An epigenome-wide study of selenium status and DNA methylation in the Strong Heart Study.

BACKGROUND: Selenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults. METHODS: Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels. RESULTS: The mean (standard deviation) urinary Se concentration was 51.8 (25.1) µg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [MAP4K2], cg11270656 [GPIHBP1]) identified in linear regressions. CONCLUSIONS: Urinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints.

A multiplexed high throughput screening assay using flow cytometry identifies glycolytic molecular probes in bloodstream form Trypanosoma brucei.

Kinetoplastid organisms, including Trypanosoma brucei, are a significant health burden in many tropical and semitropical countries. Much of their metabolism is poorly understood. To better study kinetoplastid metabolism, chemical probes that inhibit kinetoplastid enzymes are needed. To discover chemical probes, we have developed a high-throughput flow cytometry screening assay that simultaneously measures multiple glycolysis-relevant metabolites in live T. brucei bloodstream form parasites. We transfected parasites with biosensors that measure glucose, ATP, or glycosomal pH. The glucose and ATP sensors were FRET biosensors, while the pH sensor was a GFP-based biosensor. The pH sensor exhibited a different fluorescent profile from the FRET sensors, allowing us to simultaneously measure pH and either glucose or ATP. Cell viability was measured in tandem with the biosensors using thiazole red. We pooled sensor cell lines, loaded them onto plates containing a compound library, and then analyzed them by flow cytometry. The library was analyzed twice, once with the pooled pH and glucose sensor cell lines and once with the pH and ATP sensor cell lines. Multiplexing sensors provided some internal validation of active compounds and gave potential clues for each compound's target(s). We demonstrated this using the glycolytic inhibitor 2-deoxyglucose and the alternative oxidase inhibitor salicylhydroxamic acid. Individual biosensor-based assays exhibited a Z'-factor value acceptable for high-throughput screening, including when multiplexed. We tested assay performance in a pilot screen of 14,976 compounds from the Life Chemicals Compound Library. We obtained hit rates from 0.2 to 0.4% depending on the biosensor, with many compounds impacting multiple sensors. We rescreened 44 hits, and 28 (64%) showed repeatable activity for one or more sensors. One compound exhibited EC50 values in the low micromolar range against two sensors. We expect this method will enable the discovery of glycolytic chemical probes to improve metabolic studies in kinetoplastid parasites.

Does an improvement in cord-level intraoperative neuromonitoring data lead to a reduced risk for postoperative neurologic deficit in spine deformity surgery?

PURPOSE: To determine if an improvement in cord-level intraoperative neuromonitoring (IONM) data following data loss results in a reduced risk for new postoperative motor deficit in pediatric and adult spinal deformity surgery. METHODS: A consecutive series of 1106 patients underwent spine surgery from 2015 to 2023 by a single surgeon. Cord alerts were defined by Somatosensory-Evoked Potentials (SSEP; warning criteria: 10% increase in latency or > 50% loss in amplitude) and Motor-Evoked Potentials (MEP; warning criteria: 75% loss in amplitude without return to acceptable limits after stimulation up 100 V above baseline level). Timing of IONM loss and recovery, interventions, and baseline/postoperative day 1 (POD1) lower extremity motor scores were analyzed. RESULTS: IONM Cord loss was noted in 4.8% (53/11,06) of patients and 34% (18/53) with cord alerts had a POD1 deficit compared to preoperative motor exam. MEP and SSEP loss attributed to 98.1% (52/53) and 39.6% (21/53) of cord alerts, respectively. Abnormal descending neurogenic-evoked potential (DNEP) was seen in 85.7% (12/14) and detected 91.7% (11/12) with POD1 deficit. Abnormal wake-up test (WUT) was seen in 38.5% (5/13) and detected 100% (5/5) with POD1 deficit. Most cord alerts occurred during a three-column osteotomy (N = 23/53, 43%); decompression (N = 12), compression (N = 7), exposure (N = 4), and rod placement (N = 14). Interventions were performed in all 53 patients with cord loss and included removing rods/less correction (N = 11), increasing mean arterial pressure alone (N = 10), and further decompression with three-column osteotomy (N = 9). After intervention, IONM data improved in 45(84.9%) patients (Full improvement: N = 28; Partial improvement: 17). For those with full and partial IONM improvement, the POD1 deficit was 10.7% (3/28) and 41.2% (7/17), respectively. For those without any IONM improvement (15.1%, 8/53), 100% (8/8) had a POD1 deficit, P < 0.001. CONCLUSION: A full or partial improvement in IONM data loss after intraoperative intervention was significantly associated with a lower risk for POD1 deficit with an absolute risk reduction of 89.3% and 58.8%, respectively. All patients without IONM improvement had a POD1 neurologic deficit.

