Rapamycin-encapsulated nanoparticle delivery in polycystic kidney disease mice.

Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.

Optical Aptamer-Based Cytokine Nanosensor Detects Macrophage Activation by Bacterial Toxins.

Overactive or dysregulated cytokine expression is a hallmark of many acute and chronic inflammatory diseases. This is true for acute or chronic infections, neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, cancer, and others. Cytokines such as interleukin-6 (IL-6) are known therapeutic targets and biomarkers for such inflammatory diseases. Platforms for cytokine detection are, therefore, desirable tools for both research and clinical applications. Single-walled carbon nanotubes (SWCNT) are versatile nanomaterials with near-infrared fluorescence that can serve as transducers for optical sensors. When functionalized with an analyte-specific recognition element, SWCNT emission may become sensitive and selective toward the desired target. SWCNT-aptamer sensors are easily assembled, inexpensive, and biocompatible. In this work, we introduced a nanosensor design based on SWCNT and a DNA aptamer specific to IL-6. We first evaluated several SWCNT-aptamer constructs based on this simple direct complexation method, wherein the aptamer both solubilizes the SWCNT and confers sensitivity to IL-6. The sensor limit of detection, 105 ng/mL, lies in the relevant range for pathological IL-6 levels. Upon investigation of sensor kinetics, we found rapid response within seconds of antigen addition which continued over the course of 3 h. We found that this sensor construct is stable and the aptamer is not displaced from the nanotube surface during IL-6 detection. Finally, we investigated the ability of this sensor construct to detect macrophage activation caused by bacterial lipopolysaccharides (LPS) in an in vitro model of disease, finding rapid and sensitive detection of macrophage-expressed IL-6. We are confident that further development of this sensor will have novel implications for diagnosis of acute and chronic inflammatory diseases, in addition to contributing to the understanding of the role of cytokines in these diseases.

Optical Nanosensor Passivation Enables Highly Sensitive Detection of the Inflammatory Cytokine Interleukin-6.

Interleukin-6 (IL-6) is known to play a critical role in the progression of inflammatory diseases such as cardiovascular disease, cancer, sepsis, viral infection, neurological disease, and autoimmune diseases. Emerging diagnostic and prognostic tools, such as optical nanosensors, experience challenges in translation to the clinic in part due to protein corona formation, dampening their selectivity and sensitivity. To address this problem, we explored the rational screening of several classes of biomolecules to be employed as agents in noncovalent surface passivation as a strategy to screen interference from nonspecific proteins. Findings from this screening were applied to the detection of IL-6 by a fluorescent-antibody-conjugated single-walled carbon nanotube (SWCNT)-based nanosensor. The IL-6 nanosensor exhibited highly sensitive and specific detection after passivation with a polymer, poly-l-lysine, as demonstrated by IL-6 detection in human serum within a clinically relevant range of 25 to 25,000 pg/mL, exhibiting a limit of detection over 3 orders of magnitude lower than prior antibody-conjugated SWCNT sensors. This work holds potential for the rapid and highly sensitive detection of IL-6 in clinical settings with future application to other cytokines or disease-specific biomarkers.

The impact of race and ethnicity on diffuse large B-cell lymphoma outcomes within the veterans health administration (VHA).

We performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. The 3178 patients who met inclusion criteria were predominantly male (97%) and white (75%). Median age of diagnosis for Black patients was 63 years vs 69 years for the entire cohort (p < 0.001). However, patients in each race/ethnicity subgroup presented with similar rates of stage I/II and III/IV disease, IPI score, cell of origin and HIT status. Outcomes analysis revealed similar treatment, response rates, median overall survival, and 1-, 3-, and 5-year survival across all subgroups. Hispanic patients had a 21% lower risk of death (HR = 0.79) than white patients, and Black patients had no significant difference in survival (HR = 0.98). This large retrospective study shows that when standard of care therapy is given within an equal access system, short-term treatment and survival outcomes are the same for all races.

Rapid differentiation of estrogen receptor status in patient biopsy breast cancer aspirates with an optical nanosensor.

