A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis.

Tissue fibrosis contributes to pathology in vital organs including the lung. Curative therapies are scant. Myofibroblasts, pivotal effector cells in tissue fibrosis, accumulate via incompletely understood interactions with their microenvironment. In an investigative platform grounded in experimental lung biology, we find that sympathetic innervation stimulates fibrotic remodeling via noradrenergic α1-adrenergic receptor engagement in myofibroblasts. We demonstrate the anti-fibrotic potential of targeted sympathetic denervation and pharmacological disruption of noradrenergic neurotransmitter functions mediated by α1-adrenoreceptors (α1-ARs). Using the α1-adrenoreceptor subtype D as a representative α1-AR, we discover direct noradrenergic input from sympathetic nerves to lung myofibroblasts utilizing established mouse models, genetic denervation, pharmacologic interventions, a newly invented transgenic mouse line, advanced tissue mimetics, and samples from patients with diverse forms of pulmonary fibrosis. The discovery of this previously unappreciated nerve-fibroblast axis in the lung demonstrates the crucial contribution of nerves to tissue repair and heralds a novel paradigm in fibrosis research.

Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism.

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimer's disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosylceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results suggest that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases.

Distribution and Disparities of Industry Payments to Neuroradiologists.

BACKGROUND AND PURPOSE: Physician-industry relationships can be useful for driving innovation and technologic progress, though little is known about the scale or impact of industry involvement in neuroradiology. The purpose of this study was to assess the trends and distributions of industry payments to neuroradiologists. MATERIALS AND METHODS: Neuroradiologists were identified using a previously-validated method based on Work Relative Value Units and Neiman Imaging Types of Service classification. Data on payments from industry were obtained from the Open Payments database from the Centers for Medicare & Medicaid Services, from 2016 to 2021. Payments were grouped into 7 categories, including consulting fees, education, gifts, medical supplies, research, royalties/ownership, and speaker fees. Descriptive statistics were calculated. RESULTS: A total of 3019 neuroradiologists were identified in this study. Between 2016 and 2021, 48% (1440/3019) received at least 1 payment from industry, amounting to a total number of 21,967 payments. Each year, among those receiving payments from industry, each unique neuroradiologist received between a mean of 5.49-7.42 payments and a median of 2 payments, indicating a strong rightward skew to the distribution of payments. Gifts were the most frequent payment type made (60%, 13,285/21,967) but accounted for only 4.1% ($689,859/$17,010,546) of payment value. The greatest aggregate payment value came from speaker fees, which made up 36% ($6,127,484/$17,010,546) of the total payment value. The top 5% highest paid neuroradiologists received 42% (9133/21,967) of payments, which accounted for 84% ($14,284,120/$17,010,546) of the total dollar value. Since the start of the coronavirus 2019 (COVID-19) pandemic, the number of neuroradiologists receiving industry payments decreased from a mean of 671 neuroradiologists per year prepandemic (2016-2019) to 411 in the postpandemic (2020-2021) era (P = .030). The total number of payments to neuroradiologists decreased from 4177 per year prepandemic versus 2631 per year postpandemic (P = .011). CONCLUSIONS: Industry payments to neuroradiologists are highly concentrated among top earners, particularly among the top 5% of payment recipients. The number of payments decreased during the COVID-19 pandemic, though the dollar value of payments was offset by coincidental increases in royalty payments. Further investigation is needed in subsequent years to determine if the postpandemic changes in industry payment trends continue.

Proportion of industry payment value by category in radiology relative to other specialties.

BACKGROUND: Industry payments to physicians are common, but it is unknown how the payments in different categories to radiologists compare to other specialties. OBJECTIVE: The aim of this study is to assess the proportion of industry payments to physicians in radiology in certain categories relative to other specialties. METHODS: The Open Payments Database was analyzed from January 1, 2017 to December 31, 2021 for industry payments to all allopathic & osteopathic physicians, and classified into distinct clinical specialties. Payments to physicians in three categories were calculated in relation to total payments in each specialty during the study period: consulting fees, research, and royalties/ownership (royalty, license, or current or prospective ownership or investment). RESULTS: The total value of industry payments to physicians across all specialties was just under $13 billion over the six-year period from 2017 to 2022. During this period, 51.4 million total payments were made to 791,746 physicians. US physicians in radiology received 452,027 payments for a total value of $357 million (2.8 % of total value). For radiologists, 32.8 % of industry payment value was attributed to royalties/ownership and 9.9 % to research, collectively adding up to 42.7 % of all industry payment. The only specialties with higher payments in these two categories considered reflective of innovation payments were the surgical specialties with higher royalty payments. CONCLUSION: The proportion of industry payments in radiology in categories reflecting innovation (royalty/ownership and research fees) is high and second only to surgical specialties.

Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts.

INTRODUCTION: The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. METHODS: We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. RESULTS: Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. DISCUSSION: In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease.

Industry relationships with interventional radiologists: Who are the high payment physicians?

PURPOSE: To identify characteristics of interventional radiologists receiving more than $100,000 in general industry payments over a 5-year period (2017-2021). METHODS: The Open Payments database was queried to identify interventional radiologists who received more than $100,000 in consulting fees, speaker fees, education, and/or gifts over a 5-year period from 2017 to 2021. The national provider identifier registry, Scopus, and a web-based search were used to identify physician characteristics, such as demographics, research profile, leadership positions, and social media presence. RESULTS: From 2017-2021, 125 interventional radiologists received cumulative payments greater than $100,000 in consulting fees, speaker fees, education, and gifts. For this subset of physicians, the median (IQR) cumulative payment value was $214,380 ($141,812 - $383,740), and the total payment value was $40 million. While the highest-paid subset of physicians represented only 3 % (125/4272) of all US interventional radiologists paid by industry, the total payment value represented 66 % ($40,039,610.08/$60,859,025) of the total payment value among all interventional radiologists. 47 % (59/125) had faculty appointments and 30 % (37/125) had hospital leadership positions. 22 % (27/125) were clinical practice guideline authors, while 18 % (23/125) served on journal editorial boards and 12 % (15/125) had positions in specialty association leadership. Castle Connolly recognized 26 % (32/125) as top doctors. Among the 96 % (120/125) with published research in the past 5 years, the median (IQR) H-index was 17 (7-31). 38 % (48/125) had a presence on Twitter with a median (IQR) Kardashian index of 2.03 (0.48-6.16). CONCLUSION: A small subset of interventional radiologists receive large payments from drug and medical device companies. These physicians are leaders in their field with influence in hospitals, research, associations, and social media. Further work is needed to understand how the concentration of these payments affects decisions in clinical practice and policy.

cGAS Expression is Enhanced in Systemic Sclerosis Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation.

Objective: The lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The innate immune DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model. Methods: Expression and localization of cGAS, cytokines, and type 1 interferons were evaluated in SSc-ILD lung tissues, bronchoalveolar lavage (BAL), and isolated lung fibroblasts. CGAS activation was assessed in a publicly available SSc-ILD single cell RNA sequencing dataset. Production of cytokines, type 1 interferons, and αSMA elicited by TGFß1 or local substrate stiffness were measured in normal human lung fibroblasts (NHLFs) via qRT-PCR, ELISA, and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human PCLS, and the bleomycin pulmonary fibrosis model. Results: SSc-ILD lung tissue and BAL are enriched for cGAS, cytokines, and type 1 interferons. The cGAS pathway shows constitutive activation in SSc-ILD fibroblasts and is inducible in NHLFs by TGFß1 or mechanical stimuli. In these settings, and in human PCLS, cGAS expression is paralleled by the production of cytokines, type 1 interferons, and αSMA that are mitigated by a small molecule cGAS inhibitor. These findings are recapitulated in the bleomycin mouse model. Conclusion: cGAS signaling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc-ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.

Patient Perspectives on a Digital Assistant for Medication Reconciliation: An Interview Study Comparing Socioeconomic Groups.

