'Eczematous' dermatitis of the nipple: clinical and histopathological differential diagnosis of Paget disease.

The nipple can be affected by many malignant and benign entities. A wide variety of diseases including Paget disease, atopic dermatitis and nipple candidiasis can cause eczema-like changes in the nipple. In cases of diagnostic uncertainty, tissue sampling may be indicated. A true eczematous lesion, such as atopic dermatitis, typically shows a spongiotic dermatitis pattern. Paget disease, on the other hand, presents with infiltration of the nipple epidermis by neoplastic cells. The presence of atypical cells scattered in the epidermis in a pagetoid pattern opens up a histopathological differential diagnosis encompassing squamous cell carcinoma in situ and malignant melanoma, among others. Immunohistochemistry is commonly used to render a diagnosis. The objective of this article is to discuss Paget disease and highlight relevant clinical and histopathological differential diagnoses.

Social media mining under the COVID-19 context: Progress, challenges, and opportunities.

Social media platforms allow users worldwide to create and share information, forging vast sensing networks that allow information on certain topics to be collected, stored, mined, and analyzed in a rapid manner. During the COVID-19 pandemic, extensive social media mining efforts have been undertaken to tackle COVID-19 challenges from various perspectives. This review summarizes the progress of social media data mining studies in the COVID-19 contexts and categorizes them into six major domains, including early warning and detection, human mobility monitoring, communication and information conveying, public attitudes and emotions, infodemic and misinformation, and hatred and violence. We further document essential features of publicly available COVID-19 related social media data archives that will benefit research communities in conducting replicable and reproducible studies. In addition, we discuss seven challenges in social media analytics associated with their potential impacts on derived COVID-19 findings, followed by our visions for the possible paths forward in regard to social media-based COVID-19 investigations. This review serves as a valuable reference that recaps social media mining efforts in COVID-19 related studies and provides future directions along which the information harnessed from social media can be used to address public health emergencies.

A community-level study on COVID-19 transmission and policy interventions in Wuhan, China.

The specific factors and response strategies that affect COVID-19 transmission in local communities remain under-explored in the current literature due to a lack of data. Based on primary COVID-19 data collected at the community level in Wuhan, China, our study contributes a community-level investigation on COVID-19 transmission and response strategies by addressing two research questions: 1) What community factors are associated with viral transmission? and 2) What are the key mechanisms behind policy interventions towards controlling viral transmission within local communities? We conducted two sets of analyses to address these two questions-quantitative analyses of the relationship between community factors and viral transmission and qualitative analyses of policy interventions on community transmission. Our findings show that the viral spread in local communities is irrelevant to the built environment of a community and its socioeconomic position but is related to its demographic composition. Specifically, groups under the age of 18 play an important role in viral transmission. Moreover, a series of community shutdown management initiatives (e.g., group buying, delivering supplies, and self-reporting of health conditions) play an important role in curbing viral transmission at the local level that can be applied to other geographic contexts.

Revealing Public Opinion Towards COVID-19 Vaccines With Twitter Data in the United States: Spatiotemporal Perspective.

