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Ebola disease (EBOD) in humans is a severe disease caused by at least four related viruses in the genus Orthoebolavirus, most often by the eponymous Ebola virus. Due to human‐to‐human transmission and incomplete success in treating cases despite promising therapeutic development, EBOD is a high priority in public health research. Yet despite almost 50 years since EBOD was first described, the sources of these viruses remain undefined and much remains to be understood about the disease epidemiology and virus emergence and spread. One important approach to improve our understanding is detection of antibodies that can reveal past human infections. However, serosurveys routinely describe seroprevalences that imply infection rates much higher than those clinically observed. Proposed hypotheses to explain this difference include existence of common but less pathogenic strains or relatives of these viruses, misidentification of EBOD as something else, and a higher proportion of subclinical infections than currently appreciated. The work presented here maps B‐cell epitopes in the spike protein of Ebola virus and describes a single epitope that is cross‐reactive with an antigen seemingly unrelated to orthoebolaviruses. Antibodies against this epitope appear to explain most of the unexpected reactivity towards the spike, arguing against common but unidentified infections in the population. Importantly, antibodies of cross‐reactive donors from within and outside the known EBOD geographic range bound the same epitope. In light of this finding, it is plausible that epitope mapping enables broadly applicable specificity improvements in the field of serology. [ABSTRACT FROM AUTHOR]

Screening tests are widely recommended for the early detection of disease among asymptomatic individuals. While detecting disease at an earlier stage has the potential to improve outcomes, screening also has negative consequences, including false positive results which may lead to anxiety, unnecessary diagnostic procedures, and increased healthcare costs. In addition, multiple false positive results could discourage participating in subsequent screening rounds. Screening guidelines typically recommend repeated screening over a period of many years, but little prior research has investigated how often individuals receive multiple false positive test results. Estimating the cumulative risk of multiple false positive results over the course of multiple rounds of screening is challenging due to the presence of censoring and competing risks, which may depend on the false positive risk, screening round, and number of prior false positive results. To address the general challenge of estimating the cumulative risk of multiple false positive test results, we propose a nonhomogeneous multistate model to describe the screening process including competing events. We developed alternative approaches for estimating the cumulative risk of multiple false positive results using this multistate model based on existing estimators for the cumulative risk of a single false positive. We compared the performance of the newly proposed models through simulation studies and illustrate model performance using data on screening mammography from the Breast Cancer Surveillance Consortium. Across most simulation scenarios, the multistate extension of a censoring bias model demonstrated lower bias compared to other approaches. In the context of screening mammography, we found that the cumulative risk of multiple false positive results is high. For instance, based on the censoring bias model, for a high-risk individual, the cumulative probability of at least two false positive mammography results after 10 rounds of annual screening is 40.4.

This case report is about a false positive ecstasy (MDMA) result in the urine substance abuse screening analysis of a person using the antidepressant drugs bupropion and sertraline with a therapeutic indication. Urine drug and stimulant screening analysis of a 25-year-old male patient who is history of bupropion (300 mg/day) and sertraline (100 mg/day) use, followed in the Amatem polyclinic due to the probation law, was performed with Syva® Emit® II Plus kits and immunoassay method. In order to confirm the ecstasy test, which was positive in the screening analysis, the substance analysis was repeated on the same sample with the gas chromatography sequential mass spectrometry (GC-MS) method and ecstasy was not detected in the confirmation analysis. At the same time, the presence of bupropion and sertraline patient declared to use, was confirmed with the LCMS-Iontrap device. In conclusion, with this case example, we wanted to highlight the potential interaction of bupropion with the Syva® Emit® II Plus urine ecstasy screening tests, which could lead to false positive results. When positive ecstasy values are detected in the urine samples analyzed with the immunoassay method in patients using bupropion, the final decision should be made after a confirmatory analysis. [ABSTRACT FROM AUTHOR]

Recently, we showed that the addition of physiological concentrations of ascorbic acid, a tear antioxidant, to the OptiSafe™ macromolecular eye irritation test reduced the false-positive (FP) rate for chemicals that had reactive chemistries, leading to the formation of reactive oxygen species (ROS) and molecular crosslinking. The purpose of the current study was to 1) increase the number of chemicals tested to comprehensibly determine whether the antioxidant-associated reduction in OD is specific to FP chemicals associated with ROS chemistries and 2) determine whether the addition of antioxidants interferes with the detection of true positive (TP) and true negative (TN) ocular irritants. We report that when ascorbic acid is added to the test reagents, retesting of FP chemicals with reactive chemistries show significantly reduced OD values (P

PurposeTo develop and evaluate an automated, portable algorithm to differentiate active corneal ulcers from healed scars using only external photographs.DesignA convolutional neural network was trained and tested using photographs of corneal ulcers and scars.ParticipantsDe-identified photographs of corneal ulcers were obtained from the Steroids for Corneal Ulcers Trial (SCUT), Mycotic Ulcer Treatment Trial (MUTT), and Byers Eye Institute at Stanford University.MethodsPhotographs of corneal ulcers (n = 1313) and scars (n = 1132) from the SCUT and MUTT were used to train a convolutional neural network (CNN). The CNN was tested on 2 different patient populations from eye clinics in India (n = 200) and the Byers Eye Institute at Stanford University (n = 101). Accuracy was evaluated against gold standard clinical classifications. Feature importances for the trained model were visualized using gradient-weighted class activation mapping.Main outcome measuresAccuracy of the CNN was assessed via F1 score. The area under the receiver operating characteristic (ROC) curve (AUC) was used to measure the precision-recall trade-off.ResultsThe CNN correctly classified 115 of 123 active ulcers and 65 of 77 scars in patients with corneal ulcer from India (F1 score, 92.0% [95% confidence interval (CI), 88.2%-95.8%]; sensitivity, 93.5% [95% CI, 89.1%-97.9%]; specificity, 84.42% [95% CI, 79.42%-89.42%]; ROC: AUC, 0.9731). The CNN correctly classified 43 of 55 active ulcers and 42 of 46 scars in patients with corneal ulcers from Northern California (F1 score, 84.3% [95% CI, 77.2%-91.4%]; sensitivity, 78.2% [95% CI, 67.3%-89.1%]; specificity, 91.3% [95% CI, 85.8%-96.8%]; ROC: AUC, 0.9474). The CNN visualizations correlated with clinically relevant features such as corneal infiltrate, hypopyon, and conjunctival injection.ConclusionsThe CNN classified corneal ulcers and scars with high accuracy and generalized to patient populations outside of its training data. The CNN focused on clinically relevant features when it made a diagnosis. The CNN demonstrated potential as an inexpensive diagnostic approach that may aid triage in communities with limited access to eye care.

We develop a statistical model for the testing of disease prevalence in a population. The model assumes a binary test result, positive or negative, but allows for biases in sample selection and both type I (false positive) and type II (false negative) testing errors. Our model also incorporates multiple test types and is able to distinguish between retesting and exclusion after testing. Our quantitative framework allows us to directly interpret testing results as a function of errors and biases. By applying our testing model to COVID-19 testing data and actual case data from specific jurisdictions, we are able to estimate and provide uncertainty quantification of indices that are crucial in a pandemic, such as disease prevalence and fatality ratios. This article is part of the theme issue 'Data science approach to infectious disease surveillance'.

