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INTRODUCTION: The central biochemical cause of gout is hyperuricemia (elevated serum urate levels). Ultrasound features of monosodium urate (MSU) crystal deposition are common in people with asymptomatic hyperuricemia. However, it is unclear whether this is a precondition for the development of gout. This study aims to determine whether ultrasound imaging evidence of MSU crystal deposition predicts development of symptomatic gout over 5 years, in people who already have an increased risk of gout due to elevated serum urate concentrations (≥8 mg/dL). METHODS AND ANALYSIS: This is a prospective, international, multicentre study. The study population comprises over 250 participants with asymptomatic hyperuricemia (serum urate ≥8.0 mg/dL). After the baseline assessments, participants are followed for 5 years or until the development of gout, defined by the 2015 American College of Rheumatology/European Alliance of Associations for Rheumatology gout classification criteria. Baseline assessments include anthropomorphic measures, laboratory tests, questionnaires, blood and urine specimen collection, plain radiographs of the feet and standardised ultrasound scans of the lower limbs, scored according to the Outcomes in Rheumatology (OMERACT) gout ultrasound scoring system. The primary outcomes are the development of gout and time course for development of gout in people with and without ultrasound evidence of MSU crystal deposition. Exploratory analyses will examine clinical, genetic and biological factors associated with development of MSU crystal deposition and gout. ETHICS AND DISSEMINATION: This study protocol was approved by the New Zealand Ministry of Health Southern Health and Disability Ethics Committee (MEC/05/10/130/AM16) on 18 December 2018. The findings from this study will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000915156.

IntroductionCoronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF).MethodsWe applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years.ResultsOver 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​

AimsStudies have indicated inconsistent results regarding the association between plasma levels of Lipoprotein(a) [Lp(a)] and coronary artery calcification (CAC). We performed a systematic review and meta-analysis to investigate the association between elevated levels of Lp(a) and risk of CAC in populations free of cardiovascular disease (CVD) symptoms.Data synthesisPubMed, Web of Science, Embase, and Scopus were searched up to July 2022 and the methodological quality was assessed using Newcastle-Ottawa Scale (NOS) scale. Random-effects meta-analysis was used to estimate pooled odds ratio (OR) and 95% confidence interval. Out of 298 studies, data from 8 cross-sectional (n = 18,668) and 4 cohort (n = 15,355) studies were used in meta-analysis. Cohort studies demonstrated a positive significant association between Lp(a) and CAC, so that individuals with Lp(a)≥30-50 exposed to about 60% risk of CAC incidence compared to those with lower Lp(a) concentrations in asymptomatic CVD subjects (OR, 1.58; 95% CI, 1.38-1.80; l2, 0.0%; P, 0.483); Subgroup analysis showed that a cut-off level for Lp(a) measurement could not statistically affect the association, but race significantly affected the relationship between Lp(a) and CAC (OR,1.60; 95% CI, 1.41-1.81). Analyses also revealed that both men and women with higher Lp(a) concentrations are at the same risk for increased CAC.ConclusionsBlood Lp(a) level was significantly associated with CAC incidence in asymptomatic populations with CVD, indicating that measuring Lp(a) may be a useful biomarker for diagnosing subclinical atherosclerosis in individuals at higher risk of CAC score.Prospero registration numberCRD42022350297.

Background Congenital absence of the pericardium (CAP) is a rare cardiac abnormality. As pericardial defects are usually asymptomatic, most cases are diagnosed during surgery or on autopsy. The patient in this case was found to have CAP during thoracoscope. Case We present the unusual case of a 69-year-old patient with CAP who experienced sudden ventricular arrhythmia and developed ventricular fibrillation during left upper lobectomy. Surgical operations, the lateral decubitus position, and other external stimuli may be important risk factors for ventricular fibrillation. The patient regained sinus rhythm soon after intrathoracic cardiac compression and pharmacological treatment, including lidocaine spray (2%, 10 ml) administered to the heart surface. The surgery was then completed without any additional instances of ventricular arrhythmia. Conclusions Patients with CAP are more susceptible to cardiac-related adverse events during thoracotomy or thoracoscopy. Treatment of ventricular arrhythmias that occur during lung resection in patients with CAP should be emphasized.

