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Migration and homing of immune cells are critical for immune surveillance. Trafficking is mediated by combinations of adhesion and chemokine receptors that guide immune cells, in response to chemokine signals, to specific locations within tissues and the lymphatic system to support tissue-localized immune reactions and systemic immunity1,2. Here we show that disruption of leukaemia inhibitory factor (LIF) production from group 2 innate lymphoid cells (ILC2s) prevents immune cells leaving the lungs to migrate to the lymph nodes (LNs). In the absence of LIF, viral infection leads to plasmacytoid dendritic cells (pDCs) becoming retained in the lungs where they improve tissue-localized, antiviral immunity, whereas chronic pulmonary allergen challenge leads to marked immune cell accumulation and the formation of tertiary lymphoid structures in the lung. In both cases immune cells fail to migrate to the lymphatics, leading to highly compromised LN reactions. Mechanistically, ILC2-derived LIF induces the production of the chemokine CCL21 from lymphatic endothelial cells lining the pulmonary lymphatic vessels, thus licensing the homing of CCR7+ immune cells (including dendritic cells) to LNs. Consequently, ILC2-derived LIF dictates the egress of immune cells from the lungs to regulate tissue-localized versus systemic immunity and the balance between allergen and viral responsiveness in the lungs.
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Background: This Site Feasibility Task Force convened to assess the complex and burdensome process of site feasibility in clinical trials. The objective was to create mutual understanding of challenges and provide suggestions for improving collaboration among sponsors, contract research organizations (CROs), and sites. Methods: The task force was composed of representatives from sponsors, CROs and sites (43 % Sites, 20 % Site Networks, 10 % Small/mid-size sponsors, 10 % Small/mid-size CROs, 10 % Large sponsors, 7 % Large CROs). The group collaborated to define the scope of the problem, identify challenges in the current process, and provide suggestions for improving the process. Results: The group found there is a need for better differentiation between the three main stages of feasibility, and the four sub-phases of Site Feasibility. The discussion brought to light emerging trends like early initiation of Site Feasibility and premature engagement of sites by CROs. To fully explain these challenges, the group analyzed the current practices and documented their downstream impact on clinical trial execution for all stakeholders. A list of best practices emerged naturally from this analysis. These findings are aggregated into short and actionable best practice guides. Conclusion: The task force suggests practical changes for the feasibility process and raises awareness of emerging trends and their associated risks. This awareness can begin to drive change in the site feasibility process, although industry-wide transformation will require new levels of collaboration, data standardization and automation tools. The potential benefits of evolving this process are significant and meaningful for more efficient and successful clinical trials.
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BACKGROUND: The link between the prostate microbiome and prostate cancer remains unclear. Few studies have analyzed the microbiota of prostate tissue, and these have been limited by potential contamination by transrectal biopsy. Transperineal prostate biopsy offers an alternative and avoids fecal cross-contamination. We aim to characterize the prostate microbiome using transperineal biopsy. METHODS: Patients with clinical suspicion for prostate cancer who were to undergo transperineal prostate biopsy with magnetic resonance imaging (MRI) fusion guidance were prospectively enrolled from 2022 to 2023. Patients were excluded if they had Prostate Imaging Reporting and Data System lesions with scores ≤ 3, a history of prostate biopsy within 1 year, a history of prostate cancer, or antibiotic use within 30 days of biopsy. Tissue was collected from the MRI target lesions and nonneoplastic transitional zone. Bacteria were identified using 16S ribosomal RNA gene sequencing. RESULTS: Across the 42 patients, 76% were found to have prostate cancer. Beta diversity indices differed significantly between the perineum, voided urine, and prostate tissue. There were no beta diversity differences between cancerous or benign tissue, or between pre- and postbiopsy urines. There appear to be unique genera more abundant in cancerous versus benign tissue. There were no differences in alpha diversity indices relative to clinical findings including cancer status, grade, and risk group. CONCLUSIONS: We demonstrate a rigorous method to better characterize the prostate microbiome using transperineal biopsy and to limit contamination. These findings provide a framework for future large-scale studies of the microbiome of prostate cancer.
