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Due to a lack of water resources, people are starting to use treated wastewater to irrigate crops and vegetables. However, the risk of micropollutant exposure from vegetables cultivated with treated wastewater has been largely underestimated. To elucidate this underestimation, a hydroponic system for lettuce cultivation using a nutrient solution spiked with three pharmaceuticals with different log K OW values (acetaminophen (0.46), ketamine (2.18) and methadone (3.93)) was examined, and the total bioconcentration factors (BCFs) (including the transformation of metabolites) of the pharmaceuticals were found to be 0, 120 ± 7.76 and 176 ± 16.0 L/kg, respectively. To simulate treated wastewater, these nutrient solutions were first treated by sunlight photolysis, chlorination, and sunlight/chlorine before use in lettuce cultivation. During the treatment, ketamine and methadone were transformed into norketamine (up to 6.0 %) and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) (up to 16 %), respectively; the BCF of norketamine (162 ± 22.6 L/kg) was found to be even greater than ketamine. In addition, other degradation byproducts (including 3 trace and 13 undetected byproducts in the nutrient solutions) were taken up by the lettuce. In parallel, ketamine and methadone can also undergo metabolism in lettuce; the conversion rate to norketamine increased from 22 ± 7.0 % to 45 ± 0.062 when the ketamine concentration decreased from 1000 to 50 μg/L., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Previous wastewater-based epidemiology (WBE) research on illicit drug use has predominantly focused on wastewater treatment plant (WWTP) influents, but information on sewer-network wastewater is very limited. This study represents a pioneering small-scale WBE investigation based on the analysis of sewer-network wastewater samples from different sewer manholes in suburban (Tamsui region) and urban areas (Zhongshan and Wanhua regions) and a comparison of the results with those obtained from corresponding WWTP influents. Among sixteen illicit drugs, methamphetamine exhibited the highest concentration in sewer-network wastewater across both areas. Suburban-urban variations were observed, with more types of illicit drugs detected in the suburban area. Back-calculation indicated that methamphetamine and ketamine were the most-consumed illicit drugs in both sewer-network wastewaters and WWTP influents. Similar types of illicit drugs were detected in the sewer-network wastewaters and WWTP influents, indicating the representativeness of WWTP influents in assessing regional illicit drug abuse. Nevertheless, the sewer-network wastewater results offered additional information making it possible to pinpoint potential hotspots of illicit drug and identify peak usage periods throughout the day, in contrast to the WWTP influent results. In the non-suspected suburban area of Tamsui, high potential hotspots of methamphetamine (sampling points 3 and 6) and ketamine (sampling points 1 and 8) were identified. Although the Zhongshan and Wanhua regions were chosen as suspected hotspots of illicit drug abuse, more severe illicit drug use was observed in Wanhua. Moreover, a trend toward higher illicit drug use from early morning to morning was observed. Despite sampling challenges and higher costs, small-scale WBE via sewer-network wastewater analysis provides superior identification of drug abuse hotspots and peak usage periods. Therefore, this study provides valuable insights for law enforcement and can help prevent and combat illicit drug abuse by targeting potential hotspots and understanding daily illicit drug use dynamics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, lecanemab administered as a bi-monthly infusion (typically 10 mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study, we investigated potential plasma protein binding (PPB) interaction to lecanemab using lecanemab biosimilar., Methods: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions of human plasma obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate plasma binders was confirmed by western blotting, ELISA, and surface plasmon resonance analysis., Results: Using a combination of equilibrium dialysis, ELISA, and western blotting in human plasma, we first describe the presence of likely PPB partners to lecanemab biosimilar and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta., Interpretation: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Aims: Long QT syndrome (LQTS) and coronary artery disease (CAD) are both associated with increased risk of ventricular tachyarrhythmia . However, there are limited data on the incremental risk conferred by CAD in adult patients with congenital LQTS. We aimed to investigate the risk associated with CAD and life threatening events (LTEs) in patients with LQTS after age 40 years., Methods: The risk of LTEs (comprising aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shock) from age 40 through 75 years was examined in 1,020 subjects from the Rochester LQTS registry, categorized to CAD ( n  = 137) or no-CAD ( n  = 883) subgroups., Results: Survival analysis showed that patients with CAD had a significantly higher cumulative event rate of LTEs from 40 to 75 years (35%) compared with those without CAD (7%; p  < 0.001 for the overall difference during follow-up). Consistently, multivariate analysis showed that the presence of CAD was associated with a 2.5-fold (HR = 2.47; p  = 0.02) increased risk of LTEs after age 40 years. Subgroup analyses showed that CAD vs. no CAD was associated with a pronounced >4-fold ( p  = 0.008) increased risk of LTEs among LQTS patients with a lower-range QTc (<500 ms). The increased risk of LTEs associated with CAD was not significantly different among the 3 main LQTS genotypes. Patient treatment was suboptimal, with only 63% on β-blockers and 44% on non-selective β-blockers., Conclusions: Our findings suggest that CAD is associated with a higher risk of LTEs in LQTS patients, with the risk being more pronounced in those with QTc <500 ms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Barsheshet, Goldenberg, Bjelic, Buturlin, Erez, Goldenberg, Chen, Polonsky, McNitt, Aktas, Zareba and Golovchiner.)

