Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements. METHODS: Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed. RESULTS: GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level. CONCLUSIONS: This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.

Imaging in revision total knee arthroplasty: A novel 3D classification system for tibial bone defects.

PURPOSE: The primary purpose of the study was to use pre-revision total knee arthroplasty (TKA) computer-tomography (CT)-images to analyse typical tibial bone defects and create a new schematic three-dimensional (3D)-classification system. The secondary purpose was to investigate the association between defect size and implant selection at the time of revision surgery. METHODS: Eighty-four patients with preoperative CT-scans underwent revision of a primary TKA. CT-image segmentation with the 3D-Slicer Software was performed retrospectively, and a new three-dimensional classification system was used to grade tibial bone defects. The location of tibial bone defects was recorded for all cases. Volumetric 3D bone defect measurements were used to investigate the association between the bone defect volume, the indication for rTKA, and the use of modular revision components. The t-test, the Mann-Whitney-U test, and the Fisher's exact-test were used for group comparisons, and the Kruskal-Wallis test was used for multiple group comparisons. RESULTS: The most common anatomic regions for both contained and uncontained tibial bone defects were the anteromedial epiphysis (N = 50; mean epiphyseal-defect: 5.9 cm³) and metaphysis (N = 15; mean metaphyseal-defect: 9.6 cm³). A significant association was found between patients with preoperative metaphyseal defects (N = 22) and the use of tibial augments (N = 7) (p = 0.04). The use of cones/sleeves was associated with a significantly increased 3D-CT volume of the preoperative metaphyseal bone defects (p = 0.04). Patients with osteoporosis had significantly larger volumetric defects in the metaphysis (p = 0.01). CONCLUSION: Our results emphasise the importance of considering the three-dimensional nature of tibial defects in rTKA. The findings suggest that an understanding of the volume of the defect size through CT imaging can predict the need for augments and cones/sleeves and, especially in patients with osteoporosis can help the surgeon identify larger metaphyseal defects and ensure optimal metaphyseal fixation through appropriate implant selection. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Reconstruction of Chronic Quadriceps Tendon Rupture: The Quadriceps Advancement and Imbrication Technique.

BACKGROUND: Chronic extensor mechanism disruption after total knee arthroplasty (TKA) is a rare but challenging condition. There are several surgical approaches for quadriceps tendon repairs. In this report, we present a modified surgical technique for quadriceps tendon repair in chronic extensor mechanism disruption without the use of allografts or mesh augmentation. METHODS: We retrospectively reviewed 12 consecutive cases of chronic extensor mechanism with complete quadriceps tendon ruptures after TKA that underwent the advancement and imbrication technique. Patient outcomes were evaluated using the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement, the range of motion and extensor lag measurements, and standardized lateral radiographs were reviewed for Insall-Salvati-Ratio preoperatively and at their most recent follow-up visit. RESULTS: There were 12 knees from patients who had a mean age of 72 years (range, 62 to 81) and were evaluated with a mean follow-up of 15.9 months (range, 11.4 to 50.9). The extensor lag significantly improved from 40.8 ± 31.9° (range, 10 to 90°) to 2.9 ± 6.9° (P = .014), the Insall-Salvati-Ratio significantly changed from 0.87 to 1.07 (P = .010), and the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement showed a significant difference: a raw score of 13.0 ± 5.8 versus 8.7 ± 5.6 (P = .002) and an interval score of 54.1 ± 14.0 versus 66.2 ± 15.6 (P = .001). CONCLUSIONS: Reconstruction of extensor mechanism in chronic quadriceps tendon ruptures after TKA with the advancement and imbrication technique showed excellent functional outcomes with no extensor lag and excellent restoration of motion. This technique can be combined with TKA revision surgery or used on its own. To ensure successful outcomes, the authors favor rigid immobilization for 12 weeks before starting mobilization.

Rotating-Hinge Revision Total Knee Arthroplasty Provides Greater Arc of Motion Gains for Patients Who Have Severe Arthrofibrosis.

