Rural Health Disparities in Skin Cancer Amplified Among Skin of Color.

Limited studies explore the role social determinants of health have on urban-rural health disparities, particularly for Skin of Color. To further evaluate this relationship, a cross-sectional study was conducted on data from five states using the 2018 to 2021 Behavior Risk Factor Surveillance Survey, a national state-run health survey. Prevalence of skin cancer history and urban/rural status were evaluated across these social determinants of health: sex, age, race, insurance status, number of personal healthcare providers, and household income. Overall, rural counterparts were significantly more likely to have a positive skin cancer history across most social determinants of health. Rural populations had a higher prevalence of skin cancer history across all races (P<.001). Rural non-Hispanic Whites had greater odds than their urban counterparts (OR=1.40; 95% CI 1.34 - 1.46). The odds were approximately twice as high for rural Black (OR=1.74; 95% CI 1.14 - 2.65), Hispanic (OR=2.31; 95% CI 1.56 - 3.41), and Other Race, non-Hispanic (OR=1.99; 95% CI 1.51 - 2.61), and twenty times higher for Asians (OR=20.46; 95% CI 8.63 - 48.54), although no significant difference was seen for American Indian/Alaskan Native (OR=1.5; 95% CI 0.99 - 2.28). However, when household income exceeded $100,000 no significant difference in prevalence or odds was seen between urban and rural settings. Despite increasing awareness of metropolitan-based health inequity, urban-rural disparities in skin cancer prevalence continue to persist and may be magnified by social determinants such as income and race. J Drugs Dermatol. 2024;23(6):480-484.    doi:10.36849/JDD.8094.

Opposite perceptual biases in analogous auditory and visual tasks are unique to consonant-vowel strings and are unlikely a consequence of repetition.

Despite wide reporting of a right ear (RE) advantage on dichotic listening tasks and a right visual field (RVF) advantage on visual half-field tasks, we know very little about the relationship between these perceptual biases. Previous studies that have investigated perceptual asymmetries for analogous auditory and visual consonant-vowel tasks have indicated a serendipitous finding: a RE advantage and a left visual field (LVF) advantage with poor cross-modal correlations. In this study, we examined the possibility that this LVF advantage for visual processing of consonant-vowel strings may be a consequence of repetition by examining perceptual biases in analogous auditory and visual tasks for both consonant-vowel strings and words. We replicated opposite perceptual biases for consonant-vowel strings (RE and LVF advantages). This did not extend to word stimuli where we found RE and RVF advantages. Furthermore, these perceptual biases did not differ across the three experimental blocks. Thus, we can firmly conclude that this LVF advantage is unique to consonant-vowel strings and is not a consequence of the repetition of a relatively limited number of stimuli. Finally, a test of covariances indicated no cross-modal relationships between laterality indices suggesting that perceptual biases are dissociable within individuals and cluster on mode of presentation.

Prevalence and molecular epidemiology of carbapenemase-producing Enterobacterales isolated from dog and cat faeces submitted to veterinary laboratories in the USA.

AIMS: To estimate the prevalence of carbapenemase-producing Enterobacterales (CPE) carriage among pets using faecal specimens submitted to veterinary diagnostic laboratories throughout the US. A secondary aim was to employ whole-genome sequencing (WGS) to characterize isolates of CPE from companion animals and compare them to publicly available CPE genomes. METHODS AND RESULTS: To estimate the prevalence of CPE in companion animals in the USA, a multicenter surveillance study including 8 different veterinary diagnostic laboratories from across the USA was conducted. Briefly, remnant faecal specimens from dogs and cats were screened using two selective agar plates (CHROMID Carba and MacConkey with 1 mg/L cefotaxime and 0.125 mg/L meropenem) and presumptive CPE isolates screened by the modified carbapenemase inactivation method for carbapenemase production. A total of 2393 specimens were screened and yielded 196 isolates for carbapenemase screening. A total of 5 isolates from 4 dogs and 1 cat at 3 different veterinary diagnostic laboratories were confirmed to produce a carbapenemase (0.21%). Whole-genome sequencing (WGS) revealed two E. coli (ST167) isolates that both produced an NDM-5 carbapenemase, two Enterobacter hormaechei (ST171) isolates that produced an NDM-5 carbapenemase and a KPC-4 carbapenemase respectively and one Klebsiella oxytoca (ST199) that produced an Oxa-48-type carbapenemase. Both E. coli isolates were found to be within at least 22 SNPs of previously characterized canine and human CPE isolates. CONCLUSIONS: This study demonstrates that the prevalence of CPE among companion animals is relatively low (0.21%) but that given the genetic relatedness of animal isolates to human isolates, additional surveillance is needed.