Dementia specialists-neurologists, geriatricians, and geriatric psychiatrists-serve a critical clinical function in diagnosing early-stage Alzheimer's disease and determining eligibility for treatment with disease-modifying therapies. However, the availability of dementia specialists is limited and varies across the United States. Using data from the Area Health Resources Files, we found that the median density of dementia specialists across hospital referral regions in United States is 28.8 per 100 000 population aged 65 years and older (interquartile range 19.3-43.6). We derived thresholds of 33-45 dementia specialists per 100 000 population aged 65 years and older as the provider density necessary to care for older adults with mild cognitive impairment and dementia. Based on these thresholds, we estimated that 34%-59% of the population aged 65 years and older resided in areas with potential dementia specialist shortfalls. The extent of potential shortfalls varied by state and rurality. A better understanding of potential gaps in the availability of dementia specialists will inform policies and practices to ensure access to services for people with cognitive impairment and dementia., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Taiwan, identified as pivotal in the Asian drug trafficking chain, has been experiencing a surge in illicit drug-related issues. Wastewater-based epidemiology (WBE) has emerged as a promising approach for comprehensive evaluation of actual illicit drug usage. This study presents the first WBE investigation of illicit drug consumption in Taiwan based on the analysis of wastewater from four wastewater treatment plants (WWTPs) in the Taipei metropolitan area. Additionally, it demonstrates a high correlation between the amounts of illicit drugs seized and influent concentrations over an extended period of time. The reliability of solid-phase extraction and analysis via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was validated for 16 illicit drugs (methamphetamine, ketamine, cocaine, codeine, methadone, morphine, meperidine, fentanyl, sufentanil, para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 3,4-methylenedioxymethamphetamine (MDMA), cathinone, methcathinone, mephedrone (MEPH), and 4-methylethcathinone (4-MEC)). Methamphetamine, ketamine, and 4-MEC were consistently detected in all wastewater samples, underscoring their prevalence in the Taipei metropolitan area. Biochemical oxygen demand (BOD) and ammonia nitrogen (ammonia N) were employed to reduce uncertainty in estimations of population size during back-calculation of illicit drug consumption. The results indicate that methamphetamine was the most consumed drug (175-740 mg day -1 1000 people -1 ), followed by ketamine (22-280 mg day -1 1000 people -1 ). In addition, urban-related WWTPs exhibited higher consumption of methamphetamine and ketamine than did the suburban-related WWTP, indicating distinct illicit drug usage patterns between suburban and urban regions. Moreover, an examination of temporal trends in wastewater from the Dihua WWTP revealed a persistent predominance of ketamine and methamphetamine, consistent with statistical data pertaining to seizure quantities and urine test results. The study provides encouraging insight into spatial and temporal variations in illicit drug usage in the Taipei metropolitan area, emphasizing the complementary role of WBE in understanding trends in illicit drug abuse., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

3-Hydroxy-3-methylbutyrate (HMB) is a five-carbon branch-chain hydroxy acid currently used as a dietary supplement to treat sarcopenia and exercise training. However, its current production relies on conventional chemical processes which require toxic substances and are generally non-sustainable. While bio-based syntheses of HMB have been developed, they are dependent on biotransformation of its direct precursors which are generally costly. Therefore, in this work, we developed a synthetic de novo HMB biosynthetic pathway that enables HMB production from renewable resources. This novel HMB biosynthesis employs heterologous enzymes from mevalonate pathway and myxobacterial iso-fatty acid pathway for converting acetyl-CoA to HMB-CoA. Subsequently, HMB-CoA is hydrolyzed by a thioesterase to yield HMB. Upon expression of this pathway, our initial Escherichia coli strain produced 660 mg/L of HMB from glucose in 48 hours. Through optimization of coenzyme A removal from HMB-CoA and genetic operon structure, our final strain achieved HMB production titer of 17.7 g/L in glucose minimal media using a bench-top bioreactor. This engineered strain was further demonstrated to produce HMB from other renewable carbon sources such as xylose, glycerol, and acetate. The results from this work provided a flexible and environmentally benign method for producing HMB., (Copyright © 2024 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To identify factors associated with clinicians' likelihood and intensity of applying fluoride varnish (FV) overall and for visits paid by Medicaid and private insurers., Study Design: Observational study using claims data., Methods: Using the Massachusetts All-Payer Claims Database (2016-2018), we conducted a repeated cross-sectional study of 2911 clinicians (7277 clinician-year observations) providing well-child visits to children aged 1 to 5 years. Zero-inflated negative binomial models estimated the probability of a clinician applying FV and the number of visits with FV applications, overall and separately for visits paid by Medicaid and private insurers., Results: A total of 30.9% of clinician-years applied FV at least once, and overall, an average of 8.4% of a clinician's well-child visits included FV annually. Controlling for all covariates, having a higher percentage of patients insured by Medicaid was associated with applying FV (OR, 1.35; 95% CI, 1.23-1.45) and a higher expected number of applications (OR, 1.05; 95% CI, 1.02-1.09). Additionally, having a higher percentage of patients aged 1 to 5 years was associated with applying FV (OR, 1.20; 95% CI, 1.01-1.43), but not the number of applications. Similar associations were observed among visits paid by private insurers., Conclusions: Despite clinical recommendations and mandated insurance reimbursements, the likelihood and intensity of FV applications was low for most pediatric primary care clinicians. Clinician behavior was associated with patient-panel characteristics, suggesting the need for interventions that account for these differences.

Background: Cardioneuroablation (CNA) has shown encouraging results in patients with vasovagal syncope (VVS). However, data on different subtypes was scarce., Methods: This observational study retrospectively enrolled 141 patients [mean age: 40 ± 18 years, 51 males (36.2%)] with the diagnosis of VVS. The characteristics among different types of VVS and the outcomes after CNA were analyzed., Results: After a mean follow-up of 4.3 ± 1.5 years, 41 patients (29.1%) experienced syncope/pre-syncope events after CNA. Syncope/pre-syncope recurrence significantly differed in each subtype ( P = 0.04). The cardioinhibitory type of VVS had the lowest recurrence rate after the procedure ( n = 6, 16.7%), followed by mixed ( n = 26, 30.6%) and vasodepressive ( n = 9, 45.0%). Additionally, a significant difference was observed in the analyses of the Kaplan-Meier survival curve ( P = 0.02). Syncope/pre-syncope burden was significantly reduced after CNA in the vasodepressive type ( P < 0.01). Vasodepressive types with recurrent syncope/pre-syncope after CNA have a lower baseline deceleration capacity (DC) level than those without (7.4 ± 1.0 ms vs. 9.0 ± 1.6 ms, P = 0.01). Patients with DC < 8.4 ms had an 8.1 (HR = 8.1, 95% CI: 2.2-30.0, P = 0.02) times risk of syncope/pre-syncope recurrence after CNA compared to patients with DC ≥ 8.4 ms, and this association still existed after adjusting for age and sex (HR = 8.1, 95% CI: 2.2-30.1, P = 0.02)., Conclusions: Different subtypes exhibit different event-free rates. The vasodepressive type exhibited the lowest event-free rate, but those patients with DC ≥ 8.4 ms might benefit from CNA., (© 2024 JGC All rights reserved; www.jgc301.com.)