Breast cancer is a substantial source of morbidity and mortality worldwide. It is particularly more difficult to treat at later stages, and treatment regimens depend heavily on both staging and the molecular subtype of the tumor. However, both detection and molecular analyses rely on standard imaging and histological method, which are costly, time-consuming, and lack necessary sensitivity/specificity. The estrogen receptor (ER) is, along with the progesterone receptor (PR) and human epidermal growth factor (HER-2), among the primary molecular markers which inform treatment. Patients who are negative for all three markers (triple negative breast cancer, TNBC), have fewer treatment options and a poorer prognosis. Therapeutics for ER+ patients are effective at preventing disease progression, though it is necessary to improve the speed of subtyping and distribution of rapid detection methods. In this work, we designed a near-infrared optical nanosensor using single-walled carbon nanotubes (SWCNT) as the transducer and an anti-ERα antibody as the recognition element. The nanosensor was evaluated for its response to recombinant ERα in buffer and serum prior to evaluation with ER- and ER+ immortal cell lines. We then used a minimal volume of just 10 µL from 26 breast cancer biopsy samples which were aspirated to mimic fine needle aspirates. 20 samples were ER+, while 6 were ER-, representing 13 unique patients. We evaluated the potential of the nanosensor by investigating several SWCNT chiralities through direct incubation or fractionation deployment methods. We found that the nanosensor can differentiate ER- from ER+ patient biopsies through a shift in its center wavelength upon sample addition. This was true regardless of which of the three SWCNT chiralities we observed. Receiver operating characteristic area under the curve analyses determined that the strongest classifier with an AUC of 0.94 was the (7,5) chirality after direct incubation and measurement, and without further processing. We anticipate that further testing and development of this nanosensor may push its utility toward field-deployable, rapid ER subtyping with potential for additional molecular marker profiling.

An optical aptamer-based cytokine nanosensor detects macrophage activation by bacterial toxins.

Overactive or dysregulated cytokine expression is hallmark of many acute and chronic inflammatory diseases. This is true for acute or chronic infection, neurodegenerative diseases, autoimmune diseases, cardiovascular disease, cancer, and others. Cytokines such as interleukin-6 (IL-6) are known therapeutic targets and biomarkers for such inflammatory diseases. Platforms for cytokine detection are therefore desirable tools for both research and clinical applications. Single-walled carbon nanotubes (SWCNT) are versatile nanomaterials with near-infrared fluorescence that can serve as transducers for optical sensors. When functionalized with an analyte-specific recognition element, SWCNT emission may become sensitive and selective towards the desired target. SWCNT-aptamer sensors are easily assembled, inexpensive, and biocompatible. In this work, we introduced a nanosensor design based on SWCNT and a DNA aptamer specific to IL-6. We first evaluated several SWCNT-aptamer constructs based on this simple direct complexation method, wherein the aptamer both solubilizes the SWCNT and confers sensitivity to IL-6. The sensor limit of detection, 105 ng/mL, lies in the relevant range for pathological IL-6 levels. Upon investigation of sensor kinetics, we found rapid response within seconds of antigen addition which continued over the course of three hours. We found that this sensor construct is stable, and the aptamer is not displaced from the nanotube surface during IL-6 detection. Finally, we investigated the ability of this sensor construct to detect macrophage activation caused by bacterial lipopolysaccharides (LPS) in an in vitro model of disease, finding rapid and sensitive detection of macrophage-expressed IL-6. We are confident further development of this sensor will have novel implications for diagnosis of acute and chronic inflammatory diseases, in addition to contributing to the understanding of the role of cytokines in these diseases.

Comparing interventions for early psychosis: a systematic review and component network meta-analysis.

Background: 'Early Intervention in Psychosis' (EIP) services have been associated with improved outcomes for early psychosis. However, these services are heterogeneous and many provide different components of treatment. The impact of this variation on the sustained treatment effects is unknown. Methods: We performed a systematic review and component network meta-analysis (cNMA) of randomised controlled trials (RCTs) that compared specialised intervention services for early psychosis. We searched CENTRAL (published and unpublished), EMBASE, MEDLINE, CINAHL, PsycINFO and Web of Science from inception to February 2023. Primary outcomes were negative and positive psychotic symptoms at 3-month and 1-year follow-up and treatment dropouts. Secondary outcomes were depressive symptoms and social functioning at 1-year follow-up. We registered a protocol for our study in PROSPERO (CRD42017057420). Findings: We identified 37 RCTs including 4599 participants. Participants' mean age was 25.8 years (SD 6.0) and 64.0% were men. We found evidence that psychological interventions (this component grouped all psychological treatment intended to treat, or ameliorate the consequences of, psychotic symptoms) are beneficial for reducing negative symptoms (iSMD -0.24, 95% CI -0.44 to -0.05, p = 0.014) at 3-month follow-up and may be associated with clinically relevant benefits in improving social functioning scores at 1-year follow-up (iSMD -0.52, 95% CI -1.05 to 0.01, p = 0.052). The addition of case management has a beneficial effect on reducing negative symptoms (iSMD -1.17, 95% CI -2.24 to -0.11, p = 0.030) and positive symptoms (iSMD -1.05, 95% CI -2.02 to -0.08, p = 0.033) at 1-year follow-up. Pharmacotherapy was present in all trial arms, meaning it was not possible to examine the specific effects of this component. Interpretation: Our findings suggest psychological interventions and case management in addition to pharmacotherapy as the core components of services for early psychosis to achieve sustained clinical benefits. Our conclusions are limited by the small number of studies and sparsely connected networks. Funding: National Institute for Health and Care Research.

