Supplementary orthopaedic screening for children and adolescents to prevent permanent skeletal deformities - protocol for the "OrthoKids" study.

BACKGROUND: Skeletal deformities (SD) in children and adolescents can lead to arthritic conditions, impairment of quality of life, and high treatment costs in the long term. However, comprehensive data on the prevalence of SDs in children and adolescents are limited and it remains therefore unclear whether there is a healthcare gap. "OrthoKids" is a project that addresses this evidence gap by implementing an orthopaedic screening for children and adolescents that supplements existing detection examinations within statutory standard care in Germany. OBJECTIVE: To detect SDs so that they can be treated as needed at an early stage. METHODS: The implementation of the supplementary orthopaedic screening will be evaluated through an exploratory cohort study that is set up in the German state Baden-Wuerttemberg. 20,000 children and adolescents aged 10 to 14 years will be recruited as a prospective cohort. A retrospective control cohort will be formed based on claims data provided by two cooperating statutory health insurances (SHIs). Participating children and adolescents receive a one-time orthopaedic screening. If at least one SD is diagnosed, treatment will be provided as part of the statutory standard care. Within the scope of the project, a follow-up examination will be performed after one year. An IT-platform will complement the study. The primary outcome measure is the point prevalence of scoliosis, genu varum/valgum, hip dysplasia, and flat feet. Secondary outcome measures are (i) the point prevalence of further less common SDs, (ii) health-related quality of life (HRQoL), (iii) sports ability based on activity (physical/athletic), physical constraints, and (sports) injuries, as well as (iv) monetary consequences of the orthopaedic screenings' implementation. Implementation determinants will be evaluated, too. DISCUSSION: If the supplementary orthopaedic screening proves to be viable, it could be considered as a supplementary examination for children and adolescents within the frame of SHI in Germany. This could relieve the burden of disease among children and adolescents with SDs. In addition, it could disburden SHIs in the medium to long term. TRIAL REGISTRATION: The OrthoKids study was registered in the German Clinical Trials Registry (Deutsches Register Klinischer Studien (DRKS)) on 26th July 2022 under the number 00029057.

CUSHING'S SYNDROME, A RISK FACTOR FOR VENOUS THROMBOEMBOLISM IS A CANDIDATE FOR GUIDELINES.

OBJECTIVES: The present paper aims to review important contemporary information about VTE risk in endogenous and exogenous CS, as a substantial discrepancy exists between the results of a recent meta-analysis confirming the increased risk for VTE and the absence of CS in VTE guidelines. METHODS: An extensive search of relevant databases (e.g. PubMed, Google Scholar, and Scopus) was performed in order to establish the interconnectedness of the following terms: Cushing's syndrome, venous thromboembolism, deep vein thrombosis, pulmonary embolism. RESULTS: The analysis demonstrated that patients with CS have about ten times the risk for VTE, particularly during the first year following the diagnosis of CS. Oral glucocorticoid users (with iatrogenic CS) have a 3-fold increase in risk of VTE in comparison with non-users. The most recent 2019 meta-analysis encompassed 7142 patients with endogenous CS (including Cushing's disease) undergoing transsphenoidal surgery or adrenalectomy, and their risk of unprovoked VTE was almost 18 times higher in comparison with a healthy population. CONCLUSION: Over the past 50 years considerable evidence of increased VTE risk in CS has been accumulated. It pertains to both endogenous and exogenous type of CS and has been confirmed in the vast majority, if not all the available studies, including meta-analyses. Nevertheless, official CS guidelines make no mention of CS as a VTE risk factor, even though it is important that not only physicians who treat CS, but also physicians who manage patients with suspected VTE be aware of increased VTE risk.

The implementation of knowledge dissemination in the prevention of occupational skin diseases.