T lymphocytes expressing CD57 and lacking costimulatory receptors CD27/CD28 have been reported to accumulate with aging, chronic infection, and cancer. These cells are described as senescent, with inability to proliferate but enhanced cytolytic and cytokine-producing capacity. However, robust functional studies on these cells taken directly from cancer patients are lacking. We isolated these T cells and their CD27/28+ counterparts from blood and tumor samples of 50 patients with previously untreated head and neck cancer. Functional studies confirmed that these cells have enhanced ability to degranulate and produce IFN-γ. They also retain the ability to proliferate, thus are not senescent. These data suggest that CD27/28-CD57+ CD8+ T cells are a subset of highly differentiated, CD45RA+ effector memory (T EMRA ) cells with retained proliferative capacity. Patients with > 34% of these cells among CD8+ T cells in the blood had a higher rate of locoregional disease relapse, suggesting these cells may have prognostic significance., Competing Interests: NCS discloses consulting fees from Sensorion, Regeneron, and GeoVax in addition to research funding from Astex Pharmaceuticals. The authors have no conflicting financial interests related to this work., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The coexistence of free chlorine and bromide under sunlight irradiation (sunlight/FC with Br - ) is unavoidable in outdoor seawater swimming pools, and the formation of brominated disinfection byproducts could act more harmful than chlorinated disinfection byproducts. In this study, benzotriazole was selected as a model compound to investigate the degradation rate and the subsequent formation of disinfection byproducts via sunlight/FC with Br - process. The rate constants for the degradation of benzotriazole under pseudo first order conditions in sunlight/FC with Br - and sunlight/FC are 2.3 ± 0.07 × 10 -1  min -1 and 6.0 ± 0.7 × 10 -2  min -1 , respectively. The enhanced degradation of benzotriazole can be ascribed to the generation of HO•, bromine species, and reactive halogen species (RHS) during sunlight/FC with Br - . Despite the fact that sunlight/FC with Br - process enhanced benzotriazole degradation, the reaction results in increasing tribromomethane (TBM) formation. A high concentration (37.8 μg/L) of TBM was detected in the sunlight/FC with Br - , which was due to the reaction of RHS. The degradation of benzotriazole was notably influenced by the pH value (pH 4 - 11), the concentration of bromide (0 - 2 mM), and free chlorine (1 - 6 mg/L). Furthermore, the concentration of TBM increased when the free chlorine concentrations increased, implying the formation potential of harmful TBM in chlorinated seawater swimming pools., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

During the unprecedented COVID-19 city lockdown, a unique opportunity arose to dissect the intricate dynamics of urban air quality, focusing on ultrafine particles (UFPs) and volatile organic compounds (VOCs). This study delves into the nuanced interplay between traffic patterns and UFP emissions in a subtropical urban setting during the spring-summer transition of 2021. Leveraging meticulous roadside measurements near a traffic nexus, our investigation unravels the intricate relationship between particle number size distribution (PNSD), VOCs mixing ratios, and detailed vehicle activity metrics. The soft lockdown era, marked by a 20-27% dip in overall traffic yet a surprising surge in early morning motorcycle activity, presented a natural experiment. We observed a consequential shift in the urban aerosol regime: the decrease in primary emissions from traffic substantially amplified the role of aged particles and secondary aerosols. This shift was particularly pronounced under stagnant atmospheric conditions, where reduced dilution exacerbated the influence of alternative emission sources, notably solvent evaporation, and was further accentuated with the resumption of normal traffic flows. A distinct seasonal trend emerged as warmer months approached, with aromatic VOCs such as toluene, ethylbenzene, and xylene not only increasing but also significantly contributing to more frequent particle growth events. These findings spotlight the criticality of targeted strategies at traffic hotspots, especially during periods susceptible to weak atmospheric dilution, to curb UFP and precursor emissions effectively. As we stand at the cusp of widespread vehicle electrification, this study underscores the imperative of a holistic approach to urban air quality management, embracing the complexities of primary emission reductions and the resultant shifts in atmospheric chemistry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo 1 . The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy 2-6 , suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states., (© 2024. The Author(s).)

Competing Interests: The authors have no conflicts to report.

Urine source separation, as an innovative concept for the reuse of microlevel nutrients in human urine, has drawn increasing attention recently. Consequently, removing coexisting pharmaceuticals in urine is necessary for further reuse. This study is the first to apply the solar-driven persulfate process (Solar/PS) to the investigation of cephradine (CFD) and caffeine (CAF) degradation in synthetic human urine. The results showed that significantly more degradation of CFD and CAF occurs with the Solar/PS process than with persulfate oxidation and direct sunlight photolysis, respectively. The generated reactive species ·OH, SO 4 · - , O 2 · - and 1 O 2 were identified in the Solar/PS process. While SO 4 · - played a dominant role at pH 6, it played a minor role at pH 9 due to the lower amount generated under alkaline conditions. The presence of chloride and ammonia negatively impacted the photodegradation of both compounds. In contrast, bicarbonate exhibited no effect on CAF but enhanced CFD degradation owing to its amino-acid-like structure, which has a higher reactivity toward CO 3 · - . Although total organic carbon (TOC) was partially mineralized after 6 h of operation, no Microtox® toxicity was observed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Peracetic acid (PAA) has garnered significant interest as a novel alternative to chlorine-based disinfectants for water treatment due to its broad-spectrum antimicrobial activity and its ability of reactive species generation when exposed to UV light. However, limited studies have investigated micropollutant degradation in the presence of PAA under solar irradiation. This is the first study to comprehensively investigate the photodegradation of caffeine (CAF) and 4-methylbenzylidene camphor (4-MBC) and the removal of disinfection byproducts (DBPs) in the presence of PAA under simulated solar light. The study revealed that the photodegradation of CAF and 4-MBC was significantly enhanced in the presence of PAA, following pseudo-first-order kinetics (R 2 > 0.98) with reaction rates (k obs ) of 0.220 and 0.111 h -1 , respectively. In addition, substantial reduction of 21 DBPs, including trihalomethanes, haloacetic acids and haloacetonitriles, and no DBPs formation were observed in the presence of PAA and simulated solar irradiation. The proportion of coexisting H 2 O 2 in the PAA solution considerably influenced target compounds degradation. CAF and 4-MBC were degraded faster under acidic conditions than under alkaline conditions. Hydroxyl radicals (·OH) dominated the degradation of CAF at different pH values, while direct photolysis and other reactive species played a major role in the degradation of 4-MBC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS., Methods and Results: The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and β-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs ( P <0.001), whereas intermediate-risk patients had a 2.1-fold ( P =0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%., Conclusions: Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.

