Einfluss einer pharmakologischen Hemmung der P38alpha-mitogen-aktivierten Proteinkinase auf die experimentelle pulmonale Hypertonie und Rechtsherzhypertrophie

Die pulmonal arterielle Hypertonie ist eine lebensbedrohliche, progredient voranschreitende Erkrankung mit eingeschränkter Überlebensprognose. Die Prävalenz liegt bei 10,6 / 1 Million Einwohner mit einer 5-Jahres-Mortalität von 65%. Pathophysiologisch unterliegen die arteriellen Lungengefäße einem Remodeling mit Proliferation der Intima, Media und Adventitia. Das Remodeling, eine In-Situ-Thrombosierung und Vasokonstriktion führen zu Obstruktion und Obliteration des Gefäßlumens. In der Folge steigt die rechtskardiale Belastung, welche anfangs durch kardiale Hypertrophie kompensiert wird. Die zunehmende Insuffizienz des Herzens, den erhöhten Afterload zu kompensieren, stellt für die Patienten den prognostisch limitierenden Faktor dar. Gegenwärtig existieren medikamentöse Ansätze mit Prostazyklinanaloga, ETR-Antagonisten, Stimulatoren der löslichen Guanylatzyklase und PDE-5-Hemmern. Ein kurativer Ansatz existiert nicht. In dieser Dissertation wurde eine P38alpha-Inhibition durch PH-797804 untersucht. Als Stress-aktivierte Kinase reagiert sie auf extrazelluläre Veränderungen und reguliert vielfältige zelluläre und subzelluläre Prozesse. Durch die zentrale Rolle der P38-MAPK wurde diese bis heute in Zusammenhang mit einer großen Zahl weiterer Krankheitsbilder erforscht. Die vorliegende Arbeit nutze zwei Tiermodelle. Das erste Modell erzeugte durch einen verminderten Sauerstoffgehalt der Umgebungsluft eine pulmonal arterielle Hypertonie, das zweite Modell induzierte durch eine pulmonalarterielle Partialstenose mittels Titanclip einen erhöhten, rechtskardialen Afterload. Die Auswertung der Tiermodelle und der Therapieerfolg wurden mittels Echokardiographie, hämodynamischer Links- und Rechtsherzkatheterisierung und histologischer Aufarbeitung evaluiert. Beide Tiermodelle wurden erfolgreich induziert. Die Therapiegruppe zeigte in einigen funktionellen und histologischen Parametern eine signifikante Verbesserung. Sowohl im Hypoxie- als auch im Stenosemodell wurde unter Therapie eine Verbesserung der kardialen Funktion erreicht. Im Hypoxiemodell verminderte die P38-Inhibition den Anteil muskularisierter Lungengefäße und im Stenosemodell den kardialen Kollagengehalt. Zusammenfassend stellen P38-MAPK im Rahmen der Erforschung der pulmonal arteriellen Hypertonie einen interessanten Ansatz dar. Die vorliegende Arbeit konnte Verbesserungen im pulmonalen Gefäßsystem und der kardialen Performance nachweisen.Pulmonary arterial Hypertension is a life-threatening, progressive disease with a poor prognosis. It has a prevalence of 10.6 per 1 Million inhabitants and a 5-year-mortality of 65%. The pulmonary arteries are subject to remodeling processes including Proliferation of the intima, media and adventitia of the vessels. Due to in-situ-thrombosis and vasoconstriction an obstruction and Obliteration of the lumen results. As consequence, the right ventricular pressure increases, which in turn leads to hypertrophy to compensate the elevated afterload. In later stages, cardiac insufficiency is a prognosis relevant factor. Nowadays four Basic therapeutic ways exist, including prostacyclin analogues, endothelial receptor antagonists, Stimulators of soluble guanylate cyclase and phosphodiesterase-5-inhibitors. A curative Approach does not exist. In this Thesis, we analyzed the effects of P38alpha-Inhibition with PH-797804. P38-mitogen-activated Protein kinase is upregulated due to extracellular changes and is involved in a number of cellular and subcellular processes. The p38-pathway was investigated in relation to several diseases. In this Thesis, we employed two animal models: The first animal model induced PAH due to chronic hypoxia, the second model induced an increased right afterload by using a titanium Clip to achieve a Stenosis of the pulmonary artery lumen. We used echocardiography, hemodynamic measurement of the right and left ventricle and histological analyses of the tissue to evaluate the models and the therapeutic Efficiency of p38 Inhibition. The treated animals showed a significant improvement in functional and histological Parameters. The hypoxic model and the banding model improved the cardiac function in Response to Treatment with PH-797804. The histological Analysis revealed a decreased muscularization of pulmonary arteries in the hypoxic model and a significant reduction of cardiac Collagen in the banding model. In summary, the Family of p38-mitogen-activated Protein kinases represents a promising therapeutic Approach. This Thesis presented improvements in the pulmonary artery remodeling and the cardiac Performance due to Treatment with p38alpha-mitogen-activated Protein kinase Inhibitor

Establishing an institutional reverse total shoulder arthroplasty registry

Background The number of implanted reverse total shoulder arthroplasties (RTSA) is increasing worldwide. To improve patient care, institutional and national arthroplasty registries are being established worldwide to record outcome data. This article aims to describe the setup of an RTSA database in a high-volume university orthopedic hospital. Methods All patients who received an RTSA at the authors’ tertiary referral hospital have been followed and individual datasets have been systematically recorded in a REDCap database since 2005. The data are captured longitudinally as a primary preoperative survey and as a regular or irregular postoperative follow-up. All baseline demographic data, patient history, surgical details, arthroplasty details, adverse events, and radiographic and clinical outcome scores (Constant–Murley score, Subjective Shoulder Value, range of motion) are recorded. Results A total of 1433 RTSA were implanted between January 2005 and December 2020. Of these, 1184 (83%) were primary implantations and 249 (17%) were secondary cases. The cohort had a mean age of 70 ± 10 years, was 39% male, and was classified ASA II in 59%. The lost to follow-up rate was 18% after 2 years, 22% after 5 years, and 53% after 10 years. The overall complication rate with 2 years minimum follow-up was 18% (156/854 shoulders) with reintervention in 10% (82/854 shoulders). Conclusion A well-managed institutional arthroplasty registry, including structured clinical and radiological follow-up assessments, offers the opportunity for high-quality long-term patient and arthroplasty outcome analysis. Such data are not only helpful for analyzing patient outcome and implant survival, but will be increasingly important to justify our daily clinical practice against different stakeholders in the various health care systems. = Hintergrund Die Zahl implantierter inverser Schultertotalprothesen (RTSA) ist international steigend. Um die Patientenversorgung zu verbessern, werden weltweit institutionelle und nationale Prothesenregister etabliert. Die vorliegende Arbeit beschreibt den Aufbau einer RTSA-Datenbank in einer orthopädischen Universitätsklinik mit hoher Fallzahl. Methoden Alle Patienten, welche eine RTSA an unserer Klinik erhielten, wurden seit 2005 nachkontrolliert und systematisch in einer REDCap-Datenbank erfasst. Die Übertragung erfolgt longitudinal als präoperative Erhebung und als reguläre oder irreguläre Verlaufskontrolle. Erfasst werden alle demographischen Basisdaten, die Patientenanamnese, die Operationsdetails, Prothesendetails, Komplikationen, radiologische und klinische Outcome-Scores (Constant-Murley-Score, Subjective Shoulder Value, Bewegungsmaße). Ergebnisse Im Zeitraum von Januar 2005 bis Dezember 2020 wurden insgesamt 1433 RTSA implantiert. Von diesen waren 1184 (83 %) primäre Implantationen und 249 (25 %) sekundäre Implantationen. Die Kohorte war im Mittel 70 ± 10 Jahre alt, zu 39 % männlich und zu 59 % als ASA II klassifiziert. Die Lost-to-follow-up-Rate betrug 18 % nach 2 Jahren, 22 % nach 5 Jahren und 53 % nach 10 Jahren. Die generelle Komplikationsrate nach einem Mindest-Follow-up von 2 Jahren betrug 18 % (156/854 Schultern) mit notwendiger Revisionsoperation bei 10 % (82/854 Schultern). Schlussfolgerung Ein sorgfältig geführtes lokales Endoprothesenregister mit strukturierten klinischen und radiologischen Nachuntersuchungen bietet die Möglichkeit einer qualitativ hochwertigen Langzeitanalyse der Patienten- und Endoprothesenergebnisse. Solche Daten sind nicht nur hilfreich für die Analyse des Patientenergebnisses und des Implantatüberlebens, sondern werden auch immer wichtiger in der Rechtfertigung unserer täglichen klinischen Praxis gegenüber verschiedenen Kostenträgern im Gesundheitssystem

A Statistical Shape Model-Based Analysis of Periacetabular Osteotomies: Technical Considerations to Achieve the Targeted Correction

