The repeatability of tests for dry eye signs and symptoms in the dry eye assessment and management (DREAM) study.

PURPOSE: To assess the repeatability of measures for dry eye disease (DED) symptoms and signs in the DREAM study. METHODS: At screening and baseline visits approximately 2 weeks apart, participants were assessed for symptoms by Ocular Surface Disease Index (OSDI) and Brief Ocular Discomfort Index (BODI), and signs by the same physician in the same order: tear break-up time (TBUT), corneal staining, conjunctival staining, Meibomian gland evaluation, and the Schirmer test. The repeatability of DED symptoms and signs was assessed by interclass correlation coefficient (ICC), 95 % limits of agreement, and the percent of eyes with inter-visit difference above the clinically significant threshold. RESULTS: Among 1046 eyes (523 participants), ICC for signs ranged from 0.53 (TBUT) to 0.73 (corneal staining). A substantial percentage of eyes showed clinically significant inter-visit differences: ≥2 points in 17.8 % of eyes for conjunctival staining; ≥3 points in 18.8 % for corneal staining; >2 s in 14.1 % for TBUT; ≥5 mm/5 min in 29.9 % for the Schirmer test, and ≥ 2 points in 27.5 % for Meibomian gland plugging and lid secretion. The OSDI and BODI had ICC of 0.64 and 0.63 respectively, and nearly 40 % of participants had inter-visit score differences ≥ 10 points. CONCLUSION: In DREAM participants with moderate-to-severe DED, DED signs and symptoms had moderate repeatability, with ocular surface staining scores being the most repeatable and TBUT the least repeatable. A notable percentage of participants had inter-visit differences above the clinically meaningful threshold. These test-retest variabilities in DED signs and symptoms should be considered for designing clinical trials and monitoring disease progression.

Quality of Life in Patients with Malignant Wounds Treated at a Wound Care Clinic.

Background: Malignant wounds can present in up to 14.5% of patients with advanced cancer, significantly reducing quality of life (QoL). Management of malignant wounds is generally palliative, with the goal of improving or maintaining QoL. There is a lack of data on the impact of wound care clinics on QoL in patients with malignant wounds. Objectives: We sought to assess the QoL in patients with malignant wounds attending a wound care clinic. We also aimed to describe the baseline QoL, trends in QoL, physical symptoms, and treatment modalities that affect QoL in patients with malignant wounds over time. Methods: This retrospective observational study included 36 patients attending a wound care clinic at an oncologic hospital from 1/1/2016-4/1/2023. As part of the standard of care, these patients complete a Skindex-16 QoL survey at each visit. The Skindex-16 is a validated instrument to measure the effects of skin diseases on QoL. Data were extracted from the electronic medical record. Descriptive statistics, graphical methods, and random effects models for change were used to describe the patient population and the QoL measures over time. Results: Of the 36 patients who completed at least one Skindex-16 questionnaire, 69.4% were female, and 50.0% developed malignant wounds from breast cancer, 30.5% from nonmelanoma skin cancer, and 8.3% from sarcoma. At the initial visit, 86.1% of patients had exudate associated with their malignant wound, 52.7% of patients had malodor, 63.9% had bleeding, 69.4% had pain, and 50% had pruritus. The mean baseline Skindex-16 score was 54.5, falling into the "extremely severe" category, with a mean score of 15.4, 18.8, and 20.3 for the symptoms, emotions, and functioning domains, respectively. Nineteen patients completed at least one additional Skindex-16 questionnaire at follow-up visits (visit two 52.8%, visit three 33.3%, visit four 19.4%, visit five or greater 13.9%). Compared to the mean Skindex-16 score at baseline, there was an 18.5 point improvement at visit 2 (95% CI: 3.3-33.7, p = 0.018). Conclusion: Malignant wounds severely adversely affect patients' quality of life. However, patients experienced improved quality of life after being treated at a dedicated wound clinic.

Diabetes and Early Development: Epigenetics, Biological Stress, and Aging.