Use of the kickstand rod improves coronal alignment and maintains correction compared to control at 2 year follow-up.

PURPOSE: To assess and compare coronal alignment correction at 2 year follow-up in adult spinal deformity (ASD) patients treated with and without the kickstand rod (KSR) construct. METHODS: ASD patients who underwent posterior spinal fusion at a single-center with a preoperative coronal vertical axis (CVA) ≥ 3 cm and a minimum of 2 year clinical and radiographic follow-up were identified. Patients were divided into two groups: those treated with a KSR and those who were not. Patients were propensity score-matched (PSM) controlling for preoperative CVA and instrumented levels to limit potential biases that my influence the magnitude of coronal correction. RESULTS: One hundred sixteen patients were identified (KSR = 42, Control = 74). There were no statistically significant differences in patient characteristics (p > 0.05). At baseline, the control group presented with a greater LS curve (29.0 ± 19.6 vs. 21.5 ± 10.8, p = 0.0191) while the KSR group presented with a greater CVA (6.3 ± 3.6 vs. 4.5 ± 1.8, p = 0.0036). After 40 PSM pairs were generated, there were no statistically significant differences in baseline patient and radiographic characteristics. Within the matched cohorts, the KSR group demonstrated greater CVA correction at 1 year (4.7 ± 2.4 cm vs. 2.9 ± 2.2 cm, p = 0.0012) and 2 year follow-up (4.7 ± 2.6 cm vs. 3.1 ± 2.6 cm, p = 0.0020) resulting in less coronal malalignment one (1.5 ± 1.3 cm vs. 2.4 ± 1.6 cm, p = 0.0056) and 2 year follow-up (1.6 ± 1.0 vs. 2.5 ± 1.5 cm, p = 0.0110). No statistically significant differences in PROMs, asymptomatic mechanical complications, reoperations for non-mechanical complications were observed at 2 year follow-up. However, the KSR group experienced a lesser rate of mechanical complications requiring reoperations (7.1% vs. 24.3%. OR = 0.15 [0.03-0.72], p = 0.0174). CONCLUSIONS: Patients treated with a KSR had a greater amount of coronal realignment at the 2 year follow-up time period and reported less mechanical complications requiring reoperation. However, 2 year patient-reported outcomes were similar between the two groups.

Are There Differences in Performance Among Femoral Stem Brands Utilized in Cementless Hemiarthroplasty for Treatment of Geriatric Femoral Neck Fractures?

