Personalized circulating tumor DNA for monitoring disease status in head and neck squamous cell carcinoma.

BACKGROUND: Many patients with locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) relapse. Circulating tumor (ct)DNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. METHODS: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera™, Natera) during clinical care of patients treated for predominantly newly diagnosed HPV-negative HNSCC. Signatera™ utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes post-treatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65, 68% male, 65% smokers); testing failed in 16 (14%) due to insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III-IV disease (82, 71%) while 17 (15%) had distant metastases. Pre-treatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 MTM/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive vs. negative post-treatment (HR 7.33, 95%CI 3.12-17.2, p<0.001); 1-year overall survival was 89.1% vs. 100%, respectively (HR 7.46, 95%CI 0.46-119.5; p=0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in non-viral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.

Differences in regional brain structure in toddlers with autism are related to future language outcomes.

Language and social symptoms improve with age in some autistic toddlers, but not in others, and such outcome differences are not clearly predictable from clinical scores alone. Here we aim to identify early-age brain alterations in autism that are prognostic of future language ability. Leveraging 372 longitudinal structural MRI scans from 166 autistic toddlers and 109 typical toddlers and controlling for brain size, we find that, compared to typical toddlers, autistic toddlers show differentially larger or thicker temporal and fusiform regions; smaller or thinner inferior frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most differences are replicated in an independent cohort of 75 toddlers. These brain alterations improve accuracy for predicting language outcome at 6-month follow-up beyond intake clinical and demographic variables. Temporal, fusiform, and inferior frontal alterations are related to autism symptom severity and cognitive impairments at early intake ages. Among autistic toddlers, brain alterations in social, language and face processing areas enhance the prediction of the child's future language ability.

Role of Intraoperative Electroencephalography in Predicting Postoperative Delirium in Patients Undergoing Cardiovascular Surgeries.

OBJECTIVE: To determine the utility of electroencephalography (EEG) in predicting postoperative delirium (POD) in patients who underwent cardiovascular surgeries with EEG monitoring. METHODS: A total of 1161 patients who underwent cardiovascular surgeries with EEG monitoring were included in the study, and their data were retrospectively reviewed. POD assessment was done utilizing Intensive Care Delirium Screening Checklist (ICDSC). Patients with a score of > 4 on ICDSC were diagnosed with POD. RESULTS: Of 1161 patients, 131 patients had EEG changes and 56 (42.74%) of 131 patients experienced POD. Of 1030 patients without EEG changes, 219 (21.26%) experienced POD. EEG showed specificity of 91.5% and negative predictive value of 78.7% in detecting POD. On multivariable analysis, EEG changes showed a strong association with POD (ORadj 1.97 CI (1.30-2.99), p = 0.001) with persistent EEG changes showing even a higher risk of developing POD (ORadj 2.65 (1.43-4.92), p = 0.002). CONCLUSION: EEG change has specificity of 91.5% emphasizing the need for its implementation as a diagnostic tool for predicting POD. Patients with POD are two times more likely to experience significant EEG changes, especially persistent EEG changes when undergoing cardiovascular surgeries. SIGNIFICANCE: Intraoperative EEG can detect POD, and EEG changes based therapeutic interventions can mitigate POD.

Technical note: Impact of linear array transducer Doppler aperture location on spectral peak velocity measurements - A phantom study.

OBJECTIVE: Ultrasound beams sometimes need to be steered from the edge of linear array transducers to reach the sample volume with a desired Doppler angle in vascular exams. This phantom study aims to evaluate the impact of apertures located at the array edge on peak velocity (PV) measurements. METHODS: Three ultrasound scanner systems equipped with eight transducers from 3 major ultrasound vendors were tested using a flow phantom with a horizontal tube. Five spectral Doppler measurements with the aperture positioned at one edge of the array and 5 with the aperture at the center of the array were obtained using all available scanner-transducer combinations while maintaining all scan parameters and the sample volume in the same tube location. Differences in PVs between center and edge apertures were compared across 4 constant flow rates. RESULTS: The averaged PVs for all phantom flow rates ranged from 24.4 cm/s to 138.2 cm/s from the array center. The averaged PVs from the center aperture were significantly greater than the corresponding measurements from the edge aperture for each flow rate (all p < 0.001). The relative PV differences ranged from 6.7% to 19.4% across all transducers and flow rates. CONCLUSION: Significantly lower PVs were consistently shown with the Doppler beam aperture at the array edge compared to center among all tested systems. This may be due to a narrower aperture width, shifted central axis, and less intrinsic spectral broadening error at the array edge. Controlling variations in Doppler aperture location is important in clinical applications which depend on consistent velocity measurements.

CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex.

CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.

BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.

