Purpose
The peri-operative and short-term benefits of unicompartmental knee arthroplasty (UKA) are well supported in the literature. However, there remains concern regarding the higher revision rate ...when compared with total knee replacement. This manuscript reports the functional outcome and survivorship of a large series of fixed bearing, medial unicompartmental replacements (St Georg Sled), with a minimum of 20 years follow-up.
Methods
Between 1974 and 1994, 399 patients (496 knees) underwent a medial fixed-bearing UKA. Prospective data were collected pre-operatively and at regular intervals post-operatively using the Bristol Knee Score (BKS), Oxford Knee (OKS) and Western Ontario MacMaster (WOMAC) scores. Kaplan–Meier survival analysis was used to determine survivorship, with revision or need for revision as end point, and differences assessed using Mantel–Cox log rank test.
Results
Functional knee scores improved post-operatively, but demonstrated a slight decline from 10 years of follow-up onwards. Survivorship is estimated as 86% at 10 years, 80% at 15 years, and 78% at 20 years. Sixty knees were revised, with progression of disease in another compartment the commonest reason. Eighty eight percent were revised using a primary prosthesis. For patients over the age of 65 years at the time of index procedure, 93% died with a functioning prosthesis in situ.
Conclusion
Medial UKA demonstrates good long-term function and survivorship, and represents an excellent surgical option for patients aged over 65 years of age, where few patients will require a revision procedure.
Level of evidence
IV.
Although there is growing evidence of brain abnormalities among individuals with conduct disorder (CD), the structural neuroimaging literature is mixed and frequently aggregates cortical volume ...rather than differentiating cortical thickness from surface area. The current study assesses CD-related differences in cortical thickness, surface area, and gyrification as well as volume differences in subcortical structures critical to neurodevelopmental models of CD (amygdala; striatum) in a carefully characterized sample. We also examined whether group structural differences were related to severity of callous-unemotional (CU) traits in the CD sample.
Participants were 49 community adolescents aged 10 to 18 years, 22 with CD and 27 healthy comparison youth. Structural MRI was collected and the FreeSurfer image analysis suite was used to provide measures of cortical thickness, surface area, and local gyrification as well as subcortical (amygdala and striatum) volumes.
Youths with CD showed reduced cortical thickness in the superior temporal cortex. There were also indications of reduced gyrification in the ventromedial frontal cortex, particularly for youths with CD without comorbid attention-deficit/hyperactivity disorder. There were no group differences in cortical surface area. However, youths with CD also showed reduced amygdala and striatum (putamen and pallidum) volumes. Right temporal cortical thickness was significantly inversely related to severity of CU traits.
Youths with CD show reduced cortical thickness within superior temporal regions, some indication of reduced gyrification within ventromedial frontal cortex and reduced amygdala and striatum (putamen and pallidum) volumes. These results are discussed with reference to neurobiological models of CD.
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of ...circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (
= 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders 5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35;
= 0.007 and HR 6.91; 95% CI, 1.37-34.97;
= 0.02, respectively, which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (
= 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.
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Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. ...Metabolites and genes related to BCAA metabolism and nitrogen handling were strongly associated with glycine in correlation analyses. Stable isotope labeling in Zucker fatty rats (ZFRs) shows that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner. Inhibition of the BCAA transaminase (BCAT) enzymes depletes plasma pools of alanine and raises glycine levels. In high-fat-fed ZFRs, dietary glycine supplementation raises urinary acyl-glycine content and lowers circulating triglycerides but also results in accumulation of long-chain acyl-coenzyme As (acyl-CoAs), lower 5’ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in muscle, and no improvement in glucose tolerance. Collectively, these studies frame a mechanism for explaining obesity-related glycine depletion and also provide insight into the impact of glycine supplementation on systemic glucose, lipid, and amino acid metabolism.
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•Glycine levels are inversely associated with cardiometabolic disease phenotypes•High BCAA levels trigger glycine use as a carbon donor for the pyruvate-alanine cycle•Inhibition of BCATs raises glycine levels•Glycine supplementation improves lipid homeostasis, but not glucose intolerance
White et al. provide a mechanism to explain why glycine levels are inversely associated with branched-chain amino acid (BCAA) levels and cardiometabolic disease phenotypes. Static metabolomics and stable isotope tracing technologies are used to demonstrate that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner.