INTRODUCTION: Arthrofibrosis is a common postoperative total knee arthroplasty (TKA) complication that results in limited range of motion (ROM). There is limited literature on outcomes after revision TKA (rTKA) for arthrofibrosis based on preoperative ROM restriction. The aims of this study were to: (1) examine ROM trajectory after rTKA for arthrofibrosis patients who have severe versus non-severe limitations; (2) compare ROM gains and final arc of motion (AOM) between severe and non-severe cohorts; (2a) compare ROM gain in a severe cohort treated with a rotating hinge (RH) versus a non-rotating hinge (non-RH) construct; and (3) assess the impact of arthrofibrosis severity on patient-reported outcome measures (PROMs). METHODS: Patients were divided into 2 groups: Group A had preoperative ROM < 70o (severe), and Group B had preoperative ROM > 70o (non-severe). Patients were assessed clinically using AOM gain, absolute ROM, Knee injury and Osteoarthritis Outcomes Score for Joint Replacement (KOOS, JR), Lower Extremity Activity Scale (LEAS), and pain scores. Postoperative gains in AOM were compared between both groups. RESULTS: A total of 56 rTKAs (Group A (severe): n = 36, Group B (non-severe): n = 20) were performed for patients who have postoperative fibrosis. Group B had better ROM at the one-year timepoint (Group B: 95.9 ± 22.5 versus Group A: 83.2 ± 25.7). Group A had significantly better improvement in absolute AOM than Group B (31.1 ± 20.9 versus 11.4 ± 25.0, P < 0.01). The RH group demonstrated significantly better absolute AOM gain than the non-RH group (41.3 ± 19.4 versus 18.3 ± 15.2, P < 0.001). However, there were no significant differences in PROMs between Groups A and B or between RH and NRH groups at the final follow-up. DISCUSSION: Final ROM achieved between severe and non-severe arthrofibrosis groups were similar, and patients who have severe arthrofibrosis can expect greater absolute ROM gains and similar functional outcomes than non-severe arthrofibrosis patients. The RH rTKAs provided greater AOM gains for patients who have severe arthrofibrosis, with equivalent functional outcomes to non-RH implants. For severe arthrofibrosis patients, RH designs provided twice the overall ROM gain, however, longer follow-up is necessary to determine whether RH designs have inferior overall implant survivorship.

How safe are intra-articular corticosteroid injections to the hip?

BACKGROUND: Intra-articular corticosteroid injections (ICSI) are an effective symptomatic treatment for osteoarthritis of the hip. However, the safety of ICSI has been questioned and a relatively high risk for septic arthritis, rapidly progressive osteoarthritis (RPIO) and periprosthetic joint infections (PJI) in patients undergoing subsequent total hip arthroplasty (THA) have been suggested. METHODS: This is a retrospective evaluation of 682 hips that underwent ICSI with 40 mg of Triamcinolone for primary osteoarthritis of the hip. All ICSI were performed using sterile techniques, the number of ICSI in each hip and the cumulative corticosteroid dosage were assessed. Pre- and post-injection radiographs were compared to identify cases with RPIO. Native joint septic arthritis, surgical site infections and PJI were identified by chart review. RESULTS: 4 hips (0.6%) developed RPIO 2-4 months following ICSI. The cumulative Triamcinolone dose was not associated with the development of RPIO (p = 0.281). 1 case was diagnosed with septic arthritis and treated with staged THA, there were no signs of infection at a 5 years follow-up. 483 hips (75.7%) underwent THA, including 199 hips with THA less than 3 months following ICSI and 181 hips with > 1 ICSI prior to THA. There were 3 superficial surgical site infections/wound dehiscence and no PJI. CONCLUSION: The rate of RPIO was 0.6%. The current findings suggest that if ICSI is performed under sterile conditions, the risk for septic arthritis or PJI following THA, even in patients with multiple ICSI or ICSI within 3 months prior to surgery, is minimal.

Tibial bone defect prediction based on preoperative artefact-reduced CT imaging is superior to standard radiograph assessment.