Ex vivo drug testing of patient-derived lung organoids to predict treatment responses for personalized medicine.

Lung cancer is the leading cause of global cancer-related mortality resulting in âˆ¼ 1.8 million deaths annually. Systemic, molecular targeted, and immune therapies have provided significant improvements of survival outcomes for patients. However, drug resistance usually arises and there is an urgent need for novel therapy screening and personalized medicine. 3D patient-derived organoid (PDO) models have emerged as a more effective and efficient alternative for ex vivo drug screening than 2D cell culture and patient-derived xenograft (PDX) models. In this review, we performed an extensive search of lung cancer PDO-based ex vivo drug screening studies. Lung cancer PDOs were successfully established from fresh or bio-banked sections and/or biopsies, pleural effusions and PDX mouse models. PDOs were subject to ex vivo drug screening with chemotherapy, targeted therapy and/or immunotherapy. PDOs consistently recapitulated the genomic alterations and drug sensitivity of primary tumors. Although sample sizes of the previous studies were limited and some technical challenges remain, PDOs showed great promise in the screening of novel therapy drugs. With the technical advances of high throughput, tumor-on-chip, and combined microenvironment, the drug screening process using PDOs will enhance precision care of lung cancer patients.

Collaboration across the primary/specialist interface in early intervention in psychosis services: a qualitative study.

Background People with new psychotic symptoms may be managed within an Early Intervention in Psychosis service (EIP). They may be discharged back to primary care at the end of their time in an EIP service. Aim To explore the role of primary care in supporting people with psychosis in an EIP service. Design and Setting Qualitative study, within a programme of work to explore the optimum duration of management within an EIP service. Methods Semi-structured interviews with people in EIP services, carers, general practitioners (GPs) and EIP practitioners. Findings GPs report difficulties in referring people into EIP services, have little contact with people who are supported by EIP services and are not included in planning discharge from EIP service to primary care. Conclusions This study suggests that GPs should have a role in the support of people within EIP services (in particular monitoring and managing physical health) and their carers. Inclusion of GPs in managing discharge from EIP services is vital. We suggest that a joint consultation with the service user, their carer (if they wish) along with EIP care co-ordinator and GP would make this transition smoother.

Predictive Modeling of Phenotypic Antimicrobial Susceptibility of Selected Beta-Lactam Antimicrobials from Beta-Lactamase Resistance Genes.

