The genomes of aerobic organisms suffer chronic oxidation of guanine to the genotoxic product 8-oxoguanine (oxoG). Replicative DNA polymerases misread oxoG residues and insert adenine instead of cytosine opposite the oxidized base. Both bases in the resulting A*oxoG mispair are mutagenic lesions, and both must undergo base-specific replacement to restore the original C*G pair. Doing so represents a formidable challenge to the DNA repair machinery, because adenine makes up roughly 25% of the bases in most genomes. The evolutionarily conserved enzyme adenine DNA glycosylase (called MutY in bacteria and hMYH in humans) initiates repair of A*oxoG to C*G by removing the inappropriately paired adenine base from the DNA backbone. A central issue concerning MutY function is the mechanism by which A*oxoG mispairs are targeted among the vast excess of A*T pairs. Here we report the use of disulphide crosslinking to obtain high-resolution crystal structures of MutY-DNA lesion-recognition complexes. These structures reveal the basis for recognizing both lesions in the A*oxoG pair and for catalysing removal of the adenine base.

Skin and subcutaneous conditions affect an estimated 1.9 billion people at any given time and remain the fourth leading cause of non-fatal disease burden worldwide.Access to dermatology care is limited due to a shortage of dermatologists, causing long wait times and leading patients to seek dermatologic care from general practitioners.However, the diagnostic accuracy of general practitioners has been reported to be only 0. 24-0. 70 (compared to 0. 77-0. 96 for dermatologists), resulting in over-and under-referrals, delays in care, and errors in diagnosis and treatment. In this paper, we developed a deep learning system (DLS) to provide a differential diagnosis of skin conditions for clinical cases (skin photographs and associated medical histories). The DLS distinguishes between 26 of the most common skin conditions, representing roughly 80% of the volume of skin conditions seen in a primary care setting. The DLS was developed and validated using de-identified cases from a teledermatology practice serving 17 clinical sites via a temporal split: the first 14,021 cases for development and the last 3,756 cases for validation. On the validation set, where a panel of three board-certified dermatologists defined the reference standard for every case, the DLS achieved 0.71 and 0.93 top-1 and top-3 accuracies respectively, indicating the fraction of cases where the DLS's top diagnosis and top 3 diagnoses contains the correct diagnosis. For a stratified random subset of the validation set (n=963 cases), 18 clinicians (of three different training levels) reviewed the cases for comparison. On this subset, the DLS achieved a 0.67 top-1 accuracy, non-inferior to board-certified dermatologists (0.63, p<0.001), and higher than primary care physicians (PCPs, 0.45) and nurse practitioners (NPs, 0.41). The top-3 accuracy showed a similar trend: 0.90 DLS, 0.75 dermatologists, 0.60 PCPs, and 0.55 NPs . These results highlight the potential of the DLS to augment the ability of general practitioners who did not have additional specialty training to accurately diagnose skin conditions by suggesting differential diagnoses that may not have been considered. Future work will be needed to prospectively assess the clinical impact of using this tool in actual clinical workflows.

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SOX2 is a gene located on chromosome 3q26.33 that encodes a transcription factor important to maintenance of embryonic neural crest stem cell pluripotency. We have identified rare SOX2-immunoreactive cells in normal human skin at or near the established stem cell niches. Three subsets of SOX2-positive cells were defined in these regions: those expressing only SOX2 and those that co-expressed SOX2 and either CK20 or microphthalmia-associated transcription factor , which are consistent with dichotomous differentiation of SOX2-expressing precursors along neuroendocrine (Merkel cell) or melanocytic lines , respectively. Examination of Merkel cell carcinomas confirmed nuclear SOX2 expression in this tumor type. In human patient melanoma , strong nuclear expression of SOX2 was noted in a subset of tumors , and the ability to detect SOX2 in lesional cells significantly correlated with primary tumor thickness in a survey cohort. To assess the potential role of SOX2 in melanoma growth , an in vivo tumorigenesis assay was used. Whereas SOX2 knockdown failed to influence proliferation of cultured melanoma cells in vitro , tumor xenografts generated with the SOX2-knockdown cell line showed significant decrease in mean tumor volume as compared with controls. In aggregate , these findings suggest that SOX2 is a novel biomarker for subpopulations of normal skin cells that reside in established stem cell niches and that might relate to Merkel cell and melanocyte ontogeny and tumorigenesis.

Squamous cell carcinomas (SCC) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T cell immunosuppressant medications. Imiquimod is a topical immune response modifier and TLR7 agonist that induces the immunologic destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunologic memory are ultimately T cell mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod prior to excision contained dense T cell infiltrates associated with tumor cell apoptosis and histologic evidence of tumor regression. Effector T cells from treated SCC produced more IFN-γ, granzyme and perforin and less IL-10 and TGF-β than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-γ, perforin or granzyme, suggesting that these latter effects arise from recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.

