Awareness and Counseling Among Dermatologists of the Association Between Hydrochlorothiazide and Nonmelanoma Skin Cancer: Barriers and Opportunities.

BACKGROUND: Cumulative hydrochlorothiazide (HCTZ) use is linked to the development of nonmelanoma skin cancers. In August 2020, the U.S. FDA approved changes to the HCTZ drug label to indicate this. OBJECTIVE: To uncover what proportion of dermatologists are aware of this association and how often screening and counseling are performed. MATERIALS AND METHODS: An observational, cross-sectional survey assessing risk awareness and counseling frequency and barriers was distributed among academic dermatologists. Chi-square tests compared resident and attending respondent data. RESULTS: A total of 83 respondents completed the questionnaire; most endorsed awareness of the association between HCTZ use and nonmelanoma skin cancer development before the survey, yet only 28.9% of respondents were aware of changes to the HCTZ drug label. A greater proportion of attendings than residents were aware of the association and drug label changes. The most reported barrier to counseling was the lack of specific screening guidelines for patients taking HCTZ. CONCLUSION: Concerted efforts should be made in residency training and continuing medical education to ensure dermatologists are aware of this well-established link. Specialty-specific efforts should be made to implement clear guidelines on best screening practices and optimized counseling strategies for patients taking HCTZ.

Chemical pulldown combined with mass spectrometry to identify the molecular targets of antimalarials in cell-free lysates.

Here, we provide a protocol using chemical pulldown combined with mass spectrometry (LC-MS/MS) to identify drug targets in Plasmodium falciparum. This approach works upon the principle that a resin-bound inhibitor selectively binds its molecular target(s) in cell-free lysates. We describe the preparation of drug beads and P. falciparum lysate, followed by chemical pulldown, sample fractionation, and LC-MS/MS analysis. We then detail how to identify specifically bound proteins by comparing protein enrichment in DMSO-treated relative to drug-treated lysates via quantitative proteomics. For complete details on the use and execution of this protocol, please refer to Milne et al. (2022).1.

Climate warming causes photobiont degradation and carbon starvation in a boreal climate sentinel lichen.

PREMISE: The long-term potential for acclimation by lichens to changing climates is poorly known, despite their prominent roles in forested ecosystems. Although often considered "extremophiles," lichens may not readily acclimate to novel climates well beyond historical norms. In a previous study (Smith et al., 2018), Evernia mesomorpha transplants in a whole-ecosystem climate change experiment showed drastic mass loss after 1 yr of warming and drying; however, the causes of this mass loss were not addressed. METHODS: We examined the causes of this warming-induced mass loss by measuring physiological, functional, and reproductive attributes of lichen transplants. RESULTS: Severe loss of mass and physiological function occurred above +2°C of experimental warming. Loss of algal symbionts ("bleaching") and turnover in algal community compositions increased with temperature and were the clearest impacts of experimental warming. Enhanced CO2 had no significant physiological or symbiont composition effects. The functional loss of algal photobionts led to significant loss of mass and specific thallus mass (STM), which in turn reduced water-holding capacity (WHC). Although algal genotypes remained detectable in thalli exposed to higher stress, within-thallus photobiont communities shifted in composition toward greater diversity. CONCLUSIONS: The strong negative impacts of warming and/or lower humidity on Evernia mesomorpha were driven by a loss of photobiont activity. Analogous to the effects of climate change on corals, the balance of symbiont carbon metabolism in lichens is central to their resilience to changing conditions.

The CROWNing Event on Hair Loss in Women of Color: A Framework for Advocacy and Community Engagement (FACE) Survey Analysis.

Hair loss is a primary reason for women with skin of color to seek dermatologic care. In addition to physical disfigurement, patients with hair loss are more likely to report feelings of depression, anxiety, and low self-esteem. There is a critical gap in dermatology advocacy efforts and educational information intended for women with skin of color. In July 2021, the Virginia Dermatology Society planned a virtual event on hair loss and practical political advocacy for women of color. Event attendees completed pre- and postevent Likert scale surveys that assessed participant attitudes, knowledge, and awareness surrounding hair loss. A resource toolkit for both patients and physicians also was created, which included articles about evaluating, diagnosing, and treating different types of hair loss that would be beneficial for dermatologists, as well as informational articles, links, and videos that would be helpful to patients. Resource toolkits combined with outreach events can be used to engage communities, disseminate information, and close gaps that have led to health care disparities.

Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase.

There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages.

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C.

C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascular dysfunction. As such, NPR-C is a novel therapeutic target to treat cardiovascular diseases. A series of novel small molecules have been designed and synthesized, and their structure-activity relationships were evaluated by a surface plasmon resonance binding assay. The biological activity of hit compounds was confirmed through organ bath assays measuring vascular relaxation and inhibition of cAMP production, which was shown to be linked to its NPR-C activity. Lead compound 1 was identified as a potent agonist (EC50 ∼ 1 µM) with promising in vivo pharmacokinetic properties.

Effects of dipeptidyl peptidase-4 inhibitors and sulphonylureas on cognitive and physical function in nursing home residents.

AIMS: Dipeptidyl peptidase-4 inhibitors (DPP4Is) may mitigate hypoglycaemia-mediated declines in cognitive and physical functioning compared with sulphonylureas (SUs), yet comparative studies are unavailable among older adults, particularly nursing home (NH) residents. We evaluated the effects of DPP4Is versus SUs on cognitive and physical functioning among NH residents. MATERIALS AND METHODS: This new-user cohort study included long-stay NH residents aged ≥65 years from the 2007-2010 national US Minimum Data Set (MDS) clinical assessments and linked Medicare claims. We measured cognitive decline from the validated 6-point MDS Cognitive Performance Scale, functional decline from the validated 28-point MDS Activities of Daily Living scale, and hospitalizations or emergency department visits for altered mental status from Medicare claims. We compared 180-day outcomes in residents who initiated a DPP4I versus SU after 1:1 propensity score matching using Cox regression models. RESULTS: The matched cohort (N = 1784) had a mean ± SD age of 80 ± 8 years and 73% were women. Approximately 46% had no or mild cognitive impairment and 35% had no or mild functional impairment before treatment initiation. Compared with SU users, DPP4I users had lower 180-day rates of cognitive decline [hazard ratio (HR) = 0.61, 95% confidence interval (CI) 0.31-1.19], altered mental status events (HR = 0.71, 95% CI 0.39-1.27), and functional decline (HR = 0.89, 95% CI 0.51-1.56), but estimates were imprecise. CONCLUSIONS: Rates of cognitive and functional decline may be reduced among older NH residents using DPP4Is compared with SUs, but larger studies with greater statistical power should resolve the remaining uncertainty by providing more precise effect estimates.

Lichen-based critical loads for deposition of nitrogen and sulfur in US forests.

Critical loads are thresholds of atmospheric deposition below which harmful ecological effects do not occur. Because lichens are sensitive to atmospheric deposition, lichen-based critical loads can foreshadow changes of other forest processes. Here, we derive critical loads of nitrogen (N) and sulfur (S) deposition for continental US and coastal Alaskan forests, based on nationally consistent lichen community surveys at 8855 sites. Across the eastern and western US ranges of 459 lichen species, each species' realized optimum was the N or S atmospheric deposition value at which it most frequently occurred. The mean of optima for all species at a site, weighted by their abundances, was defined as a community "airscore" indicative of species' collective responses to atmospheric deposition. To determine critical loads for adverse community compositional shifts, we then modeled changes in airscores as a function of deposition, climate and forest habitat predictors in nonparametric multiplicative regression. Critical loads, indicative of initial shifts from pollution-sensitive toward pollution-tolerant species, occurred at 1.5 kg N ha-1 y-1 and 2.7 kg S ha-1 y-1. Importantly, these critical loads remain constant under any climate regime nationwide, suggesting both simplicity and nationwide applicability. Our models predict that preventing excess N deposition of just 0.2-2.0 kg ha-1 y-1 in the next century could offset the detrimental effects of predicted climate warming on lichen communities. Because excess deposition and climate warming both harm the most ecologically influential species, keeping conditions below critical loads would sustain both forest ecosystem functioning and climate resilience.