Head and neck squamous cell carcinoma (HNSCC) has a high mortality rate. In this study, we developed a Stokes-vector-derived polarized hyperspectral imaging (PHSI) system for H&E-stained pathological slides with HNSCC and built a dataset to develop a deep learning classification method based on convolutional neural networks (CNN). We use our polarized hyperspectral microscope to collect the four Stokes parameter hypercubes (S0, S1, S2, and S3) from 56 patients and synthesize pseudo-RGB images using a transformation function that approximates the human eye's spectral response to visual stimuli. Each image is divided into patches. Data augmentation is applied using rotations and flipping. We create a four-branch model architecture where each branch is trained on one Stokes parameter individually, then we freeze the branches and fine-tune the top layers of our model to generate final predictions. Our results show high accuracy, sensitivity, and specificity, indicating that our model performed well on our dataset. Future works can improve upon these results by training on more varied data, classifying tumors based on their grade, and introducing more recent architectural techniques.

Background: Pre-transplant deceased donor liver biopsy may impact decision making; however, interpretation of the results remains variable and depends on accepting center practice patterns., Methods: In this cohort study, adult recipients from 04/01/2015-12/31/2020 were identified using the UNOS STARfile data. The deceased donor liver biopsies were stratified by risk based on degree of fibrosis, macrovesicular fat content, and level of portal infiltration (low-risk: no fibrosis, no portal infiltrates, and <30% macrosteatosis; moderate-risk: some fibrosis or mild infiltrates and <30% macrosteatosis; high-risk: most fibrosis, moderate/marked infiltrates, or ≥30% macrosteatosis). Graft utilization, donor risk profile, and recipient outcomes were compared across groups., Results: Of the 51,094 donor livers available, 20,086 (39.3%) were biopsied, and 34,606 (67.7%) were transplanted. Of the transplanted livers, 14,908 (43.1%) were biopsied. The transplanted grafts had lower mean macrovesicular fat content (9.3% transplanted vs. 26.9% non-transplanted, P < 0.001) and less often had any degree of fibrosis (20.9% vs. 39.9%, P < 0.001) or portal infiltration (51.3% vs. 58.2%, P < 0.001) versus non-transplanted grafts. Post-transplant recipient LOS (14.2 days high-risk vs. 15.2 days low-risk, P = 0.170) and 1-year graft survival (90.5% vs. 91.7%, P = 0.137) did not differ significantly between high- versus low-risk groups. Kaplan-Meier survival estimates further revealed no differences in the 5-year graft survival across risk strata (P = 0.833). Of the 5178 grafts biopsied and turned down, PSM revealed 1338 (26.0%) were potentially useable based on biopsy results and donor characteristics., Conclusion: Carefully matched deceased donor livers with some fibrosis, inflammation, or steatosis ≥30% may be suitable for transplantation. Further study of this group of grafts may decrease turndowns of potentially useable organs., (© 2023 The Authors. World Journal of Surgery published by John Wiley & Sons Ltd on behalf of International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background: Historically, norepinephrine has been administered through a central venous catheter (CVC) because of concerns about the risk of ischemic tissue injury if extravasation from a peripheral IV catheter (PIVC) occurs. Recently, several reports have suggested that peripheral administration of norepinephrine may be safe., Research Question: Can a protocol for peripheral norepinephrine administration safely reduce the number of days a CVC is in use and frequency of CVC placement?, Study Design and Methods: This was a prospective observational cohort study conducted in the medical ICU at a quaternary care academic medical center. A protocol for peripheral norepinephrine administration was developed and implemented in the medical ICU at the study site. The protocol was recommended for use in patients who met prespecified criteria, but was used at the treating clinician's discretion. All adult patients admitted to the medical ICU receiving norepinephrine through a PIVC from February 2019 through June 2021 were included., Results: The primary outcome was the number of days of CVC use that were avoided per patient, and the secondary safety outcomes included the incidence of extravasation events. Six hundred thirty-five patients received peripherally administered norepinephrine. The median number of CVC days avoided per patient was 1 (interquartile range, 0-2 days per patient). Of the 603 patients who received norepinephrine peripherally as the first norepinephrine exposure, 311 patients (51.6%) never required CVC insertion. Extravasation of norepinephrine occurred in 35 patients (75.8 events/1,000 d of PIVC infusion [95% CI, 52.8-105.4 events/1,000 d of PIVC infusion]). Most extravasations caused no or minimal tissue injury. No patient required surgical intervention., Interpretation: This study suggests that implementing a protocol for peripheral administration of norepinephrine safely can avoid 1 CVC day in the average patient, with 51.6% of patients not requiring CVC insertion. No patient experienced significant ischemic tissue injury with the protocol used. These data support performance of a randomized, prospective, multicenter study to characterize the net benefits of peripheral norepinephrine administration compared with norepinephrine administration through a CVC., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Cortical hyperarousal and ruminative thinking are common aspects of insomnia that have been linked with greater connectivity in the default mode network (DMN). Therefore, disrupting network activity within the DMN may reduce cortical and cognitive hyperarousal and facilitate better sleep., Objective: This trial aims to establish a novel, noninvasive method for treating insomnia through disruption of the DMN with repetitive transcranial magnetic stimulation, specifically with continuous theta burst stimulation (cTBS). This double-blind, pilot randomized controlled trial will assess the efficacy of repetitive transcranial magnetic stimulation as a novel, nonpharmacological approach to improve sleep through disruption of the DMN prior to sleep onset for individuals with insomnia. Primary outcome measures will include assessing changes in DMN functional connectivity before and after stimulation., Methods: A total of 20 participants between the ages of 18 to 50 years with reported sleep disturbances will be recruited as a part of the study. Participants will then conduct an in-person screening and follow-on enrollment visit. Eligible participants then conduct at-home actigraphic collection until their first in-residence overnight study visit. In a double-blind, counterbalanced, crossover study design, participants will receive a 40-second stimulation to the left inferior parietal lobule of the DMN during 2 separate overnight in-residence visits. Participants are randomized to the order in which they receive the active stimulation and sham stimulation. Study participants will undergo a prestimulation functional magnetic resonance imaging scan and a poststimulation functional magnetic resonance imaging scan prior to sleep for each overnight study visit. Sleep outcomes will be measured using clinical polysomnography. After their first in-residence study visit, participants conduct another at-home actigraphic collection before returning for their second in-residence overnight study visit., Results: Our study was funded in September 2020 by the Department of Defense (W81XWH2010173). We completed the enrollment of our target study population in the October 2022 and are currently working on neuroimaging processing and analysis. We aim to publish the results of our study by 2024. Primary neuroimaging outcome measures will be tested using independent components analysis, seed-to-voxel analyses, and region of interest to region of interest analyses. A repeated measures analysis of covariance (ANCOVA) will be used to assess the effects of active and sham stimulation on sleep variables. Additionally, we will correlate changes in functional connectivity to polysomnography-graded sleep., Conclusions: The presently proposed cTBS protocol is aimed at establishing the initial research outcomes of the effects of a single burst of cTBS on disrupting the network connectivity of the DMN to improve sleep. If effective, future work could determine the most effective stimulation sites and administration schedules to optimize this potential intervention for sleep problems., Trial Registration: ClinicalTrials.gov NCT04953559; https://clinicaltrials.gov/ct2/show/NCT04953559., International Registered Report Identifier (irrid): DERR1-10.2196/51212., (©Lindsey Hildebrand, Alisa Huskey, Natalie Dailey, Samantha Jankowski, Kymberly Henderson-Arredondo, Christopher Trapani, Salma Imran Patel, Allison Yu-Chin Chen, Ying-Hui Chou, William D S Killgore. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.01.2024.)