The objective of this integrative literature review is to discuss the perspectives regarding the early surgical approach of asymptomatic children with congenital pulmonary airway malformation. The review was conducted by performing electronic searches from May to July 2023, in the PUBMED database - National Library of Medicine. Studies published from January 2013 to January 2023, clinical trials, retrospective studies, case studies, series and cases and mixed studies available in English were included. Elementary information was collected from the articles selected after the filters, such as study design (main methodological aspects), key findings and conclusion (based on the problem question that guided this study). Initially, 125 articles were identified from the search in the selected database. After the analysis regarding the application of the inclusion and exclusion criteria, 9 manuscripts remained, all of them of the retrospective type. In conclusion, although there is currently a divergence of opinions regarding the performance of an early surgical procedure in children diagnosed with asymptomatic congenital pulmonary airways malformation, current studies point to the procedure as they consider several factors, including patient safety. [ABSTRACT FROM AUTHOR]

Background: While it has been demonstrated that large asymptomatic pulmonary embolism (PE) can occur, many studies have assessed inpatients or patients with known risk factors for venous thromboembolism (such as malignancy). There are few data regarding incidental PE in outpatients with deep vein thrombosis (DVT) or assessing whether these emboli occur centrally or peripherally in the pulmonary arteries. Aims: To determine the rates of incidental central and peripheral PE in outpatients with proximal and distal DVT. Methods: This was a retrospective cross‐sectional study of 120 patients attending our community imaging clinic between January 2015 and March 2020, with ultrasound‐confirmed lower limb DVT, and subsequent computed tomography pulmonary angiogram (CTPA) within 24 h. Exclusion criteria were symptoms indicative of PE. Imaging reports were retrospectively reviewed to record the proximity of DVT and the location of any PE as either central (pulmonary trunk or main pulmonary arteries) or peripheral (lobar, segmental or subsegmental pulmonary arteries). Results: Incidental PE occurred in 71 patients (59.2%), with a rate of 77.5% in proximal and 50.0% in distal DVT. Sixteen patients had central PE (13.3% of all patients with DVT; 22.5% of all patients with PE). Two patients (both with proximal DVT) had PE in the pulmonary trunk. Conclusions: Incidental PE occur frequently in outpatients with lower limb DVT, including the possibility of asymptomatic central emboli. Further studies with larger patient cohorts would be useful to assess the utility of baseline chest imaging in outpatients with DVT. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the influence of the initial clinical presentation (symptomatic vs. asymptomatic) on histopathological tumor features in patients with upper tract urothelial carcinoma (UTUC). Methods: We conducted a single-center, cross-sectional, and retrospective study that enrolled 72 adults with primary UTUC who underwent radical nephroureterectomy at our institution over a period of 4 years (April 2019–April 2023). Results: Symptomatic patients exhibited significantly higher frequencies of high-grade UTUC (73.6% vs. 36.8%, p = 0.006), ≥ T2 stage UTUC (60.4% vs. 26.3%, p = 0.007), and larger tumor sizes (median 5 vs. 4 cm, p = 0.015) compared to asymptomatic patients. Multiple regression analyses demonstrated significant associations between symptomatic presentation and the presence of high-grade UTUC (OR 6.35, 95% CI 1.81–22.27, p = 0.004), ≥ T2 stage UTUC (OR 5.98, 95% CI 1.62–22.08, p = 0.007), and larger tumor size (B 3.14, 95% CI 0.62–5.66, p = 0.015). A subset of patients with hematuria was separately analyzed to assess the influence of hematuria severity (gross vs. microscopic) on UTUC characteristics. Patients with gross hematuria exhibited significantly higher frequencies of high-grade UTUC (72.9% vs. 33.3%, p = 0.048) and ≥ T2 stage UTUC (58.3% vs. 22.2%, p = 0.001). Multiple regression analyses showed significant associations between gross hematuria and the presence of high-grade UTUC (OR 6.34, 95% CI 1.15–34.95, p = 0.034) and ≥ T2 stage UTUC (OR 6.54, 95% CI 1.11–38.93, p = 0.039). Conclusion: Initial symptomatic presentation was independently associated with adverse histopathological UTUC characteristics, potentially attributed to earlier detection of UTUC in asymptomatic patients, before the onset of symptoms. [ABSTRACT FROM AUTHOR]