Ending of the COVID-19 Related Public and National Health Emergency Declarations: Implications for Medically Underserved Populations in Tennessee.

The Biden administration decided to end the COVID-19 National and Public Health emergencies on May 11, 2023. These emergency declarations were established by the Trump Administration in early 2020. Under the COVID-19 emergency declarations, US citizens were provided with COVID-19 testing, vaccines, and treatments at little or no cost. The declarations allowed the federal government the option of waiving and or modifying government programs such Medicare, Medicaid. The emergency declarations were directly tied to other COVID-19 related provisions that have also expired that includes Economic Security (CARES) Act, the American Rescue Plan Act (ARPA), the Families First Coronavirus Response Act (FFCRA), the Coronavirus Aid, Relief, and the Inflation Reduction Act (IRA), the Consolidated Appropriations Act, 2023 (CAA). In addition, there were other federal and state emergency programs that were provided and too numerous to report here. At the time of this writing, the state of Tennessee continues to have moderate and sporadic spikes in COVID-19 cases and hospitalizations. Tennessee has higher than the national average of uninsured and underinsured people in the US. In Tennessee, more than 600,000 people are uninsured or underinsured in 2023 according to a study by the Kaiser Family Foundation. The ending of the PHE greatly impact coverage, cost, and access to COVID related services that will disproportionately affect the uninsured and medically underserved populations in Tennessee, the south in general, and throughout the US. Medically underserved populations are those groups with disparities in primary care, living in poverty, older, or having higher than expected infant mortality.

Prevalence of Age-Related Macular Degeneration in Patients with Chronic Exposure to P2X7R Inhibitors.

PURPOSE: P2X7 receptor (P2X7R) is a purinergic cation channel whose activation has been linked with age-related macular degeneration (ARMD). Several nucleoside reverse transcriptase inhibitors, zidovudine (AZT), lamivudine (3TC) and abacavir (ABC), have been shown to inhibit P2X7R and improve outcomes in animal models of ARMD. Our aim is to investigate the association between chronic AZT, 3TC, and ABC therapy and ARMD in a clinical setting. METHODS: This is a retrospective cohort study comparing 445 patients with HIV and confirmed usage of AZT, 3TC, and ABC against 200 patients with HIV without usage of AZT, 3TC, and ABC and 445 non-HIV infected patients. Fundus examination and spectral domain optical coherence tomography (SD-ODT) were used to measure prevalence of early-intermediate stage ARMD, geographic atrophy, and exudative ARMD. RESULTS: There was no statistically significant difference in the prevalence of early-intermediate stage ARMD between the HIV infected patients with a history of AZT, 3TC, and ABC use and the HIV infected patients without AZT, 3TC, and ABC use (p = 0.887). There was also no statistically significant difference in the prevalence of geographical atrophy (p = 0.062) and exudative AMD (p > 0.999) between the HIV infected patients with a history of AZT, 3TC, and ABC use and non-HIV infected patients. CONCLUSION: We did not find an effect of P2X7R inhibiting antiretrovirals usage on early-intermediate stage ARMD, geographical atrophy, or exudative ARMD. Studies with larger cohort and more rigorous medication history are needed to assess the effects on geographical atrophy or exudative ARMD.

Factors associated with increased 30-day re-operation risk in anterior cruciate ligament reconstruction.

BACKGROUND: Revision surgery following isolated anterior cruciate ligament reconstruction (ACLR) has often focused on mid- to long-term revisions due to re-rupture, while short-term 30-day revision is a rare, but underappreciated entity. This study aims to characterize incidence and risk factors for reoperations following isolated ACLR. METHODS: This is a retrospective case-control analysis of the American College of Surgeons National Surgical Quality Improvement Program Database (NSQIP) database from 2005 to 2017. Current Procedural Terminology codes were used to identify elective isolated ACLR patients. Patients undergoing reoperations were analyzed using bivariate analysis against their respective perioperative variables. Multivariate stepwise logistic regression was used to identify independent risk factors for reoperations after ACLR. RESULTS: 12,790 patients were included in the study. 37.0% of patients were female. Mean age was 32.2+/-10.7 years and mean body mass index (BMI) was 27.8+/-6.5 kg/m2, with 28.9% of patients with BMI > 30. The most frequently reported reason for reoperation based on CPT and ICD-9/10 codes was postoperative infection (0.5%). Overall reoperation rate was approximately 0.5%. Multivariate analysis identified operative time >1.5 h (OR 2.6 [95% CI; 1.5-4.4]), dependent functional status (OR 14.0 [1.4-141.6]), and adjunctive anesthesia (OR 2.4 [95% CI; 1.1-5.0]) as independent risk factors for reoperation. Female sex was a protective factor against reoperations (OR 0.6 [0.3-0.98]). CONCLUSION: Primary, isolated ACLR is associated with extremely low rates of short-term reoperations. Operative time >1.5 h, dependent functional status, and adjunctive anesthesia were independent risk factors for reoperation and female sex was a protective factor against reoperation. LEVEL OF EVIDENCE: Level III. Retrospective cohort study.

