Nanoscale water-polymer interactions tune macroscopic diffusivity of water in aqueous poly(ethylene oxide) solutions.

The separation and anti-fouling performance of water purification membranes is governed by both macroscopic and molecular-scale water properties near polymer surfaces. However, even for poly(ethylene oxide) (PEO) - ubiquitously used in membrane materials - there is little understanding of whether or how the molecular structure of water near PEO surfaces affects macroscopic water diffusion. Here, we probe both time-averaged bulk and local water dynamics in dilute and concentrated PEO solutions using a unique combination of experimental and simulation tools. Pulsed-Field Gradient NMR and Overhauser Dynamic Nuclear Polarization (ODNP) capture water dynamics across micrometer length scales in sub-seconds to sub-nanometers in tens of picoseconds, respectively. We find that classical models, such as the Stokes-Einstein and Mackie-Meares relations, cannot capture water diffusion across a wide range of PEO concentrations, but that free volume theory can. Our study shows that PEO concentration affects macroscopic water diffusion by enhancing the water structure and altering free volume. ODNP experiments reveal that water diffusivity near PEO is slower than in the bulk in dilute solutions, previously not recognized by macroscopic transport measurements, but the two populations converge above the polymer overlap concentration. Molecular dynamics simulations reveal that the reduction in water diffusivity occurs with enhanced tetrahedral structuring near PEO. Broadly, we find that PEO does not simply behave like a physical obstruction but directly modifies water's structural and dynamic properties. Thus, even in simple PEO solutions, molecular scale structuring and the impact of polymer interfaces is essential to capturing water diffusion, an observation with important implications for water transport through structurally complex membrane materials.

Understanding Prescribing Practices and Patient Experiences with Renin Angiotensin System Inhibitors Use in Chronic Kidney Disease: A Qualitative Study.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve outcomes but are underutilized in patients with chronic kidney disease (CKD). Little is known about reasons for discontinuation and lack of reinitiating these medications. We aimed to explore clinicians' and patients' experiences and perceptions of ACEI/ARB use in CKD. METHODS: A multi-profession sample of health care clinicians and patients with documented ACEI/ARB-associated side effects in the past 6 months. Participants were recruited from 2 Veterans Affairs healthcare systems in Texas and Tennessee. A total of 15 clinicians and 10 patients completed interviews. We used inductive and deductive qualitative data analysis approaches to identify themes related to clinician and patient experiences with ACEI/ARB. Thematic analysis focused on prescribing decisions and practices, clinical guidelines, and perception of side effects. Data were analyzed as they amassed, and recruitment was stopped at the point of thematic saturation. RESULTS: Clinicians prescribe ACEI/ARB for blood pressure control and kidney protection and underscored the importance of these medications in patients with diabetes. While clinicians described providing comprehensive patient education about ACEI/ARB in CKD, patient interviews revealed significant knowledge gaps about CKD and ACEI/ARB use. Many patients were unaware of their CKD status, and some did not know why they were prescribed ACEI/ARB. Clinicians' drug management strategies varied widely, as did their understanding of prescribing guidelines. They identified structural and patient-level barriers to prescribing and many endorsed the development of a decision support tool to facilitate ACEI/ARB prescribing and management. DISCUSSION/CONCLUSION: Our qualitative study of clinicians and providers identified key target areas for improvement to increase ACEI/ARB utilization in patients with CKD with the goal to improve long-term outcomes in high-risk patients. These findings will also inform the development of a decision support tool to assist with prescribing ACEI/ARBs for patients with CKD.

Case Sampling for Evaluating Hospital Postoperative Morbidity in US Surgical Quality Improvement Programs.

