A cross-sectional study to validate an administrative back pain severity classification tool based on the graded chronic pain scale.

Treatment of chronic lower back pain (CLBP) should be stratified for best medical and economic outcome. To improve the targeting of potential participants for exclusive therapy offers from payers, Freytag et al. developed a tool to classify back pain chronicity classes (CC) based on claim data. The aim of this study was to evaluate the criterion validity of the model. Administrative claim data and self-reported patient information from 3,506 participants (2014-2021) in a private health insurance health management programme in Germany were used to validate the tool. Sensitivity, specificity, and Matthews' correlation coefficient (MCC) were calculated comparing the prediction with actual grades based on von Korff's graded chronic pain scale (GCPS). The secondary outcome was an updated view on direct health care costs (€) of patients with back pain (BP) grouped by GCPS. Results showed a fair correlation between predicted CC and actual GCPS grades. A total of 69.7% of all cases were correctly classified. Sensitivity and specificity rates of 54.6 and 76.4% underlined precision. Correlation between CC and GCPS with an MCC of 0.304 also indicated a fair relationship between prediction and observation. Cost data could be clearly grouped by GCPS: the higher the grade, the higher the costs and the use of health care. This was the first study to compare the predicted severity of BP using claim data with the actual severity of BP by GCPS. Based on the results, the usage of CC as a single tool to determine who receives CLBP treatment cannot be recommended. CC is a good tool to segment candidates for specific types of intervention in BP. However, it cannot replace a medical screening at the beginning of an intervention, as the rate of false negatives is too high. Trial registration The study was conducted using routinely collected data from an intervention, which was previously evaluated and registered retrospectively in the German Registry of Clinical Trials under DRKS00015463 (04/09/2018). Informed consent and the self-reported questionnaire have remained unchanged since the study and, therefore, are still valid according to the ethics proposal.

Association between chronic low back pain and regular exercise, sedentary behaviour and mental health before and during COVID-19 pandemic: insights from a large-scale cross-sectional study in Germany.

BACKGROUND: Nonspecific chronic low back pain (CLBP) is a complex symptom with numerous possible causes and influencing factors. Understanding how modifiable factors affect the course of CLBP is important for preventing progression. As the COVID-19 pandemic has changed the lifestyle of many people, this study paper assessed whether it also changed the influence of modifiable lifestyle factors (regular exercise and sedentary behaviour) and mental health factors (anxiety and depression) on CLBP pain intensity and disability by comparing the strength of these associations before and during the pandemic. We hypothesised that the importance of regular physical activity and good mental health for CLBP patients would increase during the pandemic. METHODS: These questions were investigated in a cross-sectional study of insurance claims data and self-reported data from various questionnaires from 3,478 participants in a German CLBP health intervention (2014-2021) by calculating pre- and intra-pandemic odds ratios (OR) and 95% confidence intervals (CI) for each variable of interest and outcome. Potential confounders were also considered. Pandemic status was treated as an effect modifier. Based on the date of enrolment, participants were classified as "pre-pandemic" or "pandemic". RESULTS: Regularly exercising ≥ 4 h/week significantly reduced the odds of high disability for men (OR 0.49, 95% CI 0.31 - 0.79, p = 0.003) and women (OR 0.30, 95% CI 0.14 - 0.563, p = 0.002) and reduced the probability of severe pain in women (OR 0.37, 95% CI 0.21 - 0.65, p < 0.001). Each one-point increase in PHQ-4 score for anxiety and depression increased the OR of high pain intensity by 1.25 points (95% CI 1.18 - 1.34, p < 0.001). A clear impact of COVID-19 lockdowns was observed. In individuals who exercised ≥ 4 h/week the OR of high disability was 0.57 (95% CI 0.36 - 0.92, p = 0.021) in the pre-pandemic group compared to 0.29 (95% CI 0.12 - 0.56, p = 0.002) in the pandemic group. The probability of high disability increased from an OR of 1.42 (95% CI 1.33 - 1.52, p < 0.001) per marginal increase in the PHQ-4 scale before the pandemic, to an OR of 1.73 (95% CI 1.58 - 1.89, p < 0.001) during the pandemic. CONCLUSIONS: The magnitude of association of the factors that influenced high pain intensity and disability increased during the pandemic. On the one hand, the protective effect of regular exercising was greater in participants surveyed during lockdown. On the other hand, a higher risk through anxiety or depression during the lockdown was identified. An additional study with objective measures of sedentary behaviour and physical activity is needed to validate these results. More in-depth investigation of lockdown-induced associations between reduced daily physical activity, increased levels of anxiety and depression, and their effects on CLPB could also be worthwhile. TRIAL REGISTRATION: This study used routinely collected data from a CLBP intervention that was previously evaluated and registered in the German Registry of Clinical Trials under DRKS00015463 (04/09/2018). The original ethics approval, informed consent and self-reported questionnaire have remained unchanged and are still valid.

Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.

Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.

Cost-effectiveness analysis of a chronic back pain multidisciplinary biopsychosocial rehabilitation (MBR) compared to standard care for privately insured in Germany.

BACKGROUND: Multidisciplinary biopsychosocial rehabilitation (MBR) is highly recommended for chronic lower back pain (CLBP) treatment, but its economic benefit remains to be clearly demonstrated. The purpose of this study is to analyse the effect of a 12-month MBR programme of behavioural change coaching and device-supported exercise on direct medical costs, sick leave and health-related quality of life (HRQOL) at 24 months. METHODS: An incremental cost-effectiveness analysis was conducted in Germany from a private health insurance perspective using data from a multi-centre, two-arm randomised controlled trial with parallel-group Zelen's randomisation and 24-month follow-up. After removing dissimilarities in characteristics between MBR and usual care (control) via propensity score matching, treatment effects were calculated using a difference-in-difference approach. RESULTS: Base-case analysis of the MBR (n=112) and usual care group (n=111) showed an incremental cost-effectiveness ratio (ICER) of €8,296 per quality-adjusted life year (QALY) gained, indicating that the intervention was cost-effective. Compared to the controls, MBR reduced economically unaccounted sick leave due to back pain in the last six months by 17.5 days (p = 0.001) and had a positive effect on health-related quality of life (HRQOL) (0.046, p=0.026). Subgroup analysis of participants with major impairment demonstrated that a dominant intervention was possible, as reflected by an ICER of - €7,302 per QALY. Savings were driven by a - €1,824 reduction in back pain-specific costs. Moreover, sick leave was 27 days (p = 0.006) less in the MBR group. CONCLUSIONS: This first cost-effectiveness study with combined data from a private health insurer and a controlled trial in Germany demonstrated that long term MBR for the treatment of CLBP is cost-effective. Subgroups with major impairment from back pain benefitted more from the intervention than those with minor impairment. MBR significantly reduced sick leave in all participants. Hence, it is a profitable intervention from a societal point of view. TRIAL REGISTRATION: The trial of the evaluation study was retrospectively registered in the German Clinical Trials Register under trial number DRKS00015463 retrospectively (dated 4 Sept 2018).

In Search of Patient Zero: Visual Analytics of Pathogen Transmission Pathways in Hospitals.

Pathogen outbreaks (i.e., outbreaks of bacteria and viruses) in hospitals can cause high mortality rates and increase costs for hospitals significantly. An outbreak is generally noticed when the number of infected patients rises above an endemic level or the usual prevalence of a pathogen in a defined population. Reconstructing transmission pathways back to the source of an outbreak - the patient zero or index patient - requires the analysis of microbiological data and patient contacts. This is often manually completed by infection control experts. We present a novel visual analytics approach to support the analysis of transmission pathways, patient contacts, the progression of the outbreak, and patient timelines during hospitalization. Infection control experts applied our solution to a real outbreak of Klebsiella pneumoniae in a large German hospital. Using our system, our experts were able to scale the analysis of transmission pathways to longer time intervals (i.e., several years of data instead of days) and across a larger number of wards. Also, the system is able to reduce the analysis time from days to hours. In our final study, feedback from twenty-five experts from seven German hospitals provides evidence that our solution brings significant benefits for analyzing outbreaks.

