Role of Salt Concentration in Stabilizing Charged Ni-Rich Cathode Interfaces in Li-Ion Batteries.

The cathode-electrolyte interphase (CEI) in Li-ion batteries plays a key role in suppressing undesired side reactions while facilitating Li-ion transport. Ni-rich layered cathode materials offer improved energy densities, but their high interfacial reactivities can negatively impact the cycle life and rate performance. Here we investigate the role of electrolyte salt concentration, specifically LiPF6 (0.5-5 m), in altering the interfacial reactivity of charged LiN0.8Mn0.1Co0.1O2 (NMC811) cathodes in standard carbonate-based electrolytes (EC/EMC vol %/vol % 3:7). Extended potential holds of NMC811/Li4Ti5O12 (LTO) cells reveal that the parasitic electrolyte oxidation currents observed are strongly dependent on the electrolyte salt concentration. X-ray photoelectron and absorption spectroscopy (XPS/XAS) reveal that a thicker LixPOyFz-/LiF-rich CEI is formed in the higher concentration electrolytes. This suppresses reactions with solvent molecules resulting in a thinner, or less-dense, reduced surface layer (RSL) with lower charge transfer resistance and lower oxidation currents at high potentials. The thicker CEI also limits access of acidic species to the RSL suppressing transition-metal dissolution into the electrolyte, as confirmed by nuclear magnetic resonance (NMR) spectroscopy and inductively coupled plasma optical emission spectroscopy (ICP-OES). This provides insight into the main degradation processes occurring at Ni-rich cathode interfaces in contact with carbonate-based electrolytes and how electrolyte formulation can help to mitigate these.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer.

Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state-specific "regulatory transposable elements." Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a subset of regulatory transposable elements shared with pluripotent/stem cells, including Tigger3a. Using chromatin editing technology, we show how such elements promote prostate cancer growth by regulating AR transcriptional activity. Collectively, our results suggest that oncogenesis arises from lineage-specific transcription factors hijacking pluripotent/stem cell regulatory transposable elements. SIGNIFICANCE: We show that oncogenesis relies on co-opting transposable elements from pluripotent stem cells as regulatory elements altering the recruitment of lineage-specific transcription factors. We further discover how co-option is dependent on active chromatin states with important implications for developing treatment options against drivers of oncogenesis across the repetitive DNA. This article is featured in Selected Articles from This Issue, p. 2293.

Optically Driven Rotation of Exciton-Polariton Condensates.

The rotational response of quantum condensed fluids is strikingly distinct from rotating classical fluids, especially notable for the excitation and ordering of quantized vortex ensembles. Although widely studied in conservative systems, the dynamics of rotating open-dissipative superfluids such as exciton-polariton condensates remains largely unexplored, as it requires high-frequency rotation while avoiding resonantly driving the condensate. We create a rotating polariton condensate at gigahertz frequencies by off-resonantly pumping with a rotating optical stirrer composed of the time-dependent interference of two frequency-offset, structured laser modes. Acquisition of angular momentum exceeding the critical 1ℏ/particle is directly measured, accompanied by the deterministic nucleation and capture of quantized vortices with a handedness controlled by the pump rotation direction. The demonstration of controlled optical rotation of a spontaneously formed polariton condensate enables new opportunities for the study of open dissipative superfluidity, ordering of non-Hermitian quantized vortex matter, and topological states in a highly nonlinear, photonic platform.

Understanding Factors Influencing Decision Making by State Health Officials in a Public Health Emergency.

State and territorial health officials (STHOs) play a critical role in leading public health emergency response in their respective states. Through an exploratory qualitative study with 21 current or former STHOs, we sought to understand the issues that impact STHO decision making in public health responses. Initial findings suggest the need for structured decision making tools for use by leaders responding to public health emergencies, including COVID-19. Such tools could lead to more systematic responses by STHOs during public health crises.

Weaving and Layering Funding: A Territorial Health Agency's Guide to Effective Health Financing.

CONTEXT: State and territorial health agencies can optimize programmatic funding through braiding and layering strategies. IMPLEMENTATION: The Commonwealth Healthcare Corporation, a territorial health agency located on the Pacific Island of Saipan, Commonwealth of the Northern Mariana Islands (CNMI), restructured its Non-Communicable Disease Bureau into 4 new units. Existing funding streams were braided and layered to support the restructuring. A shared vision of strengthening crosscutting connections to improve population health outcomes helped guide the restructuring process. Vision planning with leaders and funding partners, establishing buy-in within agency and external partners, and assessing immediate impacts were a few of the steps taken by the agency to ensure a successful restructuring. IMPACT: The immediate impact of the restructure has been positive. In both the CNMI and select states that have undertaken similar efforts, braiding and layering funding has facilitated more streamlined processes, coordinated approaches across programs and funding partners, and provided deeper levels of trust in partnerships. Although it is still too early to draw long-term assessments in the CNMI, the agency projects that coordinated funds will strengthen its foundational capabilities and promote a more community-centered, collaborative, and effective approach to public health. Restructuring the Non-Communicable Disease Bureau through braiding and layering funds gives the agency the flexibility it needs to more effectively address the social determinants of health and local population health priorities through a client-centered approach, ultimately improving health outcomes for the commonwealth. LESSONS LEARNED AND IMPLICATIONS: The agency experienced several challenges throughout the restructuring process that offer lessons learned for addressing effective health financing. For example, ample time is needed at the beginning of the braiding and layering process to establish policies and procedures for efficient accounting, documenting, and reporting. In addition, ongoing support and training opportunities for programmatic teams can smooth out the transition from siloed to braided and layered funding structures. These lessons, in addition to key elements mapped out by experienced state health agencies, can guide and prepare other agencies interested in implementing innovative funding mechanisms.

