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.

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.

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.

Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.

Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

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.

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.

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.

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.

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).

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.

BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

The BCG (Bacille Calmette-Guérin) vaccine, introduced 100 years ago for tuberculosis prevention, has emerging therapeutic off-target benefits for autoimmunity. In randomized controlled trials, BCG vaccinations were shown to gradually improve two autoimmune conditions, type 1 diabetes (T1D) and multiple sclerosis. Here, we investigate the mechanisms behind the autoimmune benefits and test the hypothesis that this microbe synergy could be due to an impact on the host T cell receptor (TCR) and TCR signal strength. We show a quantitative TCR defect in T1D subjects consisting of a marked reduction in receptor density on T cells due to hypermethylation of TCR-related genes. BCG corrects this defect gradually over 3 years by demethylating hypermethylated sites on members of the TCR gene family. The TCR sequence is not modified through recombination, ruling out a qualitative defect. These findings support an underlying density defect in the TCR affecting TCR signal strength in T1D.

Short term, low dose alpha-ketoglutarate based polymeric nanoparticles with methotrexate reverse rheumatoid arthritis symptoms in mice and modulate T helper cell responses.

Activated effector T cells induce pro-inflammatory responses in rheumatoid arthritis (RA) which then lead to inflammation of the joints. In this report, we demonstrate that polymeric nanoparticles with alpha keto-glutarate (aKG) in their polymer backbone (termed as paKG NPs) modulate T cell responses in vitro and in vivo. Impressively, a low dose of only three administrations of methotrexate, a clinically and chronically administered drug for RA, in conjunction with two doses of paKG NPs, reversed arthritis symptoms in collagen-induced arthritis (CIA) mice. This was further followed by significant decreases in pro-inflammatory antigen-specific T helper type 17 (TH17) responses and a significant increase in anti-inflammatory regulatory T cell (TREG) responses when CIA treated splenic cells were isolated and re-exposed to the CIA self-antigen. Overall, this study supports the concurrent and short term, low dose of paKG NPs and methotrexate for the reversal of RA symptoms.

Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes.

There is a need for safe and effective platform vaccines to protect against coronavirus disease 2019 (COVID-19) and other infectious diseases. In this randomized, double-blinded, placebo-controlled phase 2/3 trial, we evaluate the safety and efficacy of a multi-dose Bacillus Calmette-Guérin (BCG) vaccine for the prevention of COVID-19 and other infectious disease in a COVID-19-unvaccinated, at-risk-community-based cohort. The at-risk population is made of up of adults with type 1 diabetes. We enrolled 144 subjects and randomized 96 to BCG and 48 to placebo. There were no dropouts over the 15-month trial. A cumulative incidence of 12.5% of placebo-treated and 1% of BCG-treated participants meets criteria for confirmed COVID-19, yielding an efficacy of 92%. The BCG group also displayed fewer infectious disease symptoms and lesser severity and fewer infectious disease events per patient, including COVID-19. There were no BCG-related systemic adverse events. BCG's broad-based infection protection suggests that it may provide platform protection against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and other pathogens.

A deep learning-based system for survival benefit prediction of tyrosine kinase inhibitors and immune checkpoint inhibitors in stage IV non-small cell lung cancer patients: A multicenter, prognostic study.