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Microbiota , Perineo , Próstata , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/microbiología , Próstata/patología , Próstata/microbiología , Próstata/diagnóstico por imagen , Estudios Prospectivos , Persona de Mediana Edad , Anciano , Perineo/microbiología , Perineo/patología , Imagen por Resonancia Magnética/métodos , Biopsia/métodos , Biopsia Guiada por Imagen/métodos , ARN Ribosómico 16S/análisis , ARN Ribosómico 16S/genéticaRESUMEN
Over the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer depressive mood. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data. Here, we report high-quality longitudinal validated assessments of depressive mood from computerized adaptive testing paired with continuous digital assessments of behavior from smartphone sensors for up to 40 weeks on 183 individuals experiencing mild to severe symptoms of depression. We apply a combination of cubic spline interpolation and idiographic models to generate individualized predictions of future mood from the digital behavioral phenotypes, achieving high prediction accuracy of depression severity up to three weeks in advance (R2 ≥ 80%) and a 65.7% reduction in the prediction error over a baseline model which predicts future mood based on past depression severity alone. Finally, our study verified the feasibility of obtaining high-quality longitudinal assessments of mood from a clinical population and predicting symptom severity weeks in advance using passively collected digital behavioral data. Our results indicate the possibility of expanding the repertoire of patient-specific behavioral measures to enable future psychiatric research.
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We aim to compare complications, readmission, survival, and prescribing patterns of opioids for post-operative pain management for Robotic-assisted laparoscopic radical cystectomy (RARC) as compared to open radical cystectomy (ORC). Patients that underwent RARC or ORC for bladder cancer at a tertiary care center from 2005 to 2021 were included. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and multivariable Cox proportional hazards regression models. Comparisons of narcotic usage were completed with oral morphine equivalents (OMEQ). Multivariable linear regression was used to assess predictors of OMEQ utilization. A total of 128 RARC and 461 ORC patients were included. There was no difference in rates of Clavien-Dindo grade ≥ 3 complications between RARC and ORC (36.7 vs 30.1%, p = 0.16). After a mean follow up of 3.4 years, RFS (HR 0.96, 95%CI 0.58-1.56) and OS (HR 0.69, 95%CI 0.46-1.05) were comparable between RARC and ORC. There was no difference in the narcotic usage between patients in the RARC and ORC groups during the last 24 h of hospitalization (median OMEQ: 0 vs 0, p = 0.33) and upon discharge (median OMEQ: 178 vs 210, p = 0.36). Predictors of higher OMEQ discharge prescriptions included younger age [(- )3.46, 95%CI (-)5.5-(-)0.34], no epidural during hospitalization [- 95.85, 95%CI (- )144.95-(- )107.36], and early time-period of surgery [(- )151.04, 95%CI (- )194.72-(- )107.36]. RARC has comparable 90-day complication rates and early survival outcomes to ORC and remains a viable option for bladder cancer. RARC results in comparable levels of opioid utilization for pain management as ORC.
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Procedimientos Quirúrgicos Robotizados , Neoplasias de la Vejiga Urinaria , Humanos , Cistectomía/efectos adversos , Cistectomía/métodos , Analgésicos Opioides/uso terapéutico , Procedimientos Quirúrgicos Robotizados/métodos , Resultado del Tratamiento , Complicaciones Posoperatorias/etiología , Pautas de la Práctica en Medicina , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugía , NarcóticosRESUMEN
INTRODUCTION: We aimed to assess utilization of neoadjuvant chemotherapy (NAC) and etiologies for lack of NAC receipt among patients with muscle-invasive bladder cancer (MIBC). METHODS: Patients diagnosed with MIBC undergoing radical cystectomy at a single institution (2005-2021) were included. Patients were categorized by receipt of NAC, and reasons for no NAC were categorized into eligibility and elective factors. Overall survival was analyzed using univariable and multivariable Cox proportional hazards regression models and modeled with Kaplan-Meier curves. RESULTS: Three hundred eighty patients with MIBC were included; 154 (40.5%) received NAC. Patients were not candidates for NAC due to renal dysfunction (16.6%), clinical contraindications (4.7%), salvage setting (2.1%), and histology (5.3%; total N = 109). Among 271 (71.3%) who were eligible, utilization increased from early (2005-2016) to recent (2016-2021) time periods (34.2% to 85.7% among NAC-eligible, P < .001; 22.8% vs 67.1% among all MIBC, P < .001). Elective factors for not receiving NAC included patient symptoms (7.8%), disease progression concern (7.0%), patient preference/refusal (20.3%) and provider discretion (8.1%) among 271 NAC-eligible patients. Notably, patient preference/refusal decreased from 33.6% to 3.4% in recent years (P < .001). On multivariable analysis, lack of NAC utilization due to renal dysfunction (HR 2.18, P = .002), clinical contraindications (HR 2.62, P = .01), and elective factors (HR 1.88, P = .01) were associated with worse overall survival. CONCLUSIONS: NAC utilization increased over time with 85.7% of eligible patients with MIBC receiving NAC in recent years. Renal dysfunction, patient preference, and clinical contraindications were primary etiologies for lack of NAC. Fewer patients refused NAC in recent years leading to a potential ceiling for NAC utilization.
