin tests.

Applying ONCO-RADS to whole-body MRI cancer screening in a retrospective cohort of asymptomatic individuals

BackgroundWhole-body magnetic resonance imaging (WB-MRI) has emerged as a valuable tool for cancer detection. This study evaluated the prevalence rates of cancer in asymptomatic individuals undergoing WB-MRI according to the Oncologically Relevant Findings Reporting and Data System (ONCO-RADS) classifications in order to assess the reliability of the classification method.MethodsWe retrospectively enrolled 2064 asymptomatic individuals who participated in a WB-MRI cancer screening program between 2017 and 2022. WB-MRI was acquired on a 3-T system with a standard protocol, including regional multisequence and gadolinium-based contrast agent-enhanced oncologic MRI. Results of further examinations, including additional imaging and histopathology examinations, performed at our institute were used to validate the WB-MRI findings. Two radiologists blinded to the clinical outcome classified the WB-MRI findings according to the ONCO–RADS categories as follows: 1 (normal), 2 (benign finding highly likely), 3 (benign finding likely), 4 (malignant finding likely), and 5 (malignant finding highly likely). Firth logistic regression analysis was performed to determine the associations between participant characteristics and findings of ONCO-RADS category ≥ 4.ResultsOf the 2064 participants with median age of 55 years, 1120 (54.3%) were men, 43 (2.1%) had findings of ONCO-RADS category ≥ 4, and 24 (1.2%) had confirmed cancer. The cancer prevalence rates were 0.1%, 5.4%, 42.9%, and 75% for ONCO-RADS categories 2, 3, 4, and 5, respectively. In the multivariable model, older age (OR: 1.035, p = 0.029) and history of hypertension (OR: 2.051, p = 0.026), hepatitis B carrier (OR: 2.584, p = 0.013), or prior surgery (OR: 3.787, p < 0.001) were independently associated with the findings for ONCO-RADS category ≥ 4.ConclusionsThe ONCO-RADS categories for cancer risk stratification were validated and found to be positively correlated with cancer risk. The application of ONCO-RADS facilitates risk-based management after WB-MRI for cancer screening.

(149) Prevalence of Lumbosacral Annular Tears in Individuals with Hard Flaccid Syndrome

Abstract Introduction Hard flaccid syndrome (HFS), characterized by the penis in an unwanted persistent semi-rigid flaccid state, is an acquired, painful, and bothersome sexual dysfunction that is poorly understood. We have previously postulated that HFS is, in part, a consequence of pathological activation of a somato-visceral and/or a viscero-visceral reflex that we term the “pelvic/pudendal-hypogastric” reflex. In patients with HFS, physical examination reveals a hypercontracted flaccid penis that feels hard on palpation. Biological complaints include penile morphometric changes such as wrinkles or indents; cold-feeling glans with decreased penile sensation; urinary symptoms such as decreased force of stream; constipation; high tone pelvic floor; perineal and penile pain during ejaculation; and erectile dysfunction. Since there is limited understanding of HFS and its pathophysiologic triggers, men with these complaints often seek help from online support groups. Objective To assess the prevalence of lumbosacral annular tears in individuals participating in an HFS online support group and compare this to the prevalence reported in asymptomatic individuals in the peer-reviewed literature. Methods A sexual medicine clinic patient with HFS likely from a lumbosacral annular tear causing sacral radiculopathy who leads an HFS online support group shared his information regarding the suspected pathophysiology. Consequently, other members of the group contacted the sexual medicine clinic to share lumbar MRI images for the spine surgeon to read. All lumbar MRIs had been performed within the last year. They were uploaded to an image sharing service for the spine surgeon to read the sagittal and axial views to assess for the presence of lumbosacral annular tears. For comparison, the literature was reviewed regarding the prevalence of lumbosacral spine disease in asymptomatic individuals. Results A total of 21 individuals, mean age 28 (range 19-42) years, with symptoms consistent with HFS contacted our sexual medicine clinic. Symptoms were verified during the courtesy triage call after which a lumbar MRI was submitted by each individual for evaluation. 16/21 (76%) had surgically treatable annular tears, the most common location being L5-S1 and L4-L5. In addition to HFS symptoms, 38% had concomitant complaints of low back pain and lower extremity sciatica. In a systematic review of 33 peer-reviewed articles reporting imaging findings for &amp;gt;3000 asymptomatic individuals, the prevalence of lumbosacral annular tear varied from 19% to 29% in individuals aged 20 to 80 years [Brinjikji et al, 2015]. Conclusions There is a higher prevalence of lumbosacral annular tears among HFS individuals in this support group who had a lumbar MRI compared to the rate in asymptomatic individuals from peer-reviewed literature. This further supports our hypothesis that HFS is the result of a hyperactive “pelvic/pudendal-hypogastric” reflex. In those men with lumbosacral annular tears, HFS may be triggered by the cauda equina pathology causing sacral radiculopathy that reflexively induces excess sympathetic activity in the efferent hypogastric nerve causing the unwanted HFS symptoms. Disclosure No.

