Recent Submissions

  • Journal Article

    The virtue of optimistic realism - expectation fulfillment predicts patient-rated global effectiveness of total hip arthroplasty 

    Kästner, Anne; Ng Kuet Leong, Virginie S C; Petzke, Frank; Budde, Stefan; Przemeck, Michael; Müller, Martin; Erlenwein, Joachim
    BMC Musculoskeletal Disorders. 2021 Feb 13;22(1):180
    Abstract Background Emerging evidence highlights the importance of preoperative expectations in predicting patient-reported outcomes of orthopedic surgeries. To date, it is still a matter of controversy whether patient satisfaction can be maximized by promoting either optimistic or realistic outcome expectations before surgery. Adjusting overly optimistic outcome expectancies in favor of a more realistic outlook on the limitations of total hip arthroplasty could reduce the risk of disappointment and lead to greater satisfaction with surgery outcomes. Our prospective cohort study was aimed at comparing the relative predictive influence of baseline expectations, expectation fulfillment and symptomatic improvement on the global effectiveness of total hip arthroplasty. Methods Ninety patients (49 female, 41 male; mean age: 63 ± 12.87 years) fulfilled inclusion criteria and completed a comprehensive preoperative assessment comprising sociodemographic, clinical, functional and psychological phenotypes. Moreover, the strengths of preoperative expectations for improvements in eight pain-related and functional domains were recorded on a 5-point Likert-scale. At 12 months after surgery, patients were asked to rate perceived improvements in each of these domains as well as the global effectiveness of the total hip replacement on a 5-point Likert-scale. To evaluate the relative impact of preoperative expectations, symptom improvement and the fulfillment of expectations on the global effectiveness of surgery, a sequential multiple regression analysis was performed. Results Compared with the actual improvement at 12-months follow-up, prior expectations had been overly optimistic in about 28% of patients for hip pain, in about 45% for walking ability and around 60% for back pain, independence in everyday life, physical exercise, general function social interactions and mental well-being. An optimistic hip pain expectation, walking ability at baseline and the fulfillment of expectations for walking ability, general function and independence in everyday life were found to independently predict global effectiveness ratings. Conclusions Positive expectation about pain and the fulfillment of expectations concerning functional domains predicted higher global effectiveness ratings. In line with many authors investigating the relationship between the fulfillment of expectations and satisfaction with medical interventions, we suggest that professionals should explicitly address their patients’ expectations during the preoperative education and consultation.
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  • Journal Article

    Identification of subgroup effect with an individual participant data meta-analysis of randomised controlled trials of three different types of therapist-delivered care in low back pain 

    Hee, Siew W; Mistry, Dipesh; Friede, Tim; Lamb, Sarah E; Stallard, Nigel; Underwood, Martin; Patel, Shilpa
    BMC Musculoskeletal Disorders. 2021 Feb 16;22(1):191
    Abstract Background Proven treatments for low back pain, at best, only provide modest overall benefits. Matching people to treatments that are likely to be most effective for them may improve clinical outcomes and makes better use of health care resources. Methods We conducted an individual participant data meta-analysis of randomised controlled trials of three types of therapist delivered interventions for low back pain (active physical, passive physical and psychological treatments). We applied two statistical methods (recursive partitioning and adaptive risk group refinement) to identify potential subgroups who might gain greater benefits from different treatments from our individual participant data meta-analysis. Results We pooled data from 19 randomised controlled trials, totalling 9328 participants. There were 5349 (57%) females with similar ratios of females in control and intervention arms. The average age was 49 years (standard deviation, SD, 14). Participants with greater psychological distress and physical disability gained most benefit in improving on the mental component scale (MCS) of SF-12/36 from passive physical treatment than non-active usual care (treatment effects, 4.3; 95% confidence interval, CI, 3.39 to 5.15). Recursive partitioning method found that participants with worse disability at baseline gained most benefit in improving the disability (Roland Morris Disability Questionnaire) outcome from psychological treatment than non-active usual care (treatment effects, 1.7; 95% CI, 1.1 to 2.31). Adaptive risk group refinement did not find any subgroup that would gain much treatment effect between psychological and non-active usual care. Neither statistical method identified any subgroups who would gain an additional benefit from active physical treatment compared to non-active usual care. Conclusions Our methodological approaches worked well and may have applicability in other clinical areas. Passive physical treatments were most likely to help people who were younger with higher levels of disability and low levels of psychological distress. Psychological treatments were more likely to help those with severe disability. Despite this, the clinical importance of identifying these subgroups is limited. The sizes of sub-groups more likely to benefit and the additional effect sizes observed are small. Our analyses provide no evidence to support the use of sub-grouping for people with low back pain.
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  • Journal Article

