Correlation functions from tensor network influence functionals: The case of the spin-boson model.

We investigate the application of matrix product state (MPS) representations of the influence functionals (IFs) for the calculation of real-time equilibrium correlation functions in open quantum systems. Focusing specifically on the unbiased spin-boson model, we explore the use of IF-MPSs for complex time propagation, as well as IF-MPSs for constructing correlation functions in the steady state. We examine three different IF approaches: one based on the Kadanoff-Baym contour targeting correlation functions at all times, one based on a complex contour targeting the correlation function at a single time, and a steady state formulation, which avoids imaginary or complex times, while providing access to correlation functions at all times. We show that within the IF language, the steady state formulation provides a powerful approach to evaluate equilibrium correlation functions.

Reliability of patient-reported comorbidities: a systematic review and meta-analysis.

Self-reported questionnaires have become a widely adopted method of reviewing patients in clinical practice. This systematic review aimed to determine the reliability of patient-reported comorbidities and to identify which patient factors influence the reliability. Included studies assessed the reliability of at least one patient-reported comorbidity against their medical record or clinical assessment as gold standard. Twenty-four eligible studies were included in the meta-analysis. Only endocrine diseases (Cohen's Kappa Coefficient (CKC) 0.81 (95% CI 0.76 to 0.85)), consisting of diabetes mellitus (CKC 0.83 (95% CI 0.80 to 0.86)) and thyroid disease (CKC 0.68 (95% CI 0.50 to 0.86)), showed good-to-excellent reliability. Factors most frequently reported to influence concordance included age, sex and educational level. This systematic review demonstrated poor-to-moderate reliability for most systems, except for endocrine which showed good-to-excellent reliability. Although patient self-reporting can be a useful guide to clinical management, several patient factors were demonstrated to affect reliability therefore it should be avoided as a standalone measure.

Distal radius malunion: outcomes following an ulnar shortening osteotomy.

PURPOSE: Positive ulnar variance following a distal radius malunion can lead to ulnar-sided wrist pain, loss of grip strength, and distal radioulnar joint impingement. The primary aim of this study is to describe upper limb-specific functional outcomes following ulnar shortening osteotomy (USO) for ulnar-sided wrist pain associated with malunion of the distal radius. METHODS: We retrospectively identified 40 adult patients from a single centre over a 9-year period that had undergone an USO for symptomatic malunion of the distal radius. The primary outcome was the patient-rated wrist evaluation (PRWE). Secondary outcomes were the QuickDASH, EQ-5D-5L, complications, and net promoter score (NPS). RESULTS: Outcomes were available for 37 patients (93%). The mean age was 56 years and 25 patients were female (68%). At a mean follow-up of 6 years (range 1-10 years) the median PRWE was 11 (IQR 0-29.5), the median QuickDASH 6.8 (IQR 0-29.5), and the median EQ-5D-5L index was 0.88 (IQR 0.71-1). The NPS was 73. Complications occurred in nine patients (24%) and included non-union (n = 4), early loss of fixation requiring revision surgery (n = 1), superficial wound infection (n = 2), neurological injury (n = 1), and further surgery for symptomatic hardware removal (n = 1). CONCLUSIONS: For patients with a symptomatic distal radius malunion where the predominant deformity is ulnar positive variance, this study has demonstrated that despite 1 in 4 patients experiencing a complication, USO can result in excellent patient reported outcomes with high levels of satisfaction. LEVEL OF EVIDENCE: III (Cohort Study).

Robotic-arm assisted total knee arthroplasty is associated with improved accuracy and patient reported outcomes: a systematic review and meta-analysis.