Loss of Postnatal Arx Transcriptional Activity in Parvalbumin Interneurons Reveals Non-cell Autonomous Disturbances in CA1 Pyramidal Cells.

Maintenance of proper electrophysiological and connectivity profiles in the adult brain may be a perturbation point in neurodevelopmental disorders (NDDs). How these profiles are maintained within mature circuits is unclear. We recently demonstrated that postnatal ablation of the Aristaless (Arx) homeobox gene in parvalbumin interneurons (PVIs) alone led to dysregulation of their transcriptome and alterations in their functional as well as network properties in the hippocampal cornu Ammoni first region (CA1). Here, we characterized CA1 pyramidal cells (PCs) responses in this conditional knockout (CKO) mouse to further understand the circuit mechanisms by which postnatal Arx expression regulates mature CA1 circuits. Field recordings of network excitability showed that CA1 PC ensembles were less excitable in response to unpaired stimulations but exhibited enhanced excitability in response to paired-pulse stimulations. Whole-cell voltage clamp recordings revealed a significant increase in the frequency of spontaneous inhibitory postsynaptic currents onto PCs. In contrast, excitatory drive from evoked synaptic transmission was reduced while that of inhibitory synaptic transmission was increased. Current clamp recordings showed increase excitability in several sub- and threshold membrane properties that correlated with an increase in the conductance of Na+ current. Our data suggest that, in addition to cell-autonomous disruption in PVIs, loss of Arx postnatal transcriptional activity in PVIs led to complex dysfunctions in PCs in CA1 microcircuits. These non-cell autonomous effects are likely the product of breakdown in feedback and/or feedforward processes and should be considered as fundamental contributors to the circuit mechanisms of NDDs such as Arx-linked early-onset epileptic encephalopathies.

Clinically relevant humanized mouse models of metastatic prostate cancer facilitate therapeutic evaluation.

There is tremendous need for improved prostate cancer (PCa) models. The mouse prostate is anatomically and developmentally different from the human prostate and does not spontaneously form tumors. Genetically engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts are an alternative but must rely on an immunocompromised host. Therefore, we generated PCa murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic PCa and the impact of androgen receptor-targeted and immunotherapies. These mice maintain multiple human immune cell lineages, including functional human T-cells and myeloid cells. Implications: To our knowledge, results illustrate the first model of human PCa that has an intact human immune system, metastasizes to clinically relevant locations, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment.

The changing landscape of electrical stimulation language mapping with subdural electrodes and stereoelectroencephalography for pediatric epilepsy: A literature review and commentary.

Electrical stimulation mapping (ESM) is used to locate the brain areas supporting language directly within the human cortex to minimize the risk of functional decline following epilepsy surgery. ESM is completed by utilizing subdural grid or depth electrodes (stereo-electroencephalography [sEEG]) in combination with behavioral evaluation of language. Despite technological advances, there is no standardized method of assessing language during pediatric ESM. To identify current clinical practices for pediatric ESM of language, we surveyed neuropsychologists in the Pediatric Epilepsy Research Consortium. Results indicated that sEEG is used for functional mapping at >80% of participating epilepsy surgery centers (n = 13/16) in the United States. However, >65% of sites did not report a standardized protocol to map language. Survey results indicated a clear need for practice recommendations regarding ESM of language. We then utilized PubMed/Medline and PsychInfo to identify 42 articles that reported on ESM of language, of which 18 met inclusion criteria, which included use of ESM/signal recording to localize language regions in children (<21 years) and a detailed account of the procedure and language measures used, and region-specific language localization outcomes. Articles were grouped based on the language domain assessed, language measures used, and the brain regions involved. Our review revealed the need for evidence-based clinical guidelines for pediatric language paradigms during ESM and a standardized language mapping protocol as well as standardized reporting of brain regions in research. Relevant limitations and future directions are discussed with a focus on considerations for pediatric language mapping.

Perspectives on Referral Pathways for Timely Head and Neck Cancer Care.