The semiconductor industry has claimed that perfluorooctanesulfonate (PFOS), a persistent per- and polyfluoroalkyl substance (PFAS), has been eliminated from semiconductor production; however, information about the use of alternative compounds remains limited. This study aimed to develop a nontarget approach to discovering diverse PFAS substitutions used in semiconductor manufacturing. A distinct fragment-based approach has been established to identify the hydrophobic and hydrophilic features of acidic and neutral fluorosurfactants through fragments and neutral losses, including those outside the homologous series. Ten sewage samples from 5 semiconductor plants were analyzed with target and nontarget analysis. Among the 20 identified PFAS spanning 12 subclasses, 15 were reported in semiconductor sewage for the first time. The dominant identified PFAS compounds were C4 sulfonamido derivatives, including perfluorobutane sulfonamido ethanol (FBSE), perfluorobutane sulfonamide (FBSA), and perfluorobutane sulfonamido diethanol (FBSEE diol), with maximum concentrations of 482 μg/L, 141 μg/L, and 83.5 μg/L in sewage, respectively. Subsequently, three ultrashort chain perfluoroalkyl acids (PFAAs) were identified in all samples, ranging from 0.004 to 19.9 μg/L. Three effluent samples from the associated industrial wastewater treatment plants (WWTPs) were further analyzed. This finding, that the C4 sulfonamido acetic acid series constitutes a significant portion (65%-82%) of effluents from WWTP3 and WWTP4, emphasizes the conversion of fluorinated alcohols to fluorinated acids during aerobic treatment. The identification of the intermediate metabolites of FBSEE diol, further supported by our laboratory batch studies, prompts the proposal of a novel metabolic pathway for FBSEE diol. The total amount of perfluorobutane sulfonamido derivatives reached 1934 μg/L (90%), while that of PFAAs, which have typically received attention, was only 205 μg/L (10%). This suggests that perfluorobutane sulfonamido derivatives are emerging as a new trend in fluorosurfactants used in the semiconductor industry, serving as PFAS precursors and contributing to the release of their metabolites into the environment.

Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated and profiled in vitro and in vivo. Their selectivity, ready availability and CNS penetration should enable them to serve as the tool compounds of choice in future TRPML1 channel activation studies. SAR studies on conformationally locked macrocyclic analogs further improved the TRPML1 agonist potency while retaining the selectivity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: XP, CJH, AMFA, MGO, AYPC, RG, SMM, GK, RSH, JFB, JCL and DAB are currently, or were at the time the work was performed, employees of Arkuda Therapeutics with stock ownership. MS and AP are currently, or were at the time the work was performed, employees of BioAscent Discovery Ltd. MRO and IDF are currently, or were at the time the work was performed, employees of Symeres Inc. Both BioAscent Discovery Ltd and Symeres Inc have been business partners with Arkuda Therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Precision targeting is crucial to successful stereotactic radiosurgery for trigeminal neuralgia (TGN). We investigated the impact of intra-fractional 6-dimensional corrections during frameless image-guided radiosurgery (IGRS) for pain outcome in TGN patients., Materials and Methods: A total of 41 sets of intra-fractional corrections from 35 patients with TGN treated by frameless IGRS from 2009 to 2013 were retrospectively studied. For each IGRS, the intra-fractional 6-dimensional shifts were conducted at 6 couch angles. Clinical pain outcome was recorded according the Barrow Neurological Institute (BNI) 5-points score. The relationship in 6-dimensional corrections and absolute translational distances between patients with pain relief score points <2 versus ≥2 were analyzed., Results: The absolute mean lateral, longitudinal, and vertical translational shifts were 0.46 ± 0.15 mm, 0.36 ± 0.16 mm and 0.21 ± 0.08 mm, respectively, with 97% of translational shifts being within 0.7 mm. The absolute mean lateral (pitch), longitudinal (roll), and vertical (yaw) rotational corrections are 0.33 ± 0.24°, 0.18 ± 0.09°, and 0.27 ± 0.15°, respectively, with 97% of rotational corrections being within 0.6°. The median follow-up duration for pain outcome was 26 months after IGRS. The average calculated absolute shift for patients with pain relief <2 and ≥2 BNI points, were 0.228 ± 0.008 mm and 0.259 ± 0.007 mm, respectively. There was no statistically significant difference in the translational shifts, rotational corrections or absolute distances between these two patient groups., Conclusions: Our data demonstrate high spatial targeting accuracy of frameless IGRS for TGN with only nominal intra-fraction 6-dimensional corrections., Competing Interests: The authors would like to thank Ms. Q-J. Li’s kindly assistance in data retrieval, as well as Dr. Patricia Chen for helpful comments during preparation of the manuscript and for critical reading of the manuscript. Authors’ disclosure of potential conflicts of interest The authors have nothing to disclose., (© 2024 Old City Publishing, Inc.)

Significance: Polarized hyperspectral microscopes with the capability of full Stokes vector imaging have potential for many biological and medical applications., Aim: The aim of this study is to investigate polarized hyperspectral imaging (PHSI) for improving the visualization of collagen fibers, which is an important biomarker related to tumor development, and improving the differentiation of normal and tumor cells on pathologic slides., Approach: We customized a polarized hyperspectral microscopic imaging system comprising an upright microscope with a motorized stage, two linear polarizers, two liquid crystal variable retarders (LCVRs), and a compact SnapScan hyperspectral camera. The polarizers and LCVRs worked in tandem with the hyperspectral camera to acquire polarized hyperspectral images, which were further used to calculate four Stokes vectors: S 0 , S 1 , S 2 , and S 3 . Synthetic RGB images of the Stokes vectors were generated for the visualization of cellular components in PHSI images. Regions of interest of collagen, normal cells, and tumor cells in the synthetic RGB images were selected, and spectral signatures of the selected components were extracted for comparison. Specifically, we qualitatively and quantitatively investigated the enhanced visualization and spectral characteristics of dense fibers and sparse fibers in normal stroma tissue, fibers accumulated within tumors, and fibers accumulated around tumors., Results: By employing our customized polarized hyperspectral microscope, we extract the spectral signatures of Stokes vector parameters of collagen as well as of tumor and normal cells. The measurement of Stokes vector parameters increased the image contrast of collagen fibers and cells in the slides., Conclusions: With the spatial and spectral information from the Stokes vector data cubes ( S 0 , S 1 , S 2 , and S 3 ), our PHSI microscope system enhances the visualization of tumor cells and tumor microenvironment components, thus being beneficial for pathology and oncology., (© 2024 The Authors.)