PURPOSE: The purpose of this study was to evaluate the accuracy of preoperative CT-based Anderson Orthopaedic Research Institute (AORI)-grading and to correlate Computed tomography (CT)-based volumetric defect measurements with intraoperative AORI findings. METHODS: 99 patients undergoing revision total knee arthroplasty (rTKA) with preoperative CT-images were identified in an institutional revision registry. CT-image segmentation with 3D-Slicer Software was used to create 3D tibial bone defects which were then graded according to the AORI-classification. The AORI classification categorizes tibial defects into three types: Type I has healthy cortical and cancellous bone near the joint line, Type II involves metaphyseal bone loss affecting one or both condyles, and Type III indicates deficient metaphyseal bone with distal defects and potential damage to the patellar tendon and collateral ligament attachments. These 3D-CT gradings were compared to preoperative X-ray and intraoperative AORI grading. The Friedman test was used to investigate differences between AORI values of each measurement method. Volumetric 3D-bone defect measurements were used to investigate the relationship between AORI classification and volumetric defect size in the three anatomic zones of the tibia. RESULTS: Substantial agreements between preoperative 3D-CT AORI and intraoperative AORI (kappa = 0.663; P < 0.01) and fair agreements between preoperative X-ray AORI and intraoperative AORI grading (kappa = 0.304; P < 0.01) were found. Moderate correlations between volume of remaining bone and intraoperative AORI grading were found in epiphysis (rS = - 0.529; P < 0.001), metaphysis (rS = - 0.557; P < 0.001) and diaphysis (rS = - 0.421; P < 0.001). Small volumetric differences between AORI I vs. AORI II defects and relatively large differences between AORI II and AORI III defects in each zone were detected. CONCLUSION: Tibial bone defect prediction based on preoperative 3D-CT segmentation showed a substantial agreement with intraoperative findings and is superior to standard radiograph assessment. The relatively small difference in defect volume between AORI I, IIa and IIb suggests that updated CT-based classifications might hold benefits for the planning of rTKA. LEVEL OF EVIDENCE: Retrospective Cohort Study; III.

Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs.

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.

Clinical outcomes in patients receiving edoxaban or phenprocoumon for prevention of stroke in atrial fibrillation: a German real-world cohort study.

BACKGROUND: Appropriate and timely anticoagulant therapy with vitamin K antagonists (VKAs) or non-vitamin K oral antagonists (NOACs) is essential for stroke prevention in non-valvular atrial fibrillation (NVAF). Comparative data regarding effectiveness and safety for edoxaban vs phenprocoumon, the predominant VKA in Germany, are scarce. OBJECTIVES: The study evaluates effectiveness and safety of edoxaban vs phenprocoumon in NVAF patients in a German real-world setting. METHODS: German statutory health insurance claims data of the Institute for Applied Health Research Berlin (InGef) Research Database from 2014 until 2019 were analyzed. In NVAF patients, new users of edoxaban and phenprocoumon were compared to assess effectiveness (stroke/systemic embolism (SE)) and safety (bleeding) during therapy. Hazard ratios (HR) were estimated through multiple outcome-specific cox proportional hazard models adjusting for baseline characteristics. Outcomes of geriatric patients were analyzed in subgroup analyses. RESULTS: Between 2015 and 2018, 7,975 and 13,319 NVAF patients newly initiated treatment with edoxaban or phenprocoumon. After adjusting for baseline confounders, the risk of stroke/SE (HR: 0.85, 95% CI: 0.70-1.02) was numerically but not significantly lower, while the risk of major bleeding (HR: 0.69, 95% CI: 0.58-0.81) was significantly lower for edoxaban. In the geriatric subgroups, homogenous results compared to the main analysis were obtained. CONCLUSION: The results of this real-world analysis indicated better effectiveness and safety outcomes in patients with NVAF initiating edoxaban treatment compared to phenprocoumon. The findings confirm that the beneficial effects observed in the pivotal ENGAGE AF-TMI 48 trial can also be achieved in real-world use of edoxaban.

Correlation between Adrenoceptor Expression and Clinical Parameters in Degenerated Lumbar Intervertebral Discs.

Despite advanced knowledge of the cellular and biomechanical processes of intervertebral disc degeneration (IVDD), the trigger and underlying mechanisms remain unclear. Since the sympathetic nervous system (SNS) has been shown to exhibit catabolic effects in osteoarthritis pathogenesis, it is attractive to speculate that it also influences IVDD. Therefore, we explored the adrenoceptor (AR) expression profile in human IVDs and correlated it with clinical parameters of patients. IVD samples were collected from n = 43 patients undergoing lumbar spinal fusion surgery. AR gene expression was analyzed by semi-quantitative polymerase chain reaction. Clinical parameters as well as radiological Pfirrmann and Modic classification were collected and correlated with AR expression levels. In total human IVD homogenates α1A-, α1B-, α2A-, α2B-, α2C-, ß1- and ß2-AR genes were expressed. Expression of α1A- (r = 0.439), α2A- (r = 0.346) and ß2-AR (r = 0.409) showed a positive and significant correlation with Pfirrmann grade. α1A-AR expression was significantly decreased in IVD tissue of patients with adjacent segment disease (p = 0.041). The results of this study indicate that a relationship between IVDD and AR expression exists. Thus, the SNS and its neurotransmitters might play a role in IVDD pathogenesis. The knowledge of differential AR expression in different etiologies could contribute to the development of new therapeutic approaches for IVDD.