Compound identification in small-molecule research, such as untargeted metabolomics or exposome research, relies on matching tandem mass spectrometry (MS/MS) spectra against experimental or in silico mass spectral libraries. Most software programs use dot product similarity scores. Here we introduce the concept of MS/MS spectral entropy to improve scoring results in MS/MS similarity searches via library matching. Entropy similarity outperformed 42 alternative similarity algorithms, including dot product similarity, when searching 434,287 spectra against the high-quality NIST20 library. Entropy similarity scores proved to be highly robust even when we added different levels of noise ions. When we applied entropy levels to 37,299 experimental spectra of natural products, false discovery rates of less than 10% were observed at entropy similarity score 0.75. Experimental human gut metabolome data were used to confirm that entropy similarity largely improved the accuracy of MS-based annotations in small-molecule research to false discovery rates below 10%, annotated new compounds and provided the basis to automatically flag poor-quality, noisy spectra.

BackgroundReidentification of prior nodules for temporal comparison is an important but time-consuming step in lung cancer screening. We develop and evaluate an automated nodule detector that utilizes the axial-slice number of nodules found in radiology reports to generate high precision nodule predictions.Methods888 CTs from Lung Nodule Analysis were used to train a 2-dimensional (2D) object detection neural network. A pipeline of 2D object detection, 3D unsupervised clustering, false positive reduction, and axial-slice numbers were used to generate nodule candidates. 47 CTs from the National Lung Cancer Screening Trial (NLST) were used for model evaluation.ResultsOur nodule detector achieved a precision of 0.962 at a recall of 0.573 on the NLST test set for any nodule. When adjusting for unintended nodule predictions, we achieved a precision of 0.931 at a recall 0.561, which corresponds to 0.06 false positives per CT. Error analysis revealed better detection of nodules with soft tissue attenuation compared to ground glass and undeterminable attenuation. Nodule margins, size, location, and patient demographics did not differ between correct and incorrect predictions.ConclusionsUtilization of axial-slice numbers from radiology reports allowed for development of a lung nodule detector with a low false positive rate compared to prior feature-engineering and machine learning approaches. This high precision nodule detector can reduce time spent on reidentification of prior nodules during lung cancer screening and can rapidly develop new institutional datasets to explore novel applications of computer vision in lung cancer imaging.

BackgroundA paucity of research addresses breast cancer screening strategies for women at lower-than-average breast cancer risk. The aim of this study was to examine screening harms and benefits among women aged 50-74 years at lower-than-average breast cancer risk by breast density.MethodsThree well-established, validated Cancer Intervention and Surveillance Network models were used to estimate the lifetime benefits and harms of different screening scenarios, varying by screening interval (biennial, triennial). Breast cancer deaths averted, life-years and quality-adjusted life-years gained, false-positives, benign biopsies, and overdiagnosis were assessed by relative risk (RR) level (0.6, 0.7, 0.85, 1 [average risk]) and breast density category, for US women born in 1970.ResultsScreening benefits decreased proportionally with decreasing risk and with lower breast density. False-positives, unnecessary biopsies, and the percentage overdiagnosis also varied substantially by breast density category; false-positives and unnecessary biopsies were highest in the heterogeneously dense category. For women with fatty or scattered fibroglandular breast density and a relative risk of no more than 0.85, the additional deaths averted and life-years gained were small with biennial vs triennial screening. For these groups, undergoing 4 additional screens (screening biennially [13 screens] vs triennially [9 screens]) averted no more than 1 additional breast cancer death and gained no more than 16 life-years and no more than 10 quality-adjusted life-years per 1000 women but resulted in up to 232 more false-positives per 1000 women.ConclusionTriennial screening from age 50 to 74 years may be a reasonable screening strategy for women with lower-than-average breast cancer risk and fatty or scattered fibroglandular breast density.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

A hallmark of coronavirus transcription is the generation of negative-sense RNA intermediates that serve as the templates for the synthesis of positive-sense genomic RNA (gRNA) and an array of subgenomic mRNAs (sgRNAs) encompassing sequences arising from discontinuous transcription. Existing PCR-based diagnostic assays for SAR-CoV-2 are qualitative or semi-quantitative and do not provide the resolution needed to assess the complex transcription dynamics of SARS-CoV-2 over the course of infection. We developed and validated a novel panel of sensitive, quantitative RT-ddPCR assays designed to target regions spanning the genome of SARS-CoV-2. Our assays target untranslated regions (5', 3') as well as different coding regions, including non-structural genes that are only found in full length (genomic) RNA and structural genes that are found in genomic as well as different subgenomic RNAs. Application of these assays to clinically relevant samples will enhance our understanding of SARS-CoV-2 gene expression and may also inform the development of improved diagnostic tools and therapeutics.

ObjectivesThe inconclusive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) result causes confusion and delay for infection prevention precautions and patient management. We aimed to develop a quantitative algorithm to assess and interpret these inconclusive results.MethodsWe created a score-based algorithm by combining laboratory, clinical, and epidemiologic data to evaluate 69 cases with inconclusive coronavirus disease 2019 (COVID-19) PCR results from the Centers for Disease Control and Prevention (CDC) assay (18 cases) and the TaqPath assay (51 cases).ResultsWe determined 5 (28%) of 18 (CDC assay) and 20 (39%) of 51 (TaqPath assay) cases to be false positive. Lowering the cycle threshold cutoff from 40 to 37 in the TaqPath assay resulted in a dramatic reduction of the false-positive rate to 14%. We also showed testing of asymptomatic individuals is associated with a significantly higher probability of having a false-positive result.ConclusionsA substantial percentage of inconclusive SARS-CoV-2 PCR results can be false positive, especially among asymptomatic patients. The quantitative algorithm we created was shown to be effective and could provide a useful tool for clinicians and hospital epidemiologists to interpret inconclusive COVID-19 PCR results and provide clinical guidance when additional PCR or antibody test results are available.

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).

Population screening played a substantial role in safely reopening the economy and avoiding new outbreaks of COVID-19. PCR-based pooled screening makes it possible to test the population with limited resources by pooling multiple individual samples. Our study compared different population-wide screening methods as transmission-mitigating interventions, including pooled PCR, individual PCR, and antigen screening. Incorporating testing-isolation process and individual-level viral load trajectories into an epidemic model, we further studied the impacts of testing-isolation on test sensitivities. Results show that the testing-isolation process could maintain a stable test sensitivity during the outbreak by removing most infected individuals, especially during the epidemic decline. Moreover, we compared the efficiency, accuracy, and cost of different screening methods during the pandemic. Our results show that PCR-based pooled screening is cost-effective in reversing the pandemic at low prevalence. When the prevalence is high, PCR-based pooled screening may not stop the outbreak. In contrast, antigen screening with sufficient frequency could reverse the epidemic, despite the high cost and the large numbers of false positives in the screening process.

ImportancePrevalence of hypertension (both primary and secondary) in children and adolescents in the US ranges from 3% to 4%. Primary hypertension in children and adolescents occurs primarily in children older than 13 years and has no known cause but is associated with several risk factors, including family history and higher body mass index. Secondary hypertension occurs primarily in younger children and is most commonly caused by genetic disorders, renal disease, endocrine disorders, or cardiovascular abnormalities.ObjectiveTo update its 2013 recommendation, the USPSTF commissioned a review of the evidence on the benefits and harms of screening, test accuracy, the effectiveness and harms of treatment, and the association between hypertension and markers of cardiovascular disease in childhood and adulthood.PopulationThis recommendation statement applies to children and adolescents aged 3 to 18 years not known to have hypertension or who are asymptomatic.Evidence assessmentThe USPSTF concludes that the evidence to support screening for high blood pressure in children and adolescents is insufficient and that the balance of benefits and harms cannot be determined.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents. (I statement).