Immune checkpoint inhibitor associated epidermal necrosis, beyond SJS and TEN: a review of 98 cases.

Immune checkpoint inhibitor (ICI) therapies carry the risk of major immune-related adverse events (irAEs). Among the most severe irAEs is epidermal necrosis that may clinically mimic Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The aim of this study was to provide a summary of the clinical and histological features of ICI-associated epidermal necrosis, with a special focus on factors associated with fatal outcomes in cases of extensive disease. A total of 98 cases, 2 new cases and 96 reported on PubMed and in the literature, of ICI-associated epidermal necrosis were assessed. Development of epidermal necrosis occurred between 1 day and 3 years after starting ICI therapy, with an average onset of 13.8 weeks for patients with limited (< 30% BSA) and 11.3 weeks for those with extensive (≥ 30% BSA) involvement, and a median onset of 5.8 weeks and 4 weeks respectively. A preceding rash was seen in 52 cases and was more common in extensive cases. Mucosal involvement was only reported in 65% of extensive cases but was significantly associated with fatal reactions. Co-administration of cytotoxic chemotherapy was associated with more extensive disease. Recovery was observed in 96% and 65% of those with limited and extensive involvement respectively and no specific therapy was associated with improved survival. Young age was significantly associated with poor outcomes in extensive disease, the average age of surviving patients was 64.5 years old versus 55.1 years old for deceased patients, p < 0.01. Both superficial perivascular and interface/lichenoid inflammatory infiltrates were commonly seen. These findings suggest that ICI-associated epidermal necrosis should be considered a distinct clinical entity from drug-induced SJS/TEN.

Assessing Time of Onset for Interstitial Lung Disease in Anti-MDA5 Antibody-Positive Dermatomyositis.

This cohort study seeks to describe the time interval between interstitial lung disease and anti­melanoma differentiation-associated gene 5 antibody-positive dermatomyositis diagnoses.

Toxic Ingredients in Personal Care Products: A Dermatological Perspective.

Environmental dermatology is the study of how environmental factors affect the integumentary system. The environment includes natural and built habitats, encompassing ambient exposure, occupational exposures, and lifestyle exposures secondary to dietary and personal care choices. This review explores common toxins found in personal care products and packaging, such as bisphenols, parabens, phthalates, per- and poly-fluoroalkyl substances, p-phenylenediamine, and formaldehyde. Exposure to these toxins has been associated with carcinogenic, obesogenic, or proinflammatory effects that can potentiate disease. In addition, these compounds have been implicated as endocrine-disrupting chemicals that can worsen dermatological conditions such as acne vulgaris, or dermatitis. Certain pollutants found in personal care products are not biodegradable and have the potential to bioaccumulate in humans. Therefore, even short-term exposure can cause long-lasting issues for communities. The skin is often the first point of contact for environmental exposures and serves as the conduit between environmental toxins and the human body. Therefore, it is important for dermatologists to understand common pollutants and their acute, subacute, and chronic impact on dermatological conditions to better diagnose and manage disease.

Colorectal Cancer Screening Disparities Among Race: A Zip Code Level Analysis.