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Enfermedades Renales , Neoplasias de la Vejiga Urinaria , Humanos , Terapia Neoadyuvante/efectos adversos , Cistectomía/efectos adversos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Músculos/patologíaRESUMEN
Nitrous oxide is a potent greenhouse gas and ozone-depleting agent with a long atmospheric lifetime. Several previous reports indicate that over half of supplied nitrous oxide is wasted from leaking manifold-pipeline systems infrastructure prior to patient use, and that remediating leaks can have significant environmental benefits. We describe an accurate, simple and cost-effective cylinder weighing method to quantify nitrous oxide leak from the manifold-pipeline network at our tertiary non-obstetric facility. Nitrous oxide cylinder depletion was prospectively compared with clinical usage derived from the electronic medical record over an 18-day period. A total of 1932 l (3.62 kg) of nitrous oxide was used in 35 operating theatre cases during the period. This was only 16.5% of actual cylinder depletion (11,686 l; 21.88 kg), indicating that 83.5% (9754 l; 18.26 kg) of nitrous oxide had leaked to the atmosphere (376 ml/minute; 22.6 l/hour; 542 l/day). The fraction of nitrous oxide wasted was consistent with a retrospective analysis of the previous 2-year period at the site that compared purchasing records with estimated clinical use. If maintained over a year, the leak would be equivalent to 101 tonnes of carbon dioxide per annum.
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Dióxido de Carbono , Óxido Nitroso , Humanos , Estudios Retrospectivos , Quirófanos , HospitalesRESUMEN
[This corrects the article PMC10399976.].
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Abnormal gait is a significant non-cognitive biomarker for Alzheimer's disease (AD) and AD-related dementia (ADRD). Micro-Doppler radar, a non-wearable technology, can capture human gait movements for potential early ADRD risk assessment. In this research, we propose to design STRIDE integrating micro-Doppler radar sensors with advanced artificial intelligence (AI) technologies. STRIDE embeds a new deep learning (DL) classification framework. As a proof of concept, we develop a "digital-twin" of STRIDE, consisting of a human walking simulation model and a micro-Doppler radar simulation model, to generate a gait signature dataset. Taking established human walking parameters, the walking model simulates individuals with ADRD under various conditions. The radar model based on electromagnetic scattering and the Doppler frequency shift model is employed to generate micro-Doppler signatures from different moving body parts (e.g., foot, limb, joint, torso, shoulder, etc.). A band-dependent DL framework is developed to predict ADRD risks. The experimental results demonstrate the effectiveness and feasibility of STRIDE for evaluating ADRD risk.
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Background: Patients diagnosed with multiple brain metastases often survive for less than 2 years, and clinicians must carefully evaluate the impact of interventions on quality of life. Three types of radiation treatment are widely accepted for patients with multiple brain metastases: Whole brain radiation therapy (WBRT), hippocampal avoidance whole-brain radiation therapy (HA-WBRT), and stereotactic radiosurgery (SRS). WBRT, the standard option, is less costly than its newer alternatives but causes more severe adverse effects such as memory loss. To determine whether the cost-effectiveness ratio of HA-WBRT and SRS are superior to WBRT, we used published data to simulate cases of multiple brain metastases. Methods: We designed a Markov model using data from previously published studies to simulate the disease course of patients with 5 to 15 brain metastases and determine the cost-effectiveness of HA-WBRT and SRS relative to WBRT. Incremental cost-effectiveness ratios (ICERs) were calculated and compared against a willingness-to-pay threshold of $100 000 per quality-adjusted life year. Results: SRS met the threshold for cost-effectiveness, with ICERs ranging $41 198-$54 852 for patients with 5 to 15 brain metastases; however, HA-WBRT was not cost-effective, with an ICER of $163 915 for all simulated patients. Model results were robust to sensitivity analyses. Conclusions: We propose that SRS, but not HA-WBRT, should be offered to patients with multiple brain metastases as a treatment alternative to standard WBRT. Incorporating these findings into clinical practice will help promote patient-centered care and decrease national healthcare expenditures, thereby addressing issues around health equity and access to care.