Generation of Matrix Degradation Products Using an In Vitro MMP Cleavage Assay.

Matrix metalloproteinases (MMPs) play crucial roles in tissue homeostasis and pathologies by remodeling the extracellular matrix. Previous studies have demonstrated the biological activities of MMP-derived cleavage products. Furthermore, specific fragments can serve as biomarkers. Therefore, an in vitro cleavage assay to identify substrates and characterize cleavage patterns could provide important insight in disease-relevant mechanisms and the identification of novel biomarkers. In the pathogenesis of osteoarthritis (OA), MMP-2, -8, -9 and -13 are of vital importance. However, it is unclear which protease can cleave which matrix component. To address this question, we established an in vitro cleavage assay using recombinantly expressed MMPs and the two cartilage matrix components, COMP and thrombospondin-4. We found a time- and concentration-dependent degradation and an MMP-specific cleavage pattern for both proteins. Cleavage products can now be enriched and purified to investigate their biological activity. To verify the in vivo relevance, we compared the in vitro cleavage patterns with serum and synovial fluid from OA patients and could indeed detect fragments of similar size in the human samples. The cleavage assay can be adapted to other MMPs and substrates, making it a valuable tool for many research fields.

[Scheuermann's disease]. / Morbus Scheuermann.

Scheuermann's disease represents the second most common deformity of the growing spine after the various forms of scoliosis. In cases of early diagnosis and mild kyphotic deformity conservative treatment with a brace and physiotherapy shows very good results; however, in cases of neurologic deficits, curve progression despite conservative treatment and increasing pain symptoms with a Stagnara angle of more than 70-75°, surgical treatment is meaningful. The surgical strategy can include posterior spondylodesis with prior anterior release or posterior instrumentation with posterior column osteotomy depending on the surgeon's experience. The choice of the extent of the operation with the vertebrae to be instrumented and including the straightening method should be oriented to the avoidance of complications, such as proximal or distal junctional kyphosis.

Safety and Persistence of Nalmefene Treatment for Alcohol Dependence. Results from Two Post-authorisation Safety Studies.

AIMS: Two post-authorisation studies assessed the safety and persistence of patients' use of nalmefene. METHODS: The START study (EUPAS5678) was a non-interventional, multi-country, prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted 'all comers' without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities. RESULTS: START study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were 'goal reached' and 'drug cost'. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups.MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year. CONCLUSIONS: Despite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits.

Accuracy of Preoperative Templating in Total Hip Arthroplasty With Special Focus on Stem Morphology: A Randomized Comparison Between Common Digital and Three-Dimensional Planning Using Biplanar Radiographs.

BACKGROUND: Accurate preoperative planning is a key component of successful total hip arthroplasty (THA). The purpose of the present study was to compare the accuracy and reliability of three-dimensional (hipEOS) and common digital two-dimensional (TraumaCad) templating with special focus on stem morphology. METHODS: 51 patients undergoing THA were randomized to two groups. Preoperative planning was performed on 23 patients with hipEOS (3D) and on 28 patients with TraumaCad (2D) planning software. Planning results were compared with the implanted component size. Inter- and intraobserver reliability as well as planning accuracy of both planning methods with special focus on straight and short stem design were recorded. RESULTS: Intraobserver reliability of both planning methods was good for component planning (ICC2,1: 0.835-0.967). Interobserver ICC2,1 for stem and cup planning were higher for 3D templating (3D ICC2,1: 0.906-0.918 vs. 2D ICC2,1: 0.835-0.843). Total stem and cup size predictions were within 2 sizes for 3D and within 3 sizes for 2D planning. Comparing short stem planning accuracy of both planning methods, absolute difference between implanted and planned component size was significantly lower in 3D planning (P = .029). There was no significant difference in straight stem (P = .935) and cup (P = .954) planning accuracy. CONCLUSION: Our findings suggest that 3D templating with hipEOS software has a good overall reliability and may have a better planning accuracy of short stem prostheses than digital templating with TraumaCad software. Assuming that the number of implanted short stem prostheses will further increase in coming years, a more precise planning with 3D technique can contribute to improve surgery outcome.

[Radiographic analysis of limb malalignment in the frontal plane]. / Radiologische Analyse von Achsfehlstellungen des Knies in der Frontalebene.