BACKGROUND: Colorectal cancer (CRC) screening can prevent disease by early identification. Existing disparities in CRC screening have been associated with factors including race, socioeconomic status, insurance, and even geography. Our study takes a deeper look into how social determinants related to zip code tabulation areas affect CRC screenings. MATERIALS AND METHODS: We conducted a retrospective cross-sectional study of CRC screenings by race at a zip code level, evaluating for impactful social determinant factors such as the social deprivation index (SDI). We used publicly available data from CDC 500 Cities Project (2016-2019), PLACES Project (2020), and the American Community Survey (2019). We conducted multivariate and confirmatory factor analyses among race, income, health insurance, check-up visits, and SDI. RESULTS: Increasing the tertile of SDI was associated with a higher likelihood of being Black or Hispanic, as well as decreased median household income (P < .01). Lower rates of regular checkup visits were found in the third tertile of SDI (P < .01). The multivariate analysis showed that being Black, Hispanic, lower income, being uninsured, lack of regular check-ups, and increased SDI were related to decreased CRC screening. In the confirmatory factor analysis, we found that SDI and access to insurance were the variables most related to decreased CRC screening. CONCLUSION: Our results reveal the top 2 factors that impact a locality's CRC screening rates are the social deprivation index and access to health care. This data may help implement interventions targeting social barriers to further promote CRC screenings within disadvantaged communities and decrease overall mortality via early screening.

Finger-powered fluidic actuation and mixing via MultiJet 3D printing.

Additive manufacturing, or three-dimensional (3D) printing, has garnered significant interest in recent years towards the fabrication of sub-millimeter scale devices for an ever-widening array of chemical, biological and biomedical applications. Conventional 3D printed fluidic systems, however, still necessitate the use of non-portable, high-powered external off-chip sources of fluidic actuation, such as electro-mechanical pumps and complex pressure-driven controllers, thus limiting their scope towards point-of-need applications. This work proposes entirely 3D printed sources of human-powered fluidic actuation which can be directly incorporated into the design of any 3D printable sub-millifluidic or microfluidic system where electrical power-free operation is desired. Multiple modular, single-fluid finger-powered actuator (FPA) designs were fabricated and experimentally characterized. Furthermore, a new 3D fluidic one-way valve concept employing a dynamic bracing mechanism was developed, demonstrating a high diodicity of ∼1117.4 and significant reduction in back-flow from the state-of-the-art. As a result, fabricated FPA prototypes achieved tailorable experimental fluid flow rates from ∼100 to ∼3000 µL min-1 without the use of electricity. Moreover, a portable human-powered two-fluid pulsatile fluidic mixer, capable of generating fully-mixed fluids in 10 seconds, is presented, demonstrating the application of FPAs towards on-chip integration into more complex 3D printed fluidic networks.

Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease.

Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington disease (HD). In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128 mouse model of HD. Treatment with laquinimod for 6 months rescued atrophy in the striatum, in certain cortical regions, and in the corpus callosum of YAC128 HD mice. Diffusion tensor imaging showed that white matter microstructural abnormalities in the posterior corpus callosum were improved following treatment with low dose (1 mg/kg) laquinimod, and were paralleled by reduced levels of interleukin-6 in the periphery of YAC128 HD mice. Functionally, treatment with laquinimod (1 and 10 mg/kg) led to modest improvements in motor function and in depressive-like behaviour. Taken together, these results suggest that laquinimod may improve some features of pathology in HD, and provides support for the role of immune activation in the pathogenesis of HD.

Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease.

Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from patients with HD and in human and rodent HD neural cells. Using the YAC128 mouse model of HD, we studied the effect of an irreversible MAO-A inhibitor, clorgyline, on the levels of select monoamine neurotransmitters associated with affective function. We observed a decrease in striatal levels of the MAO-A/B substrates, dopamine and norepinephrine, in YAC128 HD mice compared with wild-type mice, which was accompanied by increased anxiety- and depressive-like behaviour at five months of age. Treatment for 26 days with clorgyline restored dopamine, serotonin, and norepinephrine neurotransmitter levels in the striatum and reduced anxiety- and depressive-like behaviour in YAC128 HD mice. This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD.

Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.

PURPOSE: To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models. METHODS: The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models. RESULTS: Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3-4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios. CONCLUSIONS: This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.

Methionine aminopeptidase 2 is required for HSC initiation and proliferation.