This systematic review and meta-analysis were conducted to compare the accuracy of component positioning, alignment and balancing techniques employed, patient-reported outcomes, and complications of robotic-arm assisted total knee arthroplasty (RATKA) with manual TKA (mTKA) and the associated learning curve. Searches of PubMed, Medline and Google Scholar were performed in October 2020 using PRISMA guidelines. Search terms included "robotic", "knee" and "arthroplasty". The criteria for inclusion were published clinical research articles reporting the learning curve for RATKA and those comparing the component position accuracy, alignment and balancing techniques, functional outcomes, or complications with mTKA. There were 198 articles identified, following full text screening, 16 studies satisfied the inclusion criteria and reported the learning curve of rTKA (n=5), component positioning accuracy (n=6), alignment and balancing techniques (n=7), functional outcomes (n=7), or complications (n=5). Two studies reported the learning curve using CUSUM analysis to establish an inflexion point for proficiency which ranged from 7 to 11 cases and there was no learning curve for component positioning accuracy. The meta-analysis showed a significantly lower difference between planned component position and implanted component position, and the spread was narrower for RATKA compared with the mTKA group (Femur coronal: mean 1.31, 95% confidence interval (CI) 1.08-1.55, p<0.00001; Tibia coronal: mean 1.56, 95% CI 1.32-1.81, p<0.00001). Three studies reported using different alignment and balancing techniques between mTKA and RATKA, two studies used the same for both group and two studies did not state the methods used in their RATKA groups. RATKA resulted in better Knee Society Score compared to mTKA in the short-to-mid-term follow up (95%CI [- 1.23, - 0.51], p=0.004). There was no difference in arthrofibrosis, superficial and deep infection, wound dehiscence, or overall complication rates. RATKA demonstrated improved accuracy of component positioning and patient-reported outcomes. The learning curve of RATKA for operating time was between 7 and 11 cases. Future well-powered studies on RATKAs should report on the knee alignment and balancing techniques utilised to enable better comparisons on which techniques maximise patient outcomes.Level of evidence III.

Nonuniqueness of generalized quantum master equations for a single observable.

When deriving exact generalized master equations for the evolution of a reduced set of degrees of freedom, one is free to choose what quantities are relevant by specifying projection operators. However, obtaining a reduced description does not always need to be achieved through projections-one can also use conservation laws for this purpose. Such an operation should be considered as distinct from any kind of projection; that is, projection onto a single observable yields a different form of master equation compared to that resulting from a projection followed by the application of a constraint. We give a simple example to show this point and give relationships that the different memory kernels must satisfy to yield the same dynamics.

Reliability of patient-reported comorbidities: a systematic review and meta-analysis.

Self-reported questionnaires have become a widely adopted method of reviewing patients in clinical practice. This systematic review aimed to determine the reliability of patient-reported comorbidities and to identify which patient factors influence the reliability. Included studies assessed the reliability of at least one patient-reported comorbidity against their medical record or clinical assessment as gold standard. Twenty-four eligible studies were included in the meta-analysis. Only endocrine diseases (Cohen's Kappa Coefficient (CKC) 0.81 (95% CI 0.76 to 0.85)), consisting of diabetes mellitus (CKC 0.83 (95% CI 0.80 to 0.86)) and thyroid disease (CKC 0.68 (95% CI 0.50 to 0.86)), showed good-to-excellent reliability. Factors most frequently reported to influence concordance included age, sex and educational level. This systematic review demonstrated poor-to-moderate reliability for most systems, except for endocrine which showed good-to-excellent reliability. Although patient self-reporting can be a useful guide to clinical management, several patient factors were demonstrated to affect reliability therefore it should be avoided as a standalone measure.

A Novel Coupled Reaction-Diffusion System for Explainable Gene Expression Profiling.

Machine learning (ML)-based algorithms are playing an important role in cancer diagnosis and are increasingly being used to aid clinical decision-making. However, these commonly operate as 'black boxes' and it is unclear how decisions are derived. Recently, techniques have been applied to help us understand how specific ML models work and explain the rational for outputs. This study aims to determine why a given type of cancer has a certain phenotypic characteristic. Cancer results in cellular dysregulation and a thorough consideration of cancer regulators is required. This would increase our understanding of the nature of the disease and help discover more effective diagnostic, prognostic, and treatment methods for a variety of cancer types and stages. Our study proposes a novel explainable analysis of potential biomarkers denoting tumorigenesis in non-small cell lung cancer. A number of these biomarkers are known to appear following various treatment pathways. An enhanced analysis is enabled through a novel mathematical formulation for the regulators of mRNA, the regulators of ncRNA, and the coupled mRNA-ncRNA regulators. Temporal gene expression profiles are approximated in a two-dimensional spatial domain for the transition states before converging to the stationary state, using a system comprised of coupled-reaction partial differential equations. Simulation experiments demonstrate that the proposed mathematical gene-expression profile represents a best fit for the population abundance of these oncogenes. In future, our proposed solution can lead to the development of alternative interpretable approaches, through the application of ML models to discover unknown dynamics in gene regulatory systems.

Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation.

Over 1250 mutations in SCN1A, the Nav1.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEFS+. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies.

Brain Iron Assessment after Ferumoxytol-enhanced MRI in Children and Young Adults with Arteriovenous Malformations: A Case-Control Study.

Background Iron oxide nanoparticles are an alternative contrast agent for MRI. Gadolinium deposition has raised safety concerns, but it is unknown whether ferumoxytol administration also deposits in the brain. Purpose To investigate whether there are signal intensity changes in the brain at multiecho gradient imaging following ferumoxytol exposure in children and young adults. Materials and Methods This retrospective case-control study included children and young adults, matched for age and sex, with brain arteriovenous malformations who received at least one dose of ferumoxytol from January 2014 to January 2018. In participants who underwent at least two brain MRI examinations (subgroup), the first and last available examinations were analyzed. Regions of interests were placed around deep gray structures on quantitative susceptibility mapping and R2* images. Mean susceptibility and R2* values of regions of interests were recorded. Measurements were assessed by linear regression analyses: a between-group comparison of ferumoxytol-exposed and unexposed participants and a within-group (subgroup) comparison before and after exposure. Results Seventeen participants (mean age ± standard deviation, 13 years ± 5; nine male) were in the ferumoxytol-exposed (case) group, 21 (mean age, 14 years ± 5; 11 male) were in the control group, and nine (mean age, 12 years ± 6; four male) were in the subgroup. The mean number of ferumoxytol administrations was 2 ± 1 (range, one to four). Mean susceptibility (in parts per million [ppm]) and R2* (in inverse seconds [sec-1]) values of the dentate (case participants: 0.06 ppm ± 0.04 and 23.87 sec-1 ± 4.13; control participants: 0.02 ppm ± 0.03 and 21.7 sec-1 ± 5.26), substantia nigrae (case participants: 0.08 ppm ± 0.06 and 27.46 sec-1 ± 5.58; control participants: 0.04 ppm ± 0.05 and 24.96 sec-1 ± 5.3), globus pallidi (case participants: 0.14 ppm ± 0.05 and 30.75 sec-1 ± 5.14; control participants: 0.08 ppm ± 0.07 and 28.82 sec-1 ± 6.62), putamina (case participants: 0.03 ppm ± 0.02 and 20.63 sec-1 ± 2.44; control participants: 0.02 ppm ± 0.02 and 19.65 sec-1 ± 3.6), caudate (case participants: -0.1 ppm ± 0.04 and 18.21 sec-1 ± 3.1; control participants: -0.06 ppm ± 0.05 and 18.83 sec-1 ± 3.32), and thalami (case participants: 0 ppm ± 0.03 and 16.49 sec-1 ± 3.6; control participants: 0.02 ppm ± 0.02 and 18.38 sec-1 ± 2.09) did not differ between groups (susceptibility, P = .21; R2*, P = .24). For the subgroup, the mean interval between the first and last ferumoxytol administration was 14 months ± 8 (range, 1-25 months). Mean susceptibility and R2* values of the dentate (first MRI: 0.06 ppm ± 0.05 and 25.78 sec-1 ± 5.9; last MRI: 0.06 ppm ± 0.02 and 25.55 sec-1 ± 4.71), substantia nigrae (first MRI: 0.06 ppm ± 0.06 and 28.26 sec-1 ± 9.56; last MRI: 0.07 ppm ± 0.06 and 25.65 sec-1 ± 6.37), globus pallidi (first MRI: 0.13 ppm ± 0.07 and 27.53 sec-1 ± 8.88; last MRI: 0.14 ppm ± 0.06 and 29.78 sec-1 ± 6.54), putamina (first MRI: 0.03 ppm ± 0.03 and 19.78 sec-1 ± 3.51; last MRI: 0.03 ppm ± 0.02 and 19.73 sec-1 ± 3.01), caudate (first MRI: -0.09 ppm ± 0.05 and 21.38 sec-1 ± 4.72; last MRI: -0.1 ppm ± 0.05 and 18.75 sec-1 ± 2.68), and thalami (first MRI: 0.01 ppm ± 0.02 and 17.65 sec-1 ± 5.16; last MRI: 0 ppm ± 0.02 and 15.32 sec-1 ± 2.49) did not differ between the first and last MRI examinations (susceptibility, P = .95; R2*, P = .54). Conclusion No overall significant differences were found in susceptibility and R2* values of deep gray structures to suggest retained iron in the brain between ferumoxytol-exposed and unexposed children and young adults with arteriovenous malformations and in those exposed to ferumoxytol over time. © RSNA, 2020.