Feasibility and long-term efficacy of a proactive health program in the treatment of chronic back pain: a randomized controlled trial.

BACKGROUND: To facilitate access to evidence-based care for back pain, a German private medical insurance offered a health program proactively to their members. Feasibility and long-term efficacy of this approach were evaluated. METHODS: Using Zelen's design, adult members of the health insurance with chronic back pain according to billing data were randomized to the intervention (IG) or the control group (CG). Participants allocated to the IG were invited to participate in the comprehensive health program comprising medical exercise therapy and life style coaching, and those allocated to the CG to a longitudinal back pain survey. Primary outcomes were back pain severity (Korff's Chronic Pain Grade Questionnaire) as well as health-related quality of life (SF-12) assessed by identical online questionnaires at baseline and 2-year follow-up in both study arms. In addition to analyses of covariance, a subgroup analysis explored the heterogeneity of treatment effects among different risks of back pain chronification (STarT Back Tool). RESULTS: Out of 3462 persons selected, randomized and thereafter contacted, 552 agreed to participate. At the 24-month follow-up, data on 189 of 258 (73.3%) of the IG were available, in the CG on 255 of 294 (86.7%). Significant, small beneficial effects were seen in primary outcomes: Compared to the CG, the IG reported less disability (1.6 vs 2.0; p = 0.025; d = 0.24) and scored better at the SF-12 physical health scale (43.3 vs 41.0; p < 0.007; d = 0.26). No effect was seen in back pain intensity and in the SF-12 mental health scale. Persons with medium or high risk of back pain chronification at baseline responded better to the health program in all primary outcomes than the subgroup with low risk at baseline. CONCLUSIONS: After 2 years, the proactive health program resulted in small positive long-term improvements. Using risk screening prior to inclusion in the health program might increase the percentage of participants deriving benefits from it. TRIAL REGISTRATION: The trial was registered at the German Clinical Trials Register under DRKS00015463 retrospectively (dated 4 Sept 2018).

A novel approach to support formulation design on twin screw wet granulation technology: Understanding the impact of overarching excipient properties on drug product quality attributes.

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models' validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes.

Identifying overarching excipient properties towards an in-depth understanding of process and product performance for continuous twin-screw wet granulation.

The overall objective of this work is to understand how excipient characteristics influence the process and product performance for a continuous twin-screw wet granulation process. The knowledge gained through this study is intended to be used for a Quality by Design (QbD)-based formulation design approach and formulation optimization. A total of 9 preferred fillers and 9 preferred binders were selected for this study. The selected fillers and binders were extensively characterized regarding their physico-chemical and solid state properties using 21 material characterization techniques. Subsequently, principal component analysis (PCA) was performed on the data sets of filler and binder characteristics in order to reduce the variety of single characteristics to a limited number of overarching properties. Four principal components (PC) explained 98.4% of the overall variability in the fillers data set, while three principal components explained 93.4% of the overall variability in the data set of binders. Both PCA models allowed in-depth evaluation of similarities and differences in the excipient properties.

[Unusual masquerade of an ocular carcinoma metastasis]. / Untypische Masquerade einer okulären Karzinommetastase.

BACKGROUND: Idiopathic and therapy resistant uveitis especially of unclear origin, is a diagnostic challenge for ophthalmologists. Metastases to the anterior chamber or vitreous body can occasionally mimic the clinical picture of uveitis, a variant on the usual lymphomatous masquerade syndrome. The underlying pathological pathways leading to the metastatic spread of tumor cells within the fluid compartments of the eye remain unclear. CASE REPORT: We present an unusual case of vitreous metastases to the right eye of a patient in whom an underlying primary malignancy was unknown. After recurrent episodes of cortisone-refractive panuveitis with pseudohypopyon, a diagnostic vitreous biopsy was performed. Cytopathological examination of the vitreous sample revealed carcinoma cells with an immune profile suggestive of lung cancer metastasis. Subsequent staging investigations revealed a primary lung adenocarcinoma as well as cerebral, adrenal and osseous metastases. THERAPY: Due to the extent of dissemination of this non-small cell lung cancer (NSCLC), only palliative treatment including external beam irradiation and systemic chemotherapy was possible to reduce pain and to maintain vision as well as an attempt at systemic control of the disease.