In a chemical screening, we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models. Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue, and pronephric duct. metap2 was inhibited by morpholino and fumagillin treatment, resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization. It also disrupted intersegmental vessels in Tg(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34(+) cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice. metap2 knock-down in zebrafish and inhibition by fumagillin in zebrafish and human CB CD34(+) cells inhibited Calmodulin Kinase II activity and induced ERK phosphorylation. This study demonstrated a hitherto-undescribed role of MetAP2 in definitive hematopoiesis and a possible link to noncanonical Wnt and ERK signaling.

6-Sulphated chondroitins have a positive influence on axonal regeneration.

Chondroitin sulphate proteoglycans (CSPGs) upregulated in the glial scar inhibit axon regeneration via their sulphated glycosaminoglycans (GAGs). Chondroitin 6-sulphotransferase-1 (C6ST-1) is upregulated after injury leading to an increase in 6-sulphated GAG. In this study, we ask if this increase in 6-sulphated GAG is responsible for the increased inhibition within the glial scar, or whether it represents a partial reversion to the permissive embryonic state dominated by 6-sulphated glycosaminoglycans (GAGs). Using C6ST-1 knockout mice (KO), we studied post-injury changes in chondroitin sulphotransferase (CSST) expression and the effect of chondroitin 6-sulphates on both central and peripheral axon regeneration. After CNS injury, wild-type animals (WT) showed an increase in mRNA for C6ST-1, C6ST-2 and C4ST-1, but KO did not upregulate any CSSTs. After PNS injury, while WT upregulated C6ST-1, KO showed an upregulation of C6ST-2. We examined regeneration of nigrostriatal axons, which demonstrate mild spontaneous axon regeneration in the WT. KO showed many fewer regenerating axons and more axonal retraction than WT. However, in the PNS, repair of the median and ulnar nerves led to similar and normal levels of axon regeneration in both WT and KO. Functional tests on plasticity after the repair also showed no evidence of enhanced plasticity in the KO. Our results suggest that the upregulation of 6-sulphated GAG after injury makes the extracellular matrix more permissive for axon regeneration, and that the balance of different CSs in the microenvironment around the lesion site is an important factor in determining the outcome of nervous system injury.

Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.

BACKGROUND: Tapentadol is a new, centrally active analgesic agent with two modes of action--mu opioid receptor agonism and norepinephrine reuptake inhibition--and the immediate-release (IR) formulation is approved in the US for the relief of moderate to severe acute pain. The aims of this analysis were to develop a population pharmacokinetic model to facilitate the understanding of the pharmacokinetics of tapentadol IR in healthy subjects and patients following single and multiple dosing, and to identify covariates that might explain variability in exposure following oral administration. METHODS: The analysis included pooled data from 11,385 serum pharmacokinetic samples from 1827 healthy subjects and patients with moderate to severe pain. Population pharmacokinetic modelling was conducted using nonlinear mixed-effects modelling (NONMEM) software to estimate population pharmacokinetic parameters and the influence of the subjects' demographic characteristics, clinical laboratory chemistry values and disease status on these parameters. Simulations were performed to assess the clinical relevance of the covariate effects on tapentadol exposure. RESULTS: A two-compartment model with zero-order release followed by first-order absorption and first-order elimination best described the pharmacokinetics of tapentadol IR following oral administration. The interindividual variability (coefficient of variation) in apparent oral clearance (CL/F) and the apparent central volume of distribution after oral administration were 30% and 29%, respectively. An additive error model was used to describe the residual variability in the log-transformed data, and the standard deviation values were 0.308 and 0.314 for intensively and sparsely sampled data, respectively. Covariate analysis showed that sex, age, bodyweight, race, body fat, hepatic function (using total bilirubin and total protein as surrogate markers), health status and creatinine clearance were statistically significant factors influencing the pharmacokinetics of tapentadol. Total bilirubin was a particularly important factor that influenced CL/F, which decreased by more than 60% in subjects with total bilirubin greater than 50 micromol/L. CONCLUSIONS: The population pharmacokinetic model for tapentadol IR identified the relationship between pharmacokinetic parameters and a wide range of covariates. The simulations of tapentadol exposure with identified, statistically significant covariates demonstrated that only hepatic function (as characterized by total bilirubin and total protein) may be considered a clinically relevant factor that warrants dose adjustment. None of the other covariates are of clinical relevance, nor do they necessitate dose adjustment.