Pregestational diabetes, either type 1 or type 2 diabetes, induces structural birth defects including neural tube defects and congenital heart defects in human fetuses. Rodent models of type 1 and type 2 diabetic embryopathy have been established and faithfully mimic human conditions. Hyperglycemia of maternal diabetes triggers oxidative stress in the developing neuroepithelium and the embryonic heart leading to the activation of proapoptotic kinases and excessive cell death. Oxidative stress also activates the unfolded protein response and endoplasmic reticulum stress. Hyperglycemia alters epigenetic landscapes by suppressing histone deacetylation, perturbing microRNA (miRNA) expression, and increasing DNA methylation. At cellular levels, besides the induction of cell apoptosis, hyperglycemia suppresses cell proliferation and induces premature senescence. Stress signaling elicited by maternal diabetes disrupts cellular organelle homeostasis leading to mitochondrial dysfunction, mitochondrial dynamic alteration, and autophagy impairment. Blocking oxidative stress, kinase activation, and cellular senescence ameliorates diabetic embryopathy. Deleting the mir200c gene or restoring mir322 expression abolishes maternal diabetes hyperglycemia-induced senescence and cellular stress, respectively. Both the autophagy activator trehalose and the senomorphic rapamycin can alleviate diabetic embryopathy. Thus, targeting cellular stress, miRNAs, senescence, or restoring autophagy or mitochondrial fusion is a promising approach to prevent poorly controlled maternal diabetes-induced structural birth defects. In this review, we summarize the causal events in diabetic embryopathy and propose preventions for this pathological condition. KEY POINTS: · Maternal diabetes induces structural birth defects.. · Kinase signaling and cellular organelle stress are critically involved in neural tube defects.. · Maternal diabetes increases DNA methylation and suppresses developmental gene expression.. · Cellular apoptosis and senescence are induced by maternal diabetes in the neuroepithelium.. · microRNAs disrupt mitochondrial fusion leading to congenital heart diseases in diabetic pregnancy..

The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Review of laser and energy-based devices to treat rosacea in skin of color.

The prevalence of rosacea in skin of color (SOC) populations is estimated to be as high as 10% in some countries. Traditionally, intense pulsed light (IPL) and pulsed dye laser (PDL) have been the laser and energy-based devices (EBDs) used to treat rosacea. However, not all laser and EBDs are safe for SOC (Fitzpatrick skin types IV-VI) due to increased absorption of energy in pigmented skin and increased risk of post-inflammatory hyperpigmentation and scarring. This review summarizes the use of the top seven laser and EBDs for treating rosacea in SOC.

Retrospective analysis of Braak stage- and APOE4 allele-dependent associations between MR spectroscopy and markers of tau and neurodegeneration in cognitively unimpaired elderly.

PURPOSE: The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS: We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS: There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS: Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

Budget impact analysis of including biosimilar adalimumab on formulary: A United States payer perspective.

BACKGROUND: The biosimilar market is growing rapidly, as evidenced by 41 approvals and 37 launches to date. As adalimumab biosimilars launch in the United States, competition among biosimilar and reference adalimumab will likely increase across multiple reference indications, including rheumatology, dermatology, and gastrointestinal diseases, which may lead to decreased payer costs. OBJECTIVE: To evaluate the costs of adding biosimilar adalimumab to a US commercial plan by exploring various utilization and price differential scenarios. METHODS: A 3-year budget impact model for a US commercial plan of 1 million people was developed to assess switching from reference adalimumab or any self-injectable reference tumor necrosis factor (TNF) inhibitor to biosimilar adalimumab. Pharmacy and medical costs were analyzed through high- and low-conversion scenarios from reference adalimumab and the TNF inhibitor class. Price reductions of 5% to 60% relative to reference adalimumab based on previous biosimilar launches were also explored. Short-term medical costs were evaluated as additional simple and complex office visits, with scenarios of half of switch patients having 1 visit up to all switch patients having 10 visits. RESULTS: In a target population of 1,863 patients, switching from reference adalimumab to biosimilar adalimumab had cumulative cost savings of $5,756,073 with slow conversion (10%-20% over 3 years) and $28,780,365 with fast conversion (50%-100% over 3 years). Similar results were seen when switching from any other self-injectable reference TNF inhibitor. Cost savings more than $1 million were seen with a 10% conversion from reference adalimumab and a 15% price reduction from reference adalimumab. Additional office visit scenarios had a negligible impact on budget, with no changes in per-member-per-month costs until all switch patients had 10 additional complex visits, in which per-member-per-month costs increased by $0.02. CONCLUSIONS: In a hypothetical plan of 1 million lives, use of biosimilar adalimumab in commercial plans can lead to significant cost savings for payers because of increased competition. Greater and faster biosimilar conversion rates from reference adalimumab and other reference TNF inhibitors resulted in decreased costs. Additionally, even with short-term medical expenditures, cost savings were still realized when switching to biosimilar adalimumab.