Missing covariate data commonly occur in epidemiological and clinical research, and are often dealt with using multiple imputation. Imputation of partially observed covariates is complicated if the ...substantive model is non-linear (e.g. Cox proportional hazards model), or contains non-linear (e.g. squared) or interaction terms, and standard software implementations of multiple imputation may impute covariates from models that are incompatible with such substantive models. We show how imputation by fully conditional specification, a popular approach for performing multiple imputation, can be modified so that covariates are imputed from models which are compatible with the substantive model. We investigate through simulation the performance of this proposal, and compare it with existing approaches. Simulation results suggest our proposal gives consistent estimates for a range of common substantive models, including models which contain non-linear covariate effects or interactions, provided data are missing at random and the assumed imputation models are correctly specified and mutually compatible. Stata software implementing the approach is freely available.
Lateral unicompartmental arthroplasty (UKA) constitutes only 5–10% of all unicompartmental replacements performed. Whilst the short and medium term benefits are well documented, there remains concern ...regarding the higher revision rate when compared with total knee replacement. We report the long term clinical outcome and survivorship of a large series of lateral UKA.
Between 1974 and 1994, 71 patients (82 knees) underwent a lateral fixed-bearing St Georg Sled UKA. Prospective data was collected pre-operatively and at regular intervals post-operatively using the Bristol Knee Score (BKS), with later introduction of the Oxford Knee (OKS) and Western Ontario MacMaster (WOMAC) scores. Kaplan Meier survival analysis was used, with revision, or need for revision, as end point. 85% of the patients were female. No patients were lost to follow-up.
Functional knee scores improved post-operatively up to 10 years, at which point they demonstrated a steady decline. Survivorship was 72% at 15 years, and 68% at 20 and 25 years. Nineteen knees were revised, with progression of disease in another compartment the commonest reason. There were two revisions due to implant fracture. In patients aged over 70 years at time of index procedure, 81% died with a functioning prosthesis in situ.
This represents the longest follow-up of a large series of lateral UKA. Results of this early design of fixed bearing UKA demonstrate satisfactory long term survivorship. In elderly patients, further intervention is rarely required. More contemporary designs or techniques may show improved long term survivorship in time.
Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses ...of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.
Next-generation sequencing technologies have decentralized sequence acquisition, increasing the demand for new bioinformatics tools that are easy to use, portable across multiple platforms, and ...scalable for high-throughput applications. Cloud computing platforms provide on-demand access to computing infrastructure over the Internet and can be used in combination with custom built virtual machines to distribute pre-packaged with pre-configured software.
We describe the Cloud Virtual Resource, CloVR, a new desktop application for push-button automated sequence analysis that can utilize cloud computing resources. CloVR is implemented as a single portable virtual machine (VM) that provides several automated analysis pipelines for microbial genomics, including 16S, whole genome and metagenome sequence analysis. The CloVR VM runs on a personal computer, utilizes local computer resources and requires minimal installation, addressing key challenges in deploying bioinformatics workflows. In addition CloVR supports use of remote cloud computing resources to improve performance for large-scale sequence processing. In a case study, we demonstrate the use of CloVR to automatically process next-generation sequencing data on multiple cloud computing platforms.
The CloVR VM and associated architecture lowers the barrier of entry for utilizing complex analysis protocols on both local single- and multi-core computers and cloud systems for high throughput data processing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectiveYouths with disruptive behavior disorders, including conduct disorder and oppositional defiant disorder, show major impairments in reinforcement-based decision making. However, the neural ...basis of these difficulties remains poorly understood. This partly reflects previous failures to differentiate responses during decision making and feedback processing and to take advantage of computational model-based functional MRI (fMRI).MethodParticipants were 38 community youths ages 10–18 (20 had disruptive behavior disorders, and 18 were healthy comparison youths). Model-based fMRI was used to assess the computational processes involved in decision making and feedback processing in the ventromedial prefrontal cortex, insula, and caudate.ResultsYouths with disruptive behavior disorders showed reduced use of expected value information within the ventromedial prefrontal cortex when choosing to respond and within the anterior insula when choosing not to respond. In addition, they showed reduced responsiveness to positive prediction errors and increased responsiveness to negative prediction errors within the caudate during feedback.ConclusionsThis study is the first to determine impairments in the use of expected value within the ventromedial prefrontal cortex and insula during choice and in prediction error-signaling within the caudate during feedback in youths with disruptive behavior disorders.
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