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

The utility of ambulatory electrocardiography (AECG) to evaluate cats with subclinical hypertrophic cardiomyopathy (HCM) for arrhythmias and heart rate variability (HRV) is not well defined but may provide information regarding risk stratification. This prospective study used AECG to evaluate ectopy and HRV in subclinical HCM cats compared to healthy controls and is the first to implement a pharmacologic cardiac stress test. Twenty-three purpose-bred, Maine coon cross cats (16 HCM, 7 control) underwent 48-h of continuous AECG. Terbutaline (0.2-0.3 mg/kg) was administered orally at 24 and 36 h. Heart rate, ectopy frequency and complexity and HRV parameters, including standard deviation of normal R-R intervals (SDNN), were compared pre-terbutaline and post-terbutaline and across phenotype, genotype and sex. Genotype for an HCM-causative mutation was significantly associated with the frequency of supraventricular (P = 0.033) and ventricular (P = 0.026) ectopy across all cats. Seven HCM cats and zero healthy cats had a sinus arrhythmia. Mean heart rate was significantly higher post-terbutaline (p

Background: In cases of chronic otitis media (COM) presenting with unilateral squamosal disease, there may be the possibility of a potential disease in the opposite ear, which may lead to future complications. Therefore, it needs to be known whether there is any silent pathological process in the contralateral ear (CLE) that is currently asymptomatic but likely to be diseased in the near future. Therefore, this study was undertaken to analyze the fate of the contralateral asymptomatic ear in patients with unilateral squamosal disease. Results: A total of 32 patients with COM squamosal disease were included. All the patients were subjected to clinical examination and a high-resolution computed tomography (CT) scan of bilateral temporal bones. The mean duration of age at presentation was 20.4 years. The male-to-female ratio was 1.28. Out of 32 patients, 11 (34%) showed either clinical or radiological findings in the asymptomatic CLE, out of which 7 showed both abnormal clinical and radiological findings, 3 demonstrated only abnormal clinical findings, and 1 showed only abnormal CT changes without obvious clinical findings in the CLE. In the CLE, 7 (21%) patients had mild conductive hearing loss. There was no statistically significant association of clinical findings or radiological findings in CLE to that of the unilateral squamosal diseased ear. Conclusion: In cases with unilateral squamosal disease, an asymptomatic CLE can undergo subclinical changes and conductive hearing loss. Patients can also have silent radiological changes in the CLE detected on the CT scan, which are significant but remain undetected. No statistical significance could be reported in this study, yet other studies with even larger samples are required to show a causal relation between unilateral squamosal disease and a quiescent process in the asymptomatic CLE.