Importance: Timely diagnosis and treatment are of paramount importance for patients with head and neck cancer (HNC) because delays are associated with reduced survival rates and increased recurrence risk. Prompt referral to HNC specialists is crucial for the timeliness of care, yet the factors that affect the referral and triage pathway remain relatively unexplored. Therefore, to identify barriers and facilitators of timely care, it is important to understand the complex journey that patients undertake from the onset of HNC symptoms to referral for diagnosis and treatment. Objective: To investigate the referral and triage process for patients with HNC and identify barriers to and facilitators of care from the perspectives of patients and health care workers. Design, Participants, and Setting: This was a qualitative study using semistructured interviews of patients with HNC and health care workers who care for them. Participants were recruited from June 2022 to July 2023 from HNC clinics at 2 tertiary care academic medical centers in Boston, Massachusetts. Data were analyzed from July 2022 to December 2023. Main Outcomes and Measures: Themes identified from the perspectives of both patients and health care workers on factors that hinder or facilitate the HNC referral and triage process. Results: In total, 72 participants were interviewed including 42 patients with HNC (median [range] age, 60.5 [19.0-81.0] years; 27 [64%] females) and 30 health care workers (median [range] age, 38.5 [20.0-68.0] years; 23 [77%] females). Using thematic analysis, 4 major themes were identified: the HNC referral and triage pathway is fragmented; primary and dental care are critical for timely referrals; efficient interclinician coordination expedites care; and consistent patient-practitioner engagement alleviates patient fear. Conclusions and Relevance: These findings describe the complex HNC referral and triage pathway, emphasizing the critical role of initial symptom recognition, primary and dental care, patient information flow, and interclinician and patient-practitioner communication, all of which facilitate prompt HNC referrals.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men.

BACKGROUND: Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. METHODS: We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. RESULTS: After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. CONCLUSIONS: These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Friends or Foes: Fundamental Principles of Th-Organic Scaffold Chemistry Using Zr-Analogs as a Guide.

The fundamental interest in actinide chemistry, particularly for the development of thorium-based materials, is experiencing a renaissance owing to the recent and rapidly growing attention to fuel cycle reactors, radiological daughters for nuclear medicine, and efficient nuclear stockpile development. Herein, we uncover fundamental principles of thorium chemistry on the example of Th-based extended structures such as metal-organic frameworks in comparison with the discrete systems and zirconium extended analogs, demonstrating remarkable over two-and-half-year chemical stability of Th-based frameworks as a function of metal node connectivity, amount of defects, and conformational linker rigidity through comprehensive spectroscopic and crystallographic analysis as well as theoretical modeling. Despite exceptional chemical stability, we report the first example of studies focusing on the reactivity of the most chemically stable Th-based frameworks in comparison with the discrete Th-based systems such as metal-organic complexes and a cage, contrasting multicycle recyclability and selectivity (>97%) of the extended structures in comparison with the molecular compounds. Overall, the presented work not only establishes the conceptual foundation for evaluating the capabilities of Th-based materials but also represents a milestone for their multifaceted future and foreshadows their potential to shape the next era of actinide chemistry.

SARS-CoV-2 live virus culture and sample freeze-thaw stability.

The effect of freeze-thaw on SARS-CoV-2 viral viability is not well established. We isolated virus from 31 split clinical samples cultured fresh or after a 7- or 17/18-day freeze. We found that freeze-thaw did not significantly affect viral culture isolation. Therefore, frozen samples may be used to assess SARS-CoV-2 infectiousness.

Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Thermodynamics, Adhesion, and Wetting at Li/Cu(-Oxide) Interfaces: Relevance for Anode-Free Lithium-Metal Batteries.

A rechargeable battery that employs a Li metal anode requires that Li be plated in a uniform fashion during charging. In "anode-free" configurations, this plating will occur on the surface of the Cu current collector (CC) during the initial cycle and in any subsequent cycle where the capacity of the cell is fully accessed. Experimental measurements have shown that the plating of Li on Cu can be inhomogeneous, which can lower the efficiency of plating and foster the formation of Li dendrites. The present study employs a combination of first-principles calculations and sessile drop experiments to characterize the thermodynamics and adhesive (i.e., wetting) properties of interfaces involving Li and other phases present on or near the CC. Interfaces between Li and Cu, Cu2O, and Li2O are considered. The calculations predict that both Cu and Cu2O surfaces are lithiophilic. However, sessile drop measurements reveal that Li wetting occurs readily only on pristine Cu. This apparent discrepancy is explained by the occurrence of a spontaneous conversion reaction, 2 Li + Cu2O → Li2O + 2 Cu, that generates Li2O as one of its products. Calculations and sessile drop measurements show that Li does not wet (newly formed) Li2O. Hence, Li that is deposited on a Cu CC where surface oxide species are present will encounter a compositionally heterogeneous substrate comprising lithiophillic (Cu) and lithiophobic (Li2O) regions. These initial heterogeneities have the potential to influence the longer-term behavior of the anode under cycling. In sum, the present study provides insights into the early stage processes associated with Li plating in anode-free batteries and describes mechanisms that contribute to inefficiencies in their operation.

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant Gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected/inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistin's toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin's renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs.