Miracle-dz/UniFAR-FTUs huggingface dataset:
Methods for Assessing Improvement in Specificity When a Biomarker is Combined With a Standard Screening Test

Biomarkers that can be used in combination with established screening tests to reduce false positive rates are in considerable demand. In this article, we present methods for evaluating the diagnostic performance of combination tests that require positivity on a biomarker test in addition to a standard screening test. These methods rely on relative true- and false-positive rates to measure the loss in sensitivity and gain in specificity associated with the combination relative to the standard test. Inference about the relative rates follows from noting their interpretation as conditional probabilities. These methods are extended to evaluate combinations with continuous biomarker tests by introducing a new statistical entity, the relative receiver operating characteristic (rROC) curve. The rROC curve plots the relative true positive rate versus the relative false positive rate as the biomarker threshold for positivity varies. Inference can be made by applying existing ROC methodology. We illustrate the methods with two examples: a breast cancer biomarker study proposed by the Early Detection Research Network (EDRN) and a prostate cancer case-control study examining the ability of free prostate-specific antigen (PSA) to improve the specificity of the standard PSA test.
Reporting genetic results in research studies: Summary and recommendations of an NHLBI working group

Prospective epidemiologic studies aid in identifying genetic variants associated with diseases, health risks, and physiologic traits. These genetic variants may eventually be measured clinically for purposes of diagnosis, prognosis, and treatment. As evidence of the potential clinical value of such information accrues, research studies face growing pressure to report these results to study participants or their physicians, even before sufficient evidence is available to support widespread screening of asymptomatic persons. There is thus a need to begin to develop consensus on whether and when genetic findings should be reported to participants in research studies. The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on Reporting Genetic Results in Research Studies to discuss if, when, and how genetic information should be reported to study participants. The Working Group concluded that genetic test results should be reported to study participants when the associated risk for the disease is significant; the disease has important health implications such as premature death or substantial morbidity or has significant reproductive implications; and proven therapeutic or preventive interventions are available. Finally, the Working Group recommended procedures for reporting genetic research results and encouraged increased efforts to create uniform guidelines for this activity. Published 2006 Wiley‐Liss, Inc.
Host gene targets for novel influenza therapies elucidated by high‐throughput RNA interference screens

Influenza virus encodes only 11 viral proteins but replicates in a broad range of avian and mammalian species by exploiting host cell functions. Genome‐wide RNA interference (RNAi) has proven to be a powerful tool for identifying the host molecules that participate in each step of virus replication. Meta‐analysis of findings from genome‐wide RNAi screens has shown influenza virus to be dependent on functional nodes in host cell pathways, requiring a wide variety of molecules and cellular proteins for replication. Because rapid evolution of the influenza A viruses persistently complicates the effectiveness of vaccines and therapeutics, a further understanding of the complex host cell pathways coopted by influenza virus for replication may provide new targets and strategies for antiviral therapy. RNAi genome screening technologies together with bioinformatics can provide the ability to rapidly identify specific host factors involved in resistance and susceptibility to influenza virus, allowing for novel disease intervention strategies. —Meliopoulos, V. A. , Andersen, L. E. , Birrer, K. F. , Simpson, K. J., Lowenthal, J. W. , Bean, A. G. D. , Stambas, J., Stewart, C. R. , Tompkins, S. M. , van Beusechem, V. W. , Fraser, I. , Mhlanga, M. , Barichievy, S. , Smith, Q. , Leake, D. , Karpilow, J., Buck, A. , Jona, G. , Tripp, R. A. Host gene targets for novel influenza therapies elucidated by high‐throughput RNA interference screens. FASEB J. 26, 1372‐1386 (2012). www.fasebj. org
Maternal history of neglect, mind-mindedness, and the cycle of neglect

