Inference of Markovian Properties of Molecular Sequences from NGS Data and Applications to Comparative Genomics

Next Generation Sequencing (NGS) technologies generate large amounts of short read data for many different organisms. The fact that NGS reads are generally short makes it challenging to assemble the reads and reconstruct the original genome sequence. For clustering genomes using such NGS data, word-count based alignment-free sequence comparison is a promising approach, but for this approach, the underlying expected word counts are essential. A plausible model for this underlying distribution of word counts is given through modelling the DNA sequence as a Markov chain (MC). For single long sequences, efficient statistics are available to estimate the order of MCs and the transition probability matrix for the sequences. As NGS data do not provide a single long sequence, inference methods on Markovian properties of sequences based on single long sequences cannot be directly used for NGS short read data. Here we derive a normal approximation for such word counts. We also show that the traditional Chi-square statistic has an approximate gamma distribution, using the Lander-Waterman model for physical mapping. We propose several methods to estimate the order of the MC based on NGS reads and evaluate them using simulations. We illustrate the applications of our results by clustering genomic sequences of several vertebrate and tree species based on NGS reads using alignment-free sequence dissimilarity measures. We find that the estimated order of the MC has a considerable effect on the clustering results, and that the clustering results that use a MC of the estimated order give a plausible clustering of the species.Comment: accepted by RECOMB-SEQ 201

Use of Physiotherapy Prior to Total Knee Arthroplasty-Results of the Prospective FInGK Study

Background: Data regarding physiotherapy (PT) utilization prior to total knee arthroplasty (TKA) are insufficient. Therefore, this study aims to examine which percentage of patients receive PT within 12 months prior to TKA and which factors are associated with its use. Methods: Consecutive patients (≥18 years) undergoing primary or revision TKA in a German university hospital were recruited. A questionnaire including information on PT utilization, demography, and socioeconomics was collected one day prior to surgery and linked to medical hospital records. Multivariable logistic regression was conducted to determine variables associated with the use of PT. Results: A total of 241 out of 283 (85%) patients participated (60% female; mean age: 68.4 years). Overall, 41% received PT at least once during 12 months prior to TKA, women more frequently than men (48% vs. 29%). Although high disease burden was associated with increased utilization, about one in two in this condition did not receive PT. Multivariable logistic regression showed that age 75+ years, low education level, and moderate-to-severe depressive symptoms were associated with decreased PT utilization. Conclusions: We found low use of recommended PT management in patients prior to TKA. This potential underuse was even higher in some vulnerable subgroups, indicating inequalities. Prescribers as well as patients should integrate PT more consistently into osteoarthritis management

Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis

To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10(-5 )M to 10(-11 )M. Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-γ and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-γ, TNF-α, and IL-10 at a concentration of 10(-5 )M. In addition, IFN-γ release was suppressed by 10(-7 )M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10(-5 )M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-γ production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-γ production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-γ production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation

Validation of mobile eye-tracking as novel and efficient means for differentiating progressive supranuclear palsy from Parkinson's disease

Background: The decreased ability to carry out vertical saccades is a key symptom of Progressive Supranuclear Palsy (PSP). Objective measurement devices can help to reliably detect subtle eye movement disturbances to improve sensitivity and specificity of the clinical diagnosis. The present study aims at transferring findings from restricted stationary video-oculography (VOG) to a wearable head-mounted device, which can be readily applied in clinical practice. Methods: We investigated the eye movements in 10 possible or probable PSP patients, 11 Parkinson's disease (PD) patients, and 10 age-matched healthy controls (HCs) using a mobile, gaze-driven video camera setup (EyeSeeCam). Ocular movements were analyzed during a standardized fixation protocol and in an unrestricted real-life scenario while walking along a corridor. Results: The EyeSeeCam detected prominent impairment of both saccade velocity and amplitude in PSP patients, differentiating them from PD and HCs. Differences were particularly evident for saccades in the vertical plane, and stronger for saccades than for other eye movements. Differences were more pronounced during the standardized protocol than in the real-life scenario. Conclusions: Combined analysis of saccade velocity and saccade amplitude during the fixation protocol with the EyeSeeCam provides a simple, rapid (<20 s), and reliable tool to differentiate clinically established PSP patients from PD and HCs. As such, our findings prepare the ground for using wearable eye-tracking in patients with uncertain diagnoses

