34745 US and EU sunscreens: A review of ultraviolet (UV) filters and safety data

A broad range of UV filters are available for use in sunscreen products. Knowledge of UV filters available both domestically and abroad remains important, since these products can be found in the online marketplace and may be included in future FDA monographs as a shift is made to an administrative order process. We reviewed the mechanism and safety data of all US and EU approved UV filters. Currently, there are 17 US FDA approved UV filters while the EU possesses an additional 16 UV filters. Of the US filters, 88.2% (15/17) are organic and 11.8% (2/17) are inorganic filters, with 35.3% (6/17) broad-spectrum, 52.9% (9/17) UVB only, and 11.8% (2/17) UVA only. Notably, 94.1% (16/17) have available human data. Of the EU exclusive filters, all (100%, 16/16) are organic filters. 50% (8/16) have human data while the remaining 50% (8/16) have data primarily related to physiochemical or toxicology profiles. Of these EU exclusive UV filters, 43.75% (7/16) are broad-spectrum, 50% (8/16) cover UVB only, and 6.25% (1/16) cover UVA only. Our review demonstrates that the EU possesses an exciting pool of novel UV filters with expanded options for coverage of all forms of UV radiation. Critically, the majority of sunscreens, both in the US and EU, have limited human data available due to prior limited requirements for such information. This information is likely forthcoming in the US as the FDA updates data requirement guidelines for sunscreens to be generally recognized as safe and effective

32131 Updating the relative risk of ultraviolet exposure and melanoma in fair skin types: A systematic review

In 2005, a meta-analysis found that varying types of UV exposure contributed to an increased relative risk of melanoma. Recently, a 2021 review failed to establish a similar link in individuals with skin of color. Within the last 2 decades, no studies have comprehensively reviewed the risk of varying types of UV exposure on melanoma in fair skin. Thus, we performed a systematic review from 2002-2021 analyzing UV exposure and melanoma risk in Fitzpatrick type I-IV individuals. Out of 12,263 studies, 26 met inclusion criteria. A majority showed an association with UV index (6/9), left-sided laterality (1/1), sunburn history (11/13), and outdoor leisure activity (3/3). UV index studies were all ecological and presented primarily positive correlations. For sunburn history, studies encompassed 2309 melanomas, and significant odds ratios (OR) ranged from 1.69 (1.00-2.98) to 8.48 (4.35-16.54) with higher odds ratios for increasing numbers of sunburns. For outdoor leisure correlating with prior definitions of intermittent sun exposure, studies encompassed 514 melanomas, and ORs ranged from 2.70 (1.04-6.80) to 4.18 (1.83-9.93). A positive association was found in 2 (n = 2/6) studies for cumulative or annual sun exposure, 2 (n = 2/5) studies with occupational sun exposure, 2 (n = 2/4) studies with sun vacations, and 0 (n = 0/2) studies with latitude. This study highlights the significant relationships between specific types of UV exposure and melanoma at higher rates than previously summarized due to an emphasis on fair skin types. Critically, there remains high heterogeneity in how UV exposure is captured that may contribute to mixed results

367 Googling acne: Analyzing ingredients and price of over the counter acne products

Introduction: Given the convenience of the over-the-counter (OTC) market, many individuals trial OTC products as a means to combat their acne. Within the OTC acne market, there is great heterogeneity in ingredients and price. Herein, we analyze the distribution of ingredients and price among OTC acne products in top Google searches, which the public may encounter when performing an online search. Methods: Google searches for key terms “acne”, “acne treatment”, “top acne treatment”, and “best acne regimen” were performed. Unique acne products for the first 100 websites for each term were collected. Summary statistics for median, range, mean, and standard deviation for price per topical therapy were analyzed. A factorial ANOVA was performed assessing effect of ingredient on price. Results: A total of 272 unique products were collected out of the 400 websites analyzed. The mean price per ounce of all products was $24.79 (standard deviation of$31.84) and median[range] was $10.40 [ Conclusion: Providers play an important role in educating and helping patients to navigate the OTC market. Based on efficacy and affordability, benzoyl peroxide and adapalene should remain the active ingredient of choice when turning to the OTC market. Given the heterogeneity of the OTC market, patients should carefully evaluate OTC products and be aware that not all products will have ingredients containing a grade A strength of recommendation and know that products with the same topical therapy can vary dramatically in price