BACKGROUND: The COVID-19 pandemic has imposed a large, initially uncontrollable, public health crisis both in the United States and across the world, with experts looking to vaccines as the ultimate mechanism of defense. The development and deployment of COVID-19 vaccines have been rapidly advancing via global efforts. Hence, it is crucial for governments, public health officials, and policy makers to understand public attitudes and opinions towards vaccines, such that effective interventions and educational campaigns can be designed to promote vaccine acceptance. OBJECTIVE: The aim of this study was to investigate public opinion and perception on COVID-19 vaccines in the United States. We investigated the spatiotemporal trends of public sentiment and emotion towards COVID-19 vaccines and analyzed how such trends relate to popular topics found on Twitter. METHODS: We collected over 300,000 geotagged tweets in the United States from March 1, 2020 to February 28, 2021. We examined the spatiotemporal patterns of public sentiment and emotion over time at both national and state scales and identified 3 phases along the pandemic timeline with sharp changes in public sentiment and emotion. Using sentiment analysis, emotion analysis (with cloud mapping of keywords), and topic modeling, we further identified 11 key events and major topics as the potential drivers to such changes. RESULTS: An increasing trend in positive sentiment in conjunction with a decrease in negative sentiment were generally observed in most states, reflecting the rising confidence and anticipation of the public towards vaccines. The overall tendency of the 8 types of emotion implies that the public trusts and anticipates the vaccine. This is accompanied by a mixture of fear, sadness, and anger. Critical social or international events or announcements by political leaders and authorities may have potential impacts on public opinion towards vaccines. These factors help identify underlying themes and validate insights from the analysis. CONCLUSIONS: The analyses of near real-time social media big data benefit public health authorities by enabling them to monitor public attitudes and opinions towards vaccine-related information in a geo-aware manner, address the concerns of vaccine skeptics, and promote the confidence that individuals within a certain region or community have towards vaccines.

Alopecia areata in a patient with WNT10A heterozygous ectodermal dysplasia.

We report a case of a patient with ectodermal dysplasia attributed to a heterozygous 321C>A mutation in WNT10A who developed overlying autoimmune mediated hair loss. To the best of our knowledge this is the first reported case of alopecia areata in a patient with WNT10A heterozygous ectodermal dysplasia. This case highlights the importance of considering multiple pathways of hair loss in patients with underlying genetic defects and raises the possibility of a shared genetic predisposition.

Racial Segregation, Testing Site Access, and COVID-19 Incidence Rate in Massachusetts, USA.

The U.S. has merely 4% of the world population, but contains 25% of the world's COVID-19 cases. Since the COVID-19 outbreak in the U.S., Massachusetts has been leading other states in the total number of COVID-19 cases. Racial residential segregation is a fundamental cause of racial disparities in health. Moreover, disparities of access to health care have a large impact on COVID-19 cases. Thus, this study estimates racial segregation and disparities in testing site access and employs economic, demographic, and transportation variables at the city/town level in Massachusetts. Spatial regression models are applied to evaluate the relationships between COVID-19 incidence rate and related variables. This is the first study to apply spatial analysis methods across neighborhoods in the U.S. to examine the COVID-19 incidence rate. The findings are: (1) Residential segregations of Hispanic and Non-Hispanic Black/African Americans have a significantly positive association with COVID-19 incidence rate, indicating the higher susceptibility of COVID-19 infections among minority groups. (2) Non-Hispanic Black/African Americans have the shortest drive time to testing sites, followed by Hispanic, Non-Hispanic Asians, and Non-Hispanic Whites. The drive time to testing sites is significantly negatively associated with the COVID-19 incidence rate, implying the importance of the accessibility of testing sites by all populations. (3) Poverty rate and road density are significant explanatory variables. Importantly, overcrowding represented by more than one person per room is a significant variable found to be positively associated with COVID-19 incidence rate, suggesting the effectiveness of social distancing for reducing infection. (4) Different from the findings of previous studies, the elderly population rate is not statistically significantly correlated with the incidence rate because the elderly population in Massachusetts is less distributed in the hotspot regions of COVID-19 infections. The findings in this study provide useful insights for policymakers to propose new strategies to contain the COVID-19 transmissions in Massachusetts.

Investigating the reaction and substrate preference of indole-3-acetaldehyde dehydrogenase from the plant pathogen Pseudomonas syringae PtoDC3000.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.

The plant pathogen enzyme AldC is a long-chain aliphatic aldehyde dehydrogenase.