Revealing the Role of CO during CO2 Hydrogenation on Cu Surfaces with In Situ Soft X-Ray Spectroscopy.

The reactions of H2, CO2, and CO gas mixtures on the surface of Cu at 200 °C, relevant for industrial methanol synthesis, are investigated using a combination of ambient pressure X-ray photoelectron spectroscopy (AP-XPS) and atmospheric-pressure near edge X-ray absorption fine structure (AtmP-NEXAFS) spectroscopy bridging pressures from 0.1 mbar to 1 bar. We find that the order of gas dosing can critically affect the catalyst chemical state, with the Cu catalyst maintained in a metallic state when H2 is introduced prior to the addition of CO2. Only on increasing the CO2 partial pressure is CuO formation observed that coexists with metallic Cu. When only CO2 is present, the surface oxidizes to Cu2O and CuO, and the subsequent addition of H2 partially reduces the surface to Cu2O without recovering metallic Cu, consistent with a high kinetic barrier to H2 dissociation on Cu2O. The addition of CO to the gas mixture is found to play a key role in removing adsorbed oxygen that otherwise passivates the Cu surface, making metallic Cu surface sites available for CO2 activation and subsequent conversion to CH3OH. These findings are corroborated by mass spectrometry measurements, which show increased H2O formation when H2 is dosed before rather than after CO2. The importance of maintaining metallic Cu sites during the methanol synthesis reaction is thereby highlighted, with the inclusion of CO in the gas feed helping to achieve this even in the absence of ZnO as the catalyst support.

The Exodus Of State And Local Public Health Employees: Separations Started Before And Continued Throughout COVID-19.

Understanding the size and composition of the state and local governmental public health workforce in the United States is critical for promoting and protecting the health of the public. Using pandemic-era data from the Public Health Workforce Interests and Needs Survey fielded in 2017 and 2021, this study compared intent to leave or retire in 2017 with actual separations through 2021 among state and local public health agency staff. We also examined how employee age, region, and intent to leave correlated with separations and considered the effect on the workforce if trends were to continue. In our analytic sample, nearly half of all employees in state and local public health agencies left between 2017 and 2021, a proportion that rose to three-quarters for those ages thirty-five and younger or with shorter tenures. If separation trends continue, by 2025 this would represent more than 100,000 staff leaving their organizations, or as much as half of the governmental public health workforce in total. Given the likelihood of increasing outbreaks and future global pandemics, strategies to improve recruitment and retention must be prioritized.

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

Revealing solid electrolyte interphase formation through interface-sensitive Operando X-ray absorption spectroscopy.

The solid electrolyte interphase (SEI) that forms on Li-ion battery anodes is critical to their long-term performance, however observing SEI formation processes at the buried electrode-electrolyte interface is a significant challenge. Here we show that operando soft X-ray absorption spectroscopy in total electron yield mode can resolve the chemical evolution of the SEI during electrochemical formation in a Li-ion cell, with nm-scale interface sensitivity. O, F, and Si K-edge spectra, acquired as a function of potential, reveal when key reactions occur on high-capacity amorphous Si anodes cycled with and without fluoroethylene carbonate (FEC). The sequential formation of inorganic (LiF) and organic (-(C=O)O-) components is thereby revealed, and results in layering of the SEI. The addition of FEC leads to SEI formation at higher potentials which is implicated in the rapid healing of SEI defects and the improved cycling performance observed. Operando TEY-XAS offers new insights into the formation mechanisms of electrode-electrolyte interphases and their stability for a wide variety of electrode materials and electrolyte formulations.

The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors.

Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.

Isolated nerve palsy following insertion of a three-piece inflatable penile prosthesis.

Case report of a 57-year-old male who underwent insertion of an inflatable penile prosthesis due to erectile dysfunction, secondary to poorly controlled Type 2 diabetes and Peyronie's disease. The surgical procedure was uneventful and there were no immediate post-operative complications. During a routine follow-up, the patient described problems with the deflation of the implant and severe lower back and leg pain. Diagnostic MRI scans revealed reservoir migration, impingement of the obturator nerve and oedema in the adductor muscle group. The reservoir was initially repositioned, and later on removed due to ongoing symptoms.