BACKGROUND: For the vast majority of displaced femoral neck fractures in older patients, cemented femoral fixation is indicated because it is associated with a lower risk of periprosthetic fracture than cementless fixation. Nevertheless, cementless fixation continues to be utilized with high frequency for hip fractures in the United States. It is therefore helpful to understand the performance of individual cementless brands and models. Although prior studies have compared femoral stems by design type or stem geometry, there may still be a difference in revision risk according to femoral stem brand given the potential differences within design groupings with regard to manufacturing, implantation systems, and implant design nuances among vendors. QUESTIONS/PURPOSES: (1) Is there a difference in aseptic revision risk among femoral stem brands in patients ≥ 60 years of age who have displaced femoral neck fractures treated with cementless hemiarthroplasty? (2) Is there a difference in revision for periprosthetic fracture among femoral stem brands in patients ≥ 60 years of age with displaced femoral neck fractures treated with cementless hemiarthroplasty? METHODS: A retrospective, comparative, large-database cohort study was conducted using data from Kaiser Permanente's Hip Fracture Registry. This integrated healthcare system covers more than 12 million members throughout eight regions in the United States; membership has been found to be representative of the general population in the areas served. The Hip Fracture Registry collects details on all patients who undergo hip fracture repair within the organization. These patients are then longitudinally monitored for outcomes after their repair, and all identified outcomes are manually validated through chart review. Patients ages ≥ 60 years who underwent unilateral hemiarthroplasty treatment of a displaced femoral neck fracture from 2009 to 2021 were identified (n = 22,248). Hemiarthroplasties for polytrauma, pathologic or open fractures, or patients who had additional surgeries at other body sites during the same stay, as well as those with prior procedures in the same hip, were excluded (21.4% [4768]). Cemented procedures and those with missing or inconsistent implant information (for example, cement used but cementless implant recorded) were further excluded (47.1% [10,485]). To allow for enough events for evaluation, the study sample was restricted to seven stems for which there were at least 300 hemiarthroplasties performed, including four models from DePuy Synthes (Corail®, Summit®, Summit Basic, and Tri-Lock®) and three from Zimmer Biomet (Medial-Lateral [M/L] Taper®, Trabecular Metal®, and Versys® Low Demand Fracture [LD/FX]). The final sample included 5676 cementless hemiarthroplasties: 653 Corail, 402 M/L Taper, 1699 Summit, 1590 Summit Basic, 384 Tri-Lock, 637 Trabecular Metal, and 311 Versys LD/FX. Procedures were performed by 396 surgeons at 35 hospitals. The mean age and BMI for the cohort was 81 years and 24 kg/m2, respectively; most were women (66% [3733 of 5676]) and White (79% [4488 of 5676]). Based on standardized mean differences, we controlled for age, race/ethnicity, American Society of Anesthesiologist (ASA) classification, anesthesia technique, operative year, average annual surgeon hemiarthroplasty volume, and operative year across the seven stem groups. Of the 5676 patients, 7% (378 of 5676) were lost to follow-up through membership termination at a median time of 1.6 years, and 56% (3194 of 5676) of the patients died during study follow-up. A multivariable cause-specific Cox proportional hazards regression model was used to evaluate the risk for aseptic revision with adjustment for age, gender, ASA classification, depression, operating surgeon, deficiency anemias, time from admission to surgery, and average annual surgeon hemiarthroplasty volume. A random intercept was included to address effects from hemiarthroplasties performed by the same surgeon. Risk for revision for periprosthetic fracture was also evaluated as a secondary outcome. RESULTS: In the adjusted analysis, the Summit Basic (HR 1.91 [95% confidence interval 1.34 to 2.72]; p < 0.001), the M/L Taper (HR 1.91 [95% CI 1.15 to 3.15]; p = 0.01), and the Versys LD/FX (HR 2.12 [95% CI 1.25 to 3.61]; p = 0.005) had higher aseptic revision risks during follow-up when compared with the Summit. No differences were observed for the Corail (HR 0.57 [95% CI 0.29 to 1.10]; p = 0.09), the Tri-Lock (HR 1.13 [95% CI 0.62 to 2.07]; p = 0.68), or the Trabecular Metal (HR 1.14 [95% CI 0.69 to 1.89]; p = 0.61) compared with the Summit. A higher risk for revision because of periprosthetic fracture was observed with the M/L Taper (HR 2.43 [95% CI 1.29 to 4.58]; p = 0.006) and the Summit Basic (within 3 months of follow-up: HR 1.16 [95% CI 0.60 to 2.25]; p = 0.66; after 3 months of follow-up: HR 2.84 [95% CI 1.36 to 5.94]; p = 0.006) stems when compared with the Summit. CONCLUSION: In a cohort of 5676 cementless hemiarthroplasties, we found differences in revision risks among different femoral stem brands. Based on our findings, we recommend against utilization of the Zimmer M/L Taper, DePuy Summit Basic, and Zimmer Versys LD/FX in the treatment of displaced geriatric femoral neck fractures with cementless hemiarthroplasty. Future large registry studies are needed to further elucidate differences in aseptic revision risk among higher performing cementless femoral stems. Although cemented fixation remains the recommended approach based on the best available evidence in hemiarthroplasty treatment of hip fractures, our findings may help to mitigate aseptic revision risk should cementless fixation be chosen. LEVEL OF EVIDENCE: Level III, therapeutic study.