Gaze Behavior During Navigation and Visual Search of an Open-World Virtual Environment.

Eye tracking has been an essential tool within the vision science community for many years. However, the majority of studies involving eye-tracking technology employ a relatively passive approach through the use of static imagery, prescribed motion, or video stimuli. This is in contrast to our everyday interaction with the natural world where we navigate our environment while actively seeking and using task-relevant visual information. For this reason, an increasing number of vision researchers are employing virtual environment platforms, which offer interactive, realistic visual environments while maintaining a substantial level of experimental control. Here, we recorded eye movement behavior while subjects freely navigated through a rich, open-world virtual environment. Within this environment, subjects completed a visual search task where they were asked to find and count occurrence of specific targets among numerous distractor items. We assigned each participant into one of four target conditions: Humvees, motorcycles, aircraft, or furniture. Our results show a statistically significant relationship between gaze behavior and target objects across Target Conditions with increased visual attention toward assigned targets. Specifically, we see an increase in the number of fixations and an increase in dwell time on target relative to distractor objects. In addition, we included a divided attention task to investigate how search changed with the addition of a secondary task. With increased cognitive load, subjects slowed their speed, decreased gaze on objects, and increased the number of objects scanned in the environment. Overall, our results confirm previous findings and support that complex virtual environments can be used for active visual search experimentation, maintaining a high level of precision in the quantification of gaze information and visual attention. This study contributes to our understanding of how individuals search for information in a naturalistic (open-world) virtual environment. Likewise, our paradigm provides an intriguing look into the heterogeneity of individual behaviors when completing an un-timed visual search task while actively navigating.

Painful scrotal dermatitis secondary to topical 5-fluorouracil.

5-Fluorouracil (5-FU) is an antineoplastic agent that is used topically to treat actinic keratoses. Although topical 5-FU frequently causes irritant contact dermatitis at the site of application, distant skin reactions are rare and could relate to accidental transfer or systemic absorption of the drug. We present a patient who developed a painful scrotal dermatitis after applying the topical cream to actinic keratoses on his chest. Upon discontinuation of topical 5-FU, the reaction resolved over a four-week period with oral prednisone and topical betamethasone ointment. The patient was re-challenged with topical 5-FU one year later and again developed scrotal pain and erythema similar to the initial reaction. Scrotal dermatitis is a rare adverse effect of topical 5-FU therapy that can be associated with significant distress and disruption of daily activities.

Comparative safety of dipeptidyl peptidase-4 inhibitors and sulfonylureas among frail older adults.

BACKGROUND: Studies comparing dipeptidyl peptidase-4 inhibitors (DPP4Is) to sulfonylureas (SUs) are unavailable for frail older adults, especially nursing home (NH) residents. We examined the effects of DPP4Is versus SUs on severe adverse glycemic events, cardiovascular events, and death among NH residents. METHODS: We conducted a national retrospective cohort study of long-stay NH residents aged ≥65 years using 2008-2010 national US Minimum Data Set clinical assessment data and linked Medicare claims. Exposure was new DPP4I versus new SU use assessed via Medicare Part D drug claims. One-year outcomes were severe hypoglycemia, severe hyperglycemia, acute myocardial infarction (AMI), heart failure (HF), major adverse cardiovascular events plus HF (MACE+HF), and death. We compared outcomes after propensity score matching using Cox proportional hazards regression models. RESULTS: The cohort (N = 2016) had a mean (SD) age of 81 (8.1) years and was 72% female. Compared with SU users, DPP4I users had a lower 1-year rate of severe hypoglycemic events (HR = 0.57, 95% CI 0.34-0.94), but statistically similar rates of severe hyperglycemic events (HR = 0.94, 95% CI 0.52-1.72), AMI (HR = 0.76, 95% CI 0.44-1.30), HF (HR = 1.01, 95% CI 0.79-1.30), MACE+HF (HR = 0.90, 95% CI 0.72-1.12), and death (HR = 0.97, 95% CI 0.86-1.10). CONCLUSIONS: DPP4Is should be a preferred treatment option over SUs for NH residents and other frail older adults given the importance of avoiding hypoglycemia.