Maternal History of Neglect, Mind-Mindedness, and The Cycle of Neglect By Karin N. Belser Advisor: Elliot Jurist, Ph.D. Although links between history of maltreatment, attachment security, and maltreatment perpetration have been established, support for the intergenerational cycle of maltreatment remains weak due to definitional and methodological issues. In addition, less severe forms of child neglect that do not result in Child Protective Services (CPS) involvement have not been extensively studied. In order to expand our understanding of the cycle of neglect, the present study examined a model linking maternal mind-mindedness, maternal history of neglect, subthreshold neglect and child outcomes (physical, socioemotional, and intellectual). Methods. The study participants were 96 mother-child dyads assessed at child ages of 4, 8, 12, 24, and 36 months. Subthreshold neglect was operationalized using interactional parent behavior rating scales that were captured two Factors of subthreshold neglect: subthreshold neglect of children’s developmental advance needs (Factor 1) and subthreshold neglect of children’s emotional needs (Factor 2). Results. Hierarchical multiple regressions were used to test a model predicting the moderating role of maternal mind-mindedness (MM) on the relationship between mother’s history of neglect and subthreshold child neglect as measured by the two Factors. Education and mother’s age at childbirth were the only significant predictors of subthreshold child neglect. The two Factors were correlated with the Mother Child Neglect Scale (MCNS), a self-report of maternal neglect Mind-Mindedness and Neglect v potential and various child outcome measures. Post hoc analyses reexamined the hypothesized relationships and indicated that mind-mindedness moderates the relationship between maternal history of neglect and subthreshold neglect, as well as subthreshold neglect and various child outcomes. Discussion. These findings suggest that mind-mindedness operates in non-intuitive ways in mothers with histories of neglect. Overall, mothers with more severe histories of neglect and high MM tend to rate themselves as being more neglectful and have children with the poorest developmental outcomes. These findings support the need for sensitive and thoughtful methodology when examining child neglect in very young children, and can be used to inform future research as well as clinical and social services interventions for mothers as risk of child neglect. Mind-Mindedness and Neglect vi
Single-Cell Network Profiling of Peripheral Blood Mononuclear Cells from Healthy Donors Reveals Age- and Race-Associated Differences in Immune Signaling Pathway Activation

A greater understanding of the function of the human immune system at the single-cell level in healthy individuals is critical for discerning aberrant cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-cell network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race-associated variations in signaling responses in discrete cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics.
Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders

Repeated exposure to drugs of abuse produces long‐term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self‐administer drugs and disrupt drug‐associated cue‐induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so‐called proof‐of‐concept studies for drug addiction indications will be discussed.
Leptin, abdominal obesity, and onset of depression in older men and women.

OBJECTIVE The mechanisms that underlie the association between abdominal obesity and depression risk in older persons are not well known, but the "leptin hypothesis" of depression suggests that leptin resistance may be involved in mood regulation. We tested whether high circulatory concentration of leptin, alone and in combination with visceral adiposity, is associated with onset of depression in a sample of older persons. METHOD Participants were 1,220 men and 1,282 women aged 70-79 years and enrolled in the Health, Aging, and Body Composition study. Serum concentration of leptin and abdominal visceral fat, ascertained by computed tomography, were assessed at baseline (April 1997-June 1998). Onset of depression, the primary outcome measure, was defined as a Center for Epidemiologic Studies-depression scale 10-item score ≥ 10 and/or new antidepressant medication use at any annual visit over a 5-year follow-up. RESULTS Higher leptin level was associated with the risk of depression onset in men with high levels of visceral fat (hazard ratio [HR] = 1.25; 95% CI, 1.06-1.46; P = .01) but not in those with normal visceral fat (HR = 0.98; 95% CI, 0.80-1.19; P = .80) (leptin-by-visceral fat, P = .04). No interaction between leptin and visceral fat was detected in the analysis focusing on women (P = .90). CONCLUSIONS In older men, high leptin level was associated with an increased onset of depressive symptoms, especially in the presence of abdominal obesity, suggesting that underlying leptin resistance may play a role in this link. Differences in visceral fat levels and metabolic consequences may explain the absence of this association in women. These findings suggest a potential biological link between depression, obesity, and their joint association with negative health outcomes.
Coronary artery calcification screening: estimated radiation dose and cancer risk.