BACKGROUND: Occupational skin diseases (OSD) have a high medical, social, economic and political impact. Knowledge dissemination from research activities to key stakeholders involved in health care is a prerequisite to make prevention effective. OBJECTIVES: To study and prioritize different activity fields and stakeholders that are involved in the prevention of OSD, to reflect on their inter-relationships, to develop a strategic approach for knowledge dissemination and to develop a hands-on tool for OSD prevention projects METHODS: Seven different activity fields that are relevant in the prevention of OSD have been stepwise identified. This was followed by an impact analysis. Fifty-five international OSD experts rated the impact and the influence of the activity fields for the prevention of OSD with a standardized questionnaire. RESULTS: Activity fields identified to have a high impact in OSD prevention are the political system, mass media and industry. The political system has a strong but more indirect effect on the general population via the educational system, local public health services or the industry. The educational system, mass media, industry and local public health services have a strong direct impact on the OSD 'at risk' worker. Finally, a hands-on tool for future OSD prevention projects has been developed that addresses knowledge dissemination and different stakeholder needs. CONCLUSION: Systematic knowledge dissemination is important to make OSD prevention more effective and to close the gap between research and practice. This study provides guidance to identify stakeholders, strategies and dissemination channels for systematic knowledge dissemination which need to be adapted to country-specific structures, for example the social security system and healthcare systems. A key for successful knowledge dissemination is building linkages among different stakeholders, building strategic partnerships and gaining their support right from the inception phase of a project.

[Cost Effectiveness of Aftercare in the Cardiovascular Rehabilitation: A Five Years Follow-up Analysis]. / Kosteneffektive Langzeitnachsorge in der kardiovaskulären Rehabilitation: Fünf-Jahres-Follow-up der SeKoNa-Studie (ISRCTN 15954342).

OBJECTIVE: In Germany, the rehabilitative approaches towards patients with coronary artery events are not adequately sustainable despite the high costs. Both sustainability and cost effectiveness are the subjects of this 5-year analysis. METHODS: The study was initiated in 2004. One year recruiting phase was followed by 3 years aftercare with telephone as an intervention. This unicentric randomised controlled trial included 600 patients of rehabilitative aftercare (intervention group [IG] 271; control group [CG] 329). Data on (i) mortality, (ii) duration of retirement, (iii) type of retirement and (iv) status of retirement were obtained from the German Retirement Insurance.The analyses for cost-effectiveness are conducted for the intention-to-treat (ITT) approach. The general assessment basis of retirements (partial and full disability pensions) are average values for the year 2013 (year of the measurement). RESULTS: On the reporting date (31.12.2013), the values of the IG in part (early) retirement and full (early) retirement are higher than the CG (1.5 and 2.7%, n. s. and 7.4 and 13.4%, respectively n. s.). The same applies for mortality (8.1 and 9.4%, respectively n. s.).The savings through lower pension payments amount to € 1.55 million for the adjusted ITT approach. From this, € 130 080, which represents the cost of the aftercare (intervention), must be deducted. CONCLUSIONS: The results of the 5-year follow-up show that a part of pension payment could be reduced. The evidence of cost effectiveness, independently of the methodological approach, is strong. The saving potential is reached by half in both approaches.

Does the presence of secondary antiphospholipid syndrome in patients with systemic lupus erythematodes accelerate carotid arteries intima-media thickness changes?

Patients with systemic lupus erythematosus (SLE) have an increased risk of atherosclerosis. The aim of our study was to evaluate the importance of secondary antiphospholipid presence (SAPS) in light of carotid artery intima-media thickness (CIMT) changes in SLE patients. Our study included 120 patients with SLE (46.02 ± 13.16 years), 108 women and 12 men divided into two groups: 58 patients with SAPS and 62 SLE patients without SAPS taken as a control group. All patients underwent assessment of CIMT of right and left common carotid artery (CCA) and left and right internal carotid artery (ICA) by Doppler ultrasonography. In SAPS group, 48.3 % patients had significant changes of carotid arteries comparing to 16.1 % patients in control group (p = 0.008). Average CIMT values in left and right CCA and right ICA were significantly higher in SAPS group. No significant relationship between antiphospholipid antibody type and CIMT changes was established. Multivariate regression analysis revealed SAPS as a significant predictor of CIMT changes in SLE patients (p = 0.025). Presence of SAPS in SLE patients is associated with significant CIMT changes. Additional autoimmune burden leads to a need for a more aggressive education and prevention considering standard risk factors in this group of patients.