The importance of nonobstructive plaque characteristics in symptomatic and asymptomatic coronary artery disease

BackgroundWe examined obstructive and nonobstructive plaque volumes in populations with subclinical and clinically manifested coronary artery disease (CAD) using quantitative computed tomography (QCT). Methods855 participants with CAD (274 asymptomatic individuals, 254 acute chest pain patients without acute coronary syndrome (ACS), and 327 patients with ACS) underwent QCT of proximal coronary segments to assess participant-level plaque volumes of dense calcium, fibrous, fibrofatty, and necrotic core tissue. ResultsNonobstructive (<50% stenosis) plaque volumes were greater than obstructive plaque volumes, irrespective of population (all p<0.0001): Asymptomatic individuals (mean (95% CI)): 218 [190-250] vs. 16 [12-22] mm3; acute chest pain patients without ACS: 300 [263-341] vs. 51 [41-62] mm3; patients with ACS: 370 [332-412] vs. 159 [139-182] mm3. After multivariable adjustment, nonobstructive fibrous and fibrofatty tissue volumes were greater in acute chest pain patients without ACS compared to asymptomatic individuals (fibrous tissue: 122 [107-139] vs. 175 [155-197] mm3, p<0.01; fibrofatty tissue: 44 [38-50] vs. 71 [63-80] mm3, p<0.01. Necrotic core tissue was greater in ACS patients (29 [26-33] mm3) compared to both asymptomatic individuals (15 [13-18] mm3, p<0.0001) and acute chest pain patients without ACS (21 [18-24] mm3, p<0.05). Nonobstructive dense calcium volumes did not differ between the three populations: 29 [24-36], 29 [23-35], and 41 [34-48] mm3, p>0.3 respectively. ConclusionNonobstructive CAD was the predominant contributor to total atherosclerotic plaque volume in both subclinical and clinically manifested CAD. Nonobstructive fibrous, fibrofatty and necrotic core tissue volumes increased with worsening clinical presentation, while nonobstructive dense calcium tissue volumes did not.

Plasma proteomics for prediction of subclinical coronary artery calcifications in primary prevention

Recent developments in high-throughput proteomic technologies enable the discovery of novel biomarkers of coronary atherosclerosis. The aims of this study were to test if plasma protein subsets could detect coronary artery calcifications (CAC) in asymptomatic individuals and if they add predictive value beyond traditional risk factors. Using proximity extension assays, 1,342 plasma proteins were measured in 1,827 individuals from the Impaired Glucose Tolerance and Microbiota (IGTM) study and 883 individuals from the Swedish Cardiopulmonary BioImage Study (SCAPIS) aged 50-64 years without history of ischaemic heart disease and with CAC assessed by computed tomography. After data-driven feature selection, extreme gradient boosting machine learning models were trained on the IGTM cohort to predict the presence of CAC using combinations of proteins and traditional risk factors. The trained models were validated in SCAPIS. The best plasma protein subset (44 proteins) predicted CAC with an area under the curve (AUC) of 0.691 in the validation cohort. However, this was not better than prediction by traditional risk factors alone (AUC = 0.710, P = .17). Adding proteins to traditional risk factors did not improve the predictions (AUC = 0.705, P = .6). Most of these 44 proteins were highly correlated with traditional risk factors. A plasma protein subset that could predict the presence of subclinical CAC was identified but it did not outperform nor improve a model based on traditional risk factors. Thus, support for this targeted proteomics platform to predict subclinical CAC beyond traditional risk factors was not found.

The Impact of Clinical Factors and SARS-CoV-2 Variants on Antibody Production in Vaccinated German Healthcare Professionals Infected Either with the Delta or the Omicron Variant.