Budget impact analysis of biosimilar natalizumab in the US.

OBJECTIVES: Biosimilars provide an opportunity for a more sustainable and cost-effective treatment for multiple sclerosis (MS). This study evaluated the potential financial impact of implementing a formulary change from reference to biosimilar natalizumab (NTZ) from the US commercial payer perspective. STUDY DESIGN: The budget impact of transitioning to biosimilar NTZ for the treatment of relapsing-remitting MS (RRMS) was estimated over a 3-year time horizon based on real-world dosing. Additional scenario analyses were conducted by varying the price differential of biosimilar NTZ. METHODS: The target population was estimated from a 1-million-member hypothetical commercial health plan. Model inputs were drug acquisition costs and treatment-related and patient coinsurance costs. Budget impact and cost savings per member per year were calculated by assuming a biosimilar uptake of 10% in year 1 to 20% in year 3. RESULTS: Over 3 years, 255 patients were estimated to be treated with high-efficacy disease-modifying therapies for RRMS. The inclusion of biosimilar NTZ onto a formulary would result in cumulative cost savings to payers of $452,611 over 3 years, with mean savings per treated member per year of $1179, $1769, and $2359 in years 1, 2, and 3, respectively. One-way sensitivity analyses indicated that budget impact results were most sensitive to drug acquisition costs of both reference and biosimilar NTZ. CONCLUSION: Adoption of biosimilar NTZ can yield considerable cost savings to US health plans that could result in increased treatment access for patients with RRMS.

Longitudinal changes in sodium concentration and in clinical outcome in mild traumatic brain injury.

Ionic imbalances and sodium channel dysfunction, well-known sequelae of traumatic brain injury (TBI), promote functional impairment in affected subjects. Therefore, non-invasive measurement of sodium concentrations using 23Na MRI has the potential to detect clinically relevant injury and predict persistent symptoms. Recently, we reported diffusely lower apparent total sodium concentrations (aTSC) in mild TBI patients compared to controls, as well as correlations between lower aTSC and worse clinical outcomes. The main goal of this study was to determine whether these aTSC findings, and their changes over time, predict outcomes at 3- and 12-month from injury. Twenty-seven patients previously studied with 23Na MRI and outcome measures at 22 ± 10 days (average ± standard deviation) after injury (visit-1, v1) were contacted at 3- (visit-2, v2) and 12-month after injury (visit-3, v3) to complete the Rivermead post-concussion symptoms questionnaire (RPQ), the extended Glasgow outcome scale (GOSE), and the brief test of adult cognition by telephone (BTACT). Follow-up 1H and 23Na MRI were additionally scheduled at v2. Linear regression was used to calculate aTSC in global grey and white matters. Six hypotheses were tested in relation to the serial changes in outcome measures and in aTSC, and in relation to the cross-sectional and serial relationships between aTSC and outcome. Twenty patients contributed data at v2 and fifteen at v3. Total RPQ and composite BTACT z-scores differed significantly for v2 and v3 in comparison to v1 (each P < 0.01), reflecting longitudinally reduced symptomatology and improved performance on cognitive testing. No associations between aTSC and outcome were observed at v2. Previously lower grey and white matter aTSC normalized at v2 in comparison to controls, in line with a statistically detectable longitudinal increase in grey matter aTSC between v1 and v2 (P = 0.0004). aTSC values at v1 predicted a subset of future BTACT subtest scores, but not future RPQ scores nor GOSE-defined recovery status. Similarly, aTSC rates of change correlated with BTACT rates of change, but not with those of RPQ. Tissue aTSC, previously shown to be diffusely decreased compared to controls at v1, was no longer reduced by v2, suggesting normalization of the sodium ionic equilibrium. These changes were accompanied by marked improvement in outcome. The results support the notion that early aTSC from 23Na MRI predicts future BTACT, but not RPQ scores, nor future GOSE status.