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Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein-protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Células-Madre Neurales , Proteína 1 de Unión a la Caja Y , Animales , Humanos , Ratones , Neoplasias Encefálicas/metabolismo , Proliferación Celular , Neoplasias Cerebelosas/patología , Daño del ADN , Proteínas Hedgehog/metabolismo , Meduloblastoma/patología , Células-Madre Neurales/metabolismo , Proteína 1 de Unión a la Caja Y/metabolismoRESUMEN
The microbiota generates diverse metabolites to modulate host physiology and disease, but their protein targets and mechanisms of action have not been fully elucidated. To address this challenge, we explored microbiota-derived indole metabolites and developed photoaffinity chemical reporters for proteomic studies. We identified many potential indole metabolite-interacting proteins, including metabolic enzymes, transporters, immune sensors and G protein-coupled receptors. Notably, we discovered that aromatic monoamines can bind the orphan receptor GPRC5A and stimulate ß-arrestin recruitment. Metabolomic and functional profiling also revealed specific amino acid decarboxylase-expressing microbiota species that produce aromatic monoamine agonists for GPRC5A-ß-arrestin recruitment. Our analysis of synthetic aromatic monoamine derivatives identified 7-fluorotryptamine as a more potent agonist of GPRC5A. These results highlight the utility of chemoproteomics to identify microbiota metabolite-interacting proteins and the development of small-molecule agonists for orphan receptors.
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Microbiota , Proteómica , Receptores Acoplados a Proteínas G/metabolismo , beta-Arrestinas/metabolismo , IndolesRESUMEN
BACKGROUND: Pre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based on results of a clinical trial conducted prior to the emergence of the Omicron variant. The clinical effectiveness of T/C has not been well described in the Omicron era. We examined the incidence of symptomatic illness and hospitalizations among T/C recipients when Omicron accounted for virtually all local cases. METHODS: Through retrospective electronic medical record chart review, we identified patients who received T/C between January 1 -July 31, 2022 within our quaternary referral health system. We determined the incidence of symptomatic COVID-19 infections and hospitalizations due to or presumed to be caused by early Omicron variants before and after receiving T/C (pre-T/C and post-T/C). Chi square and Mann-Whitney Wilcoxon two-sample tests were used to examine differences between the characteristics of those who got COVID-19 before or after T/C prophylaxis, and rate ratios (RR) and 95% confidence intervals (CI) were calculated to assess differences in hospitalization rates for the two groups. RESULTS: Of 1295 T/C recipients, 105 (8.1%) developed symptomatic COVID-19 infection before receiving T/C, and 102 (7.9%) developed symptomatic disease after receiving it. Of the 105 patients who developed symptomatic infection pre-T/C, 26 (24.8%) were hospitalized, compared with six of the 102 patients (5.9%) who were diagnosed with COVID-19 post-T/C (RR = 0.24; 95% CI = 0.10-0.55; p = 0.0002). Seven of the 105 (6.7%) patients infected pre-T/C, but none of the 102 infected post-T/C required ICU care. No COVID-related deaths occurred in either group. The majority of COVID-19 cases among those infected pre-T/C treatment occurred during the Omicron BA.1 surge, while the majority of post-T/C cases occurred when Omicron BA.5 was predominant. In both groups, having at least one dose of vaccine strongly protected against hospitalization (pre-T/C group RR = 0.31, 95% CI = 0.17-0.57, p = 0.02; post-T/C group RR = 0.15; 95% CI = 0.03-0.94; p = 0.04). CONCLUSION: We identified COVID-19 infections after T/C prophylaxis. Among patients who received T/C at our institution, COVID-19 Omicron cases occurring after T/C were one-fourth as likely to require hospitalization compared to those with Omicron prior to T/C. However, due to the presence of changing vaccine coverage, multiple therapies, and changing variants, the effectiveness of T/C in the Omicron era remains difficult to assess.
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COVID-19 , Humanos , COVID-19/epidemiología , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Nanofiber-porous systems comprising a porous substrate overlaid with nanofiber weave offer the potential for higher acoustic absorption than the substrate alone with negligible increase in thickness. The characterization of nanofibers from acoustic measurements is investigated in this work, and a regression model for predicting their acoustic properties from a single physical parameter is proposed to enable the design of nanofiber-porous systems directly from fabrication parameters. Characterization as a resistive screen via Johnson-Champoux-Allard and lumped element models for transfer matrix computations of absorption coefficient for nanofiber-porous systems exhibited good agreement with the measured spectra. The lumped element model was chosen as it was defined by fewer parameters and did not require nanofiber layer thickness measurements, eliminating the associated uncertainty. A regression model for lumped element parameters vs areal density established a design tool based on a single, easily measured physical property for optimized absorption at target frequencies without prior acoustic characterization of the nanofiber layer, enabling the analysis of complex acoustic networks incorporating nanofiber-porous systems. Practical considerations of applying adhesives at the nanofiber-porous interface were studied to evaluate possible enhancement of acoustic performance. For comparison with prior work by others, flow resistances from physical measurement and acoustic characterization were compared.