Correlation between increased maternal body mass index and pregnancy complications.

OBJECTIVE: Obesity in pregnancy carries significant maternal and fetal risk. The aim of this study was to investigate the effect of maternal body mass index on pregnancy outcomes. PATIENTS AND METHODS: The study retrospectively reviewed the clinical outcome of 485 pregnant women who delivered at the Department of Obstetrics and Gynecology, Clinical Centre of Vojvodina, Novi Sad, during the period of three years (2018-2020) and compared them against the body mass index (BMI). Correlation coefficient was calculated for BMI and seven pregnancy complications (hypertensive syndrome, preeclampsia, gestational diabetes mellitus, intrauterine growth restriction, premature rupture of membranes, mode of delivery and postpartum hemorrhage). The collected data were presented in the form of median values and relative numbers (the measure of variability). The implementation of the simulation model and its verification were carried out using a specialized programming language, Python. Statistical models were created where the Chi-square and p-value were as determined for every observed outcome. RESULTS: The average age of the subjects was 35.79 years and average BMI 29.28 kg/m2. A statistically significant correlation was found between the BMI and arterial hypertension, gestational diabetes mellitus, preeclampsia and cesarean section. The correlations between the body mass index and postpartum hemorrhage, intrauterine growth restriction and premature rupture of membranes were not statistically significant. CONCLUSIONS: As high BMI correlates with a number of negative outcomes in pregnancy, weight control before and during pregnancy and proper antenatal and intranatal care are necessary to achieve a favorable pregnancy outcome.

Psoriasis patients' characteristics associated with high PASI response to tildrakizumab: an international dual center study.

OBJECTIVE: Heterogeneous real-world evidence can complement the more strictly regulated clinical trial data. A benefit of this is the wide range of backgrounds, comorbidities and characteristics that can give additional insights into treatments. Observational, retrospective studies can help to fill in the mosaic that makes up a treatments landscape. Tildrakizumab, an interleukin 23p19 inhibitor, is approved for the treatment of plaque psoriasis and has been shown to be a safe and efficacious therapy in clinical trials and emerging real-world evidence. We aimed at confirming the efficacy of tildrakizumab in patients with plaque psoriasis in a dual center setting and identifying patients' characteristics leading to better treatment response. PATIENTS AND METHODS: Patients with moderate to severe plaque psoriasis, eligible for systemic biological treatment, and treated with tildrakizumab were included in the study and the routine clinical parameters - Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and safety - were retrospectively analyzed. RESULTS: The combined cohorts included 89 patients, of which 64% were naïve to biologic therapies. At the time of analysis efficacy assessment was available for 39 patients after 12 months of treatment, 73 patients after 36 weeks, 79 patients after 16 weeks and 82 patients after 4 weeks. PASI and DLQI decreased significantly over time, with 52/73 (71.2%) patients achieving PASI 100 after 36 weeks. No severe side-effects were recorded in association with tildrakizumab. CONCLUSIONS: We confirmed the safety and efficacy of tildrakizumab in a real-world clinical setting. A higher proportion of patients naïve to biologics achieved a greater PASI response than patients who had previously been treated with biologics. The same was true for older patients and patients with a shorter history of disease.

A mutation influencing the transportation of manganese, L-dopa, and L-tryptophan.

Transportation of manganese, L-dopa, and L-tryptophan was slower through the tissues, of intact pallid mice than through those of black C57Bl/6J mice, presumably because of the influence of the gene pallid.

Myocardial bridges, neither rare nor isolated-Autopsy study.