Dermatologic support for oncology: Quantifying the consultative services received by hospitalized oncology patients.

Hospitalized oncology patients often require multidisciplinary care. Inpatient consultative dermatologists can provide expertise in the management of cutaneous complications that patients with cancer may experience. The goal of this study was to quantify the types of consults received by hospitalized oncology patients to better understand the utilization of dermatology consults in this population. Hospital billing codes were used to identify inpatient oncology patients and the types of consults they received at a single quaternary care hospital center. Between July 1, 2015, and January 31, 2020, 14,175 patients were admitted to an oncology service for more than 24 hours, and 5,243 (37%) of these patients received at least 1 consultation during their hospital admission. These patients received a total of 10,492 consults from 101 different services. Dermatology had the fifth-highest number of consults (n = 623; 5.9%). Among patients receiving consults, 608 (11.6%) received inpatient dermatology consults. Infectious disease was the service with the most consults (n = 1,485; 14.2%) and was also the service most commonly co-consulted with dermatology (n = 262; 42.1%). The inpatient consultative dermatology service is highly utilized among hospitalized oncology patients, suggesting that expertise in dermatologic care is valued by oncology teams.

Reconciling multiple counterfactuals when evaluating biodiversity conservation impact in social-ecological systems.

When evaluating the impact of a biodiversity conservation intervention, a counterfactual is typically needed. Counterfactuals are possible alternative system trajectories in the absence of an intervention. Comparing observed outcomes against the chosen counterfactual allows the impact (change attributable to the intervention) to be determined. Because counterfactuals by definition never occur, they must be estimated. Sometimes, there may be many plausible counterfactuals, including various drivers of biodiversity change and defined on a range of spatial or temporal scales. Here, we posit that, by definition, conservation interventions always take place in social-ecological systems (SES) (i.e., ecological systems integrated with human actors). Evaluating the impact of an intervention in an SES, therefore, means taking into account the counterfactuals assumed by different human actors. Use of different counterfactuals by different actors will give rise to perceived differences in the impacts of interventions, which may lead to disagreement about its success or the effectiveness of the underlying approach. Despite that there are biophysical biodiversity trends, it is often true that no single counterfactual is definitively the right one for conservation assessment, so multiple evaluations of intervention efficacy could be considered justifiable. Therefore, we propose calculating the sum of perceived differences, which captures the range of impact estimates associated with different actors in a given SES. The sum of perceived differences gives some indication of how closely actors in an SES agree on the impacts of an intervention. We applied the concept of perceived differences to a set of global, national, and regional case studies (e.g., global realization of Aichi Target 11 for marine protected areas, effect of biodiversity offsetting on vegetation condition in Australia, and influence of conservation measures on an endangered ungulate in Central Asia). We explored approaches for minimizing the sum, including a combination of negotiation and structured decision making, careful alignment of expectations on scope and measurement, and explicit recognition of any intractable differences between stakeholders.