The aim of the rapid introduction of vaccines during the COVID-19 pandemic was a reduction in SARS-CoV-2 transmission and a less frequent occurrence of severe COVID-19 courses. Thus, we evaluated COVID-19 severity in vaccinated individuals to examine variant-specific symptom characteristics and their clinical impact on the serological immune response. A total of 185 individuals previously vaccinated against and infected with the SARS-CoV-2 Delta (B.1.617.2) or Omicron (BA.4 and BA.5) variant, were enrolled for anti-SARS-CoV-2 anti-N- and anti-RBD/S1-Ig level detection. A structured survey regarding medical history was conducted. In 99.5 percent of cases, outpatient treatment was satisfactory. Specific symptoms associated with variants included ageusia and anosmia in patients with Delta infections and throat pain in Omicron infections. Among Delta-infected individuals with specific symptoms, significantly higher levels of anti-N antibodies were observed. Our study identified variant-specific differences in the amount of SARS-CoV-2 antibody production and COVID-19 symptoms. Despite this, vaccinated individuals with Omicron or Delta infections generally experienced mild disease courses. Additionally, asymptomatic individuals exhibit lower anti-SARS-CoV-2 antibody levels, indicating a clinical correlation between disease-specific antibodies and distinct symptoms, particularly in the case of the Delta variant. In follow-up studies, exploring post-COVID syndrome and focusing on cognitive symptoms in the acute phase of Omicron infections is crucial as it has the potential to longitudinally impact the lives of those affected.

Loss of symbiotic and increase of virulent bacteria through microbial networks in Lynch syndrome colon carcinogenesis.

Through a pilot study, we performed whole gut metagenomic analysis in 17 Lynch syndrome (LS) families, including colorectal cancer (CRC) patients and their healthy first-degree relatives. In a second asymptomatic LS cohort (n=150) undergoing colonoscopy-screening program, individuals with early precancerous lesions were compared to those with a normal colonoscopy. Since bacteria are organized into different networks within the microbiota, we compared related network structures in patients and controls. Fecal prokaryote DNA was extracted prior to colonoscopy for whole metagenome (n=34, pilot study) or 16s rRNA sequencing (validation study). We characterized bacteria taxonomy using Diamond/MEGAN6 and DADA2 pipelines and performed differential abundances using Shaman website. We constructed networks using SparCC inference tools and validated the construction's accuracy by performing qPCR on selected bacteria. Significant differences in bacterial communities in LS-CRC patients were identified, with an enrichment of virulent bacteria and a depletion of symbionts compared to their first-degree relatives. Bacteria taxa in LS asymptomatic individuals with colonic precancerous lesions (n=79) were significantly different compared to healthy individuals (n=71). The main bacterial network structures, constructed based on bacteria-bacteria correlations in CRC (pilot study) and in asymptomatic precancerous patients (validation-study), showed a different pattern than in controls. It was characterized by virulent/symbiotic co-exclusion in both studies and illustrated (validation study) by a higher Escherichia/Bifidobacterium ratio, as assessed by qPCR. Enhanced fecal virulent/symbiotic bacteria ratios influence bacterial network structures. As an early event in colon carcinogenesis, these ratios can be used to identify asymptomatic LS individual with a higher risk of CRC.

A prediction model for estimating NT-proBNP in a general Japanese population: the Toon Health Study.