T2-FLAIR Mismatch Sign Predicts DNA Methylation Subclass and CDKN2A/B Status in IDH-Mutant Astrocytomas.

PURPOSE: DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low- and high-grade groups. We investigated the utility of the T2-fluid-attenuated inversion recovery (T2-FLAIR) mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization classification. EXPERIMENTAL DESIGN: Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n = 71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed. RESULTS: The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (P < 0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (P = 0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for progression-free survival (P = 0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, copy number variation, and methylation grade, showed trends toward significance for DNA methylation grade with overall survival (P = 0.045) and CDKN2A/B status with progression-free survival (P = 0.052). CONCLUSIONS: The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.

Facultative symbiont virulence determines horizontal transmission rate without host specificity in Dictyostelium discoideum social amoebas.

In facultative symbioses, only a fraction of hosts are associated with symbionts. Specific host and symbiont pairings may be the result of host-symbiont coevolution driven by reciprocal selection or priority effects pertaining to which potential symbiont is associated with a host first. Distinguishing between these possibilities is important for understanding the evolutionary forces that affect facultative symbioses. We used the social amoeba, Dictyostelium discoideum, and its symbiont, Paraburkholderia bonniea, to determine whether ongoing coevolution affects which host-symbiont strain pairs naturally cooccur within a facultative symbiosis. Relative to other Paraburkholderia, including another symbiont of D. discoideum, P. bonniea features a reduced genome size that indicates a significant history of coevolution with its host. We hypothesized that ongoing host-symbiont coevolution would lead to higher fitness for naturally cooccurring (native) host and symbiont pairings compared to novel pairings. We show for the first time that P. bonniea symbionts can horizontally transmit to new amoeba hosts when hosts aggregate together during the social stage of their life cycle. Here we find evidence for a virulence-transmission trade-off without host specificity. Although symbiont strains were significantly variable in virulence and horizontal transmission rate, hosts and symbionts responded similarly to associations in native and novel pairings. We go on to identify candidate virulence factors in the genomes of P. bonniea strains that may contribute to variation in virulence. We conclude that ongoing coevolution is unlikely for D. discoideum and P. bonniea. The system instead appears to represent a stable facultative symbiosis in which naturally cooccurring P. bonniea host and symbiont pairings are the result of priority effects.

Capturing anatomy in computed tomography scans for genital pathology.