Aldehyde dehydrogenases are versatile enzymes that serve a range of biochemical functions. Although traditionally considered metabolic housekeeping enzymes because of their ability to detoxify reactive aldehydes, like those generated from lipid peroxidation damage, the contributions of these enzymes to other biological processes are widespread. For example, the plant pathogen Pseudomonas syringae strain PtoDC3000 uses an indole-3-acetaldehyde dehydrogenase to synthesize the phytohormone indole-3-acetic acid to elude host responses. Here we investigate the biochemical function of AldC from PtoDC3000. Analysis of the substrate profile of AldC suggests that this enzyme functions as a long-chain aliphatic aldehyde dehydrogenase. The 2.5 Å resolution X-ray crystal of the AldC C291A mutant in a dead-end complex with octanal and NAD+ reveals an apolar binding site primed for aliphatic aldehyde substrate recognition. Functional characterization of site-directed mutants targeting the substrate- and NAD(H)-binding sites identifies key residues in the active site for ligand interactions, including those in the "aromatic box" that define the aldehyde-binding site. Overall, this study provides molecular insight for understanding the evolution of the prokaryotic aldehyde dehydrogenase superfamily and their diversity of function.

Juvenile xanthogranulomas: Examining single, multiple, and extracutaneous presentations.

BACKGROUND: Juvenile xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis characterized by yellowish papules in the skin. JXGs most often occur in infancy or early childhood and are typically solitary and asymptomatic, often regressing after several years. While JXGs predominantly occur on the skin, extracutaneous JXGs also exist. AIMS: In this paper, we review the literature on single, multiple, and visceral JXGs and provide recommendations on monitoring and work-up. MATERIALS & METHODS: A literature review was conducted with the PubMed database using selective search terms for single, multiple, ocular, and visceral lesions as well as NF1/JMML. RESULTS / DISCUSSION: JXG is typically a self-limited disorder if lesions are cutaneous and singular. While rare, JXGs may manifest as multiple and extracutaneous lesions. Further screening and referral to specialists may be warranted in these cases based on age and extent of involvement. CONCLUSION: Our review demonstrates common presentations of single, multiple, and extracutaneous lesions in addition to those that occur with NF1 and JMML. We suggest patients be evaluated on a case-by-case basis by a dermatologist and referred to specialists as appropriate.

Targeted next-generation sequencing of 565 neuro-oncology patients at UCLA: A single-institution experience.

BACKGROUND: Targeted next-generation sequencing (NGS) is frequently obtained at the University of California, Los Angeles (UCLA) for clinical characterization of CNS tumors. In this study, we describe the diagnostic reliability of the Foundation Medicine (FM) targeted NGS platform and its ability to explore and identify tumor characteristics of prognostic significance in gliomas. METHODS: Neuro-oncology patients seen at UCLA who have received FM testing between August 2012 and March 2019 were included in this study, and all mutations from FM test reports were recorded. Initial tumor diagnoses and diagnostic markers found via standard clinical methods were obtained from pathology reports. With overall and progression-free survival data, elastic net regularized Cox regression and Cox proportional hazards models were used to determine whether any mutations of unknown significance detected by FM could predict patient outcome in glioblastoma (GBM). RESULTS: Six hundred and three samples tested by FM from 565 distinct patients were identified. Concordance of diagnostic markers was high between standard clinical testing methods and FM. Oligodendroglial markers detected via FM were highly correlated with 1p19q codeletion in IDH mutated gliomas. FM testing of multiple tumor samples from the same patient demonstrated temporal and spatial mutational heterogeneity. Mutations in BCORL1, ERBB4, and PALB2, which are mutations of unknown significance in GBM, were shown to be statistically significant in predicting patient outcome. CONCLUSIONS: In our large cohort, we found that targeted NGS can both reliably and efficiently detect important diagnostic markers in CNS tumors.

The Efficiency of Online "Inked" Videos Versus Recorded PowerPoint Lectures on Teaching Pathophysiology to Medical Students in Pre-Clerkship Years: A Pilot Study.