The Immediate Effects of Foam Rolling and Stretching on Iliotibial Band Stiffness:A Randomized Controlled Trial

BackgroundIliotibial Band Syndrome (ITBS) is a common clinical condition likely caused by abnormal compressive forces to the iliotibial band (ITB). Stretching interventions are common in ITBS treatment and may predominantly affect tensor fascia latae (TFL). Another ITBS treatment is foam rolling, which may more directly affect the ITB. Shear wave ultrasound elastography (SWUE) measures real-time soft tissue stiffness, allowing tissue changes to be measured and compared.PurposeTo examine effects of foam rolling and iliotibial complex stretching on ITB stiffness at 0 degrees and 10 degrees of hip adduction and hip adduction passive range of motion (PROM).Study DesignRandomized controlled trial.MethodsData from 11 males (age = 30.5 +/- 9.0 years, Body Mass Index (BMI) = 27.8 +/- 4.0) and 19 females (age = 23.5 +/- 4.9, BMI = 23.2 +/- 2.1) were analyzed for this study. Subjects were randomly assigned to one of three groups: control, stretching, and foam rolling. Shear wave ultrasound elastography measurements included ITB Young's modulus at the mid-thigh, the distal femur and the TFL muscle belly. ITB-to-femur depth was measured at mid-thigh level. Hip adduction PROM was measured from digital images taken during the movement.ResultsNo significant interactions or main effects were found for group or time differences in ITB Young's modulus at the three measured locations. The ITB stiffness at the mid-thigh and distal femur increased with 10 degrees adduction, but TFL stiffness did not increase. A main effect for adduction PROM was observed, where PROM increased 0.8 degrees post-treatment (p = 0.02).ConclusionA single episode of stretching and foam rolling does not affect short-term ITB stiffness. The lack of ITB stiffness changes may be from an inadequate intervention stimulus or indicate that the interventions have no impact on ITB stiffness.</p

Factors Associated With Nonunion in Arthrodesis of the First Metatarsophalangeal Joint:A Multicenter Retrospective Cohort Study

BACKGROUND: Arthrodesis of the first metatarsophalangeal joint is the current treatment of choice for symptomatic advanced hallux rigidus and moderate-to-severe hallux valgus. There are different methods to perform arthrodesis, yet no consensus on the best approach. Therefore, this study aimed to determine the effects of preoperative and postoperative hallux valgus angle (HVA), joint preparation and fixation technique, and postoperative immobilization on the incidence of nonunion.METHODS: A retrospective multicenter cohort study was performed that included 794 patients. Univariate and multiple logistic regression was conducted to determine associations between joint preparation, fixation techniques, postoperative immobilization, weightbearing, and pre- and postoperative HVA with nonunion.RESULTS: Nonunion incidence was 15.2%, with 11.1% symptomatic and revised. Joint preparation using hand instruments (OR 3.75, CI 1.90-7.42) and convex/concave reamers (OR 2.80, CI 1.52-5.16) were associated with greater odds of a nonunion compared to planar cuts. Joint fixation with crossed screws was associated with greater odds of nonunion (OR 2.00, CI 1.11-3.42), as was greater preoperative HVA (OR 1.02, CI 1.00-1.03). However, the latter effect disappeared after inclusion of postoperative HVA in the model, with a small association identified between residual postoperative HVA and nonunion (OR 1.04, CI 1.01-1.08). Similarly, we found an association between odds of nonunion and higher body weight (OR 1.02, CI 1.01-1.04) but not of body mass index.CONCLUSION: Based on our results, first metatarsophalangeal joint arthrodesis with planar cuts and fixation with a plate and interfragmentary screw is associated with the lowest odds of resulting in a nonunion. Higher body weight and greater preoperative HVA were associated with slight increase in rates of nonunion. It is crucial to properly correct the hallux valgus deformity during surgery.LEVEL OF EVIDENCE: Level III, retrospective case control study.</p