Systematic Literature Reviews Comparing the Long-Term Safety Outcomes for the Port Delivery System with Ranibizumab (PDS) Versus Other Ocular Implants.

OBJECTIVES: To determine whether the types and rates of post-surgical complications associated with the Port Delivery System with ranibizumab (PDS) are comparable with those reported for other ocular implants that cross the sclera. METHODS: Systematic literature reviews were conducted to determine the long-term (≥ 18-month) safety of ocular implants that cross the sclera in clinical trials and real-world studies. Complication types and rates were compared with those reported for the PDS in phase III clinical trials (Archway, Pagoda, and Pavilion). RESULTS: Sixteen clinical trials (24 publications) and 43 real-world studies were identified reporting 30 complications in eyes with 15 implant types and 8 ocular diseases. Implants were associated with an acceptable, well-characterized safety profile, with most complications resolving spontaneously or with treatment. Device-related complications were reported in 0.7% (0.0-5.0%) of study eyes in clinical trials and 1.3% (0.0-14.5%) of eyes in real-world studies. Rates of conjunctival complications were 2.1% (0.0-22.8%) and 2.2% (0.9-4.6%), respectively. The overall types and rates of adverse events of special interest reported for the PDS in phase III trials (cataract, conjunctival bleb, vitreous hemorrhage, conjunctival erosion, conjunctival retraction, endophthalmitis, implant dislocation, retinal detachment, and hyphema) were within the ranges reported for other ocular implants. CONCLUSIONS: The rates of complications reported in phase III clinical trials for the PDS were within the ranges reported for other ocular implants that cross the sclera. This suggests that the long-term safety of the PDS is consistent with other ocular devices established in ophthalmology clinical practice. TRIAL REGISTRATION: PROSPERO international prospective register of systematic reviews: CRD5202234129, CRD42022343129.

Association of Urinary Metals With Cardiovascular Disease Incidence and All-Cause Mortality in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Exposure to metals has been associated with cardiovascular disease (CVD) end points and mortality, yet prospective evidence is limited beyond arsenic, cadmium, and lead. In this study, we assessed the prospective association of urinary metals with incident CVD and all-cause mortality in a racially diverse population of US adults from MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: We included 6599 participants (mean [SD] age, 62.1 [10.2] years; 53% female) with urinary metals available at baseline (2000 to 2001) and followed through December 2019. We used Cox proportional hazards models to estimate the adjusted hazard ratio and 95% CI of CVD and all-cause mortality by baseline urinary levels of cadmium, tungsten, and uranium (nonessential metals), and cobalt, copper, and zinc (essential metals). The joint association of the 6 metals as mixture and the corresponding 10-year survival probability was calculated using Cox Elastic-Net. RESULTS: During follow-up, 1162 participants developed CVD, and 1844 participants died. In models adjusted by behavioral and clinical indicators, the HR (95% CI) for incident CVD and all-cause mortality comparing the highest with the lowest quartile were, respectively: 1.25 (1.03, 1.53) and 1.68 (1.43, 1.96) for cadmium; 1.20 (1.01, 1.42) and 1.16 (1.01, 1.33) for tungsten; 1.32 (1.08, 1.62) and 1.32 (1.12, 1.56) for uranium; 1.24 (1.03, 1.48) and 1.37 (1.19, 1.58) for cobalt; 1.42 (1.18, 1.70) and 1.50 (1.29, 1.74) for copper; and 1.21 (1.01, 1.45) and 1.38 (1.20, 1.59) for zinc. A positive linear dose-response was identified for cadmium and copper with both end points. The adjusted HRs (95% CI) for an interquartile range (IQR) increase in the mixture of these 6 urinary metals and the corresponding 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56) and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91) and -2.0% (-2.6, -1.5) for all-cause mortality. CONCLUSIONS: This epidemiological study in US adults indicates that urinary metal levels are associated with increased CVD risk and mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health.