BACKGROUND: As online learning develops an increasingly important role in medical education, new online teaching modalities are arising all the time. One such teaching modality that is gaining popularity among medical students is the "inked" video, a type of animated video that utilizes a virtual blackboard. Student reviews suggest that the dynamic style of the inked video allows it to teach more efficiently than traditional teaching modalities, but currently there is no quantitative evidence to support or guide the use of this teaching modality. HYPOTHESIS: When compared to the traditional recorded PowerPoint lecture, online inked videos teach the same pathophysiology concepts to pre-clerkship medical students in a shorter amount of time. METHOD: A randomized, crossover-design study was conducted with second-year medical students at the David Geffen School of Medicine at University of California, Los Angeles (n = 22). Students were randomized to 2 groups. Each group received 2 lessons on 2 different pathophysiology topics: one via a shorter inked video and the other via a longer recorded PowerPoint lecture. Two sets of dependent variables were used to test modality effects: immediate post-tests scores and delayed retention post-test scores. A perceptions survey was also administered to assess student preferences between the 2 teaching modalities. RESULTS: Students performed similarly on immediate and delayed post-tests for the shorter inked videos and the longer recorded PowerPoint lectures (P > .05). Students reported greater engagement (P < .05) and greater satisfaction with learning (P < .05) with the inked videos than the recorded PowerPoint lectures. CONCLUSIONS: This study, although limited by its small-scale and single-institution design, provides preliminary evidence that online inked videos may be a more efficient and non-inferior alternative to recorded PowerPoint lectures.

Genital nevus lipomatosus cutaneous superficialis: A diagnostic challenge in a pediatric patient.

Nevus lipomatosus cutaneous superficialis (NLCS) is an idiopathic hamartomatous condition characterized by the presence of mature adipose tissue in the dermis. We report a case of NLCS initially misdiagnosed as condyloma acuminata in a 14-year-old boy. This case highlights classic clinical and histologic features of NLCS. The case presented here underscores the need for a high degree of clinical suspicion in diagnosing NLCS and in differentiating benign anogenital lesions from sexually transmitted conditions to avoid unnecessary work-up and undue emotional stress.

cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer Independent.

Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression. Indeed, an annotated super-enhancer is dispensable for NEK6 overexpression and for maintaining the architecture of a B cell-specific regulatory hub. A CTCF cluster serves as a chromatin and architectural boundary to block communication of the NEK6 regulatory hub with neighboring genes. Our findings emphasize that validation of predicted cis-regulatory circuits and super-enhancers is needed to prioritize transcriptional control elements as therapeutic targets.

Multivariate Meta-Analysis of Heterogeneous Studies Using Only Summary Statistics: Efficiency and Robustness.

Meta-analysis has been widely used to synthesize evidence from multiple studies for common hypotheses or parameters of interest. However, it has not yet been fully developed for incorporating heterogeneous studies, which arise often in applications due to different study designs, populations or outcomes. For heterogeneous studies, the parameter of interest may not be estimable for certain studies, and in such a case, these studies are typically excluded from conventional meta-analysis. The exclusion of part of the studies can lead to a non-negligible loss of information. This paper introduces a metaanalysis for heterogeneous studies by combining the confidence density functions derived from the summary statistics of individual studies, hence referred to as the CD approach. It includes all the studies in the analysis and makes use of all information, direct as well as indirect. Under a general likelihood inference framework, this new approach is shown to have several desirable properties, including: i) it is asymptotically as efficient as the maximum likelihood approach using individual participant data (IPD) from all studies; ii) unlike the IPD analysis, it suffices to use summary statistics to carry out the CD approach. Individual-level data are not required; and iii) it is robust against misspecification of the working covariance structure of the parameter estimates. Besides its own theoretical significance, the last property also substantially broadens the applicability of the CD approach. All the properties of the CD approach are further confirmed by data simulated from a randomized clinical trials setting as well as by real data on aircraft landing performance. Overall, one obtains an unifying approach for combining summary statistics, subsuming many of the existing meta-analysis methods as special cases.

Efficient network meta-analysis: a confidence distribution approach.