Background: To achieve equitable access to cancer clinical trials (CCTs), patients must overcome structural, clinical, and attitudinal barriers to trial enrollment. The goal of this systematic review was to study the relationship between socioeconomic status (SES), assessed either by direct or proxy measures, and CCT enrollment., Methods: The review team and medical librarian developed search strategies for each database to identify studies for this systematic review, which was conducted according to PRISMA guidelines. Inclusion criteria were as follows: studies published in relevant scientific journals between January 2000 and July 2022, primary sources, English literature, and studies conducted in the US. Sixteen studies fulfilled the inclusion criteria and were reviewed. The risk of bias assessment was conducted independently by two reviewers using the Newcastle Ottawa scale., Results: The initial search yielded 4070 citations, and 16 studies were included in our review. Four of the studies included used patient reported annual income as a measure of SES, while the remaining 12 studies used patient zip code as a proxy measurement of SES. Consistent with our hypothesis, 13 studies showed a positive association between high SES (patient-reported or proxy measurement) and CCT enrollment. Two studies showed a negative association, and one study showed no relationship., Conclusions: The existing literature suggests that low SES is associated with lower participation in CCT. The small number of studies identified on this topic highlights the need for additional research on SES and other barriers to CCT participation., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4+ BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.

Background: Disuse atrophy is a frequent cause of muscle atrophy, which can occur in individuals of any age who have been inactive for a prolonged period or immobilization. Additionally, acute diseases such as COVID-19 can cause frequent sequelae and exacerbate muscle wasting, leading to additional fatigue symptoms. It is necessary to investigate potent functional nutrients for muscle reinforcement in both disuse atrophy and fatigue to ensure better physical performance., Methods: The effects of Sanghuangporus sanghuang SS-MN4 mycelia were tested on two groups of 6-week-old male mice-one with disuse atrophy and the other with fatigue. The disuse atrophy group was divided into three sub-groups: a control group, a group that underwent hind limb casting for 7 days and then recovered for 7 days and a group that was administered with SS-MN4 orally for 14 days, underwent hind limb casting for 7 days and then recovered for 7 days. The fatigue group was divided into two sub-groups: a control group that received no SS-MN4 intervention and an experimental group that was administered with SS-MN4 orally for 39 days and tested for exhaustive swimming and running on Day 31 and Day 33, respectively. RNA sequencing (RNA-seq) and western blot analysis were conducted on C2C12 cell lines to identify the therapeutic effects of SS-MN4 treatment., Results: In a disuse atrophy model induced by hind limb casting, supplementing with 250 mg/kg of SS-MN4 for 14 days led to 111.2% gastrocnemius muscle mass recovery and an 89.1% improvement in motor function on a treadmill (P < 0.05). In a fatigue animal model, equivalent SS-MN4 dosage improved swimming (178.7%) and running (162.4%) activities (P < 0.05) and reduced blood urea nitrogen levels by 18% (P < 0.05). SS-MN4 treatment also increased liver and muscle glycogen storage by 34.36% and 55.6%, respectively, suggesting a higher energy reserve for exercise. RNA-seq and western blot studies from the C2C12 myotube showed that SS-MN4 extract upregulates Myh4 and helps sustain myotube integrity against dexamethasone damage., Conclusions: Supplementation of SS-MN4 (250-mg/kg body weight) with hispidin as active compound revealed a potential usage as a muscle nutritional supplement enhancing muscle recovery, fast-twitch fibre regrowth and fatigue resistance., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Both selective and nonselective beta-blockers are used to treat patients with heart failure (HF). However, the data on the association of beta-blocker type with risk of atrial arrhythmia and ventricular arrhythmia (VA) in HF patients with a primary prevention implantable cardioverter-defibrillator (ICD) are limited., Objectives: This study sought to evaluate the effect of metoprolol vs carvedilol on the risk of atrial tachyarrhythmia (ATA) and VA in HF patients with an ICD., Methods: This study pooled primary prevention ICD recipients from 5 landmark ICD trials (MADIT-II, MADIT-CRT, MADIT-RIT, MADIT-RISK, and RAID). Fine and Gray multivariate regression models, stratified by study, were used to evaluate the risk of ATA, inappropriate ICD shocks, and fast VA (defined as ventricular tachycardia ≥200 beats/min or ventricular fibrillation) by beta-blocker type., Results: Among 4,194 patients, 2,920 (70%) were prescribed carvedilol and 1,274 (30%) metoprolol. The cumulative incidence of ATA at 3.5 years was 11% in patients treated with carvedilol vs 15% in patients taking metoprolol (P = 0.003). Multivariate analysis showed that carvedilol treatment was associated with a 35% reduction in the risk of ATA (HR: 0.65; 95% CI: 0.53-0.81; P < 0.001) when compared to metoprolol, and with a corresponding 35% reduction in the risk of inappropriate ICD shocks (HR: 0.65; 95% CI: 0.47-0.89; P = 0.008). Carvedilol vs metoprolol was also associated with a 16% reduction in the risk of fast VA. However, these findings did not reach statistical significance (HR: 0.84; 95% CI: 0.70-1.02; P = 0.085)., Conclusions: These findings suggests that HF patients with ICDs on carvedilol treatment experience a significantly lower risk of ATA and inappropriate ICD shocks when compared to treatment with metoprolol., Competing Interests: Funding Support and Author Disclosures Each of the MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The MADIT-RISK study was supported by the National Heart, Lung, and Blood Institute grant HL077478. The RAID trial was supported by National Heart, Lung, and Blood Institute grants UO1 HL096607 and UO1 HL096610 and by Gilead Sciences Inc grant IN-US-259-0125. Dr Goldenberg has received research grants from Boston Scientific, ZOLL Medical Corporation, Medtronic, Biosense-Webster, and Biotronik. Dr Kutyifa has received research grants from Boston Scientific, Biotronik, and ZOLL Medical Corporation, and Spire Inc; and has consulting agreements with ZOLL Medical Corporation and Biotronik. Dr Steinberg has received research grants from the National Institutes of Health, Medtronic, AliveCor, and Atricure. Dr Zareba has received research grants from Boston Scientific. Dr Aktas has received research grants from Boston Scientific, Abbott, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This pilot feasibility study aimed to evaluate the effects of transcranial magnetic stimulation (TMS) on chemotherapy-related cognitive impairment (CRCI), and we report here on the first patient., Background: Deleterious cognitive changes due to chemotherapy or CRCI are commonly referred to as "chemo brain". With the increasing survival of cancer patients, this poorly understood and inadequately treated condition will likewise have an increasing toll on individuals and society. Since there is no approved treatment for chemo brain, we have initiated a therapeutic trial using transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique approved in many countries for the treatment of neurologic and psychiatric conditions like migraine and depression., Case Presentation: A 58-year-old woman, diagnosed 7 years prior with left breast cancer, underwent partial mastectomy with sentinel lymph node biopsy. She then received four cycles of adjuvant chemotherapy followed by radiation therapy. Afterwards, she was on tamoxifen for 4 years and then switched to aromatase inhibitors. The patient's CRCI started during chemotherapy and severely impaired her quality of life for an additional two years. In the third year after chemotherapy, the CRCI partially cleared to stabilize to the level at the time of presentation for this trial. The patient continues to have memory difficulties and decreased concentration, which makes multi-tasking very difficult to impossible. She is reliant on memory aids at work and at home. The participant underwent 10 consecutive sessions of TMS during weekdays for 2 weeks. Stimulation was directed to the left dorsolateral prefrontal cortex. After TMS, the participant significantly improved in memory function on neuropsychological testing. While she reported no subjective differences in concentration or memory, she did report an improvement in her sleep. Functional magnetic resonance imaging of the brain before and after TMS showed increased resting-state functional connectivity between the stimulation site and several brain regions. Remarkably, after 6 years of chemo brain and remaining in the same position at work due to her inability to concentrate and multi-task, she applied for and received a promotion 5-6 months after her TMS treatments., Conclusions: This first patient in the phase 1 clinical trial testing of TMS for the treatment of "chemo brain" provided important lessons for feasibility and insights into mechanisms of potential benefit.