PURPOSE: Myocardial bridge is a congenital anomaly with a markedly variable reported incidence on autopsy (4.7%-86%), likely related to geographical regions. Our previous retrospective study showed a prevalence of 0.8%, which we doubted to be the true one in the examined sample of the Serbian population. To assess the importance of the phenomenon we conducted a 2-year prospective study at the same institution. METHODS: Ninety-six cadaver hearts from adult individuals of both genders (51 men, 45 women) who died from natural causes underwent special dissection. Tunneled coronary arteries and myocardium were examined using light microscopy. RESULTS: A total of 14 myocardial bridges were found in 13 (13.54%) hearts. This anomaly was insignificantly more common in men (13.72% vs. 13.33%, p>0.05). In one heart we noted two myocardial bridges (the left anterior interventricular artery and left marginal artery were overbridged). None of the myocardial bridges had been diagnosed during life. The most common causes of death were cardiac related. Myocardial bridges were located in the following areas: left anterior interventricular (50%), left circumflex artery (28.6%), left marginal artery (14.3%), and right coronary artery (7.1%). In 92.3% of cases, the right coronary artery was dominant. The only heart with a balanced-type had two bridges. Most of the myocardial bridges were long and deep. All tunneled coronary arteries, and although surrounded by "coronary cushion," were not protected from atherosclerosis. In 30.8% of hearts with myocardial bridges, we found additional coronary artery anomalies. CONCLUSION: Myocardial bridges were not rare in the examined sample of the Serbian population and were often associated with other coronary artery anomalies, rendering the carriers at higher risk.

Novel Biomarkers of Heart Failure.

Although substantial improvements have been made in majority of cardiac disorders, heart failure (HF) remains a major health problem, with both increasing incidence and prevalence over the past decades. For that reason, the number of potential biomarkers that could contribute to diagnosis and treatment of HF patients is, almost exponentially, increasing over the recent years. The biomarkers that are, at the moment, more or less ready for use in everyday clinical practice, reflect different pathophysiological processes present in HF. In this review, seven groups of biomarkers associated to myocardial stretch (mid-regional proatrial natriuretic peptide, MR-proANP), myocyte injury (high-sensitive troponins, hs-cTn; heart-type fatty acid-binding protein, H-FABP; glutathione transferase P1, GSTP1), matrix remodeling (galectin-3; soluble isoform of suppression of tumorigenicity 2, sST2), inflammation (growth differentiation factor-15, GDF-15), renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL; kidney injury molecule-1, KIM-1), neurohumoral activation (adrenomedullin, MR-proADM; copeptin), and oxidative stress (ceruloplasmin; myeloperoxidase, MPO; 8-hydroxy-2'-deoxyguanosine, 8-OHdG; thioredoxin 1, Trx1) in HF will be overviewed. It is important to note that clinical value of individual biomarkers within the single time points in both diagnosis and outcome prediction in HF is limited. Hence, the future of biomarker application in HF lies in the multimarker panel strategy, which would include specific combination of biomarkers that reflect different pathophysiological processes underlying HF.

Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension.

Despite evidence that essential hypertension (EH) is a state of increased oxidative stress, the data on oxidative protein modifications is lacking. Besides, the role of extracellular antioxidant enzymes in EH has not been systematically studied. Study was performed in 45 subjects with EH and 25 normotensive controls. Patients were divided into three groups according to the 2003 ESH/ESC guidelines (grade 1-3). Plasma protein reactive carbonyl derivatives (RCD) and SH-groups (as byproducts of oxidative protein damage) as well as antioxidant enzyme activities superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase were studied spectrophotometrically and correlated with blood pressure (BP). RCD levels were increased in EH patients compared to controls and correlated significantly with both systolic blood pressure (SBP) (r = 0.495, P<0.01) and diastolic blood pressure (DBP) (r = 0.534, P<0.01). Plasma SH-groups content was significantly lower in all patients with EH, with no correlation with BP. SOD and catalase activity in patients with grade 1 EH were similar to that of controls. Patients with grade 2 and 3 of EH had lower SOD and catalase activity. However, significant correlation with SBP and DBP was observed for catalase only (r = -0.331; P<0.05 and r = -0.365; P<0.05, respectively). EH patients exhibited higher plasma GPX activity compared to those in controls, and it correlated with SBP (r = 0.328; P<0.05). The results presented show that increased oxidative protein damage is present in all grades of EH. In mild hypertension extracellular antioxidant enzyme activities are not decreased, suggesting they are probably not critical in early EH, but could be important in moderate to severe EH.

Antimutagenic effect of essential oil of sage (Salvia officinalis L.) and its monoterpenes against UV-induced mutations in Escherichia coli and Saccharomyces cerevisiae.