Importance: US surgical quality improvement (QI) programs use data from a systematic sample of surgical cases, rather than universal review of all cases, to assess and compare risk-adjusted hospital postoperative complication rates. Given decreasing postoperative complication rates over time and the types of cases eligible for abstraction, it is unclear whether case sampling is robust for identifying hospitals with higher than expected complications. Objective: To compare the assessment of hospital 30-day complication rates derived from sampling strategy used by some US surgical QI programs relative to universal review of all cases. Design, Setting, and Participants: This US hospital-level analysis took place from January 1, 2016, through September 30, 2020. Data analysis was performed from July 1, 2022, through December 21, 2022. Quarterly, risk-adjusted, 30-day complication observed to expected (O-E) ratios were calculated for each hospital using the sample (n = 502 730) and universal review (n = 1 725 364). Outlier hospitals (ie, those with higher than expected mortality) were identified using an O-E ratio significantly greater than 1.0. Patients 18 years and older who underwent a noncardiac operation at US Department of Veterans Affairs (VA) hospitals with a record in the VA Surgical Quality Improvement Program (systematic sample) and the VA Corporate Data Warehouse surgical domain (100% of surgical cases) were included. Main Outcome Measure: Thirty-day complications. Results: Most patients in both the representative sample and the universal sample were men (90.2% vs 91.2%) and White (74.7% vs 74.5%). Overall, 30-day complication rates were 7.6% and 5.3% for the sample and universal review cohorts, respectively (P < .001). Over 2145 hospital quarters of data, hospitals were identified as an outlier in 15.0% of quarters using the sample and 18.2% with universal review. Average hospital quarterly complication rates were 4.7%, 7.2%, and 7.4% for outliers identified using the sample only, universal review only, and concurrent identification in both data sources, respectively. For nonsampled cases, average hospital quarterly complication rates were 7.0% at outliers and 4.4% at nonoutliers. Among outlier hospital quarters in the sample, 54.2% were concurrently identified with universal review. For those identified with universal review, 44.6% were concurrently identified using the sample. Conclusion: In this observational study, case sampling identified less than half of hospitals with excess risk-adjusted postoperative complication rates. Future work is needed to ascertain how to best use currently collected data and whether alternative data collection strategies may be needed to better inform local QI efforts.

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.

Case Sampling vs Universal Review for Evaluating Hospital Postoperative Mortality in US Surgical Quality Improvement Programs.

Importance: Representative surgical case sampling, rather than universal review, is used by US Department of Veterans Affairs (VA) and private-sector national surgical quality improvement (QI) programs to assess program performance and to inform local QI and performance improvement efforts. However, it is unclear whether case sampling is robust for identifying hospitals with safety or quality concerns. Objective: To evaluate whether the sampling strategy used by several national surgical QI programs provides hospitals with data that are representative of their overall quality and safety, as measured by 30-day mortality. Design, Setting, and Participants: This comparative effectiveness study was a national, hospital-level analysis of data from adult patients (aged ≥18 years) who underwent noncardiac surgery at a VA hospital between January 1, 2016, and September 30, 2020. Data were obtained from the VA Surgical Quality Improvement Program (representative sample) and the VA Corporate Data Warehouse surgical domain (100% of surgical cases). Data analysis was performed from July 1 to December 21, 2022. Main Outcomes and Measures: The primary outcome was postoperative 30-day mortality. Quarterly, risk-adjusted, 30-day mortality observed-to-expected (O-E) ratios were calculated separately for each hospital using the sample and universal review cohorts. Outlier hospitals (ie, those with higher-than-expected mortality) were identified using an O-E ratio significantly greater than 1.0. Results: In this study of data from 113 US Department of Veterans Affairs hospitals, the sample cohort comprised 502 953 surgical cases and the universal review cohort comprised 1 703 140. The majority of patients in both the representative sample and the universal sample were men (90.2% vs 91.1%) and were White (74.7% vs 74.5%). Overall, 30-day mortality was 0.8% and 0.6% for the sample and universal review cohorts, respectively (P < .001). Over 2145 quarters of data, hospitals were identified as an outlier in 11.7% of quarters with sampling and in 13.2% with universal review. Average hospital quarterly 30-day mortality rates were 0.4%, 0.8%, and 0.9% for outlier hospitals identified using the sample only, universal review only, and concurrent identification in both data sources, respectively. For nonsampled cases, average hospital quarterly 30-day mortality rates were 1.0% at outlier hospitals and 0.5% at nonoutliers. Among outlier hospital quarters in the sample, 47.4% were concurrently identified with universal review. For those identified with universal review, 42.1% were concurrently identified using the sample. Conclusions and Relevance: In this national, hospital-level study, sampling strategies employed by national surgical QI programs identified less than half of hospitals with higher-than-expected perioperative mortality. These findings suggest that sampling may not adequately represent overall surgical program performance or provide stakeholders with the data necessary to inform QI efforts.

Association of Atherosclerotic Cardiovascular Disease, Hypertension, Diabetes, and Hyperlipidemia With Gulf War Illness Among Gulf War Veterans.