Background: Little is known about culture-negative subclinical pulmonary tuberculosis (TB), and its diagnosis remains challenging. Therefore, this study aimed to identify the characteristics and the extent of disease associated with culture-negative subclinical pulmonary TB. Methods: This retrospective cohort study was conducted on immunocompetent individuals with subclinical pulmonary TB at a university hospital in Thailand from January 2014 to December 2019. Subclinical pulmonary TB was diagnosed based on the presence of radiographic abnormalities consistent with TB in the absence of TB symptoms. All subjects demonstrated significant improvement or resolution of radiographic abnormalities following the completion of treatment. At least two negative sputum cultures were needed to fulfill the definition of culture-negative pulmonary TB. Data were analyzed using univariate and multiple logistic regression analyses to determine the characteristics of those with culture-negative subclinical pulmonary TB compared to culture-positive ones. Results: Out of the 106 individuals identified with subclinical pulmonary TB, 84 met the criteria for inclusion in the analysis. The study found lower radiographic extent and increasing age were key attributes of culture-negative subclinical pulmonary TB. The odds ratios (95% confidence interval) were 7.18 (1.76 to 29.35) and 1.07 (1.01 to 1.13), respectively. They tend to have lower rates of bilateral involvement in both chest x-ray (8.5% vs. 32.0%, p=0.006) and computed tomography (15.4% vs. 42.9%, p=0.035). However, no other specific radiographic findings were identified. Conclusions: People with culture-negative subclinical pulmonary TB were likely to have less radiographic severity, reflecting early disease. Nevertheless, no radiographic patterns, except for unilaterality, were related to culture-negative subclinical pulmonary TB. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend treating choledocholithiasis, regardless of symptoms or stone size, with endoscopic retrograde cholangiopancreatography (ERCP). However, asymptomatic choledocholithiasis, discovered incidentally on imaging, may carry a higher risk of ERCP-related adverse events, and some asymptomatic and diminutive stones may not cause biliary adverse events during extended follow-up. Therefore, we aimed to clarify the best treatment strategies for asymptomatic choledocholithiasis based on stone size. Methods: We retrospectively identified patients with incidental imaging-found asymptomatic diminutive (≤ 4 mm) or non-diminutive (> 4 mm) choledocholithiasis and divided them into two groups: those who did not undergo ERCP and were treated when complications arose (on-demand group) and those who underwent ERCP before being symptomatic (intervention group). Adverse events were defined as any biliary or pancreatic complication related to ERCP or arising during observation or after intervention. The primary outcome was the adjusted overall adverse event-free survival using the propensity score-based matching weights method comparing the two groups of stone size. Results: Among 148 patients identified (median follow-up period, 969 days), 68 had diminutive stones and 80 had non-diminutive stones. Of the 68 patients with diminutive stones, 51 were in the on-demand group and 17 in the intervention group. The overall adjusted adverse event-free survival was significantly higher in the on-demand group for diminutive stones (97.4% and 70.1%, respectively, at 3 years; p = 0.01). Discussion: Patients with incidental imaging-detected asymptomatic diminutive choledocholithiasis may benefit from clinical observation, pursuing ERCP when symptoms develop. [ABSTRACT FROM AUTHOR]

BackgroundSmokers manifest varied phenotypes of pulmonary impairment.Research questionWhich pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers?Study design and methodsWe analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV1 to FVC ratio, < 0.70).ResultsPulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV1 and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts.InterpretationLung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV1 and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

BackgroundUsing magnetic resonance diffusion tensor imaging, we previously showed a cross-sectional association between carotid-femoral pulse wave velocity, a measure of aortic stiffness, and subtle white matter injury in clinically asymptomatic middle-age adults. While coronary artery calcium (CAC) is a robust measure of atherosclerosis, and a predictor of stroke and dementia, whether it predicts diffusion tensor imaging-based subtle white matter injury in the brain remains unknown.MethodsIn FHS (Framingham Heart Study), an observational study, third-generation participants were assessed for CAC (2002-2005) and brain magnetic resonance imaging (2009-2014). Outcomes were diffusion tensor imaging-based measures; free water, fractional anisotropy, and peak width of mean diffusivity. After excluding the participants with neurological conditions and missing covariates, we categorized participants into 3 groups according to CAC score (0, 0 < to 100, and >100) and calculated a linear trend across the CAC groups. In secondary analyses treating CAC score as continuous, we computed slope of the outcomes per 20 to 80th percentiles higher log-transformed CAC score using linear regression.ResultsIn a total of 1052 individuals analyzed (mean age 45.4 years, 45.4% women), 71.6%, 22.4%, and 6.0% had CAC score of 0, 0 < to 100, and >100, respectively. We observed a significant linear trend of fractional anisotropy, but not other measures, across the CAC groups after multivariable adjustment. In the secondary analyses, CAC was associated with lower fractional anisotropy in men but not in women.ConclusionsCAC may be a promising tool to predict prevalent subtle white matter injury of the brain in asymptomatic middle-aged men.

Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27-33 weeks of gestation).

ImportanceVitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency.ObjectiveTo update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment.PopulationCommunity-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended.Evidence assessmentThe USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement).

ImportanceVitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency.ObjectiveTo update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment.PopulationCommunity-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended.Evidence assessmentThe USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement).

ImportanceCarotid artery stenosis is atherosclerotic disease that affects extracranial carotid arteries. Asymptomatic carotid artery stenosis refers to stenosis in persons without a history of ischemic stroke, transient ischemic attack, or other neurologic symptoms referable to the carotid arteries. The prevalence of asymptomatic carotid artery stenosis is low in the general population but increases with age.ObjectiveTo determine if its 2014 recommendation should be reaffirmed, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence review. The reaffirmation update focused on the targeted key questions on the potential benefits and harms of screening and interventions, including revascularization procedures designed to improve carotid artery blood flow, in persons with asymptomatic carotid artery stenosis.PopulationThis recommendation statement applies to adults without a history of transient ischemic attack, stroke, or other neurologic signs or symptoms referable to the carotid arteries.Evidence assessmentThe USPSTF found no new substantial evidence that could change its recommendation and therefore concludes with moderate certainty that the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits.RecommendationThe USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. (D recommendation).

ImportanceCarotid artery stenosis is atherosclerotic disease that affects extracranial carotid arteries. Asymptomatic carotid artery stenosis refers to stenosis in persons without a history of ischemic stroke, transient ischemic attack, or other neurologic symptoms referable to the carotid arteries. The prevalence of asymptomatic carotid artery stenosis is low in the general population but increases with age.ObjectiveTo determine if its 2014 recommendation should be reaffirmed, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence review. The reaffirmation update focused on the targeted key questions on the potential benefits and harms of screening and interventions, including revascularization procedures designed to improve carotid artery blood flow, in persons with asymptomatic carotid artery stenosis.PopulationThis recommendation statement applies to adults without a history of transient ischemic attack, stroke, or other neurologic signs or symptoms referable to the carotid arteries.Evidence assessmentThe USPSTF found no new substantial evidence that could change its recommendation and therefore concludes with moderate certainty that the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits.RecommendationThe USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. (D recommendation).

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

BackgroundAltered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer's disease (AD) and in AD patient plasma samples.ObjectiveThis study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n = 138).MethodsSpecimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods.ResultsTotal plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and MCI relative to normal controls.ConclusionWe recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has resulted in reduced performance of elective surgeries and procedures at medical centers across the United States. Awareness of the prevalence of asymptomatic disease is critical for guiding safe approaches to operative/procedural services. As COVID-19 polymerase chain reaction (PCR) testing has been limited largely to symptomatic patients, health care workers, or to those in communal care centers, data regarding asymptomatic viral disease carriage are limited.MethodsIn this retrospective observational case series evaluating UCLA Health patients enrolled in pre-operative/pre-procedure protocol COVID-19 reverse transcriptase (RT)-PCR testing between April 7, 2020 and May 21, 2020, we determine the prevalence of COVID-19 infection in asymptomatic patients scheduled for surgeries and procedures.ResultsPrimary outcomes include the prevalence of COVID-19 infection in this asymptomatic population. Secondary data analysis includes overall population testing results and population demographics. Eighteen of 4,751 (0.38%) patients scheduled for upcoming surgeries and high-risk procedures had abnormal (positive/inconclusive) COVID-19 RT-PCR testing results. Six of 18 patients were confirmed asymptomatic and had positive test results. Four of 18 were confirmed asymptomtic and had inconclusive results. Eight of 18 had positive results in the setting of recent symptoms or known COVID-19 infection. The prevalence of asymptomatic COVID-19 infection was 0.13%. More than 90% of patients had residential addresses within a 67-mile geographic radius of our medical center, the median age was 58, and there was equal male/female distribution.ConclusionThese data demonstrating low levels (0.13% prevalence) of COVID-19 infection in an asymptomatic population of patients undergoing scheduled surgeries/procedures in a large urban area have helped to inform perioperative protocols during the COVID-19 pandemic. Testing protocols like ours may prove valuable for other health systems in their approaches to safe procedural practices during COVID-19.