Mutagenic and antimutagenic potential of essential oil (EO) of cultivated sage (S. officinalis L.) and its monoterpenes: thujone, 1,8-cineole, camphor and limonene against UVC-induced mutations was studied with Salmonella/microsome, E. coli WP2, E. coli K12 [Simic, D., Vukovic-Gacic, B., Knezevic-Vukcevic, J., 1998. Detection of natural bioantimutagens and their mechanisms of action with bacterial assay-system. Mutat. Res. 402, 51-57] and S. cerevisiae D7 reversion assays. The toxicity of EO differed, depending on the strain used. The most sensitive were permeable strains TA100, TA102, E. coli K12 IB112 and non-permeable WP2. Mutagenic potential of EO and monoterpenes was not detected, with or without S9. EO reduced the number of UV-induced revertants in a concentration-dependent manner, reaching 50-70% of inhibition at the maximum non-toxic concentrations: 3 microl/plate (TA102), 5 microl/plate (WP2), 7.5 microl/plate (IB112), 30 microl/plate (E. coli K12 SY252) and 60 microl/plate (D7). The metabolic activation had no effect on antimutagenic potential of EO. Similar toxicity of monoterpenes was observed in TA100, E. coli SY252 and D7, with the exception of limonene (less toxic to D7). Reduction of UV-induced revertants by non-toxic concentrations of monoterpenes, tested with SY252 and D7, reached 40-50% at 15-20 microl/plate of thujone, 10 microl/plate of cineole and 1-10 microg/plate of camphor. Limonene showed antimutagenic effect only in D7. Our data recommend sage monoterpenes for further chemoprevention studies.

Ultrastructural analysis and TUNEL demonstrate motor neuron apoptosis in Werdnig-Hoffmann disease.

Werdnig-Hoffmann disease (WHD) is the most severe clinical type of spinal muscular atrophy characterized by loss of lower motor neurons and paralysis. We examined the hypothesis that disease pathogenesis is based on an inappropriate persistence of normally occurring motor neuron programmed cell death. The diagnosis of WHD was made on the basis of clinical findings, electromyoneurography, and biopsy, and further confirmed by mutation analysis of the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes using PCR. We used ultrastructural analysis as well as TUNEL and ISEL methods to assess DNA fragmentation, and immunocytochemistry to identify expression of the apoptosis-related proteins bcl-2 and p53. A significant number of motor neurons in the spinal cord of children with WHD were shown to die by apoptosis. As revealed by TUNEL, dying neurons in WHD patients comprised 0.2%-6.4% of the neuron numbers counted. This finding contradicts earlier studies that failed to find such evidence and suggests that early blockade of prolonged motor neuron apoptosis may be a potential therapeutic strategy for WHD.

RecBC promoted repair of bleomycin damage in Escherichia coli.

The repair response of Escherichia coli K-12 to bleomycin was examined in Rec- mutants showing differential sensitivity to this agent. Sedimentation analysis of the cellular DNA showed incision after bleomycin treatment. The subsequent reformation of the DNA, found in the wild-type and the recD mutant, was abolished in the recB and delayed in the recF and recBC sbcB mutants. The bleomycin-induced SOS response was reduced in strains containing recB or recBC sbsB mutations. It is suggested that the RecBCD pathway has the main role in the efficient repair of bleomycin-induced DNA damage.

Influence of the recB21 mutation of Escherichia coli K12 on prophage lambda induction.

The inactivation kinetics of the lambda repressor following bleomycin (BM), UV-irradiation and nalidixic acid (NAL) treatments were studied in the recB21 mutant of E. coli K12. The results showed essentially normal induction by UV-irradiation, delayed induction by BM and no induction by NAL. The results were compared with inactivation kinetics in lexA1 and recF143 mutants.

Role of rec genes in SOS-induced inhibition of cell division in Escherichia coli.