BACKGROUND: Approximately 30% of the 700 000 Gulf War veterans report a chronic symptom-based illness of varying severity referred to as Gulf War illness (GWI). Toxic deployment-related exposures have been implicated in the cause of GWI, some of which contribute to metabolic dysregulation and lipid abnormalities. As this cohort ages, the relationship between GWI and atherosclerotic cardiovascular disease (ASCVD) is a growing concern. We evaluated associations between GWI and ASCVD, diabetes, hyperlipidemia, and hypertension in veterans of the Gulf War (1990-1991). METHODS AND RESULTS: Analysis of survey data collected in 2014 to 2016 from a national sample of deployed Gulf War veterans (n=942) and Veterans Health Administration electronic health record data (n=669). Multivariable logistic regression models tested for associations of GWI with self-reported ASCVD, diabetes, hyperlipidemia, and hypertension, controlling for confounding factors. Separate models tested for GWI associations with ASCVD and risk factors documented in the electronic health record. GWI was associated with self-reported hypertension (adjusted odds ratio [aOR], 1.67 [95% CI, 1.18-2.36]), hyperlipidemia (aOR, 1.46 [95% CI, 1.03-2.05]), and ASCVD (aOR, 2.65 [95% CI, 1.56-4.51]). In the subset of veterans with electronic health record data, GWI was associated with documented diabetes (aOR, 2.34 [95% CI, 1.43-3.82]) and hypertension (aOR, 2.84 [95% CI, 1.92-4.20]). Hyperlipidemia and hypertension served as partial mediators of the association between GWI and self-reported ASCVD. CONCLUSIONS: Gulf War veterans with GWI had higher odds of hyperlipidemia, hypertension, diabetes, and ASCVD compared with Gulf War veterans without GWI. Further examination of the mechanisms underlying this association, including a possible shared exposure-related mechanism, is necessary.

Microglial morphometric analysis: so many options, so little consistency.

Quantification of microglial activation through morphometric analysis has long been a staple of the neuroimmunologist's toolkit. Microglial morphological phenomics can be conducted through either manual classification or constructing a digital skeleton and extracting morphometric data from it. Multiple open-access and paid software packages are available to generate these skeletons via semi-automated and/or fully automated methods with varying degrees of accuracy. Despite advancements in methods to generate morphometrics (quantitative measures of cellular morphology), there has been limited development of tools to analyze the datasets they generate, in particular those containing parameters from tens of thousands of cells analyzed by fully automated pipelines. In this review, we compare and critique the approaches using cluster analysis and machine learning driven predictive algorithms that have been developed to tackle these large datasets, and propose improvements for these methods. In particular, we highlight the need for a commitment to open science from groups developing these classifiers. Furthermore, we call attention to a need for communication between those with a strong software engineering/computer science background and neuroimmunologists to produce effective analytical tools with simplified operability if we are to see their wide-spread adoption by the glia biology community.

Risk-Adjusted Cumulative Sum for Early Detection of Hospitals With Excess Perioperative Mortality.

Importance: National surgical quality improvement programs lack tools for early detection of quality or safety concerns, which risks patient safety because of delayed recognition of poor performance. Objective: To compare the risk-adjusted cumulative sum (CUSUM) with episodic evaluation for early detection of hospitals with excess perioperative mortality. Design, Setting, and Participants: National, observational, hospital-level, comparative effectiveness study of 697 566 patients. Identification of hospitals with excess, risk-adjusted, quarterly 30-day mortality using observed to expected ratios (ie, current criterion standard in the Veterans Affairs Surgical Quality Improvement Program) was compared with the risk-adjusted CUSUM. Patients included in the study underwent a noncardiac operation at a Veterans Affairs hospital, had a record in the Veterans Affairs Surgical Quality Improvement Program (January 1, 2011, through December 31, 2016), and were aged 18 years or older. Main Outcome and Measure: Number of hospitals identified as having excess risk-adjusted 30-day mortality. Results: The cohort included 697 566 patients treated at 104 hospitals across 24 quarters. The mean (SD) age was 60.9 (13.2) years, 91.4% were male, and 8.6% were female. For each hospital, the median number of quarters detected with observed to expected ratios, at least 1 CUSUM signal, and more than 1 CUSUM signal was 2 quarters (IQR, 1-4 quarters), 8 quarters (IQR, 4-11 quarters), and 3 quarters (IQR, 1-4 quarters), respectively. During 2496 total quarters of data, outlier hospitals were identified 33.3% of the time (830 quarters) with at least 1 CUSUM signal within a quarter, 12.5% (311 quarters) with more than 1 CUSUM signal, and 11.0% (274 quarters) with observed to expected ratios at the end of the quarter. The CUSUM detection occurred a median of 49 days (IQR, 25-63 days) before observed to expected ratio reporting (1 signal, 35 days [IQR, 17-54 days]; 2 signals, 49 days [IQR, 26-61 days]; 3 signals, 58 days [IQR, 44-69 days]; ≥4 signals, 49 days [IQR, 42-69 days]; trend test, P < .001). Of 274 hospital quarters detected with observed to expected ratios, 72.6% (199) were concurrently detected by at least 1 CUSUM signal vs 42.7% (117) by more than 1 CUSUM signal. There was a dose-response relationship between the number of CUSUM signals in a quarter and the median observed to expected ratio (0 signals, 0.63; 1 signal, 1.28; 2 signals, 1.58; 3 signals, 2.08; ≥4 signals, 2.49; trend test, P < .001). Conclusions: This study found that with CUSUM, hospitals with excess perioperative mortality can be identified well in advance of standard end-of-quarter reporting, which suggests episodic evaluation strategies fail to detect out-of-control processes and place patients at risk. Continuous performance evaluation tools should be adopted in national quality improvement programs to prevent avoidable patient harm.