BackgroundDetection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment.MethodsWe developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended.Results"Surveillance" using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment ("do nothing"). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and "do nothing." Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than "do nothing" for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided.ConclusionCurrent management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.

BackgroundFatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.MethodThis study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight

Health care personnel (HCP) caring for patients with coronavirus disease 2019 (COVID-19) might be at high risk for contracting SARS-CoV-2, the virus that causes COVID-19. Understanding the prevalence of and factors associated with SARS-CoV-2 infection among frontline HCP who care for COVID-19 patients are important for protecting both HCP and their patients. During April 3-June 19, 2020, serum specimens were collected from a convenience sample of frontline HCP who worked with COVID-19 patients at 13 geographically diverse academic medical centers in the United States, and specimens were tested for antibodies to SARS-CoV-2. Participants were asked about potential symptoms of COVID-19 experienced since February 1, 2020, previous testing for acute SARS-CoV-2 infection, and their use of personal protective equipment (PPE) in the past week. Among 3,248 participants, 194 (6.0%) had positive test results for SARS-CoV-2 antibodies. Seroprevalence by hospital ranged from 0.8% to 31.2% (median = 3.6%). Among the 194 seropositive participants, 56 (29%) reported no symptoms since February 1, 2020, 86 (44%) did not believe that they previously had COVID-19, and 133 (69%) did not report a previous COVID-19 diagnosis. Seroprevalence was lower among personnel who reported always wearing a face covering (defined in this study as a surgical mask, N95 respirator, or powered air purifying respirator [PAPR]) while caring for patients (5.6%), compared with that among those who did not (9.0%) (p = 0.012). Consistent with persons in the general population with SARS-CoV-2 infection, many frontline HCP with SARS-CoV-2 infection might be asymptomatic or minimally symptomatic during infection, and infection might be unrecognized. Enhanced screening, including frequent testing of frontline HCP, and universal use of face coverings in hospitals are two strategies that could reduce SARS-CoV-2 transmission.

The duration and lifetime pattern of hypertension is related to risk of stroke and dementia. In turn, cerebral small vessel disease (CSVD) is the most frequent form of cerebrovascular disease underlying dementia and stroke. Thus, study of the relation of mid to late life hypertension trends with CSVD late in life will help understand hypertension's role and inform preventive efforts of CSVD consequences. We studied 1686 Framingham Heart Study Offspring cohort participants free of stroke and dementia, who were examined in mid and late life, and had available brain magnetic resonance imaging during late life. We related hypertension trends between mid and late life (normotension-normotension N-N, normotension-hypertension N-H, hypertension-hypertension H-H) to cerebral microbleeds and covert brain infarcts (CBI), overall and stratified by brain topography. We used multivariable logistic regression analyses to calculate odds ratio and 95% CIs for CSVD measures. The prevalence of CSVD in late life was 8% for cerebral microbleeds and 13% for covert brain infarcts and increased with longer hypertension exposure across all brain regions. Compared with the trend pattern of N-N, both N-H and H-H trends had higher odds of mixed cerebral microbleeds (2.71 [1.08-6.80], and 3.44 [1.39-8.60], respectively); H-H also had higher odds of any cerebral microbleeds or covert brain infarcts (1.54 [1.12-2.20]), and any covert brain infarcts (1.55 [1.08-2.20]). The burden of CSVD also increased with longer hypertension exposure. Our results highlight hypertension having a major role in subclinical CSVD, across subtypes and brain regions, and call attention to improve recognition and treatment of hypertension early in life.