Radiographic measurement of the lower limb alignment in the frontal plane is used to assess limb deformity, to plan corrective surgery and for follow-up. It is essential that age-related normal lower limb alignment and joint orientation angles are known before planning surgical treatment. EOS (EOS™ Imaging, Paris, France) can lead to supplemental information, especially in cases of severe multidimensional joint malalignment. It allows 3D reconstruction of a bone model of the limb to assess multi-dimensional deformity.

[Nonfusion procedures in pediatric scoliosis]. / Nonfusionsverfahren bei kindlichen Skoliosen.

The treatment of early onset scoliosis (EOS) in children is a complex and demanding challenge in the treatment of spinal deformities. Conservative treatment with physiotherapy is indicated in mild forms with a Cobb angle from 10° and additionally a corset treatment with a Cobb angle of more than 20°. After exhaustion of the conservative measures or a progression of spinal scoliosis of 10° or deformities of more than 35°, a surgical approach should be considered in order to prevent respiratory insufficiency as well as severe postural and thoracic deformities. In situations where growth is still ongoing fusion operations can lead to stunted growth, a crankshaft phenomenon or degeneration of alignment. Meaningful alternatives to a fusion are so-called growing rods as a distraction-based nonfusion technique, e.g. traditional growing rods (TGR) and magnetically controlled growing rods (MCGR) or as a further method a vertical expandable prosthetic titanium rib (VEPTR) device. The advantages and disadvantages of each operative procedure must be considered with respect to the risk profile of each patient and the experience of the surgeon in order to guarantee the best possible treatment.

Burden of HPV related anogenital diseases in young women in Germany - an analysis of German statutory health insurance claims data from 2012 to 2017.

BACKGROUND: Most individuals are infected with human papillomavirus (HPV) at least once in their lifetime. Infections with low-risk types can cause genital warts, whereas high-risk types can cause malignant tumors. The aim of this study was to determine the burden of anogenital diseases potentially related to HPV in young women based on German statutory health insurance claims data. METHODS: We conducted a retrospective claims data analysis using the "Institute for Applied Health Research Berlin" (InGef) Research Database, containing claims data from approximately 4 million individuals. In the period from 2012 to 2017 all women born in1989-1992, who were continuously insured between the age of 23-25 years were identified. Using ICD-10-GM codes (verified diagnosis in the outpatient sector or primary or secondary diagnosis in the inpatient sector) the administrative prevalence (95% confidence interval) of genital warts (A63.0), anogenital diseases grade I (K62.8, N87.0, N89.0, N90.0), grade II (N87.1, N89.1, N90.1) and grade III (D01.3, D06.-, D06.0, D07.1, D07.2, N87.2, N89.2, N90.2) was calculated (women with diagnosis divided by all women). RESULTS: From 2012 to 2017, a total of 15,358 (birth cohort 1989), 16,027 (birth cohort 1990), 14,748 (birth cohort 1991) and 14,862 (birth cohort 1992) women at the age of 23-25 were identified. A decrease of the administrative prevalence was observed in genital warts (1.30% (1.12-1.49) birth cohort 1989 vs. 0.94% (0.79-1.10) birth cohort 1992) and anogenital diseases grade III (1.09% (0.93-1.26) birth cohort 1989 vs. 0.71% (0.58-0.86) birth cohort 1992). In anogenital diseases grade III, this trend was especially observed for severe cervical dysplasia (N87.2) (0.91% (0.76-1.07) birth cohort 1989 vs. 0.60% (0.48-0.74) birth cohort 1992). In contrast, anogenital diseases grade I (1.41% (1.23-1.61) birth cohort 1989 vs. 1.31% (1.14-1.51) birth cohort 1992) and grade II (0.61% (0.49-0.75) birth cohort 1989 vs. 0.52% (0.42-0.65) birth cohort 1992) remained stable. CONCLUSIONS: A decrease of the burden of anogenital disease potentially related to HPV was observed in the younger birth cohorts. This was observed especially for genital warts and anogenital diseases grade III. Further research to investigate this trend for the upcoming years in light of varying HPV vaccination coverage for newer birth cohorts is necessary.

The burden of hyperkalemia in Germany - a real world evidence study assessing the treatment and costs of hyperkalemia.