    A graph-based algorithm for detecting rigid domains in protein structures 

    Dang, Truong K L; Nguyen, Thach; Habeck, Michael; Gültas, Mehmet; Waack, Stephan
    BMC Bioinformatics. 2021 Feb 12;22(1):66
    Abstract Background Conformational transitions are implicated in the biological function of many proteins. Structural changes in proteins can be described approximately as the relative movement of rigid domains against each other. Despite previous efforts, there is a need to develop new domain segmentation algorithms that are capable of analysing the entire structure database efficiently and do not require the choice of protein-dependent tuning parameters such as the number of rigid domains. Results We develop a graph-based method for detecting rigid domains in proteins. Structural information from multiple conformational states is represented by a graph whose nodes correspond to amino acids. Graph clustering algorithms allow us to reduce the graph and run the Viterbi algorithm on the associated line graph to obtain a segmentation of the input structures into rigid domains. In contrast to many alternative methods, our approach does not require knowledge about the number of rigid domains. Moreover, we identified default values for the algorithmic parameters that are suitable for a large number of conformational ensembles. We test our algorithm on examples from the DynDom database and illustrate our method on various challenging systems whose structural transitions have been studied extensively. Conclusions The results strongly suggest that our graph-based algorithm forms a novel framework to characterize structural transitions in proteins via detecting their rigid domains. The web server is available at http://azifi.tz.agrar.uni-goettingen.de/webservice/ .
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  • Journal Article

    S-conLSH: alignment-free gapped mapping of noisy long reads 

    Chakraborty, Angana; Morgenstern, Burkhard; Bandyopadhyay, Sanghamitra
    BMC Bioinformatics. 2021 Feb 11;22(1):64
    Abstract Background The advancement of SMRT technology has unfolded new opportunities of genome analysis with its longer read length and low GC bias. Alignment of the reads to their appropriate positions in the respective reference genome is the first but costliest step of any analysis pipeline based on SMRT sequencing. However, the state-of-the-art aligners often fail to identify distant homologies due to lack of conserved regions, caused by frequent genetic duplication and recombination. Therefore, we developed a novel alignment-free method of sequence mapping that is fast and accurate. Results We present a new mapper called S-conLSH that uses Spaced context based Locality Sensitive Hashing. With multiple spaced patterns, S-conLSH facilitates a gapped mapping of noisy long reads to the corresponding target locations of a reference genome. We have examined the performance of the proposed method on 5 different real and simulated datasets. S-conLSH is at least 2 times faster than the recently developed method lordFAST. It achieves a sensitivity of 99%, without using any traditional base-to-base alignment, on human simulated sequence data. By default, S-conLSH provides an alignment-free mapping in PAF format. However, it has an option of generating aligned output as SAM-file, if it is required for any downstream processing. Conclusions S-conLSH is one of the first alignment-free reference genome mapping tools achieving a high level of sensitivity. The spaced-context is especially suitable for extracting distant similarities. The variable-length spaced-seeds or patterns add flexibility to the proposed algorithm by introducing gapped mapping of the noisy long reads. Therefore, S-conLSH may be considered as a prominent direction towards alignment-free sequence analysis.
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  • Journal Article

    Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy 

    Reinert, Marie-Christine; Pacheu-Grau, David; Catarino, Claudia B; Klopstock, Thomas; Ohlenbusch, Andreas; Schittkowski, Michael; Wilichowski, Ekkehard; Rehling, Peter; Brockmann, Knut
    Orphanet Journal of Rare Diseases. 2021 Feb 04;16(1):64
    Abstract Background Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I–XIV. Results We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control. Conclusions Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients.
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  • Journal Article

    Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host 

    Ribes, S.; Zacke, L.; Nessler, S.; Saiepour, N.; Avendaño-Guzmán, E.; Ballüer, M.; Hanisch, U. K; Nau, R.
    Journal of Neuroinflammation. 2021 Feb 02;18(1):39
    Abstract Background Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae. Methods Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)−/− mice received an intraperitoneal injection of 100 μg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed. Results Pre-treatment with 100 μg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9−/− mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection. Conclusions Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.
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