Freedom in Osteoarthritis of the Knee

The first peak of the external knee abduction moment (KAM) is often used as a surrogate measure of the medial compartment loading and has been correlated with pain and progression of knee osteoarthritis (OA). As a result, reducing the KAM is often the target of conservative interventions. OA should be considered as a “Whole Person” disease, including ecological psychosocial aspects. Scientists have developed gait alteration strategies to reduce the KAM. They attempted to force into a new position any particular part without reference to the pattern of the whole. We propose an alternative approach: in the vicinity of a special configuration of the knee, some or all of the components of the knee become overloaded. This study has shown that when six lines $1′,$2′,$3′,$4′,$5′,$6′ are so situated that forces acting along them equilibrate when applied to one degree of freedom, 1° F knee, a certain determinant vanishes. We wish to define the six lines as the knee complex in involution by virtue of some constraint upon the knee.

Changes in foot progression angle during gait reduce the knee adduction moment and do not increase hip moments in individuals with knee osteoarthritis

People with knee osteoarthritis who adopt a modified foot progression angle (FPA) during gait often benefit from a reduction in the knee adduction moment and knee pain. It is unknown, however, whether changes in the FPA increase hip moments, a surrogate measure of hip loading, which may increase the risk of hip pain or osteoarthritis. This study examined how altering the FPA affects hip moments. Individuals with knee osteoarthritis walked on an instrumented treadmill with their baseline gait, 10° toe-in gait, and 10° toe-out gait. A musculoskeletal modeling package was used to compute joint moments from the experimental data. Fifty participants were selected from a larger study who reduced their peak knee adduction moment with a modified FPA. In this group, participants reduced the first peak of the knee adduction moment by 7.6% with 10° toe-in gait and reduced the second peak by 11.0% with 10 ° toe-out gait. Modifying the FPA reduced the early-stance hip abduction moment, at the time of peak hip contact force, by 4.3% ± 1.3% for 10° toe-in gait (p=0.005) and by 4.6% ± 1.1% for 10° toe-out gait (p<0.001) without increasing the flexion and internal rotation moments (p>0.15). In summary, when adopting a FPA modification that reduced the knee adduction moment, participants did not increase surrogate measures of hip loading.

Forced Oscillation Technique: a surrogate measure of lung function in neuromuscular disease patients?

Introduction Spirometry plays an important role in the assessment of possible respiratory failure in children with neuromuscular disorders (NMDs). However, obtaining reliable spirometry results is a major challenge. We studied the relation between Forced Oscillation Technique (FOT) and spirometry results. FOT is an easy, non-invasive method to measure respiratory mechanics, i.e. respiratory resistance R and respiratory reactance X. We hypothesized an increased resistance R and reduced reactance X in patients with more reduced lung function. Methods In this prospective single center study we included all children with NMDs able to perform spirometry. We consecutively measured respiratory resistance R and reactance X at 5, 11 and 19 Hz and (Forced) Vital Capacity, Peak Expiratory Flow. Spearman correlation coefficients were calculated and regression curves were estimated. Results We included 148 patients, with a median age of 13 years (IQR 8-16). All correlation coefficients were statistically significant with p = 0.000. A negative correlation was found between resistance R and spirometry outcomes (spearman correlation coefficient (ρ) between -0.5 and -0.6). A positive correlation was found between reactance X (i.e. less negative outcomes) and spirometry outcomes (ρ between 0.4 and 0.6). Highest correlation was found at lower frequencies. Regression analysis showed a non-linear relation between FOT and spirometry results. Conclusion We found a non-linear relation between FOT and spirometry results with increased resistance R and reduced reactance X in patients with more restrictive lung function decline. Given the difficulties with performing spirometry, FOT may be a promising surrogate measure of lung function.

Quantification of Similar Neurodegeneration Across Geriatric Concussions and Alzheimer’s Disease

Geriatric mild traumatic brain injury (mTBI) is a risk factor for Alzheimer’s disease (AD), but few studies have studied how the neuroanatomic effects of these conditions can converge onto similar brain structure trajectories. Here we use magnetic resonance imaging to investigate similarities between mTBI and AD across both white and gray matter (WM and GM, respectively) using measures like fractional anisotropy (FA, a surrogate measure of WM integrity) and cortical thickness. We identify statistically significant similarities in neurodegeneration across mTBI (N = 33; age µ = 63 years (y), σ = 11 y) and AD (N = 66; age µ = 76 y, σ = 9 y) by testing for statistical equivalences of mean FA and cortical thickness. Both WM and GM are found to exhibit significant similarities in how mean FA and cortical thickness decrease, respectively, across mTBI and AD. For WM, the broadest spatial extent of statistical similarity between conditions, quantified as percentages of structures’ volumes, is found within the superior fronto-occipital fasciculus (left (L): 91%, p &lt; 0.05; right (R): 95%, p &lt; 0.05), and in the crura of the fornix (L: 65%, p &lt; 0.05; R: 80%, p &lt; 0.05). Across mTBI and AD, cortical thinning trajectories are most similar in the superior precentral sulcus (L: 91%, p &lt; 0.05; R: 100%, p &lt; 0.05), and anterior lateral sulcus (L: 75%, p &lt; 0.05; R: 86%, p &lt; 0.05). Future studies should leverage such findings to identify AD risk factors in mTBI patients.

Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation

Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene. The expanded repeat induces repressive histone changes and DNA hypermethylation, which result in epigenetic silencing and FXN transcriptional deficiency. A class I histone deacetylase inhibitor (HDACi-109) reactivates the silenced FXN gene, although with considerable inter-individual variability, which remains etiologically unexplained. Because HDAC inhibitors work by reversing epigenetic silencing, we reasoned that epigenetic heterogeneity among patients may help to explain this inter-individual variability. As a surrogate measure for epigenetic heterogeneity, a highly quantitative measurement of DNA hypermethylation via bisulfite deep sequencing, with single molecule resolution, was used to assess the prevalence of unmethylated, partially methylated, and fully methylated somatic FXN molecules in PBMCs from a prospective cohort of 50 FRDA patients. Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.

Research of Surrogate Measure for Freeway Crashes Based on Tire Skid Marks

Traditional approaches to evaluating and predicting safety issues in traffic systems are via crash records. However, considering the characteristics of scarcity, inconsistency, inaccuracy, and incompleteness of crash records, conclusions and recommendations drawn purely based on crashes have limitations. Tire skid marks are considered an indication of some safety hazards, and it could have good potential to be used as surrogates for crashes. By collecting and analyzing the data based on selected arterial and freeway segments in the Reno-Sparks area in northern Nevada, a methodology was developed to categorize different tire skid marks. Sliding window and linear regression techniques were applied to determine any correlation between tire skid marks and crashes. The analyses indicated that there was a relatively strong linear correlation between skid marks and crashes on freeway segments.

Glycosuria alters uropathogenic Escherichia coli global gene expression and virulence

Uropathogenic Escherichia coli (UPEC) is the principal etiology of more than half of urinary tract infections (UTI) in humans with diabetes mellitus. Epidemiological data and studies in mouse model of ascending UTI have elucidated various host factors responsible for increasing the susceptibility of diabetic hosts to UPEC-UTI. In contrast, the nature of alterations in UPEC physiology mediated by diabetic urinary microenvironment and the contributions of altered UPEC physiology in shaping UPEC-UTI pathogenesis in diabetes have not been examined. Our central hypothesis is that glycosuria directly induces urinary virulence of UPEC. We compared virulence characteristics and gene expression in human UPEC strains UTI89 (cystitis) and CFT073 (pyelonephritis) exposed for 2h, in vitro to human urine either in the presence or absence of glycosuria (600mg/dl glucose). Compared to control UPEC exposed to nutrient-rich culture medium LB, glycosuria-exposed UPEC exhibited significant increase in biofilm formation and reduction in the hemagglutination of Guinea pig erythrocytes (a surrogate measure of type 1 piliation). In addition, analysis of UTI89 transcriptome by RNA sequencing revealed that 2h-long, in vitro exposure to glycosuria also significantly alters expression of virulence and metabolic genes central to urinary virulence of UPEC. In summary, our results provide novel insights into how glycosuria-mediated early changes in UPEC fitness may facilitate UTI pathogenesis in the diabetic urinary microenvironment.

SP1.1.11Is polyp detection rate a suitable surrogate measure for adenoma detection rate in colonoscopy?

Aims The Joint Advisory Group on GI Endoscopy (JAG) has set key quality indicators for colonoscopy, which includes an adenoma detection rate of a minimum of 15%. Given the difficulty in reporting adenoma detection rate, JAG have stated that polyp detection rate is accepted as a surrogate measure. Our aim was to assess whether polyp detection rate can be used as a substitute marker for adenoma detection, by examining the histology of samples taken as polyps to determine what proportion are truly adenomas. Methods The pathology department provided a registry of all histological samples taken from the colon or rectum during a one-year period April 2017 to April 2018. These samples were cross-referenced with the endoscopy report to assess which were identified as “polyps” by the performing endoscopist. The pathology report was then reviewed to determine what the histological conclusion was for each “polyp”. Results A total of 1601 colorectal histology samples were reviewed, taken by 32 different endoscopists. 451 of these were identified as polyps by the performing endoscopist. On histological review 153 (33.9%) were not adenomas of the colon or rectum. Common alternative histological diagnoses were hyperplastic polyp, inflammatory polyp and normal tissue. Rarer alternative histological diagnoses were melanosis coli, submucosal leiomyoma and endometriosis of the rectum. Conclusions Polyp detection rate which is used as a surrogate marker for adenoma detection rate is an inaccurate measure of colonoscopy quality.