Medication reconciliation, the process of documenting a patient's medication, is currently a time-consuming and labor-intensive process. To make medication reconciliation more efficient, digital assistants (DAs) offer a promising solution. Especially since human-like digital interfaces tend to be appreciated by more vulnerable populations such as patients in a low socioeconomic position (SEP). Despite the potential of DAs for low-SEP populations in particular, these groups are often not involved during the development and design phase of such digital health interventions. This exclusion may explain the lower adoption rates of digital interventions among low-SEP patients and exacerbate the so-called digital divide. We explored the perceptions and needs of patients across the SEP gradient using a participatory design approach. Patients of low-, middle-, and high-SEP backgrounds were asked to interact with a DA developed for this study and were interviewed afterward. A thematic analysis revealed seven themes regarding design, input method, comprehensibility, privacy concerns, benefits, the intention to use, and reassurance. Overall, patients were afraid to make mistakes in their medication entries and therefore valued feedback from the system or caregivers. Low-SEP patients specifically seemed to value more structured input methods when using the DA, while high-SEP patients emphasized the importance of a secure environment for the DA and sought clarity about its functionalities. Our study demonstrates the importance of involving patients across the socioeconomic gradient when developing a digital health tool and offers concrete recommendations for inclusive DA design for researchers and developers.

Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA). OBJECTIVES: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor. METHODS: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. MEASUREMENTS AND MAIN RESULTS: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFß1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. CONCLUSIONS: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

Utilising raw psycho-physiological data and functional data analysis for estimating mental workload in human drivers.

Recent studies have focused on accurately estimating mental workload using machine learning algorithms and extracting features from physiological measures. However, feature extraction leads to the loss of valuable information and often results in binary classifications that lack specificity in the identification of optimum mental workload. This study investigates the feasibility of using raw physiological data (EEG, facial EMG, ECG, EDA, pupillometry) combined with Functional Data Analysis (FDA) to estimate the mental workload of human drivers. A driving scenario with five tasks was employed, and subjective ratings were collected. Results demonstrate that the FDA applied nine different combinations of raw physiological signals achieving a maximum 90% accuracy, outperforming extracted features by 73%. This study shows that the mental workload of human drivers can be accurately estimated without utilising burdensome feature extraction. The approach proposed in this study offers promise for mental workload assessment in real-world applications.

This study aimed to estimate the mental workload of human drivers using physiological signals and Functional Data Analysis (FDA). By comparing models using raw data and extracted features, the results show that the FDA with raw data achieved a high accuracy of 90%, outperforming the model with extracted features (73%).

Salary Equity in Academic Radiology Relative to Other Clinical Specialties.

BACKGROUND: Equity in faculty compensation in U.S. academic radiology physicians relative to other specialties is not well known. OBJECTIVE: The aim of this study is to assess salary equity in U.S. academic radiology physicians at different ranks relative to other clinical specialties. METHODS: The American Association of Medical Colleges (AAMC) Faculty Salary Survey was used to collect information for full-time faculty at U.S. medical schools. Financial compensation data were collected for 2023 for faculty with MD or equivalent degree in medical specialties, stratified by gender and rank. RESULTS: The AAMC Faculty Salary Survey data for 2023 included responses for 97,224 faculty members in clinical specialties, with 5847 faculty members in Radiology departments. In radiology, compared to men (n = 3839), the women faculty members (n = 1763) had a lower median faculty compensation by 6% at the rank of Assistant Professor, 3% for Associate Professors, 4% for Professors and 6% for Section Chief positions. Surgery had the highest difference in median compensation with 21%, 24%, 22% and 19% lower faculty compensation, respectively, for women faculty members at corresponding ranks. Pathology had the lowest percent difference (<1%) in median compensation for all professor ranks. Salary inequity in radiology was lower compared to most other specialties. From assistant to full professors, all other clinical specialties except Pathology and Psychiatry, had a greater salary inequity than Radiology. CONCLUSION: The salary inequity in academic radiology faculty is lower than most other specialties. Further efforts should be made to reduce salary inequities as broader efforts to provide a more diverse, equitable and inclusive environment. SUMMARY STATEMENT: Salary inequity in academic radiology faculty is lower than most other specialties.

Transurethral En Bloc Resection Versus Standard Resection of Bladder Tumour: A Randomised, Multicentre, Phase 3 Trial.