BACKGROUND Multidetector computed tomography has been proposed as a tool for routine screening for coronary artery calcification in asymptomatic individuals. As proposed, such screening could involve tens of millions of individuals, but detailed estimates of radiation doses and potential risk of radiation-induced cancer are not currently available. We estimated organ-specific radiation doses and associated cancer risks from coronary artery calcification screening with multidetector computed tomography according to patient age, frequency of screening, and scan protocol. METHODS Radiation doses delivered to adult patients were calculated from a range of available protocols using Monte Carlo radiation transport. Radiation risk models, derived using data from Japanese atomic bomb survivors and medically exposed cohorts, were used to estimate the excess lifetime risk of radiation-induced cancer. RESULTS The radiation dose from a single coronary artery calcification computed tomographic scan varied more than 10-fold (effective dose range, 0.8-10.5 mSv) depending on the protocol. In general, higher radiation doses were associated with higher x-ray tube current, higher tube potential, spiral scanning with low pitch, and retrospective gating. The wide dose variation also resulted in wide variation in estimated radiation-induced cancer risk. Assuming screening every 5 years from the age of 45 to 75 years for men and 55 to 75 years for women, the estimated excess lifetime cancer risk using the median dose of 2.3 mSv was 42 cases per 100 000 men (range, 14-200 cases) and 62 cases per 100 000 women (range, 21-300 cases). CONCLUSIONS These radiation risk estimates can be compared with potential benefits from screening, when such estimates are available. Doses and therefore risks can be minimized by the use of optimized protocols.
Shielding of Piezoelectric Ultrasonic Probes in Hall Effect Imaging

This paper addresses significant sources of electromagnetic noise in Hall effect imaging. Hall effect imaging employs large electrical pulses for signal generation and high sensitivity ultrasonic probes for signal reception. Coherent noise arises through various coupling mechanisms between the excitation pulse and the probe. In this paper, the coupling mechanisms are experimentally isolated and theoretically analyzed. Several methods of shielding the probe from electromagnetic interference are devised and tested. These methods are able to reduce the noise to levels below the random thermal noise, thereby improving the signal-to-noise ratio in HEI by two orders of magnitude.
Vaccines to combat the neglected tropical diseases

Summary: The neglected tropical diseases (NTDs) represent a group of parasitic and related infectious diseases such as amebiasis, Chagas disease, cysticercosis, echinococcosis, hookworm, leishmaniasis, and schistosomiasis. Together, these conditions are considered the most common infections in low‐ and middle‐income countries, where they produce a level of global disability and human suffering equivalent to better known conditions such as human immunodeficiency virus/acquired immunodeficiency syndrome and malaria. Despite their global public health importance, progress on developing vaccines for NTD pathogens has lagged because of some key technical hurdles and the fact that these infections occur almost exclusively in the world’s poorest people living below the World Bank poverty line. In the absence of financial incentives for new products, the multinational pharmaceutical companies have not embarked on substantive research and development programs for the neglected tropical disease vaccines. Here, we review the current status of scientific and technical progress in the development of new neglected tropical disease vaccines, highlighting the successes that have been achieved (cysticercosis and echinococcosis) and identifying the challenges and opportunities for development of new vaccines for NTDs. Also highlighted are the contributions being made by non‐profit product development partnerships that are working to overcome some of the economic challenges in vaccine manufacture, clinical testing, and global access.
Health Information System in a Cloud Computing Context