Purpose of reviewWe summarize the evidence of benefits, harms, and tools to assist in individualized decisions among older adults in screening for breast, prostate, colon, lung, and cervical cancer.Recent findingsThe benefits of cancer screening in older adults remain unclear due to minimal inclusion of adults > 75 years old in most randomized controlled trials. Indirect evidence suggests that the benefits of screening seen in younger adults (

ImportancePrevalence of hypertension (both primary and secondary) in children and adolescents in the US ranges from 3% to 4%. Primary hypertension in children and adolescents occurs primarily in children older than 13 years and has no known cause but is associated with several risk factors, including family history and higher body mass index. Secondary hypertension occurs primarily in younger children and is most commonly caused by genetic disorders, renal disease, endocrine disorders, or cardiovascular abnormalities.ObjectiveTo update its 2013 recommendation, the USPSTF commissioned a review of the evidence on the benefits and harms of screening, test accuracy, the effectiveness and harms of treatment, and the association between hypertension and markers of cardiovascular disease in childhood and adulthood.PopulationThis recommendation statement applies to children and adolescents aged 3 to 18 years not known to have hypertension or who are asymptomatic.Evidence assessmentThe USPSTF concludes that the evidence to support screening for high blood pressure in children and adolescents is insufficient and that the balance of benefits and harms cannot be determined.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents. (I statement).

Degree of memory impairment is often used to infer early versus late amnestic mild cognitive impairment (aMCI). Previously, 318 Alzheimer's Disease Neuroimaging Initiative participants with aMCI-determined by a single memory test-were divided based on Rey Auditory Verbal Learning Task (AVLT) delayed recall: AVLT-impaired (n = 225) and AVLT-normal (n = 93). Equally consistent with differential progression or differential diagnosis, the AVLT-impaired group had more abnormal Alzheimer's disease (AD) biomarkers, more neurodegeneration over time, and was more likely to develop AD. In the present study, higher AD polygenic risk scores were associated with increased odds of being AVLT-impaired (odds ratio 1.8, p < 0.001). Thus, impairment severity does not necessarily reflect early versus late aMCI because disease progression cannot alter polygenic risk. Presumed early MCI is likely a heterogeneous category that includes excess false-positives. The additional cognitive test improved diagnostic precision by reducing false positives. Impairment severity may reflect differences in underlying disease risk but cannot be used to infer early versus late MCI based on cross-sectional data alone.

It has recently been suggested that precision oncology studies should be reanalysed using the intention-to-treat (ITT) methodology developed for randomized controlled clinical trials. This reanalysis dramatically decreases response rates in precision medicine studies. We contend that the ITT analysis of precision oncology trials is invalid. The ITT methodology was developed three decades ago to mitigate the problems of randomized trials, which try to ensure that both arms have an unselected patient population free from confounders. In contrast, precision oncology trials specifically select patients for confounders (that is biomarkers) that predict response. To demonstrate the issues inherent in an ITT reanalysis for precision cancer medicine studies, we take as an example the drug larotrectinib (TRK inhibitor) approved because of remarkable responses in malignancies harbouring NTRK fusions. Based on large-scale studies, NTRK fusions are found in ~0.31% of tumours. In a non-randomized pivotal study of larotrectinib, 75% of the 55 treated patients responded. Based upon the prevalence of NTRK fusions, ~18,000 patients would need to be screened to enrol the 55 treated patients. Utilizing the ITT methodology, the revised response rate to larotrectinib would be 0.23%. This is, of course, a dramatic underestimation of the efficacy of this now Food and Drug Administration (FDA)-approved drug. Similar issues can be shown for virtually any biomarker-based precision clinical trial. Therefore, retrofitting the ITT analysis developed for unselected patient populations in randomized trials yields misleading conclusions in precision medicine studies.

The Gaussian graphical model (GGM) is an increasingly popular technique used in psychology to characterize relationships among observed variables. These relationships are represented as elements in the precision matrix. Standardizing the precision matrix and reversing the sign yields corresponding partial correlations that imply pairwise dependencies in which the effects of all other variables have been controlled for. The graphical lasso (glasso) has emerged as the default estimation method, which uses ℓ1 -based regularization. The glasso was developed and optimized for high-dimensional settings where the number of variables (p) exceeds the number of observations (n), which is uncommon in psychological applications. Here we propose to go 'back to the basics', wherein the precision matrix is first estimated with non-regularized maximum likelihood and then Fisher Z transformed confidence intervals are used to determine non-zero relationships. We first show the exact correspondence between the confidence level and specificity, which is due to 1 minus specificity denoting the false positive rate (i.e., α). With simulations in low-dimensional settings (p ≪ n), we then demonstrate superior performance compared to the glasso for detecting the non-zero effects. Further, our results indicate that the glasso is inconsistent for the purpose of model selection and does not control the false discovery rate, whereas the proposed method converges on the true model and directly controls error rates. We end by discussing implications for estimating GGMs in psychology.

The performance of urine Xpert MTB/RIF Ultra (Xpert Ultra) for pulmonary TB diagnosis is unknown. HIV-positive and HIV-negative adults were enrolled at two health facilities in Kampala, Uganda. We compared the accuracy of urine Xpert Ultra and Determine TB-LAM in reference to sputum-based testing (positive Xpert MTB/RIF or culture), and assessed incremental yield. Urine Xpert Ultra had low sensitivity (17.2%, 95% CI 12.3-23.2) but high specificity (98.1%, 95% CI 94.4-99.6). Sensitivity reached 50.0% (95% CI 28.2-71.8) among HIV-positive patients with CD4

ImportanceA deep learning system (DLS) that could automatically detect glaucomatous optic neuropathy (GON) with high sensitivity and specificity could expedite screening for GON.ObjectiveTo establish a DLS for detection of GON using retinal fundus images and glaucoma diagnosis with convoluted neural networks (GD-CNN) that has the ability to be generalized across populations.Design, setting, and participantsIn this cross-sectional study, a DLS for the classification of GON was developed for automated classification of GON using retinal fundus images obtained from the Chinese Glaucoma Study Alliance, the Handan Eye Study, and online databases. The researchers selected 241 032 images were selected as the training data set. The images were entered into the databases on June 9, 2009, obtained on July 11, 2018, and analyses were performed on December 15, 2018. The generalization of the DLS was tested in several validation data sets, which allowed assessment of the DLS in a clinical setting without exclusions, testing against variable image quality based on fundus photographs obtained from websites, evaluation in a population-based study that reflects a natural distribution of patients with glaucoma within the cohort and an additive data set that has a diverse ethnic distribution. An online learning system was established to transfer the trained and validated DLS to generalize the results with fundus images from new sources. To better understand the DLS decision-making process, a prediction visualization test was performed that identified regions of the fundus images utilized by the DLS for diagnosis.ExposuresUse of a deep learning system.Main outcomes and measuresArea under the receiver operating characteristics curve (AUC), sensitivity and specificity for DLS with reference to professional graders.ResultsFrom a total of 274 413 fundus images initially obtained from CGSA, 269 601 images passed initial image quality review and were graded for GON. A total of 241 032 images (definite GON 29 865 [12.4%], probable GON 11 046 [4.6%], unlikely GON 200 121 [83%]) from 68 013 patients were selected using random sampling to train the GD-CNN model. Validation and evaluation of the GD-CNN model was assessed using the remaining 28 569 images from CGSA. The AUC of the GD-CNN model in primary local validation data sets was 0.996 (95% CI, 0.995-0.998), with sensitivity of 96.2% and specificity of 97.7%. The most common reason for both false-negative and false-positive grading by GD-CNN (51 of 119 [46.3%] and 191 of 588 [32.3%]) and manual grading (50 of 113 [44.2%] and 183 of 538 [34.0%]) was pathologic or high myopia.Conclusions and relevanceApplication of GD-CNN to fundus images from different settings and varying image quality demonstrated a high sensitivity, specificity, and generalizability for detecting GON. These findings suggest that automated DLS could enhance current screening programs in a cost-effective and time-efficient manner.