As part of the Toon Health Study, which is an ongoing population-based cohort study, we aimed to develop a prediction model for N-terminal pro-brain natriuretic peptide (NT-proBNP) in a general Japanese population. We sought to explore the influence of various demographic and clinical factors on NT-proBNP levels and assess the model's performance. In addition, our objectives included internal validation and investigation of the diagnostic potential of the observed-to-predicted NT-proBNP ratio (OPR) at baseline for predicting the risk of heart failure with preserved ejection fraction (HFpEF). In this prospective cohort study, participants were recruited from Toon City, Japan, as part of the larger Toon Health Study, focusing on cardiovascular risk factors. We measured the NT-proBNP levels and used linear regression with penalization (ridge regression) to develop the model. The model incorporated 10 prespecified predictors (age, gender, body mass index, diastolic blood pressure, heart rate, haemoglobin, albumin, total cholesterol, haemoglobin A1c, and estimated glomerular filtration rate) and underwent assessment using R2 and root mean squared error (RMSE). Internal validation was conducted through bootstrapping. In a post hoc analysis, we explored the OPR's diagnostic potential using 5year follow-up data (n=636) to predict the elevation of NT-proBNP>125pg/mL at the 5year follow-up as the risk of HFpEF. A total of 2505 participants (age: 60.4±12.9years, men: 35%) were enrolled in this study. There was a linear relationship between the observed and predicted values of NT-proBNP in which the logarithm of observed NT-proBNP was <6, which corresponds to 403pg/mL in NT-proBNP. The prediction model demonstrated satisfactory performance (R2: 0.291, RMSE: 0.688), with age identified as a dominant predictor. The stability of the model was underscored by the internal validation. The OPR at baseline predicted NT-proBNP>125pg/mL at the 5year follow-up with an area under the curve of 0.793. This study introduces the first prediction model for NT-proBNP in a general Japanese population. Although the model has acceptable performance, ongoing refinement is essential. Our transparent approach to model development, alongside a web-based interactive tool, lays the groundwork for further improvements and external validation. The OPR holds potential for predicting the future risk of HFpEF. This research contributes to understanding the nuanced influence of patient backgrounds on levels of NT-proBNP in asymptomatic individuals within the context of a broader population-based cohort study.

Characteristics of Asymptomatic COVID-19 In SARS-COV-2 Vaccine Trial Screening Participants

Introduction We conducted a Phase I SARS-CoV-2 vaccine trial in March 2022. During the screening, we identified a significant number of asymptomatic COVID-19 cases among the candidate participants. We aimed to highlight the clinical characteristics among these asymptomatic individuals as compared to subjects negative for SARS-CoV-2. Methods This observational study was conducted during participant screening for a Phase I SARS-CoV-2 vaccine trial in Jepara and Mranggen districts in Central Java, Semarang, Indonesia. Participants who reported no symptoms associated with COVID-19, confirmed by physical examinations, were included. Data on laboratory markers were documented. An asymptomatic case was defined as showing no clinical symptoms and signs of SARS-CoV-2 infection with a positive SARS-CoV-2 RT-PCR result. Individuals who tested negative for SARS-CoV-2 were included for comparison. A chi-square test was employed to assess the differences between the two groups, with a p-value &lt;0.05 is considered significant. Results A total of 219 participants were screened and included. One hundred and six participants (48.4%) had positive SARS-CoV-2 RT-PCR results, with mean Ct values of 28.29 +/- 6.74 for the helicase gene. There was no significant difference in demographic characteristics, physical examination, and laboratory findings (p-value &gt;0.05) among individuals with positive and negative SARS-CoV-2. Conclusion In our vaccine trial screening phase, almost half were ineligible due to having asymptomatic SARS-CoV-2 infections. In addition, it is necessary that people with asymptomatic COVID-19 infection still need to be concerned because they have the same transmission potential.

Abstract 37: The Brain Care Score and Neuroimaging Markers in Asymptomatic Individuals in the UK Biobank

The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by motivating lifestyle changes (Fig 1). In this study we aimed to assess if the BCS is also associated with brain changes on MRI in people who have not yet developed dementia or stroke. Methods: This study was conducted within the MRI substudy of the longitudinal cohort study UK Biobank. The assessed MRI neuroimaging markers included: brain volume, white matter hyperintensities (WMH) volume, fractional anisotropy (FA) and mean diffusivity (MD). FA/MD metrics were calculated as the average across 48 discrete brain regions. We used multivariable linear regression to test for association between the BCS computed using baseline data (2006-2010) and neuroimaging markers, measured both during first (2014+) and repeat (2019+) MRI assessments. Results: There were 34,772 study participants with MRIs and available BCS data (mean age 55, 53% female). Every five-point increase in the BCS was associated with an 11% increase in brain volume (Beta 0.11, SE 0.01), a 26% reduction in WMH volume (Beta -0.26, SE 0.01), a 13% increase in average FA (Beta 0.13, SE 0.02), and a 9% decrease in average MD (Beta -0.09, SE 0.01). There were 3,778 study participants with first and repeat MRI (mean age 53, 53% female). Comparing the first and repeat imaging assessments, every five-point increase in baseline BCS was associated with a slower growth in WMH volume (Beta -0.08, SE 0.03) and a slower reduction in average FA (Beta 0.11, SE 0.03). Discussion: Among middle-aged adults without dementia or stroke, a higher BCS is strongly associated with better neuroimaging brain health profiles and slower rates of brain health decline. Given that the neuroimaging markers evaluated in our study are recognized risk factors that precede stroke and dementia by many years, our results support the BCS is a promising tool for early intervention to prevent these conditions.