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Understanding the interplay between phenotypic and genetic adaptation is a focus of evolutionary biology. In bacteria, the oxidative stress response prevents mutagenesis by reactive oxygen species (ROS). We hypothesise that the stress response dynamics can therefore affect the timing of the mutation supply that fuels genetic adaptation to oxidative stress. We uncover that sudden hydrogen peroxide stress causes a burst of mutations. By developing single-molecule and single-cell microscopy methods, we determine how these mutation dynamics arise from phenotypic adaptation mechanisms. H2 O2 signalling by the transcription factor OxyR rapidly induces ROS-scavenging enzymes. However, an adaptation delay leaves cells vulnerable to the mutagenic and toxic effects of hydroxyl radicals generated by the Fenton reaction. Resulting DNA damage is counteracted by a spike in DNA repair activities during the adaptation delay. Absence of a mutation burst in cells with prior stress exposure or constitutive OxyR activation shows that the timing of phenotypic adaptation directly controls stress-induced mutagenesis. Similar observations for alkylation stress show that mutation bursts are a general phenomenon associated with adaptation delays.
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Peróxido de Hidrógeno , Estrés Oxidativo , Especies Reactivas de Oxígeno , Mutación , Mutagénesis , Peróxido de Hidrógeno/toxicidad , BacteriasRESUMEN
The opioid crisis has become a significant public health concern in recent years. Although respiratory depression and overdose are the most reported side effects of fentanyl, there have been rare cases of cerebellar leukoencephalopathy (CLE) following fentanyl intoxication. A 29-year-old man with a history of opioid use disorder and intravenous drug use presented to the emergency room with significant ataxia and dysarthria following fentanyl intoxication. According to the patient, the symptoms began four days prior after "chasing the dragon" with "pure fentanyl", and he reported experiencing nausea and dizziness, particularly during ambulation. Neurological examination revealed a positive Romberg test, ataxia, and delayed speech. Brain magnetic resonance imaging (MRI) indicated there was toxic degeneration of the cerebellar white matter that extended into the posterior limbs of the internal capsule. Urine drug screening was positive for opioids, making fentanyl-induced cerebellar leukoencephalopathy the most likely diagnosis in this case. This case of opioid-induced CLE underscores the critical significance of early recognition, which is vital for enhancing a patient's recovery and averting the development of severe neurological complications.
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Bile acids are important gut microbiota metabolites that regulate both host and microbial functions. To identify the direct protein targets of bile acids in Enterococcus, we synthesized and validated the activity of a lithocholic acid (LCA) photoaffinity reporter, x-alk-LCA-3. Chemical proteomics of x-alk-LCA-3 in E. faecium Com15 reveals many candidate LCA-interacting proteins, which are involved in cell well synthesis, transcriptional regulation and metabolism. To validate the utility of bile acid photoaffinity labeling, we characterized a putative bile salt hydrolase (BSH) crosslinked by x-alk-LCA-3, and demonstrated that this BSH was effective in converting taurolithocholic acid (TLCA) to LCA in E. faecium and in vitro. Chemical proteomics should afford new opportunities to characterize bile acid-protein targets and mechanisms of action in the future.
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INTRODUCTION: Physicians assume leadership roles in their health care organizations and practices often without support or training. The Physicians Leadership Academy provides integrated leadership seminars, mindfulness training, and executive coaching in a 10-month curriculum to physicians across area organizations. METHODS: Program evaluators responded to stakeholders' need for continuous program improvement by developing a continuous feedback loop evaluation design incorporating a program monitoring system and a theory-driven program evaluation. Given the size of the 2019 to 20 cohort ( n = 19), a one-group pretest/posttest design was used to assess the mechanisms of the program (mindfulness and wellbeing) along with knowledge development, emotional intelligence, and personal and professional growth. The assessments used a combination of published and administrator-developed assessments to address the unique aspects of the program. Doing such ensured continuous improvement and sustainability for the program. RESULTS: The cohort of physicians demonstrated significant engagement and learning across the curriculum, improved mindfulness, and improved capacity of the providers to affect their health care system and communities. CONCLUSIONS: The utility of the program was demonstrated through quantitative and qualitative analyses. Implications of the methodology for future evaluations of program developments are discussed.