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PurposeEpidemic and seasonal infectious conjunctivitis outbreaks can impact education, workforce, and economy adversely. Yet conjunctivitis typically is not a reportable disease, potentially delaying mitigating intervention. Our study objective was to determine if conjunctivitis epidemics could be identified using Google Trends search data.DesignSearch data for conjunctivitis-related and control search terms from 5 years and countries worldwide were obtained. Country and term were masked. Temporal scan statistics were applied to identify candidate epidemics. Candidates then were assessed for geotemporal concordance with an a priori defined collection of known reported conjunctivitis outbreaks, as a measure of sensitivity.ParticipantsPopulations by country that searched Google's search engine using our study terms.Main outcome measuresPercent of known conjunctivitis outbreaks also found in the same country and period by our candidate epidemics, identified from conjunctivitis-related searches.ResultsWe identified 135 candidate conjunctivitis epidemic periods from 77 countries. Compared with our a priori defined collection of known reported outbreaks, candidate conjunctivitis epidemics identified 18 of 26 (69% sensitivity) of the reported country-wide or island nationwide outbreaks, or both; 9 of 20 (45% sensitivity) of the reported region or district-wide outbreaks, or both; but far fewer nosocomial and reported smaller outbreaks. Similar overall and individual sensitivity, as well as specificity, were found on a country-level basis. We also found that 83% of our candidate epidemics had start dates before (of those, 20% were more than 12 weeks before) their concurrent reported outbreak's report issuance date. Permutation tests provided evidence that on average, conjunctivitis candidate epidemics occurred geotemporally closer to outbreak reports than chance alone suggests (P < 0.001) unlike control term candidates (P = 0.40).ConclusionsConjunctivitis outbreaks can be detected using temporal scan analysis of Google search data alone, with more than 80% detected before an outbreak report's issuance date, some as early as the reported outbreak's start date. Future approaches using data from smaller regions, social media, and more search terms may improve sensitivity further and cross-validate detected candidates, allowing identification of candidate conjunctivitis epidemics from Internet search data potentially to complementarily benefit traditional reporting and detection systems to improve epidemic awareness.

BackgroundExcessive electrocardiographic alarms contribute to "alarm fatigue," which can lead to patient harm. In a prior study, one-third of audible electrocardiographic alarms were for accelerated ventricular rhythm (AVR), and most of these alarms were false. It is uncertain whether true AVR alarms are clinically relevant.ObjectivesTo determine from bedside electrocardiographic monitoring data (1) how often true AVR alarms are acknowledged by clinicians, (2) whether such alarms are actionable, and (3) whether such alarms are associated with adverse outcomes ("code blue," death).MethodsSecondary analysis using data from a study conducted in an academic medical center involving 5 adult intensive care units with 77 beds. Electronic health records of 23 patients with 223 true alarms for AVR were examined.ResultsThe mean age of the patients was 62.9 years, and 61% were white and male. All 223 of the true alarms were configured at the warning level (ie, 2 continuous beeps), and 215 (96.4%) lasted less than 30 seconds. Only 1 alarm was acknowledged in the electronic health record. None of the alarms were clinically actionable or led to a code blue or death.ConclusionsTrue AVR alarms may contribute to alarm fatigue. Hospitals should reevaluate the need for close monitoring of AVR and consider configuring this alarm to an inaudible message setting to reduce the risk of patient harm due to alarm fatigue. Prospective studies involving larger patient samples and varied monitors are warranted.

CD8+ T cells recognize and eliminate tumors in an antigen-specific manner. Despite progress in characterizing the antitumor T cell repertoire and function, the identification of target antigens remains a challenge. Here we describe the use of chimeric receptors called signaling and antigen-presenting bifunctional receptors (SABRs) in a cell-based platform for T cell receptor (TCR) antigen discovery. SABRs present an extracellular complex comprising a peptide and major histocompatibility complex (MHC), and induce intracellular signaling via a TCR-like signal after binding with a cognate TCR. We devised a strategy for antigen discovery using SABR libraries to screen thousands of antigenic epitopes. We validated this platform by identifying the targets recognized by public TCRs of known specificities. Moreover, we extended this approach for personalized neoantigen discovery.

BackgroundSemiquantitative assessment of MRI plays a central role in musculoskeletal research; however, in the clinical setting MRI reports often tend to be subjective and qualitative. Grading schemes utilized in research are not used because they are extraordinarily time-consuming and unfeasible in clinical practice.PurposeTo evaluate the ability of deep-learning models to detect and stage severity of meniscus and patellofemoral cartilage lesions in osteoarthritis and anterior cruciate ligament (ACL) subjects.Study typeRetrospective study aimed to evaluate a technical development.PopulationIn all, 1478 MRI studies, including subjects at various stages of osteoarthritis and after ACL injury and reconstruction.Field strength/sequence3T MRI, 3D FSE CUBE.AssessmentAutomatic segmentation of cartilage and meniscus using 2D U-Net, automatic detection, and severity staging of meniscus and cartilage lesion with a 3D convolutional neural network (3D-CNN).Statistical testsReceiver operating characteristic (ROC) curve, specificity and sensitivity, and class accuracy.ResultsSensitivity of 89.81% and specificity of 81.98% for meniscus lesion detection and sensitivity of 80.0% and specificity of 80.27% for cartilage were achieved. The best performances for staging lesion severity were obtained by including demographics factors, achieving accuracies of 80.74%, 78.02%, and 75.00% for normal, small, and complex large lesions, respectively.Data conclusionIn this study we provide a proof of concept of a fully automated deep-learning pipeline that can identify the presence of meniscal and patellar cartilage lesions. This pipeline has also shown potential in making more in-depth examinations of lesion subjects for multiclass prediction and severity staging.Level of evidence2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:400-410.

Functional genomics data has the potential to increase GWAS power by identifying SNPs that have a higher prior probability of association. Here, we introduce a method that leverages polygenic functional enrichment to incorporate coding, conserved, regulatory, and LD-related genomic annotations into association analyses. We show via simulations with real genotypes that the method, functionally informed novel discovery of risk loci (FINDOR), correctly controls the false-positive rate at null loci and attains a 9%-38% increase in the number of independent associations detected at causal loci, depending on trait polygenicity and sample size. We applied FINDOR to 27 independent complex traits and diseases from the interim UK Biobank release (average N = 130K). Averaged across traits, we attained a 13% increase in genome-wide significant loci detected (including a 20% increase for disease traits) compared to unweighted raw p values that do not use functional data. We replicated the additional loci in independent UK Biobank and non-UK Biobank data, yielding a highly statistically significant replication slope (0.66-0.69) in each case. Finally, we applied FINDOR to the full UK Biobank release (average N = 416K), attaining smaller relative improvements (consistent with simulations) but larger absolute improvements, detecting an additional 583 GWAS loci. In conclusion, leveraging functional enrichment using our method robustly increases GWAS power.