The outcome of bacterial infection management relies on prompt diagnosis and effective treatment, but conventional antimicrobial susceptibility testing can be slow and labor-intensive. Therefore, this study aims to predict phenotypic antimicrobial susceptibility of selected beta-lactam antimicrobials in the bacteria of the family Enterobacteriaceae from different beta-lactamase resistance genotypes. Using human datasets extracted from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program conducted by Pfizer and retail meat datasets from the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS), we used a robust or weighted least square multivariable linear regression modeling framework to explore the relationship between antimicrobial susceptibility data of beta-lactam antimicrobials and different types of beta-lactamase resistance genes. In humans, in the presence of the blaCTX-M-1, blaCTX-M-2, blaCTX-M-8/25, and blaCTX-M-9 groups, MICs of cephalosporins significantly increased by values between 0.34-3.07 µg/mL, however, the MICs of carbapenem significantly decreased by values between 0.81-0.87 µg/mL. In the presence of carbapenemase genes (blaKPC, blaNDM, blaIMP, and blaVIM), the MICs of cephalosporin antimicrobials significantly increased by values between 1.06-5.77 µg/mL, while the MICs of carbapenem antimicrobials significantly increased by values between 5.39-67.38 µg/mL. In retail meat, MIC of ceftriaxone increased significantly in the presence of blaCMY-2, blaCTX-M-1, blaCTX-M-55, blaCTX-M-65, and blaSHV-2 by 55.16 µg/mL, 222.70 µg/mL, 250.81 µg/mL, 204.89 µg/mL, and 31.51 µg/mL respectively. MIC of cefoxitin increased significantly in the presence of blaCTX-M-65 and blaTEM-1 by 1.57 µg/mL and 1.04 µg/mL respectively. In the presence of blaCMY-2, MIC of cefoxitin increased by an average of 8.66 µg/mL over 17 years. Compared to E. coli isolates, MIC of cefoxitin in Salmonella enterica isolates decreased significantly by 0.67 µg/mL. On the other hand, MIC of ceftiofur increased in the presence of blaCTX-M-1, blaCTX-M-65, blaSHV-2, and blaTEM-1 by 8.82 µg/mL, 9.11 µg/mL, 8.18 µg/mL, and 1.04 µg/mL respectively. In the presence of blaCMY-2, MIC of ceftiofur increased by an average of 10.20 µg/mL over 14 years. The ability to predict antimicrobial susceptibility of beta-lactam antimicrobials directly from beta-lactamase resistance genes may help reduce the reliance on routine phenotypic testing with higher turnaround times in diagnostic, therapeutic, and surveillance of antimicrobial-resistant bacteria of the family Enterobacteriaceae.

Impact of a positive crossmatch on pediatric heart transplant outcomes.

BACKGROUND: Pediatric heart transplant (HT) candidates experience high waitlist mortality due to a limited donor pool that is constrained in part by anti-HLA sensitization. We evaluated the impact of CDC and Flow donor-specific crossmatch (XM) results on pediatric HT outcomes. METHODS: All pediatric HTs between 1999 and 2019 in the OPTN database were included. Donor-specific XM results were sub-categorized based on CDC and Flow results. Primary outcomes were treated rejection in the first year and time to death or allograft loss. Propensity scores were utilized to adjust for differences in baseline characteristics. RESULTS: A total of 4,695 pediatric HT patients with T-cell XM data were included. After propensity score adjustment, a positive T-cell CDC-XM was associated with 2 times higher odds of treated rejection (OR 2.29 (1.56, 3.37)) and shorter time to death/allograft loss (HR 1.50 (1.19, 1.88)) compared to a negative Flow-XM. HT recipients who were Flow-XM positive with negative/unknown CDC-XM did not have higher odds of rejection or shorter time to death/allograft loss. An isolated positive B-cell XM was also not associated with worse outcomes. Over the study period XM testing shifted from CDC- to Flow-based assays. CONCLUSIONS: A positive donor-specific T-cell CDC-XM was associated with rejection and death/allograft loss following pediatric HT. This association was not observed with a positive T-cell Flow-XM or B-cell XM result alone. The shift away from performing the CDC-XM may result in loss of important prognostic information unless the clinical relevance of quantitative Flow-XM results on heart transplant outcomes is systematically studied.

Targeting the Kidneys at the Nanoscale: Nanotechnology in Nephrology.

Kidney diseases, both acute and chronic, are a substantial burden on individual and public health, and they continue to increase in frequency. Despite this and an intense focus on the study of disease mechanisms, few new therapeutic approaches have extended to the clinic. This is in part due to poor pharmacology of many, if not most, therapeutics with respect to the sites of kidney disease within the glomerulus or nephron. Considering this, within the past decade, and more pointedly over the past 2 years, there have been substantial developments in nanoparticle systems to deliver therapeutics to the sites of kidney disease. Here, we provide a broad overview of the various classes of nanomaterials that have been developed to improve therapeutic development for kidney diseases, the strategy used to provide kidney accumulation, and briefly the disease models they focused on, if any. We then focus on one specific system, polymeric mesoscale nanoparticles, which has broadly been used over 13 publications, demonstrating targeting of the tubular epithelium with 26-fold specificity compared with other organs. While there have been several nanomedicines that have advanced to the clinic in the past several decades, including mRNA-based coronavirus disease vaccines and others, none have focused on kidney diseases specifically. In total, we are confident that the rapid advancement of nanoscale-based kidney targeting and a concerted focus by clinicians, scientists, engineers, and other stakeholders will push one or more of these technologies into clinical trials over the next decade.

