Bed Bugs.

This Patient Page describes the symptoms, diagnosis, and treatment of bed bugs.

Massively parallel characterization of regulatory elements in the developing human cortex.

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

Characterization of enhancer activity in early human neurodevelopment using Massively Parallel Reporter Assay (MPRA) and forebrain organoids.

Regulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of ~ 7000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of ~ 35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community.

Metoposcopy redux.

Phrenology is the pseudoscience in which practitioners claim that they can discern one's character and personality traits by studying the structure of the skull. Long before "head bumps" were viewed as determinants of character, skin lines were analyzed to provide similar information and to divine one's future. Palmistry, also called chiromancy, is the interpretation of the lines of the palms and is one of the oldest forms of divination. A similar pseudoscience, metoposcopy, suggests that facial lines and marks, mainly forehead lines, can reveal one's personality and foretell events in one's future. Metoposcopy was first practiced by the ancient Chinese and was popularized during the Renaissance by Girolamo Cardano and later by Richard Saunders. Metoposcopy is a largely forgotten form of skin-based pseudoscience that is no longer practiced today, unlike palmistry.

Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis.

Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.

Characterization of enhancer activity in early human neurodevelopment using Massively parallel reporter assay (MPRA) and forebrain organoids.

Regulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of ~7,000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of ~35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community.

Dengue: updates for dermatologists on the world's fastest-growing vector-borne disease.

Dengue is the world's fastest-growing vector borne disease and has significant epidemic potential in suitable climates. Recent disease models incorporating climate change scenarios predict geographic expansion across the globe, including parts of the United States and Europe. It will be increasingly important in the next decade for dermatologists to become familiar with dengue, as it commonly manifests with rashes, which can be used to aid diagnosis. In this review, we discuss dengue for general dermatologists, specifically focusing on its cutaneous manifestations, epidemiology, diagnosis, treatment, and prevention. As dengue continues to spread in both endemic and new locations, dermatologists may have a larger role in the timely diagnosis and management of this disease.

RNA splicing analysis using heterogeneous and large RNA-seq datasets.

The ubiquity of RNA-seq has led to many methods that use RNA-seq data to analyze variations in RNA splicing. However, available methods are not well suited for handling heterogeneous and large datasets. Such datasets scale to thousands of samples across dozens of experimental conditions, exhibit increased variability compared to biological replicates, and involve thousands of unannotated splice variants resulting in increased transcriptome complexity. We describe here a suite of algorithms and tools implemented in the MAJIQ v2 package to address challenges in detection, quantification, and visualization of splicing variations from such datasets. Using both large scale synthetic data and GTEx v8 as benchmark datasets, we assess the advantages of MAJIQ v2 compared to existing methods. We then apply MAJIQ v2 package to analyze differential splicing across 2,335 samples from 13 brain subregions, demonstrating its ability to offer insights into brain subregion-specific splicing regulation.

Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex.

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and disease. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 sequences, including differentially accessible cell-type specific regions in the developing cortex and single-nucleotide variants associated with psychiatric disorders. In primary cells, we identified 46,802 active enhancer sequences and 164 disorder-associated variants that significantly alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning, we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

Mpox-A Rapidly Evolving Disease.

The 2022 mpox outbreak has rapidly emerged onto the global medical scene while the world continues to grapple with the COVID-19 pandemic. Unlike COVID-19, however, most patients with mpox present with skin findings, the evolving clinical presentation of which may be mistaken for other common skin diseases, particularly sexually transmitted infections. This Special Communication provides an overview of the evolution of mpox skin findings from its initial description in humans in 1970 to the present-day multinational outbreak.

Military Grooming Standards and Black Hairstyling Practices.

INTRODUCTION: Throughout history, armies of the world have codified grooming standards for their members. In the USA, the Department of Defense (DoD) provides overall guidance for grooming standards and each uniformed military service develops, promulgates, and enforces its own grooming standards. The specific details of each service's grooming standards are revised regularly to conform to contemporaneous notions of professionalism and operational necessity. In light of growing recognition of and respect for the diversity of people serving in the military, specific language used to describe certain hairstyles and hair textures as well as associated grooming policies have gained attention. Efforts have been made to modify the policy and language to be more inclusive, especially of minority groups with physiologic and cultural differences that influence grooming practices. Initial efforts in the DoD toward this endeavor were made possible with advocacy from members of the Congressional Black Caucus. MATERIALS AND METHODS: We obtained service-specific documents, current and former, from the Army, Navy, Air Force, and Marine Corps that regulate the grooming standards for military personnel. We then examined the documents for text that addressed hair and hairstyles, specifically noting language describing and regulations regarding traditionally Black or African American hairstyles (i.e., afros, dreadlocks/locks/locs, braids, twists, etc.) for female and male soldiers. We also examined recently introduced legislation which seeks to end discrimination based on a person's hair texture or hairstyle, "Creating a Respectful and Open World for Natural Hair Act," abbreviated as the CROWN Act in the context of current grooming standards. RESULTS: Our examination of the grooming regulations of four branches of the U.S. Military shows recent modifications of the language governing female hairstyles, particularly natural hairstyles seen among African American women, such as cornrows, braids, and locs (or locks). Changes made to grooming standards demonstrate a shift in language used to describe natural hairstyles. Words with negative connotations (i.e., "matted," "unkempt," and "dreadlock") have been removed. These have been replaced with more descriptive language that provides a more objective definition of certain hairstyles. While these hairstyles have some level of regulation as to exact dimensions and styling rules to fit with the goal of uniformity in appearance and do not extend to male service members, recent updates in grooming standards have expanded to be inclusive of these natural hairstyles. Recent changes in language and policy in the military have been noted as positive examples in the CROWN Act. CONCLUSIONS: The DoD has recognized that former grooming standards, specifically regarding hair and hairstyles, may have introduced inequities in the treatment of military personnel. The DoD and its component military services have long been engaged in programs to ensure equal protections among its workforces. The re-examination and clarification of grooming standards related to hair and hairstyles is another effort to ensure equity and inclusion. The military services are working with great sincerity to implement policies that promote inclusiveness broadly. Steps to remove discrimination on the basis of hair and hairstyle can make the overall work environment more inclusive for people of color. Passage of a federal CROWN Act will promote similar or parallel changes for federal employees outside the military services.

Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability.

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Dermatologic Consequences of Substandard, Spurious, Falsely Labeled, Falsified, and Counterfeit Medications.

This article explores dermatologic consequences of substandard, spurious, falsely labeled, falsified, and counterfeit (SSFFC) pharmaceutical products. Many of these SSFFC products are neither safe nor effective, and are more likely to cause adverse events than the proper preparations. These products also affect the health of populations by generating drug-resistant pathogens and failing to control the spread of disease. This article reviews classification systems for fraudulent medications, provides a general overview of medical and public health problems associated with substandard medications, provides examples of dermatologic consequences of each category, and presents recommended steps to take when clinicians encounter suspected SSFFC products.

Incidence of acute rheumatic fever in northern and western Uganda: a prospective, population-based study.

BACKGROUND: Acute rheumatic fever is infrequently diagnosed in sub-Saharan African countries despite the high prevalence of rheumatic heart disease. We aimed to determine the incidence of acute rheumatic fever in northern and western Uganda. METHODS: For our prospective epidemiological study, we established acute rheumatic fever clinics at two regional hospitals in the north (Lira district) and west (Mbarara district) of Uganda and instituted a comprehensive acute rheumatic fever health messaging campaign. Communities and health-care workers were encouraged to refer children aged 3-17 years, with suspected acute rheumatic fever, for a definitive diagnosis using the Jones Criteria. Children were referred if they presented with any of the following: (1) history of fever within the past 48 h in combination with any joint complaint, (2) suspicion of acute rheumatic carditis, or (3) suspicion of chorea. We excluded children with a confirmed alternative diagnosis. We estimated incidence rates among children aged 5-14 years and characterised clinical features of definite and possible acute rheumatic fever cases. FINDINGS: Data were collected between Jan 17, 2018, and Dec 30, 2018, in Lira district and between June 5, 2019, and Feb 28, 2020, in Mbarara district. Of 1075 children referred for evaluation, 410 (38%) met the inclusion criteria; of these, 90 (22%) had definite acute rheumatic fever, 82 (20·0%) had possible acute rheumatic fever, and 24 (6%) had rheumatic heart disease without evidence of acute rheumatic fever. Additionally, 108 (26%) children had confirmed alternative diagnoses and 106 (26%) had an unknown alternative diagnosis. We estimated the incidence of definite acute rheumatic fever among children aged 5-14 years as 25 cases (95% CI 13·7-30·3) per 100 000 person-years in Lira district (north) and 13 cases (7·1-21·0) per 100 000 person-years in Mbarara district (west). INTERPRETATION: To the best of our knowledge, this is the first population-based study to estimate the incidence of acute rheumatic fever in sub-Saharan Africa. Given the known rheumatic heart disease burden, it is likely that only a proportion of children with acute rheumatic fever were diagnosed. These data dispel the long-held hypothesis that the condition does not exist in sub-Saharan Africa and compel investment in improving prevention, recognition, and diagnosis of acute rheumatic fever. FUNDING: American Heart Association Children's Strategically Focused Research Network Grant, THRiVE-2, General Electric, and Cincinnati Children's Heart Institute Research Core.

White-nose syndrome: A novel dermatomycosis of biologic interest and epidemiologic consequence.

Over the past 10 years, the environmental and veterinary communities have sounded alarms over an insidious keratinophilous fungus, Pseudogymnoascus destructans, that has decimated populations of bats (yes, bats, chiropterans) throughout North America and, most recently, Northern China and Siberia. We as dermatologists may find this invasive keratinophilous fungus of particular interest, as its method of destruction is disruption of the homeostatic mechanism of the bat wing integument. Although it is unlikely that this pathogen will become an infectious threat to humans, its environmental impact will likely affect us all, especially as recent data have shown upregulation of naturally occurring coronaviruses in coinfected bats. Dermatologists are familiar with keratinophilous dermatophyte infections, but these rarely cause serious morbidity in individual patients and never cause crisis on a population basis. This contribution describes the effects of P destructans on both the individual and the population basis. Bringing the white-nose syndrome to the attention of human dermatologists and skin scientists may invite transfer of expertise in understanding the disease, its pathophysiology, epidemiology, treatment, and prevention.

At the dinner table with Adam and Eve.

Parents of children with atopic dermatitis often believe that dietary factors influence the course of a child's eczema. This is not a new phenomenon. In this paper, we examine two old documents that explore the relationships between diet and health. The first document is 125-years-old and real; the second document is a fictional one that we composed in the style of Mark Twain's Extracts from Adam's Diary, which Twain humorously suggested was from the time of Genesis.