Axions can be copiously produced in localized regions of neutron star magnetospheres where the ambient plasma is unable to efficiently screen the induced electric field. As these axions stream away from the neutron star they can resonantly transition into photons, generating a large broadband contribution to the neutron star's intrinsic radio flux. In this Letter, we develop a comprehensive end-to-end framework to model this process from the initial production of axions to the final detection of radio photons, and derive constraints on the axion-photon coupling, g&#95;{aγγ}, using observations of 27 nearby pulsars. We study the modeling uncertainty in the sourced axion spectrum by comparing predictions from 2.5 dimensional particle-in-cell simulations with those derived using a semianalytic model; these results show remarkable agreement, leading to constraints on the axion-photon coupling that typically differ by a factor of no more than ∼2. The limits presented here are the strongest to date for axion masses 10^{-8}  eV≲m&#95;{a}≲10^{-5}  eV, and crucially do not rely on the assumption that axions are dark matter.

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions., Competing Interests: Declaration of interests F.B. received research awards (Gilead and Kite and Bristol Myers Squibb Foundation Immunonkologie). E.S. was an advisor for Arsenal Biosciences. J.E. is a compensated co-founder at Mnemo Therapeutics and compensated scientific advisor to Cytovia Therapeutics. J.E. owns stocks in Mnemo Therapeutics and Cytovia Therapeutics. J.E. has received a consulting fee from Casdin Capital. The Eyquem lab has received research support from Cytovia Therapeutics and Takeda. T.L.R. is a compensated co-founder, member of the scientific advisory board, and previously worked as the CSO of Arsenal Biosciences. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. C.T.M. is a compensated Bio+Health Venture Fellow at Andreessen Horowitz. C.J.Y. is founder for and holds equity in DropPrint Genomics (now ImmunAI) and Survey Genomics, a scientific advisory board member for and holds equity in Related Sciences and ImmunAI, a consultant for and holds equity in Maze Therapeutics, and a consultant for TReX Bio, HiBio, ImYoo, and Santa Ana. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, Genentech, BioLegend, ScaleBio, and Illumina. A.M. is a co-founder of Arsenal Biosciences, Spotlight Therapeutics, and Survey Genomics, serves on the boards of directors at Spotlight Therapeutics and Survey Genomics, is a board observer (and former member of the board of directors) at Arsenal Biosciences, is a member of the scientific advisory boards of Arsenal Biosciences, Spotlight Therapeutics, Survey Genomics, NewLimit, Amgen, Tenaya, and Lightcast, owns stock in Arsenal Biosciences, Spotlight Therapeutics, NewLimit, Survey Genomics, PACT Pharma, Tenaya, and Lightcast and has received fees from Arsenal Biosciences, Spotlight Therapeutics, Survey Genomics, NewLimit, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Lightcast, GLG, Gilead, Trizell, Vertex, Merck, Amgen, Genentech, AlphaSights, Rupert Case Management, Bernstein, and ALDA. A.M. is an investor in and informal advisor to Offline Ventures and a client of EPIQ. The Marson laboratory received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. T.L.R., F.B., A.M., R.A., Y.Y.C., C.T.M., and E.S. are listed on patent applications related to this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Do online platforms facilitate the consumption of potentially harmful content? Using paired behavioral and survey data provided by participants recruited from a representative sample in 2020 ( n = 1181), we show that exposure to alternative and extremist channel videos on YouTube is heavily concentrated among a small group of people with high prior levels of gender and racial resentment. These viewers often subscribe to these channels (prompting recommendations to their videos) and follow external links to them. In contrast, nonsubscribers rarely see or follow recommendations to videos from these channels. Our findings suggest that YouTube's algorithms were not sending people down "rabbit holes" during our observation window in 2020, possibly due to changes that the company made to its recommender system in 2019. However, the platform continues to play a key role in facilitating exposure to content from alternative and extremist channels among dedicated audiences.

Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases., Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations., Design, Setting, and Participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control., Main Outcomes and Measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed., Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families., Conclusions and Relevance: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.