To explore the positive predictive value (PPV) in noninvasive prenatal testing (NIPT)-positive cases and analyze the effect of the Z-score intervals on PPV performance. In this retrospective study, 26,667 pregnant women underwent NIPT from November 2014 to August 2022, of which 169 were NIPT-positive cases. NIPT-positive cases were divided into three groups according to the Z-score: 3 ≤ Z < 6, 6 ≤ Z < 10, and Z ≥ 10. The PPVs of NIPT were 91.26% (94/103) for trisomy (T) 21, 80.65% (25/31) for T18, and 36.84% (7/19) for T13. The PPVs for the 3 ≤ Z < 6, 6 ≤ Z < 10, and Z ≥ 10 groups were 50%, 84.62%, and 87.95%, respectively. A higher PPV was found in the NIPT results when the Z-score was larger, with significant differences. The PPVs for T21/T18/T13 were 71.43%/42.86%/25% for 3 ≤ Z < 6, 90.32%/85.71%/57.14% for 6 ≤ Z < 10, and 93.85%/100%/25% for Z ≥ 10. For T21, T18, and T13, the correlations between the Z-score and fetal fraction concentration in true positives were r = 0.85, r = 0.59, and r = 0.71 (all p <.001), respectively. Z-score is associated with the PPV performance of NIPT in fetal T13, T18, and T21. The possibility of false positives caused by placental chimerism should be considered when determining whether high Z-values lead to high PPVs. [ABSTRACT FROM AUTHOR]

ObjectiveA cerebrospinal fluid leak is one of the most serious complications in otolaryngology. It may occur as a result of injury to the skull base, typically traumatic or iatrogenic. While the presence of a leak is often discerned in the emergent setting, distinguishing normal secretions from those containing cerebrospinal fluid can be difficult during postoperative visits in the clinic. As most current laboratory-based assays are labor intensive and require several days to result, we aim to develop a more user-friendly and rapid point-of-care cerebrospinal fluid detection device.Study designOur laboratory developed a barcode-style lateral-flow immunoassay utilizing antibodies for beta-trace protein, a protein abundant in and specific for cerebrospinal fluid, with a concentration of 1.3 mg/L delineating a positive result.SettingTertiary medical center.Subjects and methodsTests with known concentrations of resuspended beta-trace protein and the contents of discarded lumbar drains (presumed to contain cerebrospinal fluid) were performed to validate our novel device.ResultsOur results demonstrate the ability of our device to semiquantitatively identify concentrations of beta-trace protein from 0.3-90 mg/L, which is within the required range to diagnose a leak, thus making beta-trace protein an excellent target for rapid clinical detection.ConclusionHerein we detail the creation and initial validation of the first point-of-care cerebrospinal fluid detection device. This device is a feasible method to more efficiently and cost-effectively identify cerebrospinal fluid leaks, minimize costs, and improve patient outcomes.

ImportanceUntreated syphilis infection in pregnant women can be transmitted to the fetus (congenital syphilis) at any time during pregnancy or at birth. Congenital syphilis is associated with stillbirth, neonatal death, and significant morbidity in infants (eg, bone deformities and neurologic impairment). After a steady decline from 2008 to 2012, cases of congenital syphilis markedly increased from 2012 to 2106, from 8.4 to 15.7 cases per 100 000 live births (an increase of 87%). At the same time, national rates of syphilis increased among women of reproductive age.ObjectiveTo update the US Preventive Services Task Force (USPSTF) 2009 recommendation on screening for syphilis infection in pregnant women.Evidence reviewThe USPSTF commissioned a reaffirmation evidence update to identify new and substantial evidence sufficient enough to change its prior recommendation. Given the established benefits and practice of screening for syphilis in pregnant women, the USPSTF targeted its evidence review on the direct benefits of screening on the prevention of congenital syphilis morbidity and mortality and the harms of screening for and treatment of syphilis infection in pregnant women.FindingsUsing a reaffirmation process, the USPSTF found that accurate screening algorithms are available to identify syphilis infection. Effective treatment with antibiotics can prevent congenital syphilis and significantly decrease adverse pregnancy outcomes, with small associated harms, providing an overall substantial health benefit. Therefore, the USPSTF reaffirms its previous conclusion that there is convincing evidence that screening for syphilis infection in pregnant women provides substantial benefit.Conclusions and recommendationThe USPSTF recommends early screening for syphilis infection in all pregnant women. (A recommendation).

ObjectivesAlthough subjective cognitive complaints (SCC) are an integral component of the diagnostic criteria for mild cognitive impairment (MCI), previous findings indicate they may not accurately reflect cognitive ability. Within the Alzheimer's Disease Neuroimaging Initiative, we investigated longitudinal change in the discrepancy between self- and informant-reported SCC across empirically derived subtypes of MCI and normal control (NC) participants.MethodsData were obtained for 353 MCI participants and 122 "robust" NC participants. Participants were classified into three subtypes at baseline via cluster analysis: amnestic MCI, mixed MCI, and cluster-derived normal (CDN), a presumptive false-positive group who performed within normal limits on neuropsychological testing. SCC at baseline and two annual follow-up visits were assessed via the Everyday Cognition Questionnaire (ECog), and discrepancy scores between self- and informant-report were calculated. Analysis of change was conducted using analysis of covariance.ResultsThe amnestic and mixed MCI subtypes demonstrated increasing ECog discrepancy scores over time. This was driven by an increase in informant-reported SCC, which corresponded to participants' objective cognitive decline, despite stable self-reported SCC. Increasing unawareness was associated with cerebrospinal fluid Alzheimer's disease biomarker positivity and progression to Alzheimer's disease. In contrast, CDN and NC groups over-reported cognitive difficulty and demonstrated normal cognition at all time points.ConclusionsMCI participants' discrepancy scores indicate progressive underappreciation of their evolving cognitive deficits. Consistent over-reporting in the CDN and NC groups despite normal objective cognition suggests that self-reported SCC do not predict impending cognitive decline. Results demonstrate that self-reported SCC become increasingly misleading as objective cognitive impairment becomes more pronounced. (JINS, 2018, 24, 842-853).

ImportanceUntreated syphilis infection in pregnant women can be transmitted to the fetus (congenital syphilis) at any time during pregnancy or at birth. Congenital syphilis is associated with stillbirth, neonatal death, and significant morbidity in infants (eg, bone deformities and neurologic impairment). After a steady decline from 2008 to 2012, cases of congenital syphilis markedly increased from 2012 to 2106, from 8.4 to 15.7 cases per 100 000 live births (an increase of 87%). At the same time, national rates of syphilis increased among women of reproductive age.ObjectiveTo update the US Preventive Services Task Force (USPSTF) 2009 recommendation on screening for syphilis infection in pregnant women.Evidence reviewThe USPSTF commissioned a reaffirmation evidence update to identify new and substantial evidence sufficient enough to change its prior recommendation. Given the established benefits and practice of screening for syphilis in pregnant women, the USPSTF targeted its evidence review on the direct benefits of screening on the prevention of congenital syphilis morbidity and mortality and the harms of screening for and treatment of syphilis infection in pregnant women.FindingsUsing a reaffirmation process, the USPSTF found that accurate screening algorithms are available to identify syphilis infection. Effective treatment with antibiotics can prevent congenital syphilis and significantly decrease adverse pregnancy outcomes, with small associated harms, providing an overall substantial health benefit. Therefore, the USPSTF reaffirms its previous conclusion that there is convincing evidence that screening for syphilis infection in pregnant women provides substantial benefit.Conclusions and recommendationThe USPSTF recommends early screening for syphilis infection in all pregnant women. (A recommendation).