Quantifying the sensitivity of G. oxydans ATCC 621H and DSM 3504 to osmotic stress triggered by soluble buffers.

In Gluconobacter oxydans cultivations on glucose, CaCO3 is typically used as pH-buffer. This buffer, however, has disadvantages: suspended CaCO3 particles make the medium turbid, thereby, obstructing analysis of microbial growth via optical density and scattered light. Upon searching for alternative soluble pH-buffers, bacterial growth and productivity was inhibited most probably due to osmotic stress. Thus, this study investigates in detail the osmotic sensitivity of G. oxydans ATCC 621H and DSM 3504 using the Respiratory Activity MOnitoring System. The tested soluble pH-buffers and other salts attained osmolalities of 0.32-1.19 osmol kg(-1). This study shows that G. oxydans ATCC 621H and DSM 3504 respond quite sensitively to increased osmolality in comparison to other microbial strains of industrial interest. Osmolality values of >0.5 osmol kg(-1) should not be exceeded to avoid inhibition of growth and product formation. This osmolality threshold needs to be considered when working with soluble pH-buffers.

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs.

The AML1-ETO fusion protein, which is present in 10-15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.

[Analysis of spinal stress during surgery in otolaryngology]. / Analyse der Wirbelsäulenbelastung bei Operationstätigkeiten in der HNO-Heilkunde.

BACKGROUND: Back pain is a common cause of sick leave in industrialized countries. Performing surgery is often associated with considerable cervical spine disorders. However, only a few studies have examined to what extent working posture or individual surgical techniques can be seen as stress indicators. MATERIAL AND METHODS: Posture and movement of the spine and trunk were assessed by means of a newly developed analysis system (3-D-SMG). The individual-case study was carried out during six sinus operations using varying techniques (microscope, endoscope or headlamp only). RESULTS: Spine and trunk deviation from neutral position (upright standing) was strongest in the sagittal plane. Awkward distortions were primarily observed in the cervical and lumbar spine. The analysis of work characteristics revealed static postures in 65-90% of sinus operations. Isometric positions were mainly related to microscopic surgery. CONCLUSIONS: The data from this explorative individual-case study indicate that prevalence and magnitude of forced isometric and awkward postures are strongly associated with work-related spinal stress in sinus surgery. The new measurement device enables not only the recommendation of individual preventive strategies but also the objective evaluation of ergonomics.

Performance, training and lifestyle parameters of marathon runners aged 20-80 years: results of the PACE-study.

Successful finishing of marathon requires regular endurance training and appropriate lifestyle. Thus, marathon running times and training data from large samples of physically active and fit elderly are ideal for the assessment of age-related performance. In the present study we analyzed 439 278 running times from result lists of 108 marathon competitions and data from a survey via internet questionnaire about training and behavioural factors of marathon finishers. Marathon times and 6 992 data sets from the internet questionnaire were separated into groups based on age and sex and analyzed by two-way ANOVA. Our main findings are that 1) there are virtually no relevant running time differences (p<0.01) in marathon finishers from 20 to 55 years and 2) the majority of middle-aged and elderly athletes have training histories of less than seven years of running. With the exception of marathon running times we did not encounter any significant gender related differences (p>0.01). The present findings strengthen the concept that considers aging as a biological process that can be considerably speeded up or slowed down by multiple lifestyle related factors.

WHODAS II with people after stroke and their relatives.