PURPOSE: In this cross-sectional study, we aimed to characterize how frequently the anatomy of interest (AOI) was excluded when evaluating genital pathology using the current CT pelvis protocol recommended by the American College of Radiology and evaluate how AOI exclusion affects patient management. METHODS: We retrospectively reviewed medical records, using diagnosis and CPT codes, of patients admitted with genital pathology who obtained a CT scan at our institution from July 1, 2020-April 30, 2023. Baseline patient demographics were included. Data about each index CT scan (scan obtained at our institution) were recorded and assessed for exclusion of the AOI. Statistical analysis was performed to determine the rate of AOI exclusion and to compare patient management between patients with AOI excluded versus those without AOI exclusion. RESULTS: 113 presentations for genital pathology included an index CT scan and were included for analysis. Patients were primarily men (98%) with a mean age of 53.1 years (SD 13.9). The most common diagnoses were Fournier's gangrene (35%), scrotal abscess (22%) and unspecified infection (19%). 26/113 scans (23%) did not capture the entire AOI. When the AOI was missed during the index scan, there was a higher rate of obtaining additional scans (38% vs. 21%), but a similar rate of intervention (77% vs. 63%) when compared to index scans that captured the entire AOI. 35 scans (31%) had protocol-extending instructions; index scans that captured the entire AOI were more likely to have specific protocol-extending instructions (38% vs. 8% p < 0.01). CONCLUSIONS: Creating a specific CT protocol for genital pathology could decrease the amount of inappropriate irradiation and improve AOI capture rates without relying on specific request for protocol deviation.

Novel application of imidazole-based ligand-templated borates in a zinc-air battery.

Two templated borates, [Co(1-EI)2]·[B5O7(OH)3] (1) and [Ga(1-MI)2·B6O9(OH)4]·[H3BO3]·H[1-MI] (2), have been synthesized using a mild method. Notably, they exhibit an excellent ORR performance with an E1/2 value of 0.84 V and are the first to be used as the positive electrode catalyst for a zinc-air battery, which opens a pathway for the application of borate-based oxide catalysts.

Bridging the gap between academic research and industrial development in advanced all-solid-state lithium-sulfur batteries.

The energy storage and vehicle industries are heavily investing in advancing all-solid-state batteries to overcome critical limitations in existing liquid electrolyte-based lithium-ion batteries, specifically focusing on mitigating fire hazards and improving energy density. All-solid-state lithium-sulfur batteries (ASSLSBs), featuring earth-abundant sulfur cathodes, high-capacity metallic lithium anodes, and non-flammable solid electrolytes, hold significant promise. Despite these appealing advantages, persistent challenges like sluggish sulfur redox kinetics, lithium metal failure, solid electrolyte degradation, and manufacturing complexities hinder their practical use. To facilitate the transition of these technologies to an industrial scale, bridging the gap between fundamental scientific research and applied R&D activities is crucial. Our review will address the inherent challenges in cell chemistries within ASSLSBs, explore advanced characterization techniques, and delve into innovative cell structure designs. Furthermore, we will provide an overview of the recent trends in R&D and investment activities from both academia and industry. Building on the fundamental understandings and significant progress that has been made thus far, our objective is to motivate the battery community to advance ASSLSBs in a practical direction and propel the industrialized process.

Statins Do Not Significantly Affect Oxidative Nitrosative Stress Biomarkers in the PREVENT Randomized Clinical Trial.

PURPOSE: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT. PATIENTS AND METHODS: Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine-nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF. RESULTS: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05). CONCLUSIONS: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.

Argyrodite-Li6PS5Cl/Polymer-based Highly Conductive Composite Electrolyte for All-Solid-State Batteries.

Solid-state batteries (SSBs) that incorporate the argyrodite-Li6PS5Cl (LPSCl) electrolyte hold potential as substitutes for conventional lithium-ion batteries (LIBs). However, the mismatched interface between the LPSCl electrolyte and electrodes leads to increased interfacial resistance and the rapid growth of lithium (Li) dendrites. These factors significantly impede the feasibility of their widespread industrial application. In this study, we developed a composite electrolyte of the LPSCl/polymer to enhance the contact between the electrolyte and electrodes and suppress dendrite formation at the grain boundary of the LPSCl ceramic. The monomer, triethylene glycol dimethacrylate (TEGDMA), is utilized for in situ polymerization through thermal curing to create the argyrodite LPSCl/polymer composite electrolyte. Additionally, the ball-milling technique was employed to modify the morphology and particle size of the LPSCl ceramic. The ball-milled LPSCl/polymer composite electrolyte demonstrates slightly higher ionic conductivity (ca. 2.21 × 10-4 S/cm) compared to the as-received LPSCl/polymer composite electrolyte (ca. 1.65 × 10-4 S/cm) at 25 °C. Furthermore, both composite electrolytes exhibit excellent compatibility with Li-metal and display cycling stability for up to 1000 h (375 cycles), whereas the as-received LPSCl and ball-milled LPSCl electrolytes maintain stability for up to 600 h (225 cycles) at a current density of 0.4 mA/cm2. The SSB with the ball-milled LPSCl/polymer composite electrolyte delivers high specific discharge capacity (138 mA h/g), Coulombic efficiency (99.97%), and better capacity retention at 0.1C, utilizing the battery configuration of coated NMC811//electrolyte//Li-Indium (In) at 25 °C.