Barriers and Facilitators to Accessing PrEP and Other Sexual Health Services Among Immigrant Latino Men Who Have Sex with Men in Los Angeles County.

In the United States, immigrant Latino men who have sex with men (ILMSM) are, compared to white MSM, disproportionately burdened by HIV and lack access to highly effective HIV prevention strategies, such as pre-exposure prophylaxis (PrEP). Qualitative research centered on exploring barriers that ILMSM experience in accessing PrEP and other sexual services is extremely limited, despite a high prevalence of HIV in this population. In this study, a purposive sample of ILMSM (n = 25) was recruited to participate in a semi-structured in-depth interview to identify the distinct barriers and facilitators ILMSM experience in accessing sexual health services given their complex intersectional identities of being an immigrant, Latino, and a sexual minority man. Using a thematic analysis approach, nine themes were generated from the data representing barriers and facilitators. Barriers included: (1) cost and a lack of health insurance, (2) complexity of PrEP assistance programs; (3) challenges related to the immigrant experience; (4) impact of gay stigma; and (5) communication challenges. Facilitators included: (1) improving affordability and accessibility of PrEP services; (2) receiving services from LGBT- or Latine LGBT-centered clinics; (3) receiving services from medical providers who are gay and/or Latino; and (4) providing targeted community outreach, education, and promotion of PrEP to ILMSM. While many of the barriers illuminated in the study were structural (e.g., cost and lack of health insurance), and not easy to overcome, the findings highlight a range of facilitators that can support access to PrEP and other sexual health services for ILMSM. Considering these findings, we suggest strategies that may enhance access to needed sexual health services among ILMSM.

Not all maggots are created equal; not all maggots are therapeutic.

Maggots in a wound ("myiasis") cannot be considered maggot therapy (therapeutic myiasis) unless, at a minimum, the species is known to be safe and effective, and the maggots have been properly disinfected. Documenting treatment details is critical and allows us to determine the cause of problems, if they arise.

Safety Assessment of Alkanoyl Lactyl Lactate Salts as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 10 alkanoyl lactyl lactate salts. These ingredients have the surfactant function in cosmetics in common. The Panel reviewed data relevant to the safety of these ingredients, and concluded that these 10 ingredients are safe in cosmetics in the present practices of use and concentration described in the safety assessment when formulated to be nonirritating and nonsensitizing, which may be based on a quantitative risk assessment (QRA) or other accepted methodologies.

RBM10 loss induces aberrant splicing of cytoskeletal and extracellular matrix mRNAs and promotes metastatic fitness.

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse Hras G12V /Rbm1O KO thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.