Healthcare as a worldwide industry is experiencing a period of growth based on health information technology. The capabilities of cloud systems make it as an option to develop eHealth goals. The main objectives of the present study was to evaluate the advantages and limitations of health information systems implementation in a cloud-computing context that was conducted as a systematic review in 2016. Science direct, Scopus, Web of science, IEEE, PubMed and Google scholar were searched according study criteria. Among 308 articles initially found, 21 articles were entered in the final analysis. All the studies had considered cloud computing as a positive tool to help advance health technology, but none had insisted too much on its limitations and threats. Electronic health record systems have been mostly studied in the fields of implementation, designing, and presentation of models and prototypes. According to this research, the main advantages of cloud-based health information systems could be categorized into the following groups: economic benefits and advantages of information management. The main limitations of the implementation of cloud-based health information systems could be categorized into the 4 groups of security, legal, technical, and human restrictions. Compared to earlier studies, the present research had the advantage of dealing with the issue of health information systems in a cloud platform. The high frequency of studies conducted on the implementation of cloud-based health information systems revealed health industry interest in the application of this technology. Security was a subject discussed in most studies due to health information sensitivity. In this investigation, some mechanisms and solutions were discussed concerning the mentioned systems, which would provide a suitable area for future scientific research on this issue. The limitations and solutions discussed in this systematic study would help healthcare managers and decision-makers take better and more efficient advantages of this technology and make better planning to adopt cloud-based health information systems.
Molecular weaponry: diverse effectors delivered by the Type VI secretion system

The Type VI secretion system is a widespread bacterial nanomachine, used to deliver toxins directly into eukaryotic or prokaryotic target cells. These secreted toxins, or effectors, act on diverse cellular targets, and their action provides the attacking bacterial cell with a significant fitness advantage, either against rival bacteria or eukaryotic host organisms. In this review, we discuss the delivery of diverse effectors by the Type VI secretion system, the modes of action of the so‐called ‘anti‐bacterial’ and ‘anti‐eukaryotic’ effectors, the mechanism of self‐resistance against anti‐bacterial effectors and the evolutionary implications of horizontal transfer of Type VI secretion system‐associated toxins. Whilst it is likely that many more effectors remain to be identified, it is already clear that toxins delivered by this secretion system represent efficient weapons against both bacteria and eukaryotes.
Factors Influencing Learner Permit Duration

An increasing number of countries are requiring an extended learner permit prior to independent driving. The question of when drivers begin the learner permit period, and how long they hold the permit before advancing to independent licensure has received little research attention. Licensure timing is likely to be related to “push” and “pull” factors which may encourage or inhibit the process. To examine this question, we recruited a sample of 90 novice drivers (49 females and 41 males, average age of 15.6 years) soon after they obtained a learner permit and instrumented their vehicles to collect a range of driving data. Participants completed a series of surveys at recruitment related to factors that may influence licensure timing. Two distinct findings emerged from the time-to-event analysis that tested these push and pull factors in relation to licensure timing. The first can be conceptualized as teens’ motivation to drive (push), reflected in a younger age when obtaining a learner permit and extensive pre-permit driving experience. The second finding was teens’ perceptions of their parents’ knowledge of their activities (pull); a proxy for a parents’ attentiveness to their teens’ lives. Teens who reported higher levels of their parents’ knowledge of their activities took longer to advance to independent driving. These findings suggest time-to-licensure may be related to teens’ internal motivation to drive, and the ability of parents to facilitate or impede early licensure.
The Nocebo Effect and Its Relevance for Clinical Practice

Negative expectations deriving from the clinical encounter can produce negative outcomes, known as nocebo effects. Specifically, research on the nocebo effect indicates that information disclosure about potential side effects can itself contribute to producing adverse effects. Neurobiological processes play a role in the nocebo effect, and this article provides a selective review of mechanistic research on the nocebo effect. Comparatively little attention has been directed to clinical studies and their implications for daily clinical practice. The nocebo response is influenced by the content and the way information is presented to patients in clinical trials in both the placebo and active treatment conditions. Nocebo effects adversely influence quality of life and therapy adherence, emphasizing the need for minimizing these responses to the extent possible. Evidence further indicates that the informed consent process in clinical trials may induce nocebo effects. This article concludes with ethical directions for future patient-oriented research and routine practice.SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; BPH = benign prostatic hyperplasia