Analysis of combinatorial variability reveals selective accumulation of the fibronectin type III domains B and D of tenascin-C in injured brain.

Tenascin-C (Tnc) is a multimodular extracellular matrix glycoprotein that is markedly upregulated in CNS injuries where it is primarily secreted by reactive astrocytes. Different Tnc isoforms can be generated by the insertion of variable combinations of one to seven (in rats) alternatively spliced distinct fibronectin type III (FnIII) domains to the smallest variant. Each spliced FnIII repeat mediates specific actions on neurite outgrowth, neuron migration or adhesion. Hence, different Tnc isoforms might differentially influence CNS repair. We explored the expression pattern of Tnc variants after cortical lesions and after treatment of astrocytes with various cytokines. Using RT-PCR, we observed a strong upregulation of Tnc transcripts containing the spliced FnIII domains B or D in injured tissue at 2-4 days post-lesion (dpl). Looking at specific combinations, we showed a dramatic increase of Tnc isoforms harboring the neurite outgrowth-promoting BD repeat with both the B and D domains being adjacent to each other. Isoforms containing only the axon growth-stimulating spliced domain D were also dramatically enhanced after injury. Injury-induced increase of Tnc proteins comprising the domain D was confirmed by Western Blotting and immunostaining of cortical lesions. In contrast, the FnIII modules C and AD1 were weakly modulated after injury. The growth cone repulsive A1A2A4 domains were poorly expressed in normal and injured tissue but the smallest isoform, which is also repellant, was highly expressed after injury. Expression of the shortest Tnc isoform and of variants containing B, D or BD, was strongly upregulated in cultured astrocytes after TGFbeta1 treatment, suggesting that TGFbeta1 could mediate, at least in part, the injury-induced upregulation of these isoforms. We identified complex injury-induced differential regulations of Tnc isoforms that may well influence axonal regeneration and repair processes in the damaged CNS.

Population pharmacokinetics of doripenem based on data from phase 1 studies with healthy volunteers and phase 2 and 3 studies with critically ill patients.

A population pharmacokinetic model of doripenem was constructed using data pooled from phase 1, 2, and 3 studies utilizing nonlinear mixed effects modeling. A 2-compartment model with zero-order input and first-order elimination best described the log-transformed concentration-versus-time profile of doripenem. The model was parameterized in terms of total clearance (CL), central volume of distribution (V(c)), peripheral volume of distribution (V(p)), and distribution clearance between the central and peripheral compartments (Q). The final model was described by the following equations (for jth subject): CL(j) (liters/h) = 13.6.(CL(CR)(j)/98 ml/min)(0.659).(1 + CL(race)(j) [0 for Caucasian]); V(c)(j) (liters) = 11.6.(weight(j)/73 kg)(0.596); Q(j) (liters/h) = 4.74.(weight(j)/73)(1.06); and V(p)(j) (liters) = 6.04.(CL(CR)(j)/98 ml/min)(0.417).(weight(j)/73 kg)(0.840).(age(j)/40 years)(0.307). According to the final model, population mean parameter estimates and interindividual variability (percent coefficient of variation [% CV]) for CL (liters/h), V(c) (liters), V(p) (liters), and Q (liters/h) were 13.6 (19%), 11.6 (19%), 6.0 (25%), and 4.7 (42%), respectively. Residual variability, estimated using three separate additive residual error models, was 0.17 standard deviation (SD), 0.55 SD, and 0.92 SD for phase 1, 2, and 3 data, respectively. Creatinine clearance was the most significant predictor of doripenem clearance. Mean Bayesian clearance was approximately 33%, 55%, and 76% lower for individuals with mild, moderate, or severe renal impairment, respectively, than for those with normal renal function. The population pharmacokinetic model based on healthy volunteer data and patient data informs us of doripenem disposition in a more general population as well as of the important measurable intrinsic and extrinsic factors that significantly influence interindividual pharmacokinetic differences.