Background: For clinical decision making, it is crucial to identify patients with stage IV non-small cell lung cancer (NSCLC) who may benefit from tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). In this study, a deep learning-based system was designed and validated using pre-therapy computed tomography (CT) images to predict the survival benefits of EGFR-TKIs and ICIs in stage IV NSCLC patients. Methods: This retrospective study collected data from 570 patients with stage IV EGFR-mutant NSCLC treated with EGFR-TKIs at five institutions between 2010 and 2021 (data of 314 patients were from a previously registered study), and 129 patients with stage IV NSCLC treated with ICIs at three institutions between 2017 and 2021 to build the ICI test dataset. Five-fold cross-validation was applied to divide the EGFR-TKI-treated patients from four institutions into training and internal validation datasets randomly in a ratio of 80%:20%, and the data from another institution was used as an external test dataset. An EfficientNetV2-based survival benefit prognosis (ESBP) system was developed with pre-therapy CT images as the input and the probability score as the output to identify which patients would receive additional survival benefit longer than the median PFS. Its prognostic performance was validated on the ICI test dataset. For diagnosing which patient would receive additional survival benefit, the accuracy of ESBP was compared with the estimations of three radiologists and three oncologists with varying degrees of expertise (two, five, and ten years). Improvements in the clinicians' diagnostic accuracy with ESBP assistance were then quantified. Findings: ESBP achieved positive predictive values of 80·40%, 75·40%, and 77·43% for additional EGFR-TKI survival benefit prediction using the probability score of 0·2 as the threshold on the training, internal validation, and external test datasets, respectively. The higher ESBP score (>0·2) indicated a better prognosis for progression-free survival (hazard ratio: 0·36, 95% CI: 0·19-0·68, p<0·0001) in patients on the external test dataset. Patients with scores >0·2 in the ICI test dataset also showed better survival benefit (hazard ratio: 0·33, 95% CI: 0·18-0·55, p<0·0001). This suggests the potential of ESBP to identify the two subgroups of benefiting patients by decoding the commonalities from pre-therapy CT images (stage IV EGFR-mutant NSCLC patients receiving additional survival benefit from EGFR-TKIs and stage IV NSCLC patients receiving additional survival benefit from ICIs). ESBP assistance improved the diagnostic accuracy of the clinicians with two years of experience from 47·91% to 66·32%, and the clinicians with five years of experience from 53·12% to 61·41%. Interpretation: This study developed and externally validated a preoperative CT image-based deep learning model to predict the survival benefits of EGFR-TKI and ICI therapies in stage IV NSCLC patients, which will facilitate optimized and individualized treatment strategies. Funding: This study received funding from the National Natural Science Foundation of China (82001904, 81930053, and 62027901), and Key-Area Research and Development Program of Guangdong Province (2021B0101420005).

Robotic arm-assisted versus manual unicompartmental knee arthroplasty : a systematic review and meta-analysis of the MAKO robotic system.

AIMS: This systematic review aims to compare the precision of component positioning, patient-reported outcome measures (PROMs), complications, survivorship, cost-effectiveness, and learning curves of MAKO robotic arm-assisted unicompartmental knee arthroplasty (RAUKA) with manual medial unicompartmental knee arthroplasty (mUKA). METHODS: Searches of PubMed, MEDLINE, and Google Scholar were performed in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta--Analysis statement. Search terms included "robotic", "unicompartmental", "knee", and "arthroplasty". Published clinical research articles reporting the learning curves and cost-effectiveness of MAKO RAUKA, and those comparing the component precision, functional outcomes, survivorship, or complications with mUKA, were included for analysis. RESULTS: A total of 179 articles were identified from initial screening, of which 14 articles satisfied the inclusion criteria and were included for analysis. The papers analyzed include one on learning curve, five on implant positioning, six on functional outcomes, five on complications, six on survivorship, and three on cost. The learning curve was six cases for operating time and zero for precision. There was consistent evidence of more precise implant positioning with MAKO RAUKA. Meta-analysis demonstrated lower overall complication rates associated with MAKO RAUKA (OR 2.18 (95% confidence interval (CI) 1.06 to 4.49); p = 0.040) but no difference in re-intervention, infection, Knee Society Score (KSS; mean difference 1.64 (95% CI -3.00 to 6.27); p = 0.490), or Western Ontario and McMaster Universities Arthritis Index (WOMAC) score (mean difference -0.58 (95% CI -3.55 to 2.38); p = 0.700). MAKO RAUKA was shown to be a cost-effective procedure, but this was directly related to volume. CONCLUSION: MAKO RAUKA was associated with improved precision of component positioning but was not associated with improved PROMs using the KSS and WOMAC scores. Future longer-term studies should report functional outcomes, potentially using scores with minimal ceiling effects and survival to assess whether the improved precision of MAKO RAUKA results in better outcomes. Cite this article: Bone Joint J 2022;104-B(5):541-548.

Nonresponder bias in hand surgery: analysis of 1945 cases lost to follow-up over a 6-year period.