PURPOSE: The present study aimed to measure the internal consistency, inter-rater-reliability and validity of the World Health Organisation Disability Assessment Schedule II (WHODAS II) for its application to stroke patients and their closest others. METHOD: Patients were assessed 6 months and 1 year after stroke with the self- and proxy-rating versions of the WHODAS II. The modified Rankin Scale (mRS) as well as patients' statements about 'Recovery' and 'Independence' were used as measurements for validity. Patients' statements concerning individual restrictions and limitations were compared with the WHODAS II items. RESULTS: Internal consistency can be regarded as good to excellent, inter-rater-reliability as satisfactory to good. Item reliability ranged from insufficient to good, the percentage of agreements was below 80%. WHODAS II scale scores of patients with an mRS score of 0 as well as of recovered and independent patients differed significantly from others. Correlation coefficients between WHODAS II Scales and validation measures ranged from fair to high. Correspondence between stroke related problems and WHODAS II items was good. CONCLUSION: The WHODAS II is a valid, generally reliable and useful instrument for the assessment of stroke patients over the first year after stroke.

Streptavidin reduces oxygen quenching of biotinylated ruthenium(II) and palladium(II) complexes.

Transition metal complexes such as biotinylated ruthenium(II) tris(bipyridyl) and palladium(II) porphyrin show an increase in luminescence intensity and lifetime upon binding to streptavidin in aqueous solution. Here we show that this increase of luminescence lifetime and intensity are caused by the shielding of the transition metal complexes from dissolved oxygen through streptavidin rather than by hydrophobicity effects as recently claimed.

Validation of a short-term memory test for the recognition of people and faces.

Memorising and processing faces is a short-term memory dependent task of utmost importance in the security domain, in which constant and high performance is a must. Especially in access or passport control-related tasks, the timely identification of performance decrements is essential, margins of error are narrow and inadequate performance may have grave consequences. However, conventional short-term memory tests frequently use abstract settings with little relevance to working situations. They may thus be unable to capture task-specific decrements. The aim of the study was to devise and validate a new test, better reflecting job specifics and employing appropriate stimuli. After 1.5 s (short) or 4.5 s (long) presentation, a set of seven portraits of faces had to be memorised for comparison with two control stimuli. Stimulus appearance followed 2 s (first item) and 8 s (second item) after set presentation. Twenty eight subjects (12 male, 16 female) were tested at seven different times of day, 3 h apart. Recognition rates were above 60% even for the least favourable condition. Recognition was significantly better in the 'long' condition (+10%) and for the first item (+18%). Recognition time showed significant differences (10%) between items. Minor effects of learning were found for response latencies only. Based on occupationally relevant metrics, the test displayed internal and external validity, consistency and suitability for further use in test/retest scenarios. In public security, especially where access to restricted areas is monitored, margins of error are narrow and operator performance must remain high and level. Appropriate schedules for personnel, based on valid test results, are required. However, task-specific data and performance tests, permitting the description of task specific decrements, are not available. Commonly used tests may be unsuitable due to undue abstraction and insufficient reference to real-world conditions. Thus, tests are required that account for task-specific conditions and neurophysiological characteristics.

[Knowledge of support and aid after first stroke]. / Kenntnis von Unterstützungsangeboten nach erstem Schlaganfall.

BACKGROUND: The literature predicts a considerable demand of support and aid for stroke patients and their caregivers. It is not known to what extent existing resources are used by these groups. PURPOSE: The present study aimed at a survey of knowledge of and acquaintance with institutions and organizations offering support after stroke and actual use of these resources. METHODS: Six and twelve months after stroke, 84 patients and their nearest others were questioned concerning their acquaintance with and use of professional and institutional resources for support and also with respect to social support and self-efficacy. RESULTS: Six and twelve months after stroke, actual use of the various resources for support varied between 0 and 13%. Only part of the patients (11-65%) and relatives (up to 78%) knew about the professional and institutional resource available. DISCUSSION: Information about resources for support after stroke is unsatisfactory and should be established at a point in the delivery of care chain where all those affected by stroke and their caregivers are accessed.