Utility of in-session assessments during cognitive behavioral therapy for depression after traumatic brain injury: Results from a randomized controlled trial.

BACKGROUND: The development of depression after moderate to severe traumatic brain injury (TBI) is common. Cognitive-behavioral therapy (CBT) can be used to treat post-TBI depression, but the symptoms response is poorly described. OBJECTIVE: This secondary analysis assessed: (1) the trajectory of depression symptoms up to 12 sessions of CBT, (2) which depressive symptom clusters were responsive to in-person and phone CBT, and (3) whether interim depression thresholds predict 16-week treatment response. METHOD: This secondary analysis of the IRB-approved Life Improvement Following Traumatic Brain Injury trial included 100 adults with major depressive disorder (MDD) within ten years of moderate to severe traumatic brain injury from throughout the US. We used a combination of descriptive, graphical, and diagnostic accuracy methods. RESULTS: Cardinal and cognitive-affective symptom clusters improved most from CBT over 16 weeks. At 8 and 16 weeks, the most responsive individual symptoms were anhedonia, depressed mood, and fatigue; the least responsive were sleep and appetite. PHQ-9 thresholds with a Negative Predictive Value greater than 0.7 for sessions 6, 7, and 8 were, respectively: >15, >10, and >9. CONCLUSION: In-person and phone CBT led to similar symptom responses during treatment. Additionally, using PHQ-9 thresholds for predicting intervention response within eight sessions may help identify the need for treatment adjustments.

Organic chiral nano- and microfilaments: types, formation, and template applications.

Organic chiral nanofilaments are part of an important class of nanoscale chiral materials that has recently been receiving significant attention largely due to their potential use in applications such as optics, photonics, metameterials, and potentially a range of medical as well as sensing applications. This review will focus on key examples of the formation of such nano- and micro-filaments based on carbon nanofibers, polymers, synthetic oligo- and polypeptides, self-assembled organic molecules, and one prominent class of liquid crystals. The most critical aspects discussed here are the underlying driving forces for chiral filament formation, potentially answering why specific sizes and shapes are formed, what molecular design strategies are working equally well or rather differently among these materials classes, and what uses and applications are driving research in this fascinating field of materials science.

Predictors of positive outcomes from 'Early Intervention in Psychosis': protocol for a national retrospective cohort study.

Background: Psychotic disorders are severe and prevalent mental health conditions associated with long-term disability, reduced quality of life, and substantial economic costs. Early Intervention in Psychosis (EIP) services aim to provide timely and comprehensive treatment for psychotic disorders, and EIP service input is associated with improved outcomes. However, there is limited understanding of the specific components of EIP care that contribute to these improvements. There is significant nationwide variability in the commissioning and delivery of EIP, with individuals receiving different packages of components from different services. In this study, we seek to explore associations between EIP components and clinically significant outcomes, in order to understand the mechanisms underlying improved psychosis care. Methods: This national retrospective cohort study will utilize data from the 2019 National Clinical Audit of Psychosis (NCAP), examining the care received by 10,560 individuals treated by EIP services in England. Exposure data from the NCAP, capturing the components of care delivered by EIP services, will be linked with outcome data from routine NHS Digital datasets over a three-year follow-up period. This will be the first study to use this method to examine this population in England. The primary outcomes will be surrogate measures of relapse of psychosis (hospital admission and referral to community-based crisis intervention services). Secondary outcomes include duration of admissions, emergency hospital attendances, episodes of detention under the Mental Health Act, and all-cause mortality. We will use multilevel regression to examine associations between exposures and outcome events. We will handle missing data using appropriate imputation techniques. Discussion: This study aims to provide valuable insights into the long-term effects of variations in EIP service delivery. The study involves a large, diverse cohort including individuals treated by every EIP service in England. While there are limitations inherent in the observational nature of the study, any associations identified will be of great relevance to clinicians, researchers, and policymakers seeking to optimize EIP care. The results will enable more targeted treatment planning, resource allocation, and potential innovations in EIP care, ultimately leading to improved prognoses for people experiencing psychosis.

The specificity of feature-based attentional guidance is equivalent under single- and dual-target search.