Real-World Acute Toxicity and 90-Day Mortality in Patients With Stage I NSCLC Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) has firmly established its role in stage I NSCLC. Clinical trial results may not fully apply to real-world scenarios. This study aimed to uncover the real-world incidence of acute toxicity and 90-day mortality in patients with SBRT-treated stage I NSCLC and develop prediction models for these outcomes. METHODS: Prospective data from the Dutch Lung Cancer Audit for Radiotherapy (DLCA-R) were collected nationally. Patients with stage I NSCLC (cT1-2aN0M0) treated with SBRT in 2017 to 2021 were included. Acute toxicity was assessed, defined as grade greater than or equal to 2 radiation pneumonitis or grade greater than or equal to 3 non-hematologic toxicity less than or equal to 90 days after SBRT. Prediction models for acute toxicity and 90-day mortality were developed and internally validated. RESULTS: Among 7279 patients, the mean age was 72.5 years, with 21.6% being above 80 years. Most were male (50.7%), had WHO scores 0 to 1 (73.3%), and had cT1a-b tumors (64.6%), predominantly in the upper lobes (65.2%). Acute toxicity was observed in 280 (3.8%) of patients and 90-day mortality in 122 (1.7%). Predictors for acute toxicity included WHO greater than or equal to 2, lower forced expiratory volume in 1 second and diffusion capacity for carbon monoxide, no pathology confirmation, middle or lower lobe tumor location, cT1c-cT2a stage, and higher mean lung dose (c-statistic 0.68). Male sex, WHO greater than or equal to 2, and acute toxicity predicted higher 90-day mortality (c-statistic 0.73). CONCLUSIONS: This nationwide study revealed a low rate of acute toxicity and an acceptable 90-day mortality rate in patients with SBRT-treated stage I NSCLC. Notably, advanced age did not increase acute toxicity or mortality risk. Our predictive models, with satisfactory performance, offer valuable tools for identifying high-risk patients.

Safety Assessment of Vinylpyrrolidone Polymers as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 30 vinylpyrrolidone polymers as used in cosmetic products; most of these ingredients have the reported cosmetic function of film former in common. The Panel reviewed data relevant to the safety of these ingredients, and determined that 27 vinylpyrrolidone polymers are safe in cosmetics in the present practices of use and concentration described in the safety assessment. The Panel also concluded that the available data are insufficient to make a determination that 3 vinylpyrrolidone polymers (all urethanes) are safe under the intended conditions of use in cosmetic formulations.

Safety Assessment of Polyol Phosphates as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 10 polyol phosphates. Some of the possible functions in cosmetics that are reported for this ingredient group are chelating agents, oral care agents, and skin conditioning agents. The Panel reviewed relevant data relating to the safety of these ingredients under the intended conditions of use in cosmetic formulations, and concluded that Sodium Phytate, Phytic Acid, Phytin, and Trisodium Inositol Triphosphate are safe in cosmetics in the present practices of use and concentration described in the safety assessment. The Panel also concluded that the data are insufficient to determine the safety of the following 6 ingredients as used in cosmetics: Disodium Glucose Phosphate, Manganese Fructose Diphosphate, Sodium Mannose Phosphate, Trisodium Fructose Diphosphate, Xylityl Phosphate, and Zinc Fructose Diphosphate.

Safety Assessment of Methylxanthines as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of three methylxanthines, Caffeine, Theobromine, and Theophylline, as used in cosmetics. All of these ingredients are reported to function as skin-conditioning agents in cosmetic products. The Panel reviewed the data relevant to the safety of these ingredients and concluded that Caffeine, Theobromine, and Theophylline are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

An International Registry Study of Early-Stage NSCLC treatment variations (LUCAEUROPE) in Europe and the USA highlighting variations.

OBJECTIVE: Harmonized European NSCLC incidence, treatment approach, and survival based on national tumor registries are unclear. SUMMARY BACKGROUND DATA: Surgery has the potential to cure NSCLC and significantly prolong survival. This large-scale international study aimed to investigate treatment variations in Europe and the USA, as well as the determinants for its utilization. METHODS: The retrospective cohort study analyzed data from six European national population-based cancer registries (Belgium, Denmark, Estonia, Germany, the Netherlands, and Slovenia) and the US SEER database from 2010-2015. RESULTS: The study computed cancer incidence, survival, and age-standardized proportions of the use of various therapies. Multivariable logistic regression models were used to assess associations between resection and demographic and clinical parameters. A total of 428,107 records were analyzed. Among all countries, Estonia had the highest surgical resection rate (79.3 %) and the lowest radiation rate (7.3 %) for stage I patients. The Netherlands had the highest rate of radiotherapy across all years of investigation and the lowest surgery rate between 2012 and 2015. The primary treatment for early-stage NSCLC showed significant international variation, with the USA having a decrease in surgical rates from 67.6 % to 59.5 %. Resection was less frequently performed as tumor stage increased, patients aged, other lung cancer besides adenocarcinoma was present, and when the tumor site overlapped multiple lobes. CONCLUSIONS: Resection rates have declined in some studied European countries and the USA and resection rates vary substantially among countries. Interpretation of current scientific lung cancer evidence and international guidelines results in wide variations in patient treatment.