PURPOSE: This study aims to combine multiparametric magnetic resonance imaging (MRI) and digitized pathology with machine learning to generate predictive maps of histologic features for prostate cancer localization. METHODS AND MATERIALS: Thirty-nine patients underwent MRI prior to prostatectomy. After surgery, tissue was sliced according to MRI orientation using patient-specific 3-dimensionally printed slicing jigs. Whole-mount sections were annotated by our pathologist and digitally contoured to differentiate the lumen and epithelium. Slides were co-registered to the T2-weighted MRI scan. A learning curve was generated to determine the number of patients required for a stable machine-learning model. Patients were randomly stratified into 2 training sets and 1 test set. Two partial least-squares regression models were trained, each capable of predicting lumen and epithelium density. Predicted density values were calculated for each patient in the test dataset, mapped into the MRI space, and compared between regions confirmed as high-grade prostate cancer. RESULTS: The learning-curve analysis showed that a stable fit was achieved with data from 10 patients. Maps indicated that regions of increased epithelium and decreased lumen density, generated from each independent model, corresponded with pathologist-annotated regions of high-grade cancer. CONCLUSIONS: We present a radio-pathomic approach to mapping prostate cancer. We find that the maps are useful for highlighting high-grade tumors. This technique may be relevant for dose-painting strategies in prostate radiation therapy.

BackgroundThe utility of exercise-induced ST-segment depression for diagnosing ischemic heart disease (IHD) in women is unclear.HypothesisBased on evidence that IHD pathophysiology in women involves coronary vascular dysfunction, we hypothesized that coronary vascular dysfunction contributes to exercise electrocardiography (Ex-ECG) ST-depression in the absence of obstructive coronary artery disease, so-called false positive results. We tested our hypothesis in a pilot study evaluating the relationship between peripheral vascular endothelial function and Ex-ECG.MethodsTwenty-nine asymptomatic women without cardiac risk factors underwent maximal Bruce protocol exercise treadmill testing and peripheral endothelial function assessment using peripheral arterial tonometry (Itamar EndoPAT 2000) to measure reactive hyperemia index (RHI). The relationship between RHI and Ex-ECG ST-segment depression was evaluated using logistic regression and differences in subgroups using 2-tailed t tests.ResultsMean age was 54 ± 7 years, body mass index 25 ± 4 kg/m2 , and RHI 2.51 ± 0.66. Three women (10%) had RHI 0.05). RHI did not predict ST-segment depression.ConclusionsOur pilot study demonstrates high prevalence of exercise-induced ST-segment depression in asymptomatic, middle-aged, overweight women. Peripheral vascular endothelial dysfunction did not predict Ex-ECG ST-segment depression. Further work is needed to investigate the utility of vascular endothelial testing and Ex-ECG for IHD diagnostic and management purposes in women.

ImportanceIn the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 13%, and the lifetime risk of dying of prostate cancer is 2.5%. The median age of death from prostate cancer is 80 years. Many men with prostate cancer never experience symptoms and, without screening, would never know they have the disease. African American men and men with a family history of prostate cancer have an increased risk of prostate cancer compared with other men.ObjectiveTo update the 2012 US Preventive Services Task Force (USPSTF) recommendation on prostate-specific antigen (PSA)-based screening for prostate cancer.Evidence reviewThe USPSTF reviewed the evidence on the benefits and harms of PSA-based screening for prostate cancer and subsequent treatment of screen-detected prostate cancer. The USPSTF also commissioned a review of existing decision analysis models and the overdiagnosis rate of PSA-based screening. The reviews also examined the benefits and harms of PSA-based screening in patient subpopulations at higher risk of prostate cancer, including older men, African American men, and men with a family history of prostate cancer.FindingsAdequate evidence from randomized clinical trials shows that PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened. Screening programs may also prevent approximately 3 cases of metastatic prostate cancer per 1000 men screened. Potential harms of screening include frequent false-positive results and psychological harms. Harms of prostate cancer treatment include erectile dysfunction, urinary incontinence, and bowel symptoms. About 1 in 5 men who undergo radical prostatectomy develop long-term urinary incontinence, and 2 in 3 men will experience long-term erectile dysfunction. Adequate evidence shows that the harms of screening in men older than 70 years are at least moderate and greater than in younger men because of increased risk of false-positive results, diagnostic harms from biopsies, and harms from treatment. The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms.Conclusions and recommendationFor men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. (C recommendation) The USPSTF recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation).

PurposeWe sought to identify the clinical and magnetic resonance imaging variables predictive of biochemical recurrence after robotic assisted radical prostatectomy in patients who underwent multiparametric 3 Tesla prostate magnetic resonance imaging.Materials and methodsWe performed an institutional review board approved, HIPAA (Health Insurance Portability and Accountability Act) compliant, single arm observational study of 3 Tesla multiparametric magnetic resonance imaging prior to robotic assisted radical prostatectomy from December 2009 to March 2016. Clinical, magnetic resonance imaging and pathological information, and clinical outcomes were compiled. Biochemical recurrence was defined as prostate specific antigen 0.2 ng/cc or greater. Univariate and multivariate regression analysis was performed.ResultsBiochemical recurrence had developed in 62 of the 255 men (24.3%) included in the study at a median followup of 23.5 months. Compared to the subcohort without biochemical recurrence the subcohort with biochemical recurrence had a greater proportion of patients with a high grade biopsy Gleason score, higher preoperative prostate specific antigen (7.4 vs 5.6 ng/ml), intermediate and high D'Amico classifications, larger tumor volume on magnetic resonance imaging (0.66 vs 0.30 ml), higher PI-RADS® (Prostate Imaging-Reporting and Data System) version 2 category lesions, a greater proportion of intermediate and high grade radical prostatectomy Gleason score lesions, higher pathological T3 stage (all p

Importance:In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 13%, and the lifetime risk of dying of prostate cancer is 2.5%. The median age of death from prostate cancer is 80 years. Many men with prostate cancer never experience symptoms and, without screening, would never know they have the disease. African American men and men with a family history of prostate cancer have an increased risk of prostate cancer compared with other men. Objective:To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on prostate-specific antigen (PSA)-based screening for prostate cancer. Evidence Review:The USPSTF reviewed the evidence on the benefits and harms of PSA-based screening for prostate cancer and subsequent treatment of screen-detected prostate cancer. The USPSTF also commissioned a review of existing decision analysis models and the overdiagnosis rate of PSA-based screening. The reviews also examined the benefits and harms of PSA-based screening in patient subpopulations at higher risk of prostate cancer, including older men, African American men, and men with a family history of prostate cancer. Findings:Adequate evidence from randomized clinical trials shows that PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened. Screening programs may also prevent approximately 3 cases of metastatic prostate cancer per 1000 men screened. Potential harms of screening include frequent false-positive results and psychological harms. Harms of prostate cancer treatment include erectile dysfunction, urinary incontinence, and bowel symptoms. About 1 in 5 men who undergo radical prostatectomy develop long-term urinary incontinence, and 2 in 3 men will experience long-term erectile dysfunction. Adequate evidence shows that the harms of screening in men older than 70 years are at least moderate and greater than in younger men because of increased risk of false-positive results, diagnostic harms from biopsies, and harms from treatment. The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms. Conclusions and Recommendation:For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. (C recommendation) The USPSTF recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation).

