Intra-operative Raman spectroscopy and mapping for assessment of cartilage degradation

The development of a label-free, non-destructive and safe analytical method such as Raman spectroscopy for assessing cartilage degradation is highly desirable. Compared to non-optical imaging modalities, Raman mapping offers a more sensitive means of directly assessing the chemical composition of cartilage in three-dimensional space and the potential to monitor cartilage degeneration to inform intervention and treatment strategies. Herein, we report the application of Raman spectroscopic methods ex vivo and at arthroscopy to identify molecular alterations in cartilage specimens containing minor focal lesions characteristic of the early disease phase. Our initial ex vivo analysis, obtained by single-point Raman spectroscopy of cartilage samples, supports previous findings based on S-O stretching vibration bands associated with sulphated glycosaminoglycans (sGAGs). We extended the analyses to the high-wavenumber region where we observed that vibrational bands assigned to C-H and O-H stretching modes discriminated early cartilage alterations from healthy cartilage samples. Furthermore, we performed a proof-of-concept in-clinic study using a custom-built optical probe to acquire Raman spectral measurements for the first time in patients undergoing arthroscopy of knee joints. Spectra were obtained with adequate signal-to-noise ratios that similarly discriminated between lesion and adjacent cartilage sites and identified reductions in sGAGs in apparently healthy cartilage. Building on this, we present initial results from Raman mapping to spatially resolve the molecular constituents of cartilage through its depth and across a lesion. Mapping revealed a non-uniform and reduced sGAG distribution within the lesion and peripheral cartilage that was otherwise visually normal, similar to the in-clinic observations, showing that the degradative influence of the lesion extended beyond its border. This was accompanied by a decreased fluorescence signal intensity, which suggests that fluorescence may provide valuable information as an adjunct to the Raman signal in discriminating normal and degenerating cartilage. This work demonstrates the value of Raman mapping over single-point Raman measurements for the analysis of the anisotropy of articular cartilage and highlights the potential of the technology for in vivo articular joint arthroscopy applications

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Psychosocial functioning and health related quality of life in paediatric inflammatory bowel disease

Objectives: The present systematic review examined the literature focusing on psychosocial functioning and health-related quality of life (HRQOL) in young people with inflammatory bowel disease (IBD). It aimed to critique the methodological quality of the identified studies, discuss the implications of their findings, and make recommendations for future research. Patients and Methods: Relevant articles (January 1990-December 2009) were subject to strict inclusion and exclusion criteria. Identified papers were rated for methodological quality using SIGN 50 and Critical Appraisal Skills Programme guidelines before data extraction. Results: Of 2141 articles initially identified, 278 were screened in detail, leaving 12 articles for inclusion in the review: 3 having "acceptable" and 9 having "good" quality rating scores. These 12 studies yielded a combined total of 5330 participants including 790 with IBD and 4540 controls (ages 4-18 years). Five main outcomes-self-esteem, HRQOL, anxiety and depression, social competence, and behavioural functioning-were examined. Three of the 4 controlled studies addressing self-reported HRQOL found it to be significantly lower in the participants with IBD. The evidence for lowered self-esteem, self-reported symptoms of depression and anxiety, impaired social competence, and behavioural problems were conflicting. Methodological heterogeneity was noted in terms of areas of functioning addressed, measures used, sample size, and use of control groups. Conclusions: HRQOL is lower in patients with IBD, but conflicting results and methodological flaws limit conclusions on other aspects of psychosocial functioning. Future research should present data on effect sizes, avoid confounding findings by not combining across age groups or disease severity indices, and consider investigating body image disturbanc

A technique of staged lateral release to correct patellar tracking in total knee arthroplasty

Optimal patellar tracking and component alignment are important in achieving a well-functioning total knee arthroplasty (TKA). The patella is constrained partly by design of the prosthetic trochlear groove, and patellar tracking is governed by a combination of static and dynamic factors. Maltracking may result from excessive or unbalanced tension in the surrounding soft tissues. This article describes a staged progressive lateral release of the patellar retinaculum in TKA, which is classified into 6 stages. Stage 1 transects the deep lateral patellofemoral ligament; stages 2 to 6 extend the lateral patellar incision distally from vastus lateralis to the tibial tubercle. This technique was used in a series of 96 primary TKAs. We report the rates of the various stages of lateral release and the variables that might affect the decision to perform such a release

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 -12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD. © 2008 Nature Publishing Group