Genomic SNPs resolve the phylogeny of an ancient amphibian island radiation from the Seychelles.

Unusually for oceanic islands, the granitic Seychelles host multiple lineages of endemic amphibians. This includes an ancient (likely ca. 60 million years) radiation of eight caecilian species, most of which occur on multiple islands.These caecilians have a complicated taxonomic history and their phylogenetic inter-species relationships have been difficult to resolve. Double-digest RAD sequencing (ddRADseq) has been applied extensively to phylogeography and increasingly to phylogenetics but its utility for resolving ancient divergences is less well established. To address this, we applied ddRADseq to generate a genome-wide SNP panel for phylogenomic analyses of the Seychelles caecilians, whose phylogeny has so far not been satisfactorily resolved with traditional DNA markers. Based on 129,154 SNPs, we resolved deep and shallow splits, with strong support. Our findings demonstrate the capability of genome-wide SNPs for evolutionary inference at multiple taxonomic levels and support the recently proposed synonymy of Grandisonia Taylor, 1968 with Hypogeophis Peters, 1879. We revealed three clades of Hypogeophis (large-, medium- and short-bodied) and identify a single origin of the diminutive, stocky-bodied and pointy-snouted phenotype.

Safety Assessment of Triphenyl Phosphate as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Triphenyl Phosphate, which is reported to function as a plasticizer in manicuring products. The Panel reviewed the available data to determine the safety of this ingredient. The Panel concluded that Triphenyl Phosphate is safe in cosmetics in the present practices of use and concentration described in this safety assessment.

The venom and telopodal defence systems of the centipede Lithobius forficatus are functionally convergent serial homologues.

BACKGROUND: Evolution of novelty is a central theme in evolutionary biology, yet studying the origins of traits with an apparently discontinuous origin remains a major challenge. Venom systems are a well-suited model for the study of this phenomenon because they capture several aspects of novelty across multiple levels of biological complexity. However, while there is some knowledge on the evolution of individual toxins, not much is known about the evolution of venom systems as a whole. One way of shedding light on the evolution of new traits is to investigate less specialised serial homologues, i.e. repeated traits in an organism that share a developmental origin. This approach can be particularly informative in animals with repetitive body segments, such as centipedes. RESULTS: Here, we investigate morphological and biochemical aspects of the defensive telopodal glandular organs borne on the posterior legs of venomous stone centipedes (Lithobiomorpha), using a multimethod approach, including behavioural observations, comparative morphology, proteomics, comparative transcriptomics and molecular phylogenetics. We show that the anterior venom system and posterior telopodal defence system are functionally convergent serial homologues, where one (telopodal defence) represents a model for the putative early evolutionary state of the other (venom). Venom glands and telopodal glandular organs appear to have evolved from the same type of epidermal gland (four-cell recto-canal type) and while the telopodal defensive secretion shares a great degree of compositional overlap with centipede venoms in general, these similarities arose predominantly through convergent recruitment of distantly related toxin-like components. Both systems are composed of elements predisposed to functional innovation across levels of biological complexity that range from proteins to glands, demonstrating clear parallels between molecular and morphological traits in the properties that facilitate the evolution of novelty. CONCLUSIONS: The evolution of the lithobiomorph telopodal defence system provides indirect empirical support for the plausibility of the hypothesised evolutionary origin of the centipede venom system, which occurred through functional innovation and gradual specialisation of existing epidermal glands. Our results thus exemplify how continuous transformation and functional innovation can drive the apparent discontinuous emergence of novelties on higher levels of biological complexity.