Network meta-analysis synthesizes several studies of multiple treatment comparisons to simultaneously provide inference for all treatments in the network. It can often strengthen inference on pairwise comparisons by borrowing evidence from other comparisons in the network. Current network meta-analysis approaches are derived from either conventional pairwise meta-analysis or hierarchical Bayesian methods. This paper introduces a new approach for network meta-analysis by combining confidence distributions (CDs). Instead of combining point estimators from individual studies in the conventional approach, the new approach combines CDs which contain richer information than point estimators and thus achieves greater efficiency in its inference. The proposed CD approach can e ciently integrate all studies in the network and provide inference for all treatments even when individual studies contain only comparisons of subsets of the treatments. Through numerical studies with real and simulated data sets, the proposed approach is shown to outperform or at least equal the traditional pairwise meta-analysis and a commonly used Bayesian hierarchical model. Although the Bayesian approach may yield comparable results with a suitably chosen prior, it is highly sensitive to the choice of priors (especially the prior of the between-trial covariance structure), which is often subjective. The CD approach is a general frequentist approach and is prior-free. Moreover, it can always provide a proper inference for all the treatment effects regardless of the between-trial covariance structure.

Exact meta-analysis approach for discrete data and its application to 2 × 2 tables with rare events.

This paper proposes a general exact meta-analysis approach for synthesizing inferences from multiple studies of discrete data. The approach combines the p-value functions (also known as significance functions) associated with the exact tests from individual studies. It encompasses a broad class of exact meta-analysis methods, as it permits broad choices for the combining elements, such as tests used in individual studies, and any parameter of interest. The approach yields statements that explicitly account for the impact of individual studies on the overall inference, in terms of efficiency/power and the type I error rate. Those statements also give rises to empirical methods for further enhancing the combined inference. Although the proposed approach is for general discrete settings, for convenience, it is illustrated throughout using the setting of meta-analysis of multiple 2 × 2 tables. In the context of rare events data, such as observing few, zero or zero total (i.e., zero events in both arms) outcomes in binomial trials or 2 × 2 tables, most existing meta-analysis methods rely on the large-sample approximations which may yield invalid inference. The commonly used corrections to zero outcomes in rare events data, aiming to improve numerical performance can also incur undesirable consequences. The proposed approach applies readily to any rare event setting, including even the zero total event studies without any artificial correction. While debates continue on whether or how zero total event studies should be incorporated in meta-analysis, the proposed approach has the advantage of automatically including those studies and thus making use of all available data. Through numerical studies in rare events settings, the proposed exact approach is shown to be efficient and, generally, outperform commonly used meta-analysis methods, including Mental-Haenszel and Peto methods.

Psychophysiologic treatment for patients with medically unexplained symptoms: a randomized controlled trial.

BACKGROUND: Patients presenting with medically unexplained physical symptoms (MUPS) typically present with significant distress and marked impairment in functioning and pose a unique challenge to health care providers. The purpose of this study was to examine the efficacy of a psychophysiological treatment (PT) for MUPS. METHODS: Thirty-eight participants meeting criteria for subthreshold somatization disorder (abridged somatization) were randomly assigned to one of two conditions: (1) standard medical care augmented by a psychiatric consultation intervention (wait-list) or (2) a 10-session, manualized, individually-administered PT added to the psychiatric consultation intervention. Assessments were conducted at baseline, at midpoint (after four sessions), and after completing the last session. The primary outcome measure was the severity scale of the Clinical Global Impression Scale anchored for Somatic Symptoms (CGI-SD). Secondary outcome measures were responder status as determined by clinical ratings, self-report measures of mental and physical functioning. RESULTS: At the end of the trial, the severity (and frequency) of physical symptoms improved significantly more (p<0.05) in the intervention group. The average improvement in the CGI-SD was 0.80 points greater in the intervention group than in the wait-list group. PT was also associated with greater improvements in self-reported functioning and depressive symptomatology. The effect sizes at the final assessment point indicate that this intervention had a robust effect on complex somatic symptom presentations. CONCLUSION: For patients with high levels of MUPS (abridged somatization), PT produces significant improvements in symptoms and functional status.