Individuals actively maintain attentional templates to prioritize target-matching inputs. While previous works have established that multiple templates can be held simultaneously, current understanding is limited with respect to the representational quality of such templates. We thus investigated: (a) whether the maintenance of two templates is limited to broad, coarse-grained representations, and if not, (b) whether there is nonetheless a decline in the achievable level of specificity when multiple attentional templates are held simultaneously. Using a spatial cueing procedure, we probed the breadth of attentional templates while participants maintained either one (Experiment 1) or two target colors (Experiment 2) under conditions of low- or high-similarity search and found specific template maintenance during high-similarity search for both single- and dual-target conditions. We then directly compared template specificity during single- and dual-target maintenance in Experiment 3, probing at the point of differentiation between target and nontarget feature values observed during single-target search. Here we found no difference in the selectivity of cue validity effects between single- and dual-target search, suggesting equivalent template specificity regardless of whether one or two features are relevant to search. Lastly, in Experiment 4, we established that such template specificity is dependent on access to visual working memory. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Durvalumab Treatment Patterns for Patients with Unresectable Stage III Non-Small Cell Lung Cancer in the Veterans Health Administration (VHA): A Nationwide, Real-World Study.

BACKGROUND: Durvalumab is approved for the treatment of adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This real-world study describes patient characteristics and durvalumab treatment patterns (number of doses and therapy duration; treatment initiation delays, interruptions, discontinuations, and associated reasons) among VHA-treated patients. METHODS: This was a retrospective cohort study of adults with unresectable stage III NSCLC receiving durvalumab at the VHA between 1 January 2017 and 30 June 2020. Patient characteristics and treatment patterns were presented descriptively. RESULTS: A total of 935 patients were included (median age: 69 years; 95% males; 21% Blacks; 46% current smokers; 16% ECOG performance scores ≥ 2; 50% squamous histology). Durvalumab initiation was delayed in 39% of patients (n = 367). Among the 200 patients with recorded reasons, delays were mainly due to physician preference (20%) and CRT toxicity (11%). Overall, patients received a median (interquartile range) of 16 (7-24) doses of durvalumab over 9.0 (2.9-11.8) months. Treatment interruptions were experienced by 19% of patients (n = 180), with toxicity (7.8%) and social reasons (2.6%) being the most cited reasons. Early discontinuation occurred in 59% of patients (n = 551), largely due to disease progression (24.2%) and toxicity (18.2%). CONCLUSIONS: These real-world analyses corroborate PACIFIC study results in terms of the main reasons for treatment discontinuation in a VHA population with worse prognostic factors, including older age, predominantly male sex, and poorer performance score. One of the main reasons for durvalumab initiation delays, treatment interruptions, or discontinuations was due to toxicities. Patients could benefit from improved strategies to prevent, identify, and manage CRT and durvalumab toxicities timely and effectively.

Comparing individual antimicrobial resistant and multi-drug resistant Salmonella enterica across serotypes, sampling sources, sampling periods, and food animal types in the United States (2014-2018).

This study aimed to compare the antimicrobial-resistant Salmonella enterica profiles from three sampling sources cecal contents, HACCP (during processing), and retail meat using phenotypic antibiotic susceptibility and serotype data gathered from 2014 and 2018. Antimicrobial resistance data for 29 major Salmonella serotypes from three sampling sources and associated food animal types (cattle, swine, chicken, and turkey) were obtained from the database of the United States National Antimicrobial Resistance Monitoring System. Using multivariable logistic regression models, we compared individual and multi-drug resistance (MDR) in Salmonella enterica between the three sampling sources, food animal types, sampling period, and Salmonella serotypes. Across the three sources and throughout the sampling period, the recovery of antimicrobial-resistant Salmonella enterica - including MDR, MDR-AmpC, and ACSSuT - among food animal types were dependent on the sampling period and, in some cases, sampling sources and period for the selected antimicrobials. The predicted probability of antimicrobial resistance was greater in Salmonella serotypes from turkey compared to other food animal types, conditional on sampling sources. Ceftriaxone-resistant (OR=0.83, 95% CI: 0.69-0.99), and Sulfisoxazole-resistant (OR=0.84, 95% CI: 0.72-0.98) Salmonella serotypes were less likely to be recovered from the Hazard Analysis and Critical Control Point (HACCP) sources than with the cecal sources. Except for Salmonella serotypes Dublin and Newport, most of the Salmonella serotypes were less likely to be resistant to the selected antimicrobials, or found as MDR, compared to serotype Typhimurium. This study offers an integrated view on the predicted probability of MDR Salmonella serotypes, as well as insights into which serotypes are persistent, emerging or declining across sampling sources and food animal types in the United States.