Many-Body Localization in the Presence of a Central Qudit.

We consider a many-body localized system coupled globally to a central d-level system. Under an appropriate scaling of d and L, we find evidence that the localized phase survives. We argue for two possible thermalizing phases, depending on whether the qudit becomes fully ergodic. This system provides one of the first examples of many-body localization in the presence of long-range (nonconfining) interactions.

Long-Term Outcomes of Primary Cemented Total Hip Arthroplasty with Acetabular Bone Graft for Protrusio Acetabuli: Minimum 10-Year Follow-Up.

Background: This study reports the long-term survivorship of primary total hip arthroplasty (THA) for protrusio acetabuli. Methods: Patients undergoing THA utilising cement and bone graft acetabular reconstruction for protrusio acetabuli in a university teaching hospital during the period 2003 to 2014 were included. Kaplan-Meier survival estimates were calculated with 95% confidence intervals (CI) up to 15 years following surgery. PROMs were collected pre- and post-operatively for hip-specific function (Oxford Hip Score [OHS]) and health-related quality of life (HRQoL) using the EQ-5D-3L. Results: 129 consecutive THAs (96 patients) performed for protrusio acetabuli were identified (median age 69, IQR 61-75; female 115 [89.1%]; 38 [29.5%] inflammatory arthritis) with a mean follow-up of 15.7 years (range: 10.1-20.1 years). At the final follow-up, fifty-six (43.4%) patients had died and there were eleven (8.5%) reoperations, of which eight (6.2%) involved the revision of the acetabular component. The fifteen-year Kaplan-Meier any-reoperation survival estimate was 91.3% (95% CI 85.9-97.0). When considering all-cause acetabular revision only, the 15-year survival estimate was 93.1% (95% CI 88.2-98.3). The median pre-operative OHS improved significantly from baseline to 1 year post-THA, beyond the minimal important change (mean difference 28, 95% CI 25-30, p < 0.001). Similarly, there were clinically relevant improvements in HRQoL at 1 year post surgery (mean difference 0.10, 95% CI 0.06-0.15, p < 0.001). Conclusions: This study demonstrates that primary cemented THA utilising acetabular bone graft for reconstruction in patients with protrusio acetabuli was associated with 15-year survival rates of 93.1% and clinically relevant improvements in hip-specific function and HRQoL.

The spleen assumes a major role in blood glucose regulation in type 1 diabetes patients treated with BCG.

The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells' glucose metabolism from oxidative phosphorylation to aerobic glycolysis. The latter is a state of high glucose utilization that draws more glucose from the blood. Apart from blood, it is unknown whether BCG establishes residence in any organs and alters their glucose metabolism. In this two-year-long clinical trial in type 1 diabetics, we use positron emission tomography (PET) and x-ray computed tomography (CT) to map organs that increase their uptake of the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) before versus after BCG vaccinations. We also injected BALB/c mice with BCG to test for the presence of BCG in various organs. Results from both studies point to the spleen as the dominant site for glucose uptake and BCG residence. The human spleen is significant because its 47% increase in 18F-FDG uptake by a large population of lymphocytes and monocytes might help to explain BCG's systemic lowering of blood glucose to near normal levels. Findings suggest that the spleen, triggered by BCG, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas.

Patellar resurfacing was not associated with a clinically significant advantage when a modern patellar friendly total knee arthroplasty is employed: A systematic review and meta-analysis.