PurposeCentral visual field (VF) damage in glaucoma patients can significantly hinder daily activities. The present study investigates whether the presence of localized baseline damage to the central 10 degrees of the VF is predictive of faster global mean deviation (MD) progression.DesignProspective cohort study.MethodsEyes from the multicenter African Descent and Glaucoma Evaluation Study (ADAGES) with established glaucoma and VF loss and a minimum of 5 24-2 VFs were eligible. Baseline central 24-2 damage was defined as any of the 12 central-most points with total deviation (TD) values at P < 0.5% on 2 consecutive examinations. Progression was determined using trend-based and event-based criteria: (1) rates of MD change significantly faster than zero and (2) >-5 dB MD loss over the entire follow-up.ResultsA total of 827 eyes of 584 patients were studied. Mean rate of MD change of the entire sample was -0.15 dB/year (95% CI: -0.19 to -0.12, P

BackgroundPatients hospitalized for suspected acute coronary syndrome (ACS) are at risk for transient myocardial ischemia. During the "rule-out" phase, continuous ECG ST-segment monitoring can identify transient myocardial ischemia, even when asymptomatic. However, current ST-segment monitoring software is vastly underutilized due to false positive alarms, with resultant alarm fatigue. Current ST algorithms may contribute to alarm fatigue because; (1) they are not designed with a delay (minutes), rather alarm to brief spikes (i.e., turning, heart rate changes), and (2) alarm to changes in a single ECG lead, rather than contiguous leads.PurposeThis study was designed to determine sensitivity, and specificity, of ST algorithms when accounting for; ST magnitude (100μV vs 200μV), duration, and changes in contiguous ECG leads (i.e., aVL, I, - aVR, II, aVF, III; V1, V2, V3, V4, V5, V6, V6, I).MethodsThis was a secondary analysis from the COMPARE Study, which assessed occurrence rates for transient myocardial ischemia in hospitalized patients with suspected ACS using 12-lead Holter. Transient myocardial ischemia was identified from Holter using >100μV ST-segment ↑ or ↓, in >1 ECG lead, >1min. Algorithms tested against Holter transient myocardial ischemia were done using the University of California San Francisco (UCSF) ECG algorithm and included: (1)100μV vs 200μV any lead during a 5-min ST average; (2)100μV vs 200μV any lead >5min, (3) 100μV vs 200μV any lead during a 5-min ST average in contiguous leads, and (4) 100μV vs 200μV>5min in contiguous leads (Table below).ResultsIn 361 patients; mean age 63+12years, 63% male, 56% prior CAD, 43 (11%) had transient myocardial ischemia. Of the 43 patients with transient myocardial ischemia, 17 (40%) had ST-segment elevation events, and 26 (60%) ST-segment depression events. A higher proportion of patients with ST segment depression has missed ischemic events. Table shows sensitivity and specificity for the four algorithms tested.ConclusionsSensitivity was highly variable, due to the ST threshold selected, with the 100μV measurement point being superior to the 200μV amplitude threshold. Of all the algorithms tested, there was moderate sensitivity and specificity (70% and 68%) using the 100μV ST-segment threshold, integrated ST-segment changes in contiguous leads during a 5-min average.

Importance:Ovarian cancer is relatively rare but the fifth-leading cause of cancer mortality among United States women. Objective:To systematically review evidence on benefits and harms of ovarian cancer screening among average-risk women to inform the United States Preventive Services Task Force. Data Sources:MEDLINE, PubMed, Cochrane Collaboration Registry of Controlled Trials; studies published in English from January 1, 2003, through January 31, 2017; ongoing surveillance in targeted publications through November 22, 2017. Study Selection:Randomized clinical trials of ovarian cancer screening in average-risk women that reported mortality or quality-of-life outcomes. Interventions included transvaginal ultrasound, cancer antigen 125 (CA-125) testing, or their combination. Comparators were usual care or no screening. Data Extraction and Synthesis:Independent critical appraisal and data abstraction by 2 reviewers. Meta-analytic pooling of results was not conducted because of the small number of studies and heterogeneity of interventions. Main Outcomes and Measures:Ovarian cancer mortality, false-positive screening results and surgery, surgical complications, and psychological effects of screening. Results:Four trials (N = 293 587) were included; of these, 3 (n = 293 038) assessed ovarian cancer mortality, and 1 (n = 549) reported only on psychological outcomes. Evaluated screening interventions included transvaginal ultrasound alone, transvaginal ultrasound plus CA-125 testing, and CA-125 testing alone. Test positivity for CA-125 was defined by a fixed serum level cutpoint or by a proprietary risk algorithm based on CA-125 level, change in CA-125 level over time, and age (risk of ovarian cancer algorithm [ROCA]). No trial found a significant difference in ovarian cancer mortality with screening. In the 2 large screening trials (PLCO and UKCTOCS, n = 271 103), there was not a statistically significant difference in complete intention-to-screen analyses of ovarian, fallopian, and peritoneal cancer cases associated with screening (PLCO: rate ratio, 1.18 [95% CI, 0.82-1.71]; UKCTOCS: hazard ratio [HR], 0.91 [95% CI, 0.76-1.09] for transvaginal ultrasound and HR, 0.89 [95% CI, 0.74-1.08] for CA-125 ROCA). Within these 2 trials, screening led to surgery for suspected ovarian cancer in 1% of women without cancer for CA-125 ROCA and in 3% for transvaginal ultrasound with or without CA-125 screening, with major complications occurring among 3% to 15% of surgery. Evidence on psychological harms was limited but nonsignificant except in the case of repeat follow-up scans and tests, which increased the risk of psychological morbidity in a subsample of UKCTOCS participants based on the General Health Questionnaire 12 (score ≥4) (odds ratio, 1.28 [95% CI, 1.18-1.39]). Conclusions and Relevance:In randomized trials conducted among average-risk, asymptomatic women, ovarian cancer mortality did not significantly differ between screened women and those with no screening or in usual care. Screening harms included surgery (with major surgical complications) in women found to not have cancer. Further research is needed to identify effective approaches for reducing ovarian cancer incidence and mortality.

ImportanceWith approximately 14 000 deaths per year, ovarian cancer is the fifth most common cause of cancer death among US women and the leading cause of death from gynecologic cancer. More than 95% of ovarian cancer deaths occur among women 45 years and older.ObjectiveTo update the 2012 US Preventive Services Task Force (USPSTF) recommendation on screening for ovarian cancer.Evidence reviewThe USPSTF reviewed the evidence on the benefits and harms of screening for ovarian cancer in asymptomatic women not known to be at high risk for ovarian cancer (ie, high risk includes women with certain hereditary cancer syndromes that increase their risk for ovarian cancer). Outcomes of interest included ovarian cancer mortality, quality of life, false-positive rate, surgery and surgical complication rates, and psychological effects of screening.FindingsThe USPSTF found adequate evidence that screening for ovarian cancer does not reduce ovarian cancer mortality. The USPSTF found adequate evidence that the harms from screening for ovarian cancer are at least moderate and may be substantial in some cases, and include unnecessary surgery for women who do not have cancer. Given the lack of mortality benefit of screening, and the moderate to substantial harms that could result from false-positive screening test results and subsequent surgery, the USPSTF concludes with moderate certainty that the harms of screening for ovarian cancer outweigh the benefit, and the net balance of the benefit and harms of screening is negative.Conclusions and recommendationThe USPSTF recommends against screening for ovarian cancer in asymptomatic women. (D recommendation) This recommendation applies to asymptomatic women who are not known to have a high-risk hereditary cancer syndrome.