Anchor geotechnics for floating offshore wind: Current technologies and future innovations

A rapid expansion of the anchor market is required to meet the increasing demand for floating offshore wind. This paper, which is aimed at a broad readership within and beyond geotechnical engineering, summarises the current state-of-the-art and discusses future developments of anchor types and geotechnical design methods.Current anchor technologies are presented via comparative analytical assessments of performance across a range of practical scales and seabed conditions. This analysis demonstrates the relative merits and performance of different anchor types, using simplified cost-performance indicators for each anchor technology. An example outcome is the large differences in anchor efficiency (capacity per unit weight), that are linked to the different ways anchors achieve their holding capacity.Potential improvements in the performance-cost response for each anchor type, through future enhancements, are then explored. These enhancements are categorised as (1) unlocking higher anchor performance through improved design methods with a better understanding of the geotechnical response, (2) upscaling or (3) commoditising of the anchor type, by making larger versions or enabling more efficient mass production and installation, or (4) invention of new anchor technologies. Finally, findings of the different sections are summarised within a single table to enable a quick selection of anchoring solutions

LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%–26% lower than expected from Hardy–Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism.publishedVersio

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients

Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model-informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P &lt; 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

Somatic mutation landscapes at single-molecule resolution.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts

Breathing adapted radiotherapy: a 4D gating software for lung cancer

<p>Abstract</p> <p>Purpose</p> <p>Physiological respiratory motion of tumors growing in the lung can be corrected with respiratory gating when treated with radiotherapy (RT). The optimal respiratory phase for beam-on may be assessed with a respiratory phase optimizer (RPO), a 4D image processing software developed with this purpose.</p> <p>Methods and Materials</p> <p>Fourteen patients with lung cancer were included in the study. Every patient underwent a 4D-CT providing ten datasets of ten phases of the respiratory cycle (0-100% of the cycle). We defined two morphological parameters for comparison of 4D-CT images in different respiratory phases: tumor-volume to lung-volume ratio and tumor-to-spinal cord distance. The RPO automatized the calculations (200 per patient) of these parameters for each phase of the respiratory cycle allowing to determine the optimal interval for RT.</p> <p>Results</p> <p>Lower lobe lung tumors not attached to the diaphragm presented with the largest motion with breathing. Maximum inspiration was considered the optimal phase for treatment in 4 patients (28.6%). In 7 patients (50%), however, the RPO showed a most favorable volumetric and spatial configuration in phases other than maximum inspiration. In 2 cases (14.4%) the RPO showed no benefit from gating. This tool was not conclusive in only one case.</p> <p>Conclusions</p> <p>The RPO software presented in this study can help to determine the optimal respiratory phase for gated RT based on a few simple morphological parameters. Easy to apply in daily routine, it may be a useful tool for selecting patients who might benefit from breathing adapted RT.</p

Genome-wide Copy Number Profiling on High-density Bacterial Artificial Chromosomes, Single-nucleotide Polymorphisms, and Oligonucleotide Microarrays: A Platform Comparison based on Statistical Power Analysis

Recently, comparative genomic hybridization onto bacterial artificial chromosome (BAC) arrays (array-based comparative genomic hybridization) has proved to be successful for the detection of submicroscopic DNA copy-number variations in health and disease. Technological improvements to achieve a higher resolution have resulted in the generation of additional microarray platforms encompassing larger numbers of shorter DNA targets (oligonucleotides). Here, we present a novel method to estimate the ability of a microarray to detect genomic copy-number variations of different sizes and types (i.e. deletions or duplications). We applied our method, which is based on statistical power analysis, to four widely used high-density genomic microarray platforms. By doing so, we found that the high-density oligonucleotide platforms are superior to the BAC platform for the genome-wide detection of copy-number variations smaller than 1 Mb. The capacity to reliably detect single copy-number variations below 100 kb, however, appeared to be limited for all platforms tested. In addition, our analysis revealed an unexpected platform-dependent difference in sensitivity to detect a single copy-number loss and a single copy-number gain. These analyses provide a first objective insight into the true capacities and limitations of different genomic microarrays to detect and define DNA copy-number variations