Documented Adverse Drug Reactions and Discontinuation of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Chronic Kidney Disease.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are frequently discontinued in patients with chronic kidney disease (CKD). Documented adverse drug reactions (ADRs) in medical records may provide insight into the reasons for treatment discontinuation. METHODS: In this retrospective cohort of US veterans from 2005 to 2019, we identified individuals with CKD and a current prescription for an ACEi or ARB (current user group) or a discontinued prescription within the preceding 5 years (discontinued group). Documented ADRs in structured datasets associated with an ACEi or ARB were categorized into 17 pre-specified groups. Logistic regression assessed associations of documented ADRs with treatment discontinuation. RESULTS: There were 882,441 (73.0%) individuals in the current user group and 326,794 (27.0%) in the discontinued group. There were 26,434 documented ADRs, with at least one documented ADR in 7,520 (0.9%) current users and 9,569 (2.9%) of the discontinued group. ADR presence was associated with treatment discontinuation, aOR 4.16 (95% CI: 4.03, 4.29). The most common documented ADRs were cough (37.3%), angioedema (14.2%), and allergic reaction (10.4%). ADRs related to angioedema (aOR 3.81, 95% CI: 3.47, 4.17), hyperkalemia (aOR 2.03, 95% CI: 1.84, 2.24), peripheral edema (aOR 1.53, 95% CI: 1.33, 1.77), or acute kidney injury (aOR 1.32, 95% CI: 1.15, 1.51) were associated with treatment discontinuation. CONCLUSION: ADRs leading to drug discontinuation were infrequently documented. ADR types were differentially associated with treatment discontinuation. An understanding of which ADRs lead to treatment discontinuation provides an opportunity to address them at a healthcare system level.

Area deprivation index and segregation on the risk of HIV: a U.S. Veteran case-control study.

Background: Preventing HIV infection remains a critically important tool in the continuing fight against HIV/AIDS. The primary aim is to evaluate the effect and interactions between a composite area-level social determinants of health measure and an area-level measure of residential segregation on the risk of HIV/AIDS in U.S. Veterans. Methods: Using the individual-level patient data from the U.S. Department of Veterans Affairs, we constructed a case-control study of veterans living with HIV/AIDS (VLWH) and age-, sex assigned at birth- and index date-matched controls. We geocoded patient's residential address to ascertain their neighborhood and linked their information to two measures of neighborhood-level disadvantage: area deprivation index (ADI) and isolation index (ISOL). We used logistic regression to estimate the odds ratio (OR) and 95% confidence interval (CI) for comparing VLWH with matched controls. We performed analyses for the entire U.S. and separately for each U.S. Census division. Findings: Overall, living in minority-segregated neighborhoods was associated with a higher risk of HIV (OR: 1.88 (95% CI: 1.79-1.97) while living in higher ADI neighborhoods was associated with a lower risk of HIV (OR: 0.88; 95% CI: 0.84-0.92). The association between living in a higher ADI neighborhood and HIV was inconsistent across divisions, while living in minority-segregated neighborhoods was consistently associated with increased risk across all divisions. In the interaction model, individuals from low ADI and high ISOL neighborhoods had a higher risk of HIV in three divisions: East South Central; West South Central, and Pacific. Interpretation: Our results suggest that residential segregation may prevent people in disadvantaged neighborhoods from protecting themselves from HIV independent from access to health care. There is the need to advance knowledge about the neighborhood-level social-structural factors that influence HIV vulnerability toward developing interventions needed to achieve the goal of ending the HIV epidemic. Funding: US National Cancer Institute.