ImportanceWith approximately 14 000 deaths per year, ovarian cancer is the fifth most common cause of cancer death among US women and the leading cause of death from gynecologic cancer. More than 95% of ovarian cancer deaths occur among women 45 years and older.ObjectiveTo update the 2012 US Preventive Services Task Force (USPSTF) recommendation on screening for ovarian cancer.Evidence reviewThe USPSTF reviewed the evidence on the benefits and harms of screening for ovarian cancer in asymptomatic women not known to be at high risk for ovarian cancer (ie, high risk includes women with certain hereditary cancer syndromes that increase their risk for ovarian cancer). Outcomes of interest included ovarian cancer mortality, quality of life, false-positive rate, surgery and surgical complication rates, and psychological effects of screening.FindingsThe USPSTF found adequate evidence that screening for ovarian cancer does not reduce ovarian cancer mortality. The USPSTF found adequate evidence that the harms from screening for ovarian cancer are at least moderate and may be substantial in some cases, and include unnecessary surgery for women who do not have cancer. Given the lack of mortality benefit of screening, and the moderate to substantial harms that could result from false-positive screening test results and subsequent surgery, the USPSTF concludes with moderate certainty that the harms of screening for ovarian cancer outweigh the benefit, and the net balance of the benefit and harms of screening is negative.Conclusions and recommendationThe USPSTF recommends against screening for ovarian cancer in asymptomatic women. (D recommendation) This recommendation applies to asymptomatic women who are not known to have a high-risk hereditary cancer syndrome.

BackgroundResearch studies rely on accurate assessment of entry criteria in order to maintain study integrity and participant safety, however, challenges can exist with HIV studies in international settings.ObjectiveExamine the unexpectedly high proportion of study participants with an undetectable HIV viral load found in Ugandan and Russian research cohorts meeting antiretroviral therapy (ART)-naïve entry criteria.MethodsRussian participants with documented HIV and ART-naïve status were recruited between 2012 and 2015 from clinical and non-clinical sites in St. Petersburg. Participants in Uganda were recruited from Mbarara Regional Referral Hospital from 2011 to 2014 with documented HIV infection via rapid diagnostic testing and recorded ART-naïve in the clinic database. HIV viral load testing of baseline samples was performed; the lower limit of detection was 500 copies/mL in Russia and 40 in Uganda. Due to an unexpectedly high proportion of participants with undetectable viremia, additional tests were performed: enzyme-linked immunosorbent assay HIV testing and testing for ART.ResultsIn Russia, 16% (58/360) had undetectable viremia; 3% (9/360) re-tested HIV-seronegative and 4% (13/360) tested positive for ART. In Uganda 11% (55/482) had undetectable viremia; 5% (26/482) re-tested HIV-seronegative, while

PurposeTo couple quantitative compositional MRI, gait analysis, and machine learning multidimensional data analysis to study osteoarthritis (OA). OA is a multifactorial disorder accompanied by biochemical and morphological changes in the articular cartilage, modulated by skeletal biomechanics and gait. While we can now acquire detailed information about the knee joint structure and function, we are not yet able to leverage the multifactorial factors for diagnosis and disease management of knee OA.Materials and methodsWe mapped 178 subjects in a multidimensional space integrating: demographic, clinical information, gait kinematics and kinetics, cartilage compositional T1ρ and T2 and R2 -R1ρ (1/T2 -1/T1ρ ) acquired at 3T and whole-organ magnetic resonance imaging score morphological grading. Topological data analysis (TDA) and Kolmogorov-Smirnov test were adopted for data integration, analysis, and hypothesis generation. Regression models were used for hypothesis testing.ResultsThe results of the TDA showed a network composed of three main patient subpopulations, thus potentially identifying new phenotypes. T2 and T1ρ values (T2 lateral femur P = 1.45*10-8 , T1ρ medial tibia P = 1.05*10-5 ), the presence of femoral cartilage defects (P = 0.0013), lesions in the meniscus body (P = 0.0035), and race (P = 2.44*10-4 ) were key markers in the subpopulation classification. Within one of the subpopulations we observed an association between the composite metric R2 -R1ρ and the longitudinal progression of cartilage lesions.ConclusionThe analysis presented demonstrates some of the complex multitissue biochemical and biomechanical interactions that define joint degeneration and OA using a multidimensional approach, and potentially indicates that R2 -R1ρ may be an imaging biomarker for early OA.Level of evidence3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:78-90.

BackgroundTuberculosis kills more people than any other infectious disease, and new regimens are essential. The primary endpoint for confirmatory phase III trials for new regimens is a composite outcome that includes bacteriological treatment failure and relapse. Culture methodology is critical to the primary trial outcome. Patients in clinical trials can have positive cultures after treatment ends that may not necessarily indicate relapse, which was ascribed previously to laboratory cross-contamination or breakdown of old lesions. Löwenstein-Jensen (LJ) medium was the previous standard in clinical trials, but almost all current and future trials will use the Mycobacteria Growth Indicator Tube (MGIT) system due to its simplicity and consistency of use, which will affect phase III trial results. LJ was used for the definition of the primary endpoint in the REMoxTB trial, but every culture was also inoculated in parallel into the MGIT system. The data from this trial, therefore, provide a unique opportunity to investigate and compare the incidence of false 'isolated positives' in liquid and solid media and their potential impact on the primary efficacy results.MethodsAll post-treatment positive cultures were reviewed in the REMoxTB clinical trial. Logistic regression models were used to model the incidence of isolated positive cultures on MGIT and LJ.ResultsA total of 12,209 sputum samples were available from 1652 patients; cultures were more often positive on MGIT than LJ. In 1322 patients with a favourable trial outcome, 126 (9.5%) had cultures that were positive in MGIT compared to 34 (2.6%) patients with positive cultures on LJ. Among patients with a favourable outcome, the incidence of isolated positives on MGIT differed by study laboratory (p

Architect-HIV Ag/Ab combo chemiluminescence assay is globally recognized for its sensitivity but has a notable false-positive rate. In this study, we aim to evaluate the performance of a new cost-effective screening alternative, the chemiluminescence Ag/Ab combo assay (CL-900i-HIV) from Mindray, China. We selected 195 archived samples categorized according to the INNO-LIA™ HIV I/II, the gold standard confirmatory assay. These samples included true positive (n = 38; positive by Architect-HIV & INNO-LIA-HIV), true negative (n = 101; negative by Architect-HIV & INNO-LIA-HIV), false positive (n = 20; positive by Architect-HIV & negative by INNO-LIA-HIV), and indeterminate results (n = 26). We tested all samples using the Mindray CL-900i-HIV and all positive Architect-HIV samples (n = 80) were confirmed by PCR. Compared to INNO-LIA™ HIVI/II line immunoassay confirmatory assay, Mindray CL-900i-HIV demonstrated a sensitivity of 100% (95% CI 90.7-100), specificity of 100% (95% CI 97.0-100), overall percent agreement (OPA) of 100% (95% CI 97.7-100.0), and perfect agreement with the INNO-LIA confirmatory assay (κ = 1.00). Additionally, Mindray's CL-900i-HIV exhibited a significantly lower false-positive rate (8.75%) compared to Architect-HIV's (55%). Mindray CL900i demonstrated high sensitivity and very low false-positive rate, thus, has the potential to serve as an excellent, cost-effective surrogate for HIV screening, overcoming the limitations of existing automated assays., Competing Interests: Declarations Competing interests All kits of the Mindray CL-900i-HIV Ag/Ab combo assay used in this study were received from Mindray as in-kind support to Dr. Gheyath. However, it is important to note that Mindray had no influence or involvement in the study design, data collection, analysis, interpretation, or the decision to publish the results., (© 2024. The Author(s).)