The primary aim of this study was to identify factors associated with nonresponse to routinely collected patient-reported outcome measures (PROMs) after hand surgery. The secondary aim was to investigate the impact of nonresponder bias on postoperative PROMs. We identified 4357 patient episodes for which the patients received pre- and 1-year postoperative questionnaires. The response rate was 55%. Univariate and regression analyses were undertaken to determine factors predicting nonresponse. We developed a predictive model for the postoperative Quick version of the Disabilities of the Arm, Shoulder, and Hand (QuickDASH) scores for nonresponders using imputation. Younger age, increasing deprivation, higher comorbidity, worse preoperative QuickDASH scores and unemployment predicted nonresponse. No significant difference in mean postoperative QuickDASH score was observed between the responders, and the scores for the responders combined with the predicted scores for the nonresponders. Preoperative function was the primary predictor of postoperative outcome. These results challenge the dogma that 'loss to follow-up' automatically invalidates the results of a study.Level of evidence: III.

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.

Epigenetic changes related to glucose metabolism in type 1 diabetes after BCG vaccinations: A vital role for KDM2B.

BACKGROUND: A recent epigenome-wide association study of genes associated with type 2 diabetics (T2D), used integrative cross-omics analysis to identify 22 abnormally methylated CpG sites associated with insulin and glucose metabolism. Here, in this epigenetic analysis we preliminarily determine whether the same CpG sites identified in T2D also apply to type 1 diabetes (T1D). We then determine whether BCG vaccination could correct the abnormal methylation patterns, considering that the two diseases share metabolic derangements. METHODS: T1D (n = 13) and control (n = 8) subjects were studied at baseline and then T1D subjects studied yearly for 3 years after receiving BCG vaccinations in a clinical trial. In this biomarker analysis, methylation patterns were evaluated on CD4+ T-lymphocytes from baseline and yearly blood samples using the human Illumina Methylation EPIC Bead Chip. Methylation analysis combined with mRNA analysis using RNAseq. RESULTS: Broad but not complete overlap was observed between T1D and T2D in CpG sites with abnormal methylation. And in the three-year observation period after BCG vaccinations, the majority of the abnormal methylation sites were corrected in vivo. Genes of particular interest were related to oxidative phosphorylation (CPT1A, LETM1, ABCG1), to the histone lysine demethylase gene (KDM2B), and mTOR signaling through the DDIT4 gene. The highlighted CpG sites for both KDM2B and DDIT4 genes were hypomethylated at baseline compared to controls; BCG vaccination corrected the defect by hypermethylation. CONCLUSIONS: Glycolysis is regulated by methylation of genes. This study unexpectedly identified both KDM2B and DDIT4 as genes controlling BCG-driven re-methylation of histones, and the activation of the mTOR pathway for facilitated glucose transport respectively. The BCG effect at the gene level was confirmed by reciprocal mRNA changes. The DDIT4 gene with known inhibitory role of mTOR was re-methylated after BCG, a step likely to allow improved glucose transport. BCGs driven methylation of KDM2B's site should halt augmented histone activity, a step known to allow cytokine activation and increased glycolysis.

Mobile devices and wearable technology for measuring patient outcomes after surgery: a systematic review.

Complications following surgery are common and frequently occur the following discharge. Mobile and wearable digital health interventions (DHI) provide an opportunity to monitor and support patients during their postoperative recovery. Lack of high-quality evidence is often cited as a barrier to DHI implementation. This review captures and appraises the current use, evidence base and reporting quality of mobile and wearable DHI following surgery. Keyword searches were performed within Embase, Cochrane Library, Web of Science and WHO Global Index Medicus databases, together with clinical trial registries and Google scholar. Studies involving patients undergoing any surgery requiring skin incision where postoperative outcomes were measured using a DHI following hospital discharge were included, with DHI defined as mobile and wireless technologies for health to improve health system efficiency and health outcomes. Methodological reporting quality was determined using the validated mobile health evidence reporting and assessment (mERA) guidelines. Bias was assessed using the Cochrane Collaboration tool for randomised studies or MINORS depending on study type. Overall, 6969 articles were screened, with 44 articles included. The majority (n = 34) described small prospective study designs, with a high risk of bias demonstrated. Reporting standards were suboptimal across all domains, particularly in relation to data security, prior patient engagement and cost analysis. Despite the potential of DHI to improve postoperative patient care, current progress is severely restricted by limitations in methodological reporting. There is an urgent need to improve reporting for DHI following surgery to identify patient benefit, promote reproducibility and encourage sustainability.