The inhibition of cell division induced by bleomycin (BM) and UV irradiation in the set of rec mutants of E. coli K12 was studied. Data presented in this work indicate that BM treatment requires mainly the RecBC pathway for the induction of cell filamentation. In the recB21 mutant cell filamentation is delayed and reduced compared to the wild type. Cell filamentation is BM-induced with similar kinetics in strains with a proficient RecBC recombination pathway (rec+, recF143 and recN262), as well as in the strain with a fully expressed RecF pathway (recB21recC22sbcB15). Induction is completely abolished in the recB21recF143 double mutant. On the other hand cell filamentation was induced similarly by UV irradiation in all strains with a functional recF gene and in the strain with a fully operative RecF pathway, but it was delayed in the recF143 and recB21recF143 mutants.

Detection of natural bioantimutagens and their mechanisms of action with bacterial assay-system.

Escherichia coli K12 assay-system is designed in order to detect bioantimutagens, agents preventing mutagenesis by modulation of DNA repair and replication. The assay is composed of four tests aimed at the detection of inhibition of spontaneous and induced mutations (Tests A and B) and at the estimation whether the anti-mutagenic agent acts by increasing the fidelity of DNA replication (Test B), by inhibition of SOS error prone repair (Test C), or by favoring error-free recombinational repair (Test D). In Test A, repair proficient strain and its uvrA counterpart are used for detection of spontaneous and UV-induced mutations, while in Test B mismatch repair deficient strains (mutH, mutS, mutL and uvrD) are used for amplified detection of spontaneous mutations caused by replication errors. In Test C, repair proficient strain carrying sfiA::lacZ fusion is used for measuring the level of SOS induction by monitoring the level of beta-galactosidase. In Test D, the strains carrying different recA alleles (recA+, recA730 and DeltarecA) are used for measuring intrachromosomal recombination between nonoverlapping deletions in duplicated lac operon, by monitoring Lac+ recombinants. The assay-system is validated with model bioantimutagens and used for detection of anti-mutagenic potential of different terpenoid fractions from sage (Salvia officinalis L.). Extract E1/3 of cultivated sage, distinguished from others by its high content of monoterpenoid camphor, reduces UV-induced mutagenesis in Test A, while it has no effect in Tests B and C. In Test D, it enhances intrachromosomal recombination in untreated and UV-irradiated recA+ and recA730 strains. The results suggest that the protective effect is due to stimulation of recombinational repair, similarly to coumarin. We speculate that monoterpenoids from sage enhance genetic recombination by intervening in a formation of RecA-DNA complex and channeling it into recombination reaction.

Participation of rec genes of Escherichia coli K 12 in W-reactivation of UV-irradiated phage lambda.

The effect of the recombinational deficiency on W-reactivation of UV-damaged phage lambda was explored. In this paper we show that W-reactivation is reduced by the recB21 and recF143 mutations after bleomycin (BM) and UV treatment. Combination of these mutations in the recB21recF143 double mutant blocks W-reactivation completely after BM induction, but leaves residual W-reactivation ability after UV-irradiation, which is abolished by the introduction of uvrB deficiency (delta(uvrB-chlA]. W-reactivation has been rendered constitutive in recB21C22sbcB15, but the efficiency of reactivation remained virtually constant over the range of BM and UV doses, indicating the role of the RecBC(D) enzyme in W-reactivation.

Activation of RecA protein in recombination-deficient strains of Escherichia coli following DNA-damaging treatments.

Activation of the RecA protein following UV-irradiation or bleomycin (BM) treatment was measured in rec mutants of E. coli by monitoring beta-galactosidase activity. We provide evidence here that the defect in the recN mutant results in high constitutive and induced levels of activated RecA protein. In all rec mutants studied, with the exception of the recN mutant, induction of enzyme activity, following DNA-damaging treatments, was reduced relative to the wild type. The kinetics of induced sfiA expression indicates that the DNA-unwinding activity of the RecBCD enzyme plays a major role in SOS-signal formation. The RecF protein is not needed for BM induction in strains with a functional RecBCD pathway of recombination. However, a functional product of recF gene is implied in the formation of an efficient inducing signal after UV-irradiation, as well as in the additional processing of BM-induced lesions after exposure to the drug. A fully expressed RecF pathway of recombination does not provide a high level of activated RecA protein following DNA-damaging treatments.