Architecture of an HIV-1 reverse transcriptase initiation complex.

Reverse transcription of the HIV-1 RNA genome into double-stranded DNA is a central step in viral infection 1 and a common target of antiretroviral drugs 2 . The reaction is catalysed by viral reverse transcriptase (RT)3,4 that is packaged in an infectious virion with two copies of viral genomic RNA 5 each bound to host lysine 3 transfer RNA (tRNALys3), which acts as a primer for initiation of reverse transcription6,7. Upon viral entry into cells, initiation is slow and non-processive compared to elongation8,9. Despite extensive efforts, the structural basis of RT function during initiation has remained a mystery. Here we use cryo-electron microscopy to determine a three-dimensional structure of an HIV-1 RT initiation complex. In our structure, RT is in an inactive polymerase conformation with open fingers and thumb and with the nucleic acid primer-template complex shifted away from the active site. The primer binding site (PBS) helix formed between tRNALys3 and HIV-1 RNA lies in the cleft of RT and is extended by additional pairing interactions. The 5' end of the tRNA refolds and stacks on the PBS to create a long helical structure, while the remaining viral RNA forms two helical stems positioned above the RT active site, with a linker that connects these helices to the RNase H region of the PBS. Our results illustrate how RNA structure in the initiation complex alters RT conformation to decrease activity, highlighting a potential target for drug action.

A new eruption of bullous pemphigoid following mRNA COVID-19 vaccination.

The rapid development and implementation of COVID-19 vaccines throughout the global population has given rise to unique, rare, adverse skin reactions. This case report describes an elderly man with new-onset bullous pemphigoid following the second dose of the Pfizer-BioNTech (mRNA) COVID-19 vaccine.

A virtual faculty exchange program enhances dermatology resident education in the COVID-19 era: a survey study.

One of the many consequences of the COVID-19 pandemic was the cancelation of the 2020 American Academy of Dermatology Annual Meeting. This conference historically features lectures from world-renowned experts in all areas of dermatology, thus providing an important educational experience for dermatology residents. We hypothesized that the cancellation of this meeting produced a substantial educational loss for dermatology residents. To mitigate this impact, we developed a virtual faculty exchange program and surveyed dermatology residents' perspectives on its implementation. All participating residents found the virtual faculty exchange useful and would recommend it to other residents/programs. Moreover, all residents wanted to participate in more faculty exchange sessions as well as incorporate them throughout the academic year. Additionally, this educational program eliminated the potential cost of >$15,000 in flights and >24 metric tons of carbon emissions. This virtual faculty exchange program is a viable tool to enhance dermatology resident education in the COVID-19 era.

Neoadjuvant endocrine therapy in locally advanced estrogen or progesterone receptor-positive breast cancer: determining the optimal endocrine agent and treatment duration in postmenopausal women-a literature review and proposed guidelines.

INTRODUCTION: For patients with locally advanced estrogen receptor or progesterone receptor-positive breast cancer, neoadjuvant endocrine therapy (NET) facilitates down-staging of the tumor and increased rates of breast-conserving surgery. However, NET remains under-utilized, and there are very limited clinical guidelines governing which therapeutic agent to use, or the optimal duration of treatment in postmenopausal women. This literature review aims to discuss the evidence surrounding (1) biomarkers for patient selection for NET, (2) the optimal neoadjuvant endocrine agent for postmenopausal women with locally advanced breast cancer, and (3) the optimal duration of NET. In addition, we make initial recommendations towards developing a clinical guideline for the prescribing of NET. METHOD: A wide-ranging search of online electronic databases was conducted using a truncated PIC search strategy to identify articles that were relevant to these aims and revealed a number of key findings. RESULTS: Randomized trials have consistently demonstrated that aromatase inhibitors are more effective than tamoxifen, in terms of objective response rate and rate of BCS, and should be used as first-line NET. The three available aromatase inhibitors have so far been demonstrated to be biologically equivalent, with the choice of aromatase inhibitor not having been shown to affect clinical outcomes. There is increasing evidence for extending the duration of NET beyond 3 to 4 months, to at least 6 months or until maximal clinical response is achieved. While on-treatment levels of the proliferation marker Ki67 are predictive of long-term outcome, the choice of adjuvant therapy in patients who have received NET and then surgery is best guided by the preoperative endocrine prognostic index, or PEPI, which incorporates Ki67 with other clinical parameters. CONCLUSION: This study reveals that in appropriately selected patients, NET can provide equivalent clinical benefit to neoadjuvant chemotherapy in the same cohort, if suitable treatments and durations are chosen. Our findings highlight the need for better defined biomarkers both for guiding patient selection and for measuring outcomes. Development of standard guidelines for the prescribing of NET has the potential to improve both clinical outcomes and quality of life in this patient cohort.

Vancomycin-associated drug-induced hypersensitivity syndrome.

BACKGROUND: Although hypersensitivity reactions are well characterized for certain medications, vancomycin-associated drug-induced hypersensitivity syndrome (DIHS), or drug reaction with eosinophilia and systemic symptoms (DRESS), has yet to be defined. OBJECTIVE: To better define the clinical phenotype of vancomycin-associated DIHS. METHODS: A retrospective case series was conducted over an 8-year period at a single, academic institution. A total of 29 cases of DIHS/DRESS were identified, of which 4 were attributed to vancomycin. A literature review was performed; it identified 28 additional cases of vancomycin-induced DIHS. Vancomycin-associated acute interstitial nephritis was also reviewed to detect additional, previously uncharacterized cases of systemic hypersensitivity. The review yielded 11 additional cases. RESULTS: In this literature review and retrospective series, the incidence of renal dysfunction among vancomycin-induced cases (75% and 68% of cases in the series and literature, respectively) was notably higher than the overall reported incidence in DIHS (10%-40%). The degree of renal impairment was also significantly increased in the retrospective series (a median 4.98-fold change in baseline creatinine level vs a 2.25-fold increase in non-vancomycin-associated cases [P = .011]). LIMITATIONS: The principal limitation of this study is the small sample size. Other notable limitations include the retrospective nature of the study and absence of confirmatory renal biopsies. CONCLUSION: Although the current understanding of DIHS/DRESS is imperfect, our findings suggest that vancomycin-induced cases present with a unique phenotype characterized by a higher burden of renal involvement.