The nature of antiviral CD8+ T cells associated with protective and pathogenic herpes simplex virus type 1 (HSV-1) infections remains unclear. We compared the transcriptome, phenotype, and function of memory CD8+ T cells, sharing the same HSV-1 epitope-specificities, from infected HLA-A*0201 positive symptomatic (SYMP) vs. asymptomatic (ASYMP) individuals and HLA-A*0201 transgenic rabbits. Compared to higher frequencies of multifunctional effector memory CD8+ TEM cells in ASYMP individuals, the SYMP individuals presented dysfunctional CD8+ TEM cells, expressing major exhaustion pathways. Compared to protected ASYMP HLA transgenic rabbits, the trigeminal ganglia of non-protected SYMP HLA transgenic rabbits had higher frequencies of dysfunctional tissue-resident CD8+ TRM cells. Moreover, blockade of T cell exhaustion pathways restored the function of CD8+ T cells, reduced virus reactivation, and diminished recurrent disease in HLA transgenic rabbits. These findings reveal unique molecular signatures of protective CD8+ T cells and pave the way for T-cell-based immunotherapy to combat recurrent ocular herpes.

A large proportion of the world's population harbors latent HSV type 1 (HSV-1). Cross-talk between antiviral CD8+ T cells and HSV-1 appear to control latency/reactivation cycles. We found that compared with healthy asymptomatic individuals, in symptomatic (SYMP) patients, the CD8+ T cells with the same HLA-A*0201-restricted HSV-1 epitope specificities expressed multiple genes and proteins associated to major T cell exhaustion pathways and were dysfunctional. Blockade of immune checkpoints with anti-LAG-3 and anti-PD-1 antagonist mAbs synergistically restored the frequency and function of antiviral CD8+ T cells, both 1) ex vivo, in SYMP individuals and SYMP HLA-A*0201 transgenic mice; and 2) in vivo in HSV-1-infected SYMP HLA-A*0201 transgenic mice. This was associated with a significant reduction in virus reactivation and recurrent ocular herpetic disease. These findings confirm antiviral CD8+ T cell exhaustion during SYMP herpes infection and pave the way to targeting immune checkpoints to combat recurrent ocular herpes.

ObjectivesTo compare subjective and clinical outcomes in three study groups: (1) asymptomatic contact lens (CL) wearers (ASYM); (2) symptomatic CL wearers who become asymptomatic on lens removal; and (3) symptomatic CL wearers who do not resolve on lens removal.MethodsNinety-two subjects completed the Berkeley Dry Eye Flow Chart with and without lenses, ocular surface examinations, and a battery of questionnaires.ResultsThirty-seven subjects (40%) were ASYM, 30 (33%) had contact lens-induced dry eye (CLIDE), and 25 (27%) had underlying physiological DE. Visual Analog Scale ratings, OSDI score, and SPEED score were significantly better for the ASYM group (P

One hundred years after the 1918 influenza pandemic, we now face another pandemic with the severe acute respiratory syndrome-novel coronavirus-2 (SARS-CoV-2). There is considerable variability in the incidence of infection and severe disease following exposure to SARS-CoV-2. Data from China and the United States suggest a low prevalence of neonates, infants, and children, with those affected not suffering from severe disease. In this article, we speculate different theories why this novel agent is sparing neonates, infants, and young children. The low severity of SARS-CoV-2 infection in this population is associated with a high incidence of asymptomatic or mildly symptomatic infection making them efficient carriers. KEY POINTS: · There is a low prevalence of novel coronavirus disease in neonates, infants, and children.. · The fetal hemoglobin may play a protective role against coronavirus in neonates.. · Immature angiotensin converting enzyme (ACE2) interferes with coronavirus entry into the cells..