Operational Performance of a Compact Proton Therapy System: A 5-Year Experience.

Purpose: We present an analysis of various operational metrics for a novel compact proton therapy system, including clinical case mix, subsystems utilization, and quality assurance trends in beam delivery parameters over a period of 5 years. Materials and Methods: Patient-specific data from a total of 850 patients (25,567 fractions) have been collected and analyzed. The patient mix include a variety of simple, intermediate, and complex cases. Beam-specific delivery parameters for a total of 3585 beams were analyzed. In-room imaging system usage for off-line adaptive purpose is reported. We also report key machine performances metrics based on routine quality assurance in addition to uptime. Results: Our analysis shows that system subcomponents including gantry and patient positioning system have maintained a tight mechanical tolerance over the 5-year period. Various beam parameters were all within acceptable tolerances with no clear trends. Utilization frequency histograms of gantry and patient positioning system show that only a small fraction of all available angles was used for patient deliveries with cardinal angels as the most usable. Similarly, beam-specific metrics, such as range, modulation, and air gaps, were clustered unevenly over the available range indicating that this compact system was more than capable to treat the complex variety of tumors of our patient mix. Conclusion: Our data show that this compact system is versatile, robust, and capable of delivering complex treatments like a large full-gantry system. Utilization data show that a fraction of all subcomponents range of angular motion has been used. Compilation of beam-specific metrics, such as range and modulation, show uneven distributions with specific clustering over the entire usable range. Our findings could be used to further optimize the performance and cost-effectiveness of future compact proton systems.

Implementation of a Nationwide Knowledge-Based COVID-19 Contact Tracing Training Program, 2020.

In the United States, the public health response to control COVID-19 required rapid expansion of the contact tracing workforce from approximately 2200 personnel prepandemic to more than 100 000 during the pandemic. We describe the development and implementation of a free nationwide training course for COVID-19 contact tracers that launched April 28, 2020, and summarize participant characteristics and evaluation findings through December 31, 2020. Uptake of the online asynchronous training was substantial: 90 643 registrants completed the course during the first 8 months. In an analysis of a subset of course participants (n = 13 697), 7724 (56.4%) reported having no prepandemic public health experience and 7178 (52.4%) reported currently serving as case investigators, contact tracers, or both. Most participants who completed a course evaluation reported satisfaction with course utility (94.8%; 59 497 of 62 753) and improved understanding of contact tracing practice (93.0%; 66 107 of 71 048). These findings suggest that the course successfully reached the intended audience of new public health practitioners. Lessons learned from this implementation indicate that an introductory course level is appropriate for a national knowledge-based training that aims to complement jurisdiction-specific training. In addition, offering a range of implementation options can promote course uptake among public health agency staff. This course supported the emerging needs of the public health practice community by training a workforce to fill an important gap during the COVID-19 pandemic and could serve as a feasible model for enhancing workforce knowledge for future and ongoing public health threats.

Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study.

BACKGROUND: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. OBJECTIVE: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling. RESULTS AND LIMITATIONS: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset. CONCLUSIONS: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. PATIENT SUMMARY: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier.

Determining the Impact of Spatial Heterogeneity on Genomic Prognostic Biomarkers for Localized Prostate Cancer.

Localized prostate tumors show remarkably diverse clinical courses, with some being cured by local therapy alone, while others rapidly relapse and have a lethal course despite precision surgery or radiotherapy. Many genomic biomarkers have been developed to predict this clinical behavior, but these are confounded by the extreme spatial heterogeneity of prostate tumors: most are multifocal and harbor multiple subclonal populations. To quantify the influence of spatial heterogeneity on genomic prognostic biomarkers, we developed a case-control high-risk cohort (n = 42) using a prospective registry, risk matched by clinicopathologic prognostic indices. Half of the cohort had early biochemical recurrence (BCR; ie, ≤18 mo), while half remained without evidence of disease for at least 48 mo after radical prostatectomy. We then genomically profiled multiple tumor foci per patient, analyzing 119 total specimens. These data allowed us to validate three published genomic prognostic biomarkers and quantify their sensitivity to tumor spatial heterogeneity. Remarkably, all three biomarkers robustly predicted early BCR, and all three were robust to spatiogenomic variability. These data suggest that DNA-based genomic biomarkers can overcome intratumoral heterogeneity: single biopsies may be sufficient to estimate the risk of early BCR after radical treatment in patients with high-risk disease. PATIENT SUMMARY: We investigated whether heterogeneity between tumor regions within the prostate affects the accuracy of DNA-based biomarkers predicting early relapse after prostatectomy. We observed persistent accuracy in predicting disease relapse, suggesting that spatial heterogeneity may not hinder biomarker performance.