BACKGROUND: Modern total knee arthroplasty (TKA) femoral components are designed to provide a more optimal articular surface for the patella whether or not it has been resurfaced. Previous systematic reviews comparing outcomes of patellar resurfacing and no resurfacing combine both historic and modern designs. AIMS: The aim of this study was to investigate the effect of patellar resurfacing in modern "patellar friendly" implants on (1) incidence of anterior knee pain, (2) patient reported outcomes (3) complication rates, and (4) reoperation rates compared with unresurfaced patellae in primary TKA. METHODS: MEDline, PubMed and google scholar studies were evaluated using SIGN assessment tool and data analysis was conducted using Review Manager 5.2 on only randomised controlled trials. The search terms were: arthroplasty, replacement, knee (Mesh), TKA, prosthesis, patella, patellar resurfacing, patellar retaining. RESULTS: Thirty-two randomised controlled studies were identified that reported the type of TKA implant used: 11 used modern "patellar friendly" implants; and 21 older "patellar non-friendly" implants. Among "patellar friendly" TKAs there were no significant differences in anterior knee pain rates between resurfaced and unresurfaced groups. Patellar resurfacing with "patellar friendly" implants had significantly higher clinical (mean difference (MD) -0.77, p = 0.007) and functional (MD -1.87, p < 0.0001) knee society scores (KSS) than unresurfaced counterparts but these did not exceed the minimal clinically important difference (MCID). Resurfacing with "patellar friendly" implants was not associated with a significant (p = 0.59) difference in the Oxford knee score (OKS), in contrast when a "patellar non-friendly" implant was used there was a significant difference (MD 3.3, p = 0.005) in favour of resurfacing. There was an increased risk of reoperation for unresurfaced TKAs with "non-patellar friendly" implants (Odds ratio (OR) 1.68, 95% CI 1.03-2.74, p = 0.04), but not for unresurfaced patellae with "patellar friendly" implants (OR 1.17, CI 0.59-2.30). CONCLUSIONS: Patellar resurfacing in combination with a modern patellar friendly implant was not associated with a lower rate of anterior knee pain, complications, or reoperations compared to not resurfacing, nor did it give a clinically significant improvement in knee specific function. In contrast patellar resurfacing in combination with a "non-friendly" TKA implant was associated with a significantly better OKS and lower reoperation rate. Implant design should be acknowledged when patellar resurfacing is being considered.

Patellar resurfacing versus retention in cruciate-retaining and posterior-stabilized total knee arthroplasty.

Aims: This systematic review and meta-analysis aimed to compare the influence of patellar resurfacing following cruciate-retaining (CR) and posterior-stabilized (PS) total knee arthroplasty (TKA) on the incidence of anterior knee pain, knee-specific patient-reported outcome measures, complication rates, and reoperation rates. Methods: A systematic review of MEDLINE, PubMed, and Google Scholar was performed to identify randomized controlled trials (RCTs) according to search criteria. Search terms used included: arthroplasty, replacement, knee (Mesh), TKA, prosthesis, patella, patellar resurfacing, and patellar retaining. RCTs that compared patellar resurfacing versus unresurfaced in primary TKA were included for further analysis. Studies were evaluated using the Scottish Intercollegiate Guidelines Network assessment tool for quality and minimization of bias. Data were synthesized and meta-analysis performed. Results: There were 4,135 TKAs (2,068 resurfaced and 2,027 unresurfaced) identified in 35 separate cohorts from 33 peer-reviewed studies. Anterior knee pain rates were significantly higher in unresurfaced knees overall (odds ratio (OR) 1.84; 95% confidence interval (CI) 1.20 to 2.83; p = 0.006) but more specifically associated with CR implants (OR 1.95; 95% CI 1.0 to 3.52; p = 0.030). There was a significantly better Knee Society function score (mean difference (MD) -1.98; 95% CI -1.1 to -2.84; p < 0.001) and Oxford Knee Score (MD -2.24; 95% CI -0.07 to -4.41; p = 0.040) for PS implants when patellar resurfacing was performed, but these differences did not exceed the minimal clinically important difference for these scores. There were no significant differences in complication rates or infection rates according to implant design. There was an overall significantly higher reoperation rate for unresurfaced TKA (OR 1.46 (95% CI 1.04 to 2.06); p = 0.030) but there was no difference between PS or CR TKA. Conclusion: Patellar resurfacing, when performed with CR implants, resulted in lower rates of anterior knee pain and, when used with a PS implant, yielded better knee-specific functional outcomes. Patellar resurfacing was associated with a lower risk of reoperation overall, but implant type did not influence this.

Novices can assess microsurgery performance, and this is enhanced using the Manual Suture Parameters for Training and Assessment (M-SParTA) scoring system.