IMPORTANCE Most dermatologic cases are initially evaluated by nondermatologists such as primary care physicians (PCPs) or nurse practitioners (NPs). OBJECTIVE To evaluate an artificial intelligence (AI)-based tool that assists with diagnoses of dermatologic conditions. DESIGN, SETTING, AND PARTICIPANTS This multiple-reader, multiple-case diagnostic study developed an AI-based tool and evaluated its utility. Primary care physicians and NPs retrospectively reviewed an enriched set of cases representing 120 different skin conditions. Randomization was used to ensure each clinician reviewed each case either with or without AI assistance; each clinician alternated between batches of 50 cases in each modality. The reviews occurred from February 21 to

Increased ethnic diversity of physicians is associated with increased access to health care for underserved communities, better anticipation of patient needs, and acceleration of medical research. 1 Similarly, sex concordance between physicians and patients can improve communication and patient satisfaction. 2 Although sex and ethnic diversity of US physicians have both increased over the past several decades, not all clinical specialties have been impacted equally. To better characterize the dermatology field's evolution during this time period, we analyzed sex and ethnicity trends among dermatology residents and compared them with other specialties and medical school graduates over multiple decades. Methods | Thirty-six years of self-reported ethnicity and 19 years of self-reported sex composition data of American College of Graduate Medical Education (ACGME)-registered dermatology, internal medicine, emergency medicine, obstetrics/ gynecology, ophthalmology, general surgery, and orthopedic surgery residents were obtained from the National Graduate Medical Education Census. 3 Similar ethnic and sex composition data of graduating medical school classes were obtained from the Association of American Medical Colleges (AAMC) Data Book. 4 Ethnic groups were defined as white, Asian, African American, Hispanic, or other. Respondents could choose more than 1 category. The categories for sex were male or female. Changes in sex and ethnic compositions were analyzed across the periods for which data were available. Institutional review board approval was waived by the Beth Israel Deaconess Medical Center, because only publicly accessible data was used. Using Stata 14 statistical software (StataCorp), specialtyspecific logistic regression models were constructed to evaluate the proportion of residents across ethnicity and sex groups over time. Demographic differences over time between specialties were evaluated with the likelihood ratio test. To assess recent differences between specialties in sex and ethnic compositions, data from 2011 to 2013 were averaged and binomial proportions were compared using a 2-sample z test. All 2-sided P values <.05 were considered statistically significant.

BackgroundThe incidence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) has risen dramatically in the U.S., particularly among children. Although Streptococcus pneumoniae colonization has been inversely associated with S. aureus colonization in unvaccinated children, this and other risk factors for S. aureus carriage have not been assessed following widespread use of the heptavalent pneumococcal conjugate vaccine (PCV7). Our objectives were to (1) determine the prevalence of S. aureus and MRSA colonization in young children in the context of widespread use of PCV7; and (2) examine risk factors for S. aureus colonization in the post-PCV7 era, including the absence of vaccine-type S. pneumoniae colonization.MethodsSwabs of the anterior nares (S. aureus) were obtained from children enrolled in an ongoing study of nasopharyngeal pneumococcal colonization of healthy children in 8 Massachusetts communities. Children 3 months to <7 years of age seen for well child or sick visits in primary care offices from 11/03–4/04 and 10/06–4/07 were enrolled. S. aureus was identified and antibiotic susceptibility testing was performed. Epidemiologic risk factors for S. aureus colonization were collected from parent surveys and chart reviews, along with data on pneumococcal colonization. Multivariate mixed model analyses were performed to identify factors associated with S. aureus colonization.ResultsAmong 1,968 children, the mean age (SD) was 2.7 (1.8) years, 32% received an antibiotic in the past 2 months, 2% were colonized with PCV7 strains and 24% were colonized with non-PCV7 strains. The prevalence of S. aureus colonization remained stable between 2003–04 and 2006–07 (14.6% vs. 14.1%), while MRSA colonization remained low (0.2% vs. 0.9%, p = 0.09). Although absence of pneumococcal colonization was not significantly associated with S. aureus colonization, age (6–11 mo vs. ≥5 yrs, OR 0.39 [95% CI 0.24–0.64]; 1–1.99 yrs vs. ≥5 yrs, OR 0.35 [0.23–0.54]; 2–2.99 yrs vs. ≥5 yrs, OR 0.45 [0.28–0.73]; 3–3.99 yrs vs. ≥5 yrs, OR 0.53 [0.33–0.86]) and recent antibiotic use were significant predictors in multivariate models.ConclusionIn Massachusetts, S. aureus and MRSA colonization remained stable from 2003–04 to 2006–07 among children <7 years despite widespread use of pneumococcal conjugate vaccine. S. aureus nasal colonization varies by age and is inversely correlated with recent antibiotic use.