BACKGROUND AND OBJECTIVE: Conventionally, standard resection (SR) is performed by resecting the bladder tumour in a piecemeal manner. En bloc resection of the bladder tumour (ERBT) has been proposed as an alternative technique in treating non-muscle-invasive bladder cancer (NMIBC). The objective of this study is to investigate whether ERBT could improve the 1-yr recurrence rate of NMIBC, as compared with SR. METHODS: A multicentre, randomised, phase 3 trial was conducted in Hong Kong. Adults with bladder tumour(s) of ≤ 3cm were enrolled from April 2017 to December 2020, and followed up until 1 yr after surgery. Patients were randomly assigned to receive either ERBT or SR in a 1:1 ratio. The primary outcome was 1-yr recurrence rate. A modified intention-to-treat analysis on patients with histologically confirmed NMIBC was performed. The main secondary outcomes included detrusor muscle sampling rate, operative time, hospital stay, 30-d complications, any residual or upstaging of disease upon second-look transurethral resection, and 1-yr progression rate. KEY FINDINGS AND LIMITATIONS: A total of 350 patients underwent randomisation, and 276 patients were histologically confirmed to have NMIBC. At 1 yr, 31 patients in the ERBT group and 46 in the SR group developed recurrence; the Kaplan-Meier estimate of 1- yr recurrence rates were 29% (95% confidence interval, 18-37) in the ERBT group and 38% (95% confidence interval, 28-46) in the SR group (p = 0.007). Upon a subgroup analysis, patients with 1-3 cm tumour, single tumour, Ta disease, or intermediate-risk NMIBC had a significant benefit from ERBT. None of the patients in the ERBT group and three patients in the SR group developed progression to muscle-invasive bladder cancer; the Kaplan-Meier estimates of 1-yr progression rates were 0% in the ERBT group and 2.6% (95% confidence interval, 0-5.5) in the SR group (p = 0.065). The median operative time was 28 min (interquartile range, 20-45) in the ERBT group and 22 min (interquartile range, 15-30) in the SR group (p < 0.001). All other secondary outcomes were similar in the two groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with NMIBC of ≤ 3cm, ERBT resulted in a significant reduction in the 1-yr recurrence rate when compared with SR. The study results support ERBT as the first-line surgical treatment for patients with bladder tumours of≤ 3cm.

Quantitative HBeAg is a strong predictor of HBeAg loss among patients receiving pegylated interferon.

BACKGROUND: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy. AIM: To evaluate the use of serum biomarkers to predict HBeAg loss. METHODS: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated. RESULTS: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm. CONCLUSIONS: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon.

Diabetes Research Matters: A Three-Round Priority-Setting Survey Consultation with Adults Living with Diabetes and Family Members in Australia.

OBJECTIVE: We aimed to identify the health and quality-of-life research priorities of Australians with diabetes or family members. METHODS: Through an iterative, three-step, online survey process we (1) qualitatively generated research topics (long list) in response to one question "What research is needed to support people with diabetes to live a better life?"; (2) determined the most important research questions (short list); and (3) ranked research questions in order of importance (priorities). We aimed to recruit N = 800 participants, with approximate equal representation of diabetes type and family members. RESULTS: Participants (N = 661) were adults (aged 18+ years) in Australia with a self-reporting diagnosis of diabetes (type 1, n = 302; type 2, n = 204; prior/current gestational, n = 58; less common types, n = 22, or a family member, n = 75). Retention rates for Surveys 2 and 3 were 47% (n = 295) and 50% (n = 316), respectively. From 1549 open-text responses, 25 topics and 125 research questions were identified thematically. Research priorities differed by cohort, resulting in specific lists developed and ranked by each cohort. The top-ranked research question for the type 1 diabetes cohort was "How can diabetes technology be improved …?" and for the type 2 diabetes cohort: "How can insulin resistance be reversed …?". One question was common to the final lists of all cohorts: "What are the causes or triggers of diabetes?" Within cohorts, the top priorities were perceived as being of similar importance. CONCLUSIONS: The research priorities differ substantially by diabetes type and for family members. These findings should inform funding bodies and researchers, to align future research and its communication with community needs.

Anatomical Features can Affect OCT Measures Used for Clinical Decisions and Clinical Trial Endpoints.