Reconciliación de Múltiples Hipótesis de Contraste al Evaluar el Impacto de la Conservación de la Biodiversidad en los Sistemas Socio-Ecológicos Resumen Cuando se evalúa el impacto de una intervención de conservación de la biodiversidad, generalmente se requiere una hipótesis de contraste. Las hipótesis de contraste son las posibles trayectorias alternativas del sistema en ausencia de una intervención. La comparación de los resultados observados con la hipótesis de contraste elegida permite que se determine el impacto (cambio atribuible a la intervención). Ya que las hipótesis de contraste por definición nunca ocurren, éstas deben ser estimadas. En algunos casos es posible que existan muchas hipótesis de contraste, incluyendo a muchos conductores del cambio en la biodiversidad, y que estén definidas bajo una gama de escalas espaciales o temporales. En este artículo planteamos que, por definición, las intervenciones de conservación siempre ocurren en sistemas socioecológicos (SES) (es decir, sistemas ecológicos integrados con actores humanos). Por lo tanto, la evaluación del impacto de una intervención en un SES implica la consideración de las hipótesis de contraste asumidas por los diferentes actores humanos. El uso de diferentes hipótesis de contraste por los diferentes actores hará que surjan diferencias percibidas en los impactos de las intervenciones, lo que puede llegar a discrepancias sobre su éxito o sobre la efectividad de la estrategia subyacente. A pesar de que existen tendencias biofísicas de la biodiversidad, con frecuencia es cierto que no hay una sola hipótesis de contraste que sea correcta de manera definitiva para la evaluación de la conservación, por lo que múltiples evaluaciones de la eficiencia de la intervención podrían considerarse como justificables. Así, proponemos que se calcule la suma de las diferencias percibidas, la cual captura la gama de las estimaciones de impacto asociadas con diferentes actores en un SES dado. La suma de las diferencias percibidas nos da algún tipo de indicación sobre cuán de acuerdo están los actores de un SES sobre los impactos de una intervención. Aplicamos el concepto de diferencias percibidas a un conjunto de estudios de caso mundiales, nacionales y regionales (p. ej.: la realización mundial del Objetivo Aichi 11 para las áreas marinas protegidas, el efecto de la compensación de la biodiversidad sobre las condiciones botánicas en Australia y la influencia de las medidas de conservación sobre un ungulado en peligro en Asia central). Exploramos las estrategias para minimizar la suma, incluyendo una combinación de negociación y toma estructurada de decisiones, la alineación cuidadosa de las expectativas sobre el enfoque y la medida y el reconocimiento explícito de cualquier diferencia intratable entre los actores sociales.

Motivations for the use and consumption of wildlife products.

The dominant approach to combating the illegal wildlife trade has traditionally been to restrict the supply of wildlife products. Yet conservationists increasingly recognize the importance of implementing demand-side interventions that target the end consumers in the trade chain. Their aim is to curb the consumption of wildlife or shift consumption to more sustainable alternatives. However, there are still considerable knowledge gaps in understanding of the diversity of consumer motivations in the context of illegal wildlife trade, which includes hundreds of thousands of species, different uses, and diverse contexts. Based on consultation with multiple experts from a diversity of backgrounds, nationalities, and focal taxa, we developed a typology of common motivations held by wildlife consumers that can be used to inform conservation interventions. We identified 5 main motivational categories for wildlife use: experiential, social, functional, financial, and spiritual, each containing subcategories. This framework is intended to facilitate the segmentation of consumers based on psychographics and allow the tailoring of interventions-whether behavior change campaigns, enforcement efforts, or incentive programs-to the specific context in which they will be used. Underlining the importance of consumer research and collaborating with local actors is an important step toward promoting a more systematic approach to the design of demand reduction interventions.

Motivaciones para el Uso y Consumo de Productos de Fauna Resumen Tradicionalmente, la estrategia dominante para combatir el mercado ilegal de fauna ha sido restringir la oferta de productos de fauna. Aun así, los conservacionistas cada vez reconocen más la importancia de implementar intervenciones por el lado de la demanda que se enfoquen en los consumidores finales en la cadena de mercado. Su objetivo es reducir el consumo de fauna o redirigir ese consumo hacia alternativas más sustentables. Sin embargo, todavía existen vacíos de conocimiento en el entendimiento de la diversidad de motivos para los consumidores dentro del contexto del mercado ilegal de fauna, el cual incluye cientos de miles de especies, diferentes usos y contextos diversos. Con base en consultas a varios expertos con una diversidad de antecedentes, nacionalidades y taxones de enfoque desarrollamos una tipología de motivos comunes que tienen los consumidores de fauna que pueden usarse para orientar las intervenciones de conservación. Identificamos cinco categorías principales de motivos para el uso de fauna: vivencial, social, funcional, financiero y espiritual, cada uno con subcategorías. Este marco de trabajo tiene la intención de facilitar la segmentación de consumidores con base en psicográficos y permitir la personalización de las intervenciones - sean campañas de cambios en el comportamiento, esfuerzos por hacer cumplir las reglas o programas de incentivos - al contexto específico en el que serán utilizadas. Resaltar la importancia de los estudios de mercado y la colaboración con los actores locales es un paso importante hacia la promoción de una estrategia más sistemática para el diseño de intervenciones para reducir la demanda.