The Risk of Hepatocellular Carcinoma in Entecavir Versus Tenofovir Treated US Cohort With Chronic Hepatitis B Virus.

The comparative effectiveness of tenofovir (TDF) vs entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) remains unclear. Data from a retrospective Korean cohort study published by Choi et al1 initially suggested a lower-than-expected incidence of HCC in patients on long-term TDF. However, additional studies from Korea did not show a statistically significant difference in HCC incidence rate between TDF and ETV groups,2,3 and subsequent studies reported mixed results ranging from no association or a slight advantage for TDF.4 Most of these studies examined Asian patients from Korea, Taiwan, and China.

Effect of HIV and antiretroviral therapy use on body weight changes in a cohort of U.S. veterans living with and without HIV.

OBJECTIVE: People living with HIV have high rates of obesity and obesity-related comorbidities. Our study sought to evaluate weight trajectory in a retrospective cohort of people living with HIV and matched HIV-negative veterans (controls) and to evaluate risk factors for weight gain. METHODS: This was a retrospective database analysis of data extracted from the VA Corporate Data Warehouse that included people living with HIV (n = 22 421) and age-matched HIV-negative controls (n = 63 072). The main outcomes were baseline body weight and weight change from baseline at 1, 2, and 5 years after diagnosis (baseline visit for controls). RESULTS: Body weight at baseline was lower in people living with HIV than in controls. People living with HIV on antiretroviral therapy (ART) gained more weight than did controls. In a sub-analysis of ART-exposed people living with HIV, age >50 years, African American race, body mass index (BMI) <25, CD4 ≤200, and HIV diagnosis year after 2000 were associated with more weight gain at year 1. Nucleoside reverse transcriptase inhibitors (NRTI) plus non-NRTIs (NNRTIs) were associated with less weight gain than NRTIs plus protease inhibitors, NRTIs plus integrase inhibitors, or NRTIs plus other agents at year 1. CONCLUSIONS: Among US veterans, those living with HIV had lower rates of obesity than age-matched HIV-negative controls; however, primarily in the first 2 years after starting ART, people living with HIV gained more weight than did controls.

Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV-negative veterans.

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.

The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19.

During the current pandemic, the vast majority of COVID-19 patients experienced mild symptoms, but some had a potentially fatal aberrant hyperinflammatory immune reaction characterized by high levels of IL-6 and other cytokines. Modulation of this immune reaction has proven to be the only method of reducing mortality in severe and critical COVID-19. The anti-inflammatory drug baricitinib (Olumiant) has recently been strongly recommended by the WHO for use in COVID-19 patients because it reduces the risk of progressive disease and death. It is a Janus Kinase (JAK) 1/2 inhibitor approved for rheumatoid arthritis which was suggested in early 2020 as a treatment for COVID-19. In this review the AI-assisted identification of baricitinib, its antiviral and anti-inflammatory properties, and efficacy in clinical trials are discussed and compared with those of other immune modulators including glucocorticoids, IL-6 and IL-1 receptor blockers and other JAK inhibitors. Baricitinib inhibits both virus infection and cytokine signalling and is not only important for COVID-19 management but is "non-immunological", and so should remain effective if new SARS-CoV-2 variants escape immune control. The repurposing of baricitinib is an example of how advanced artificial intelligence (AI) can quickly identify new drug candidates that have clinical benefit in previously unsuspected therapeutic areas.

Design of Polymeric Zwitterionic Solid Electrolytes with Superionic Lithium Transport.

Progress toward durable and energy-dense lithium-ion batteries has been hindered by instabilities at electrolyte-electrode interfaces, leading to poor cycling stability, and by safety concerns associated with energy-dense lithium metal anodes. Solid polymeric electrolytes (SPEs) can help mitigate these issues; however, the SPE conductivity is limited by sluggish polymer segmental dynamics. We overcome this limitation via zwitterionic SPEs that self-assemble into superionically conductive domains, permitting decoupling of ion motion and polymer segmental rearrangement. Although crystalline domains are conventionally detrimental to ion conduction in SPEs, we demonstrate that semicrystalline polymer electrolytes with labile ion-ion interactions and tailored ion sizes exhibit excellent lithium conductivity (1.6 mS/cm) and selectivity (t + ≈ 0.6-0.8). This new design paradigm for SPEs allows for simultaneous optimization of previously orthogonal properties, including conductivity, Li selectivity, mechanics, and processability.