Purpose: To understand the association between anatomical parameters of healthy eyes and optical coherence tomography (OCT) circumpapillary retinal nerve fiber layer (cpRNFL) thickness measurements. Methods: OCT cpRNFL thickness was obtained from 396 healthy eyes in a commercial reference database (RDB). The temporal quadrant (TQ), superior quadrant (SQ), inferior quadrant (IQ), and global (G) cpRNFL thicknesses were analyzed. The commercial OCT devices code these values based on percentiles (red, <1%; yellow, ≥1% and <5%), after taking age and disc area into consideration. Four anatomical parameters were assessed: fovea-to-disc distance, an estimate of axial length, and the locations of the superior and the inferior peaks of the cpRNFL thickness curve. Pearson correlation values were obtained for the parameters and the thickness measures of each of the four cpRNFL regions, and t-tests were performed between the cpRNFL thicknesses coded as abnormal (red or yellow, <5%) versus normal (≥5%). Results: For each of the four anatomical parameters, the correlation with the thickness of one or more of the TQ, SQ, IQ, and G regions exceeded the correlation with age or disc area. All four parameters were significantly (P < 0.001) associated with the abnormal cpRNFL values. The significant parameters were not the same for the different regions; for example, a parameter could be negatively correlated for the TQ but positively correlated with the SQ or IQ. Conclusions: In addition to age and disc area, which are used for inferences in normative databases, four anatomical parameters are associated with cpRNFL thickness. Translational Relevance: Taking these additional anatomical parameters into consideration should aid diagnostic accuracy.

Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Financial Conflicts of Interest Among Physician Authors of ACR Appropriateness Criteria.

BACKGROUND: The accuracy and completeness of self-disclosures by authors of imaging guidelines are not well known. OBJECTIVE: The aim of this study was to assess the accuracy of financial disclosures by US authors of ACR appropriateness criteria. METHODS: We reviewed financial disclosures provided by US-based authors of all ACR-AC published in 2019, 2021 and 2023. For each US- based author, payment reports were extracted from the Open Payments Database (OPD) in the previous 36 months related to general category and research payments categories. We analyzed each author individually to determine if the reported disclosures matched results from OPD. RESULTS: A total of 633 authorships, including 333 unique authors were included from 38 ACR AC articles in 2019, with 606 authorships (387 unique authors) from 35 ACR-AC articles published in 2021, and 540 authorships (367 unique authors) from 32 ACR AC articles published in 2023. Among authors who received industry payments, failure to disclose any financial relationship was seen in 125/147 unique authors in 2019, 142/148 authors in 2021 and 95/125 unique authors in 2023. The proportion of nondisclosed total value of payments was 86.1% in 2019, 88.6% in 2021 and 56.7% in 2023. General category payments were nondisclosed in 94.1% in 2019, 89.7% in 2021 and 94.4% in 2023 by payment value. CONCLUSION: Industry payments to authors of radiology guidelines are common and frequently undisclosed.

Predicting Driver's mental workload using physiological signals: A functional data analysis approach.

This study investigates the impact of advanced driver-assistance systems on drivers' mental workload. Using a combination of physiological signals including ECG, EMG, EDA, EEG (af4 and fc6 channels from the theta band), and eye diameter data, this study aims to predict and categorize drivers' mental workload into low, adequate, and high levels. Data were collected from five different driving situations with varying cognitive demands. A functional linear regression model was employed for prediction, and the accuracy rate was calculated. Among the 31 tested combinations of physiological variables, 9 combinations achieved the highest accuracy result of 90%. These results highlight the potential benefits of utilizing raw physiological signal data and employing functional data analysis methods to understand and assess driver mental workload. The findings of this study have implications for the design and improvement of driver-assistance systems to optimize safety and performance.

Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the myeloid cells and associated cytokine responses. Along with the diminished inflammatory response, the absence of damage sensing through TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza burden in the lung. The absence of TLR9 led to extensive infection of myeloid cells including monocytes and macrophages rendering them highly inflammatory, despite having a low initial inflammatory response. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated circulating TLR9 ligands in the plasma samples of patients with influenza, demonstrating its clinical relevance. Overall, over data show an essential role of damage sensing through TLR9 in promoting anti-influenza immunity.