Development of effective prevention and treatment strategies for pre-eclampsia is limited by the lack of accurate methods for identification of at-risk pregnancies. We performed small RNA sequencing (RNA-seq) of maternal serum extracellular RNAs (exRNAs) to discover and verify microRNAs (miRNAs) differentially expressed in patients who later developed pre-eclampsia. Sera collected from 73 pre-eclampsia cases and 139 controls between 17 and 28 weeks gestational age (GA), divided into separate discovery and verification cohorts, are analyzed by small RNA-seq. Discovery and verification of univariate and bivariate miRNA biomarkers reveal that bivariate biomarkers verify at a markedly higher rate than univariate biomarkers. The majority of verified biomarkers contain miR-155-5p, which has been reported to mediate the pre-eclampsia-associated repression of endothelial nitric oxide synthase (eNOS) by tumor necrosis factor alpha (TNF-α). Deconvolution analysis reveals that several verified miRNA biomarkers come from the placenta and are likely carried by placenta-specific extracellular vesicles.

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

BackgroundAdipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults.MethodsA subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n = 1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with (1) high-attenuation areas (HAAs) from CT scans (2004-2005, n = 1,144), (2) interstitial lung abnormalities (ILAs) from CT scans (2010-2012, n = 872), and (3) FVC from spirometry (2004-2006, n = 1,446). We used -(1/HAA2), which we denoted with H, to model HAA as our outcome to meet model assumptions.ResultsHigher adiponectin was associated with lower HAA on CT imaging among adults with a BMI ≥ 25 kg/m2 (P for BMI interaction = .07). Leptin was more strongly associated with ILA among never smokers compared with ever smokers (P for smoking interaction = .004). For every 1-SD increment of log-transformed leptin, the percent predicted FVC was 3.8% lower (95% CI, -5.0 to -2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully adjusted model. For every 1-SD increment of log-transformed resistin there was an increase in H of 14.8 (95% CI, 3.4-26.3).ConclusionsHigher adiponectin levels were associated with lower HAA on CT imaging among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively.

Purpose: This study aimed to compare the characteristics of asymptomatic and symptomatic nephrolithiasis in patients who underwent surgical treatment for kidney stones. Materials and Methods: Between 2015 and 2019, 245 patients who underwent percutaneous nephrolithotomy or retrograde intrarenal surgery for kidney stones were included. The patients were divided into asymptomatic (n=124) and symptomatic (n=121) groups. All patients underwent blood and urine tests, preoperative non-contrast computed tomography, and postoperative stone composition analysis. We retrospectively analyzed and compared the characteristics of the patients and stones, operation time, stone-free rate, and postoperative complications between the two groups. Results: In the asymptomatic group, mean body mass index (BMI) was significantly higher (25.7±3.8 kg/m2 vs. 24.3±2.8 kg/m2, p=0.002) and urine pH was significantly lower (5.6±0.9 vs. 5.9±0.9, p=0.013). The ratio of calcium oxalate dihydrate stones was significantly higher in the symptomatic group (5.3% vs. 15.5%, p=0.023). No significant differences were observed in stone characteristics, postoperative outcomes, or complications. In the multivariate logistic regression analysis for predicting variables for asymptomatic renal stones, BMI (odds ratio [OR], 1.144; 95% confidence interval [CI], 1.038–1.260; p=0.007), and urine pH (OR, 0.608; 95% CI, 0.407–0.910; p=0.016) were independent predictive variables for asymptomatic renal stones. Conclusions: This study demonstrated that thorough medical check-ups are needed for the early detection of renal stones in individuals with a high BMI or low urine pH.