Where are we now with inpatient consultative dermatology?: Assessing the value and evolution of this subspecialty over the past decade.

The importance of inpatient consultative dermatology is often underrecognized and undervalued. A significant need exists because the burden of skin disease in the hospital is great and expertise regarding the recognition and management of uncommon and severe skin disorders is limited outside the field. In response to this need, the concept of a dermatology hospitalist was defined and the Society for Dermatology Hospitalists was created in 2009. Over the past decade, the subspecialty has developed and fostered both research and education. Data now exist demonstrating the value of inpatient dermatology services not only to patients but also to payors and health care systems. Future needs include strategies to improve access to expertise and additional efforts to establish our field as an indispensable and enduring component of hospital-based care.

Compliance with serial dermoscopic monitoring: An academic perspective.

BACKGROUND: For even seasoned practitioners, early melanomas can be difficult to distinguish from melanocytic nevi. Although serial digital dermoscopy is considered by many to be the gold standard for monitoring patients at high risk, poor compliance can seriously alter efficacy. In 2014, a concerning compliance rate of 25% was reported from a single, private clinic. Information is currently limited regarding the determinants of compliance and whether patients at high risk return at an acceptable rate. OBJECTIVE: We sought to determine the compliance rate within the pigmented lesions clinic at our academic institution and identify demographic variables that may influence adherence. METHODS: A retrospective review was conducted using 120 patient charts. RESULTS: An overall compliance rate of 87.5% was observed with 63.3% of patients returning within 1 month of the recommended interval. The most notable risk factor for noncompliance was patient age between 20 and 29 years. Factors promoting adherence include a personal history of melanoma, greater than 5 serially monitored nevi, and a personal history of atypical nevi. LIMITATIONS: The external validity is limited and the sample size is small. CONCLUSION: These findings contradict concerns that adherence to serial monitoring is unacceptably poor and demonstrate that compliance is highest for patients with the greatest inherent risk.

Exploring the gaps in the evidence-based application of narrowband UVB for the treatment of vitiligo.

While narrowband ultraviolet light B (NB-UVB) has become integral to the treatment of diffuse vitiligo, evidence-based guidelines have been lacking with regard to dosing and administration. This is largely the result of heterogeneous study designs, ambiguous methodologies, disparate dosing strategies, and the use of varied, and somewhat arbitrary, outcome measures. In the absence of prospective trials to address each of these concerns, the available literature regarding the application of NB-UVB for vitiligo was reviewed and the authors now pose a set of questions to the phototherapy community in an attempt to highlight gaps within our understanding. We aim to stimulate discussion, elicit expert opinion, and identify areas for future research to move toward a unified and safe treatment guideline for patients afflicted by this disease.

VEXAS Syndrome-Diagnostic Clues for the Dermatologist and Gaps in Our Current Understanding: A Narrative Review.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome is a newly recognized, acquired autoinflammatory disorder with broad systemic implications and a poor global prognosis. Because cutaneous lesions are present in the majority of those affected, it is necessary that dermatologists are equipped to recognize this important disease. Through identification, there is a greater opportunity for disease stratification, surveillance for systemic involvement, and selection of the best available therapies. As our understanding of this disease develops, dermatologists should also play a role in addressing the knowledge gaps that exist.

The United States dermatology inpatient workforce between 2013 and 2019: a Medicare analysis reveals contraction of the workforce and vast access deserts-a cross-sectional analysis.

While time spent practicing inpatient dermatology has decreased since the 1990s, less is known about the current state of inpatient dermatology. We describe the distribution and frequency of inpatient dermatology encounters servicing the United States Medicare population between 2013 and 2019. Cross-sectional analysis of publicly available inpatient Medicare Part B claims data from 2013 to 2019 was conducted. Main outcomes and measures were characteristics and trends of dermatologists performing inpatient encounters. Categorical variables were compared using χ2 analysis. Trends were analyzed for linearity using Pearson correlation coefficient. 782 physicians met inclusion criteria for inclusion. Dermatologists were more often male (56.5%), possessing allopathic Medical Doctorate (MD) (86.3%), and in metropolitan settings (98.2%). However, proportion of female inpatient dermatologists increased significantly (37.9% to 46.2%). Across rural and metropolitan practices, number of inpatient physicians (2013: 356; 2019: 281) and number of medical centers in which dermatology encounters occurred (2013: 239; 2019: 157) decreased, more significantly in non-residency-associated institutions. Spatial analysis revealed wide regions lacking dermatologists meeting defined criteria. Limitations included the need for ten Medicare inpatient encounters for inclusion, counties without reported data. In conclusion, the number of dermatologists performing > 10 inpatient encounters per year is decreasing, and large variations exist in the number of U.S. inpatient dermatology visits.

Two cases of alopecic and aseptic nodules of the scalp.

We present two cases of alopecic and aseptic nodules of the scalp (AANS) that were previously misdiagnosed. AANS is characterized by solitary or multiple dome-shaped alopecic nodules and predominantly affects young men. Dermatologists should be aware of this under recognized entity.