This study explores how novices could effectively evaluate the quality of microsurgical suturing. That would be enhanced with using a novel Manual Suture Parameters for Training and Assessment (M-SParTA), which supported novices with guidance on the objective parameters, in order to increased the accuracy of scoring ability. We also propose the following initial framework to train novices in microsuturing using a standardised task: 1) Exposure; 2) Assessment; 3) Hands-on and self-assessment. The independent learning cycle with targeted supervision provides novices with greater autonomy and a less stressful environment that could enhance skills training.

Readiness for implementation of novel digital health interventions for postoperative monitoring: a systematic review and clinical innovation network analysis.

An increasing number of digital health interventions (DHIs) for remote postoperative monitoring have been developed and evaluated. This systematic review identifies DHIs for postoperative monitoring and evaluates their readiness for implementation into routine health care. Studies were defined according to idea, development, exploration, assessment, and long-term follow-up (IDEAL) stages of innovation. A novel clinical innovation network analysis used coauthorship and citations to examine collaboration and progression within the field. 126 DHIs were identified, with 101 (80%) being early stage innovations (IDEAL stage 1 and 2a). None of the DHIs identified had large-scale routine implementation. There is little evidence of collaboration, and there are clear omissions in the evaluation of feasibility, accessibility, and the health-care impact. Use of DHIs for postoperative monitoring remains at an early stage of innovation, with promising but generally low-quality supporting evidence. Comprehensive evaluation within high-quality, large-scale trials and real-world data are required to definitively establish readiness for routine implementation.

Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages.

Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAFV600E mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

Rescue of dendritic cells from glycolysis inhibition improves cancer immunotherapy in mice.

Inhibition of glycolysis in immune cells and cancer cells diminishes their activity, and thus combining immunotherapies with glycolytic inhibitors is challenging. Herein, a strategy is presented where glycolysis is inhibited in cancer cells using PFK15 (inhibitor of PFKFB3, rate-limiting step in glycolysis), while simultaneously glycolysis and function is rescued in DCs by delivery of fructose-1,6-biphosphate (F16BP, one-step downstream of PFKFB3). To demonstrate the feasibility of this strategy, vaccine formulations are generated using calcium-phosphate chemistry, that incorporate F16BP, poly(IC) as adjuvant, and phosphorylated-TRP2 peptide antigen and tested in challenging and established YUMM1.1 tumours in immunocompetent female mice. Furthermore, to test the versatility of this strategy, adoptive DC therapy is developed with formulations that incorporate F16BP, poly(IC) as adjuvant and mRNA derived from B16F10 cells as antigens in established B16F10 tumours in immunocompetent female mice. F16BP vaccine formulations rescue DCs in vitro and in vivo, significantly improve the survival of mice, and generate cytotoxic T cell (Tc) responses by elevating Tc1 and Tc17 cells within the tumour. Overall, these results demonstrate that rescuing glycolysis of DCs using metabolite-based formulations can be utilized to generate immunotherapy even in the presence of glycolytic inhibitor.

Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models.

Although different metabolic pathways have been associated with distinct macrophage phenotypes, the field of utilizing metabolites to modulate macrophage phenotype is in a nascent stage. In this report, we developed microparticles based on polymerization of alpha-ketoglutarate (a Krebs cycle metabolite), with or without encapsulation of spermine (a polyamine metabolite), to modulate cell phenotype that are critical for resolution of inflammation. Poly (alpha-ketoglutarate) microparticles encapsulated and released spermine (spermine (encap)paKG MPs) in vitro, which was accelerated in an acidic environment. When delivered to bone marrow-derived-macrophages, spermine (encap)paKG MPs induced a complex phenotypic profile outside of the typical M1/M2 paradigm, with distinct effects in the presence or absence of the pro-inflammatory stimulus lipopolysaccharide. Of particular interest was the increase in expression of CD163, which has been linked to anti-inflammatory responses in sepsis. Therefore, we systemically administered spermine (encap)paKG MPs to two different murine models of sepsis using acute or chronic injection of LPS. Macrophages and neutrophils in the liver and spleen of animals treated with spermine (encap)paKG MPs increased expression of CD163, concomitant with normalizing of glycolysis and oxidative phosphorylation, in both models. Overall, these results show that spermine (encap)paKG MPs modulate macrophage phenotype in vitro and in vivo, with potential applications in inflammation-associated diseases.