Association of cardiometabolic and triglyceride-glucose index with left ventricular diastolic function in asymptomatic individuals

Background and aimsObesity and insulin resistance are associated with left ventricular diastolic dysfunction (LVDD) and increased risk of heart failure. Cardiometabolic index (CMI) and triglyceride glucose (TyG) are new indexes to assess visceral obesity and insulin resistance, respectively. The study aimed to investigate the clinical usefulness of these indexes for identifying LVDD individuals. Methods and resultsOverall, 1898 asymptomatic individuals were included in this cross-sectional study. Participants underwent anthropometrics, serum biochemical evaluation, and echocardiography. Multiple linear regression analysis revealed that both indexes were independent determinants of diastolic parameters among females; while for males, CMI and TyG were not associated with A velocity. In the multivariate logistic analysis, the proportion of LVDD in the third and fourth quartiles of CMI remained significantly greater than that in the lowest quartile in females (Q3 vs. Q1: odds ratio (OR) = 2.032, 95% confidence interval (CI): 1.181–3.496; Q4 vs. Q1: OR = 2.393, 95% CI: 1.347–4.249); while in males, the incidence of LVDD was significantly greater only in the fourth quartile. For TyG, the presence of LVDD in the fourth quartile was significantly greater in both genders. The discriminant values between the CMI (AUC: 0.704, 95% CI: 0.668–0.739) and TyG (AUC: 0.717, 95% CI: 0.682–0.752) were similar in females. Both indexes performed better in females than in males to identify LVDD. ConclusionThe CMI and TyG might both serve as effective tools to identify LVDD in routine health check-ups in primary care, mainly in females. With simpler parameters, the CMI could be utilized in medically resource-limited areas.

Whole-Body Positron Emission Tomography with 18F-Fluorodeoxyglucose/Magnetic Resonance Imaging as a Screening Tool for the Detection of Malignant Transformation in Individuals with Neurofibromatosis Type 1

Malignant peripheral nerve sheath tumors (MPNST) are the leading cause of death in Neurofibromatosis type 1 (NF1). They can result from premalignant neurofibromas (NF) including NF with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP). Some phenotypic characteristics have been described as associated with their development. The aim was to outline our use of whole-body 18F-FDG-PET/MRI in adults with NF1, especially in the screening of asymptomatic individuals with a higher risk of developing a MPNST, and to study its impact on NF classification (malignant vs premalignant) and MPNST staging over time. Individuals with NF1 who underwent a 18F-FDG-PET/MRI between 2017 to 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighed imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 18F-FDG-PET/MRI were performed in 241 patients including 149 asymptomatic (62%), but at risk. Eight MPNST in 8 screened individuals (5%), 6 NF with atypia in 4 (3%) and 29 ANNUBP in 23 (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (p=0.03 and p<0.001, respectively). This study emphasizes the diagnostic and screening performances of whole-body 18F-FDG-PET/MRI in adults with NF1.

C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.

A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion. One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing. We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds. Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.

Ocular surface lesions in clinical grades of Bell's phenomenon.

Bell's phenomenon, also known as the palpebral oculogyric reflex, is a critical reflex that protects the cornea. We developed an innovative, simple, and practical grading scale for Bell's phenomenon that includes the inverse Bell's phenomenon. Using this scale, we investigated the characteristics of Bell's phenomenon among asymptomatic individuals in different age groups and examined the frequency of ocular surface lesions in asymptomatic and symptomatic participants with different grades. In this cross-sectional study, we randomly included 330 eyes of 165 asymptomatic, healthy, White Turkish individuals who attended the outpatient eye clinic, with a male-to-female ratio of 1:1.4, in the control group. These were categorized into four age groups: 4 - 20 years, 21 - 40 years, 41 - 60 years, and > 60 years. Eighty eyes from 40 patients with ocular surface lesions and absence of grade + 2 Bell's phenomenon were included in the symptomatic group. Bell's phenomenon was classified into five grades: grade + 2 (strong positive), grade + 1 (weak positive), grade 0 (no Bell's phenomenon, no eye movement), grade -1 (weak inverse), and grade -2 (strong inverse). We detected higher frequencies of grade + 2, + 1, and 0 in individuals aged 4 - 40, 41 - 60, and > 60 years, respectively. There was a significant difference between age groups in the frequencies of different grades (P < 0.001). Pairwise analysis revealed a significantly lower frequency of grade + 2 in the age group > 60 years compared with the 4 - 20 and 21 - 40 year groups (both P < 0.05). Grade + 2 was the most frequent in both sexes. We detected grade 0 in 27.1% of men and 22.1% of women in the control group, with no significant difference in the frequencies of different grades between sexes (P > 0.05). We observed significant differences between grades with respect to the frequency of ocular surface lesions (P < 0.001). Pairwise analysis revealed a significantly higher frequency of ocular surface lesions in asymptomatic individuals with grade 0 and all four other grades (all P < 0.001). However, the frequency of ocular surface lesions was comparable between sexes (P > 0.05). Of the 40 symptomatic individuals, 28 (70%), 5 (12.5%), 4 (10%), and 3 (7.5%) had grade 0, + 1, -1, and -2, respectively. The number of symptomatic patients was higher in grade 0 (n = 28) than in other grades (grade + 1, -1, and -2: n = 12 patients), and these individuals had a higher frequency of ocular surface lesions (n = 38 lesions) than others (grade + 1, -1, and -2: 7 lesions). Using a simple, practical grading scale for Bell's phenomenon that includes inverse Bell's phenomenon, we observed that inverse Bell's phenomenon is a reflex that may be present in healthy individuals and could have a protective effect on the eye, although not to such a degree as a strong Bell's phenomenon. Our observations imply that bilateral conjunctival calcifications/Vogt's limbal girdle may be associated with grades 0 and + 1 Bell's phenomenon. Further large-scale studies are needed to determine the frequency of Bell's phenomenon in the general population using this innovative, simple, practical grading scale, and to identify the protective or injurious effect of each grade on the ocular surface.

MATHEMATICAL ANALYSIS OF COVID-19 INFECTION MODEL WITH DEMOGRAPHIC DYNAMICS

This study developed a deterministic mathematical model of COVID-19 infection by incorporating asymptomatically and symptomatically infectious individuals, the vital dynamics such as birth rate and mortality rate. Face mask use, diagnosis of asymptomatic infectious individuals, and isolation of infected individuals as control strategies are also incorporated. The model is shown to have two unique equilibrium states, namely: the disease-free equilibrium points and the endemic equilibrium point. The result from the stability analysis of the critical points is shown to be local asymptotic stable and also, globally asymptotically stable provided the basic reproduction number is less than one (, and the endemic equilibrium state is local asymptotic stable and also, globally asymptotically stable provided . Furthermore, results of the sensitivity index on for the different parameters of the model show that the recruitment rate and the effective contact rate are the most sensitive parameters and thus critical in disease management and eradication. Thus, efforts geared at reducing the recruitment of susceptible individuals and infection transmission rate will significantly eliminate the disease burden.

Cross-protective HCoV immunity reduces symptom development during SARS-CoV-2 infection.