Medullary thyroid carcinoma (MTC), an uncommon C cell thyroid malignancy, accounts for a disproportionate number of thyroid cancer deaths. To predict MTC clinical behavior, the recent international MTC grading system (IMTCGS) was published combining features from the Memorial Sloan Kettering Cancer Center and Royal North Shore Hospital grading systems that incorporates mitotic count, necrosis, and Ki67 proliferative index (Ki67PI). The IMTCGS appears promising, but independent validation data are limited. Here, we applied the IMTCGS to our institutional MTC cohort and assessed its ability to predict clinical outcomes. Our cohort comprised 87 MTCs (30 germline and 57 sporadic). Slides for each case were reviewed by 2 pathologists and histologic features recorded. Ki67 immunostaining was performed on all cases. Each MTC was graded with the IMTCGS based on tumor necrosis, Ki67PI, and mitotic count. Cox regression analysis was performed to assess the impact of various clinical and pathological data on disease outcomes, including overall survival (OS), disease-free survival, disease-specific survival (DSS), and distant metastasis-free survival. In our MTC cohort, 18.4% (n = 16/87) were IMTCGS high grade. IMTCGS grade was strongly prognostic for OS, disease-free survival, DSS, and distant metastasis-free survival on univariate analysis and multivariable analysis in both the entire MTC cohort and in the sporadic subset. Among the individual IMTCGS parameters, while all 3 were associated with poorer survival outcomes on univariate analysis, necrosis had the strongest association with all survival parameters on multivariable analysis, whereas Ki67PI or mitotic count was associated only with OS and DSS. This retrospective study independently demonstrates that the IMTCGS is valid for grading MTCs. Our findings support incorporating IMTCGS into routine pathology practice. IMTCGS grading may help clinicians to better predict the prognosis of MTC. Future studies may shed light on how MTC grading should impact treatment protocols., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many psychostimulants, like cocaine, inhibit the dopamine transporter (DAT), which is largely thought to account for actions related to their misuse and dependence. Cocaine-like, typical DAT inhibitors preferentially bind DAT in an outward-facing conformation, while atypical DAT inhibitors, like modafinil, prefer a more inward-facing DAT conformation. Modafinil and R -modafinil have emerged as potential therapeutic options for selected populations of individuals affected by PSUD. In addition, analogs of modafinil (JJC8-088 and JJC8-091) with different pharmacological profiles have been explored as potential PSUD medications in preclinical models. In this work, we employ fast scan cyclic voltammetry (FSCV) to probe nucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 male and female mice. We find that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. R -Modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for PSUD.

Background: Evidence regarding acute kidney injury associated with concomitant administration of vancomycin and piperacillin-tazobactam is conflicting, particularly in patients in the ICU., Research Question: Does a difference exist in the association between commonly prescribed empiric antibiotics on ICU admission (vancomycin and piperacillin-tazobactam, vancomycin and cefepime, and vancomycin and meropenem) and acute kidney injury?, Study Design and Methods: This was a retrospective cohort study using data from the eICU Research Institute, which contains records for ICU stays between 2010 and 2015 across 335 hospitals. Patients were enrolled if they received vancomycin and piperacillin-tazobactam, vancomycin and cefepime, or vancomycin and meropenem exclusively. Patients initially admitted to the ED were included. Patients with hospital stay duration of < 1 h, receiving dialysis, or with missing data were excluded. Acute kidney injury was defined as Kidney Disease: Improving Global Outcomes stage 2 or 3 based on serum creatinine component. Propensity score matching was used to match patients in the control (vancomycin and meropenem or vancomycin and cefepime) and treatment (vancomycin and piperacillin-tazobactam) groups, and ORs were calculated. Sensitivity analyses were performed to study the effect of longer courses of combination therapy and patients with renal insufficiency on admission., Results: Thirty-five thousand six hundred fifty-four patients met inclusion criteria (vancomycin and piperacillin-tazobactam, n = 27,459; vancomycin and cefepime, n = 6,371; vancomycin and meropenem, n = 1,824). Vancomycin and piperacillin-tazobactam was associated with a higher risk of acute kidney injury and initiation of dialysis when compared with that of both vancomycin and cefepime (Acute kidney injury: OR, 1.37 [95% CI, 1.25-1.49]; dialysis: OR, 1.28 [95% CI, 1.14-1.45]) and vancomycin and meropenem (Acute kidney injury: OR, 1.27 [95%, 1.06-1.52]; dialysis: OR, 1.56 [95% CI, 1.23-2.00]). The odds of acute kidney injury developing was especially pronounced in patients without renal insufficiency receiving a longer duration of vancomycin and piperacillin-tazobactam therapy compared with vancomycin and meropenem therapy., Interpretation: VPT is associated with a higher risk of acute kidney injury than both vancomycin and cefepime and vancomycin and meropenem in patients in the ICU, especially for patients with normal initial kidney function requiring longer durations of therapy. Clinicians should consider vancomycin and meropenem or vancomycin and cefepime to reduce the risk of nephrotoxicity for patients in the ICU., (Published by Elsevier Inc.)

Background: Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood., Methods: The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9 STINGwt or RMS 76-9 STING-/- , along with other murine tumor models, in C57BL/6 or STING -/- ( TMEM173 -/- ) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME)., Results: The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components., Conclusions: Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine the progress made in recent decades by assessing the employment rates of Black and non-Hispanic White (NHW) patients after traumatic brain injury (TBI), controlling for pre-TBI employment status and education status., Design: Retrospective analysis in a cohort of patients treated in Southeast Michigan at major trauma centers in more recent years (February 2010 to December 2019)., Setting: Southeastern Michigan Traumatic Brain Injury Model System (TBIMS): 1 of 16 TBIMSs across the United States., Participants: NHW (n=81) and Black (n=188) patients with moderate/severe TBI (N=269)., Intervention: Not applicable., Main Outcome Measures: Employment status, which is separated into 2 categories: student plus competitive employment and noncompetitive employment., Results: In 269 patients, NHW patients had more severe initial TBI, measured by percentage brain computed tomography with compression causing >5-mm midline shift (P<.001). Controlling for pre-TBI employment status, we found NHW participants who were students or had competitive employment prior to TBI had higher rates of competitive employment at 2-year (P=.03) follow-up. Controlling for pre-TBI education status, we found no difference in competitive and noncompetitive employment rates between NHW and Black participants at all follow-up years., Conclusions: Black patients who were students or had competitive employment before TBI experience worse employment outcomes than their NHW counterparts after TBI at 2 years post TBI. Further research is needed to understand better the factors driving these disparities and how social determinants of health affect these racial differences after TBI., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)