Stacking Faults Assist Lithium-Ion Conduction in a Halide-Based Superionic Conductor.

In the pursuit of urgently needed, energy dense solid-state batteries for electric vehicle and portable electronics applications, halide solid electrolytes offer a promising path forward with exceptional compatibility against high-voltage oxide electrodes, tunable ionic conductivities, and facile processing. For this family of compounds, synthesis protocols strongly affect cation site disorder and modulate Li+ mobility. In this work, we reveal the presence of a high concentration of stacking faults in the superionic conductor Li3YCl6 and demonstrate a method of controlling its Li+ conductivity by tuning the defect concentration with synthesis and heat treatments at select temperatures. Leveraging complementary insights from variable temperature synchrotron X-ray diffraction, neutron diffraction, cryogenic transmission electron microscopy, solid-state nuclear magnetic resonance, density functional theory, and electrochemical impedance spectroscopy, we identify the nature of planar defects and the role of nonstoichiometry in lowering Li+ migration barriers and increasing Li site connectivity in mechanochemically synthesized Li3YCl6. We harness paramagnetic relaxation enhancement to enable 89Y solid-state NMR and directly contrast the Y cation site disorder resulting from different preparation methods, demonstrating a potent tool for other researchers studying Y-containing compositions. With heat treatments at temperatures as low as 333 K (60 °C), we decrease the concentration of planar defects, demonstrating a simple method for tuning the Li+ conductivity. Findings from this work are expected to be generalizable to other halide solid electrolyte candidates and provide an improved understanding of defect-enabled Li+ conduction in this class of Li-ion conductors.

Association of Gulf War Illness-Related Symptoms with Military Exposures among 1990-1991 Gulf War Veterans Evaluated at the War-Related Illness and Injury Study Center (WRIISC).

Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of three specialty VA War-Related Illness and Injury Study Centers (WRIISC). Veterans of the 1990−1991 Gulf War have long experienced excess rates of chronic symptoms associated with the condition known as Gulf War Illness (GWI), with hundreds evaluated at the WRIISC. Here we provide the first report from a cohort of 608 Gulf War Veterans seen at the WRIISC who completed questionnaires on chronic symptoms (>6 months) consistent with GWI as well as prominent exposures during Gulf War deployment. These included veterans' reports of hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP4) gear, pesticide use, and use of pyridostigmine bromide (PB) pills as prophylaxis against the effects of nerve agents. Overall, veterans in the cohort were highly symptomatic and reported a high degree of exposures. In multivariable models, these exposures were significantly associated with moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, exposure to pesticides was associated with problems with concentration and memory, problems sleeping, unrefreshing sleep, and joint pain. Use of MOPP4 was associated with light sensitivity and unrefreshing sleep and use of PB was associated with depression. We also evaluated the association of exposures with symptom summary scores based on veterans' severity of symptoms in four domains and overall. In multivariable modeling, the pain symptom severity score was significantly associated with pesticide use (Odds ratio (OR): 4.13, 95% confidence intervals (CI): 1.78−9.57) and taking PB pills (OR: 2.28, 95% CI: 1.02−5.09), and overall symptom severity was significantly associated with use of PB pills (OR: 2.41, 95% CI: 1.01−5.75). Conclusion: Decades after deployment, Gulf War veterans referred to a VA tertiary evaluation center report a high burden of chronic symptoms, many of which were associated with reported neurotoxicant exposures during the war.

Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS).

BACKGROUND: Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed. METHODS: Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia-associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96. RESULTS: Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia-associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E-03), oxidative phosphorylation (P = 2.78E-02), and voltage-gated calcium channels (P = 1.59E-04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E-35), sarcopenia and gait speed (P = 4.78E-03), and sarcopenia and grip strength (P = 7.55E-06). There was also an over-representation of the sarcopenia, ALMi, grip strength, and gait speed-associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis. CONCLUSIONS: These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.

Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1-Mutant Diffuse Intrinsic Pontine Glioma.

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (K d = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood-brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. SIGNIFICANCE: Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275.