Numerous clinical parameters link to severe coronavirus disease 2019, but factors that prevent symptomatic disease remain unknown. We investigated the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a cross-sectional cohort including children and adults (n = 882), all first exposed to SARS-CoV-2 (March 2020 to March 2021) in Switzerland. Saliva (n = 4,993) and plasma (n = 7,486) antibody reactivity to the four HCoVs (subunit S1 [S1]) and SARS-CoV-2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARS-CoV-2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARS-CoV-2 infection was associated with a strong correlation between mucosal and systemic SARS-CoV-2 anti-spike responses. Individuals with pre-existing HCoV-S1 reactivity exhibited significantly higher antibody responses to SARS-CoV-2 in both plasma (IgG regression coefficients = 0.20, 95% CI = [0.09, 0.32], P < 0.001) and saliva (IgG regression coefficient = 0.60, 95% CI = [0.088, 1.11], P = 0.025). Saliva neutralization activity was modest but surprisingly broad, retaining activity against Wuhan (median NT50 = 32.0, 1Q-3Q = [16.4, 50.2]), Alpha (median NT50 = 34.9, 1Q-3Q = [26.0, 46.6]), and Delta (median NT50 = 28.0, 1Q-3Q = [19.9, 41.7]). In line with a rapid mucosal defense triggered by cross-reactive HCoV immunity, asymptomatic individuals presented with higher pre-existing HCoV-S1 activity in plasma (IgG HKU1, odds ratio [OR] = 0.53, 95% CI = [0.29,0.97], P = 0.038) and saliva (total HCoV, OR = 0.55, 95% CI = [0.33, 0.91], P = 0.019) and higher SARS-CoV-2 reactivity in saliva (IgG S2 fold change = 1.26, 95% CI = [1.03, 1.54], P = 0.030). By investigating the systemic and mucosal immune responses to SARS-CoV-2 and HCoVs in a population without prior exposure to SARS-CoV-2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development.IMPORTANCEKnowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is critical to understanding the coexistence of current endemic coronaviruses and to building knowledge potential future zoonotic coronavirus transmissions. This study, which retrospectively analyzed a large cohort of individuals first exposed to SARS-CoV-2 in Switzerland in 2020-2021, revealed several key findings. Pre-existing HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARS-CoV-2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARS-CoV-2, although low in magnitude, retained activity against SARS-CoV-2 variants underlining the importance of maintaining local mucosal immunity to SARS-CoV-2. While the cross-protective effect of HCoV immunity was not sufficient to block infection by SARS-CoV-2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating pan-protective coronavirus vaccines by inducing potent mucosal immune responses.

From risk communication about asymptomatic atherosclerosis to cognitive and emotional reactions and lifestyle modification

BackgroundNon-adherence in the general population to preventive guidelines on cardiovascular disease calls for an interdisciplinary approach acknowledging psychological factors of relevance for risk communication and lifestyle modification. Evidence is building up regarding the advantage of sharing arterial imaging evidence of subclinical atherosclerosis with asymptomatic individuals, but there is limited understanding of how this relates to mechanisms of importance for behavioural change. Longitudinal studies on associations between patients’ reactions and lifestyle modification are missing. The population-based randomized controlled trial VIPVIZA investigates the impact of pictorial information about subclinical atherosclerosis, added to traditional risk factor-based communication. The intervention includes a personalized, colour-coded and age-related risk communication strategy and a motivational conversation, and has been shown to reduce cardiovascular disease risk.MethodsIn the present study we assessed cognitive and emotional reactions to the intervention, and how these reactions are associated to lifestyle modification. The participants’ evaluation of the risk communication was assessed in the intervention group (n = 1749). Lifestyle modification was assessed with a lifestyle index based on physical activity, diet, smoking and alcohol consumption at baseline and after 3 years. Associations between cognitive and emotional response and lifestyle modification were tested with analyses of covariance in a subset of participants (n = 714–857).ResultsThe intervention increased understanding of personal CVD risk, the possibility to influence the risk, and how to influence the risk. Severity of atherosclerosis was associated with emotional reactions, but emotions of strong negative valence were uncommon. Cognitive response and emotional arousal evoked by the intervention were positively associated with lifestyle modification, whereas negative emotions in isolation were not. High level of cognitive response in combination with high level of emotional arousal was found to be most beneficial for lifestyle modification.ConclusionsThe results demonstrate the potential of communicating asymptomatic atherosclerosis with a pictorial, colour-coded and age-related strategy, also including a motivational conversation. Furthermore, the results show the importance of CVD risk communication evoking engagement, and that an interaction between cognitive and emotional reactions might be central for sustained lifestyle modification. Our results also indicate that, in an asymptomatic population, atherosclerosis screening may strengthen disease prevention and health promotion.Trial registrationClinicalTrials.gov identifier: NCT01849575. Registration date 08/05/2013.

How Long is Too Long? Asymptomatic Nocturnal Pauses in Athletes: A Narrative Review

Athletes undergo mandatory or voluntary cardiac testing, which may include 24-h ambulatory electrocardiogram monitoring. This study can on occasion disclose nocturnal pauses in otherwise asymptomatic healthy individuals. In some athletes, particularly those engaging in endurance or mixed sports, the pauses can be longer than 2–3 s and/or be caused by sinus arrest high-degree atrioventricular block not typical for physiological adaptation to exercise. The manuscript discusses the physiology and potential pathologies behind long nocturnal pauses in athletes. Several management strategies are proposed including emerging treatment techniques such as cardioneuroablation.