Exploring long-term global environmental impacts of chlorinated paraffins (CPs) in waste: Implications for the Stockholm and Basel Conventions and the global plastic treaty.

Chlorinated paraffins (CPs), mainly short-chain CPs (SCCPs) and medium-chain CPs (MCCPs), are currently the most produced and used industrial chemicals related to persistent organic pollutants (POPs) globally. These chemicals are widely detected in the environment and in the human body. As the release of SCCPs and MCCPs from products represents only a small fraction of their stock in products, the potential long-term release of CPs from a large variety of products at the waste stage has become an issue of great concern. The results of this study showed that, by 2050, SCCPs and MCCPs used between 2000 and 2021 will cumulatively generate 226.49 Mt of CP-containing wastes, comprising 8610.13 kt of SCCPs and MCCPs. Approximately 79.72 Mt of CP-containing wastes is predicted to be generated abroad through the international trade of products using SCCPs and MCCPs. The magnitude, distribution, and growth of CP-containing wastes subject to environmentally sound disposal will depend largely on the relevant provisions of the Stockholm and Basel Conventions and the forthcoming global plastic treaty. According to multiple scenarios synthesizing the provisions of the three conventions, 26.6-101.1 Mt of CP-containing wastes will be subject to environmentally sound disposal as POP wastes, which would pose a great challenge to the waste disposal capacity of China, as well as for countries importing CP-containing products. The additional 5-year exemption period for MCCPs is expected to see an additional 10 Mt of CP-containing wastes subject to environmentally sound disposal. Thus, there is an urgent need to strengthen the Stockholm and Basel Conventions and the global plastic treaty.

Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Mortality of older construction and craft workers employed at Department of Energy (DOE) nuclear sites: Follow-up through 2021.

BACKGROUND: To determine if construction and trades workers formerly employed at US Department of Energy (DOE) nuclear weapons sites are at significant risk for occupational diseases, we studied the mortality experience of participants in the Building Trades National Medical Screening Program (BTMed). METHODS: The cohort included 26,922 participants enrolled between 1998 and 2021 and 8367 deaths. Standardized mortality ratios were calculated based on US death rates. Cox models compared construction workers (n = 22,747; 7487 deaths) to two nonconstruction subpopulations: administrative, scientific and security workers (n = 1894; 330 deaths), and all other nonconstruction workers (n = 2218; 550 deaths). RESULTS: Mortality was elevated for all causes, all cancers, cancers of the trachea, bronchus, lung, kidneys, and lymphatic and hematopoietic system, mesothelioma, chronic obstructive pulmonary disease (COPD), asbestosis, transportation injuries, and other injuries, particularly accidental poisonings. There were 167 deaths from coronavirus disease 2019 (COVID-19), which was lower than expected using US death rates. Overall cause-specific mortality was significantly higher among construction workers than for internal comparison groups. CONCLUSIONS: Construction workers employed at DOE sites have a significantly increased risk for occupational illnesses. Apart from COVID-19 deaths, this update: (1) found that mortality among construction workers is significantly elevated compared to the US population and significantly higher than in the internal comparison populations, and (2) confirmed excess risk for these workers for first employment after 1990. Cancer mortality risks are similar to the cancers identified for DOE compensation from radiation exposures. The high lung cancer risk supports the value of early lung cancer detection. Continued medical surveillance is important.