BACKGROUND: Hyperkalemia (HK) can affect health outcomes and quality of life, as it is referred to as a potentially life-threatening condition caused by an increased serum potassium concentration in the blood. Patients suffering from heart failure or chronic kidney diseases are at a higher risk of HK, which can further be amplified by the treatment received. To date, data on HK prevalence is lacking for Germany and the aims of this study were to assess HK and compare health-relevant outcomes and healthcare costs between HK patients and non-HK patients. METHODS: The InGef research database containing healthcare claims of over 4 million individuals in Germany was utilized for this retrospective, matched cohort analysis. Patients with non-acute outpatient treated and a subgroup of patients with chronic HK, were identified in 2015 with an individual 1 year pre- and post-index period, taking the first observable HK diagnosis/treatment in 2015 into account as the index event. To identify non-acute outpatient treated HK patients, at least two ICD-10-GM diagnosis codes E87.5 "Hyperkalemia" and/or prescriptions of polystyrene sulfonate were required. Chronic HK patients had additional diagnoses and/or prescriptions in all quarters following the first observable HK diagnosis. Patients without HK were matched 1:1 to the respective HK cohorts. RESULTS: In the year 2015, 3333 patients with non-acute outpatient treated HK were identified of which 1693 were patients with chronic HK. After matching, 3191 and 1664 HK patients and controls were available for analysis. A significantly higher number of hospitalizations was observed for both HK cohorts in comparison to their matched controls. Dialysis initiation as well as the healthcare costs were higher for both HK cohorts when compared to their matched counterparts. CONCLUSIONS: The disease burden was higher for patients with HK, based on a higher proportion of patients with dialysis initiation and higher healthcare costs.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRß) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRß, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRß. The presence of a subclonal population of tumor cells characterized by PDGFRß expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRß axis.

Ankylosing spondylitis causes high burden to patients and the healthcare system: results from a German claims database analysis.

To compare healthcare resource utilization and costs between ankylosing spondylitis (AS) patients and a matched sample from the general population without AS covered by the German Statutory Health Insurance (SHI) system, a non-interventional retrospectively matched cohort analysis was conducted using anonymized SHI claims data. Data from January 1st, 2011 through December 31st, 2014 were analyzed. Individuals with a coded diagnosis of AS during the enrollment period comprising the full year of 2013 were directly matched (1:5) to individuals without AS diagnosis in the whole study period by age, gender, hospitalizations, and comorbidities. All-cause healthcare resource utilization and direct costs were analyzed for the year 2013. Statistical tests were applied to compare the differences between the two sampled populations. In 2013, 10,208 AS patients were identified and matched to a sample of 51,040 patients without AS from the general population. Healthcare resource utilization was significantly higher in all healthcare sectors (inpatient, outpatient, pharmaceuticals, remedies, devices and aids, and sick leave) in the AS cohort. Mean all-cause healthcare costs per patient were about €2475 higher in the AS cohort compared to the general population. Most important cost drivers were hospitalizations and pharmaceuticals in terms of bDMARDs prescribed in 10% of the patients. Real-world data from this German claims database analysis showed that AS is associated with a substantial incremental economic burden to the healthcare system.

Healthcare resource use and costs of multiple sclerosis patients in Germany before and during fampridine treatment.

BACKGROUND: Multiple sclerosis (MS) patients often suffer from gait impairment and fampridine is indicated to medically improve walking ability in this population. Patient characteristics, healthcare resource use, and costs of MS patients on fampridine treatment for 12 months in Germany were analyzed. METHODS: A retrospective claims database analysis was conducted including MS patients who initiated fampridine treatment (index date) between July 2011 and December 2013. Continuous insurance enrollment during 12 months pre- and post-index date was required, as was at least 1 additional fampridine prescription in the fourth quarter after the index date. Patient characteristics were evaluated and pre- vs post-index MS-related healthcare utilization and costs were compared. RESULTS: A total of 562 patients were included in this study. The mean (standard deviation [SD]) age was 50.5 (9.8) years and 63% were female. In the treatment period, almost every patient had at least 1 MS-related outpatient visit, 24% were hospitalized due to MS, and 79% utilized MS-specific physical therapy in addition to the fampridine treatment. Total MS-related healthcare costs were significantly higher in the fampridine treatment period than in the period prior to fampridine initiation (€17,392 vs €10,960, P < 0.001). While this difference was driven primarily by prescription costs, MS-related inpatient costs were lower during fampridine treatment (€1,333 vs €1,565, P < 0.001). CONCLUSIONS: Physical therapy is mainly used concomitant to fampridine treatment. While healthcare costs were higher during fampridine treatment compared to the pre-treatment period, inpatient costs were lower. Further research is necessary to better understand the fampridine influence.