BACKGROUND Classic and reverse Bernese periacetabular osteotomy (PAO) have been shown to be effective for the treatment of developmental dysplasia of the hip (by classic PAO), severe acetabular retroversion (by reverse PAO), and some protrusio acetabuli (by reverse PAO). Especially in severe cases with higher degrees of correction, a relevant overlap between the osteotomized fragment and the pelvis might occur, leading to necessary fragment translation. The aim of the present study was to analyze the necessary translation as a function of the degree of correction using a statistical mean model of the pelvis according to the technique (classic PAO or reverse PAO). METHODS A mean statistical shape model of the pelvis and 2 extreme models were used to simulate rotation of the osteotomized fragment during a classic or reverse PAO and to calculate rotations from -20° to 20° in the frontal, sagittal, and transverse planes and a combination thereof. The depth and volume of the intersection between the mobilized fragment and the pelvis were calculated, and the minimum translation of the fragment necessary to avoid segment overlap was determined. RESULTS The maximum intersection distances between the pelvis and the 20° rotated fragment were 6.7 and 15.3 mm for adduction and abduction (frontal plane), 6.4 and 4.5 mm for internal and external rotation (transverse plane), and 27.8 and 9.2 mm for extension and flexion (sagittal plane). The necessary translations for 20° of fragment rotation were 7.0 and 12.8 mm for adduction and abduction (frontal plane), 4.8 and 5.0 mm for internal and external rotation (transverse plane), and 18.5 mm and 8.8 mm for extension and flexion (sagittal plane). CONCLUSIONS Acetabular reorientation with the classic or reverse PAO results in translation of the fragment and in a consequent change in the rotational center. This finding is more pronounced with higher degrees of fragment reorientation in abduction and extension; it becomes especially pronounced in reverse PAO for acetabular retroversion or protrusio acetabuli, and might limit the ability to achieve the intended improvement in overall hip biomechanics

Greater Tuberosity Fractures after RTSA: A Matched Group Analysis

Periprosthetic fractures, such as acromial and spine fractures, are known complications following implantation of reverse shoulder arthroplasty (RTSA). The entity of greater tuberosity fractures (GTF) has rarely been studied in the literature. The purpose of this study was to analyze the outcome of postoperative greater tuberosity fractures after RTSA compared to a matched control group. The main findings of this study are that a GTF after RTSA is associated with worse clinical outcome scores (mean absolute CS 50 ± 19 (p = 0.032); SSV 63% ± 26 (p = 0.022); mean force 1 kg ± 2 kg (p = 0.044)) compared with the control group (mean absolute CS 62 ± 21; SSV 77% ± 29; mean force 2 kg ± 2 kg). In terms of postoperative range of motion, the fracture group was significantly worse in terms of external rotation (17° ± 19° vs. 30° ± 19° (p = 0.029)). Internal rotation, flexion, as well as abduction of the shoulder appear to be unaffected (internal rotation GTF 4 ± 2, control group 5 ± 3 (p = 0.138); flexion GTF 102° ± 28°, control group 114° ± 27° (p = 0.160); abduction GTF 109° ± 42°, control group 120° ± 39° (p = 0.317))

Precision of the Wilson corrective osteotomy of the first metacarpal base using specific planning and instruments for treatment of basal thumb arthritis

INTRODUCTION Arthritis of the basal thumb is a relatively common condition also affecting younger patients. Wilson et al. described a 20°-30° closing wedge osteotomy of the first metacarpal bone to unload the trapeziometacarpal joint. It was the purpose of this study to analyze the clinical and radiographic outcome of patients who underwent proximal extension osteotomy of the first metacarpal bone using patient-specific planning and instruments (PSI). METHODS All patients who underwent proximal metacarpal osteotomy for basal thumb arthritis at our tertiary referral center were retrospectively included. The patients underwent preoperative planning using computed tomography and 3D segmentation to build patient-specific guides and instruments for the operative treatment. Stable fixation of the osteotomy was achieved by internal plating. The inclusion criterion was a minimum follow-up of 1 year with clinical examination, including the Michigan Hand Outcomes Questionnaire (MHQ), and computed tomography to validate the correction. Complications and reinterventions were recorded. RESULTS A total of eight Wilson osteotomies in six patients could be included at a mean follow-up duration of 33±16 months (range, 12 to 55 months). The patients were 49±8 years (range, 36 to 58 years) at the surgery and 88% were female. The postoperative MHQ for general hand function was 77±8 (range, 45 to 100) and the MHQ for satisfaction was 77±28 (range, 17 to 100). The working status was unchanged in 7/8 hands (6/7 patients). Radiographic analysis revealed successful correction in all cases with unchanged Eaton-Littler stage in 7/8 hands. No complications were recorded. CONCLUSION The combined extending and ulnar adducting osteotomy using patient-specific guides and instrumentation provides an accurate treatment for early-stage thumb arthritis. LEVEL OF EVIDENCE Type IV-retrospective, therapeutic study

Predictive factors of acromial fractures following reverse total shoulder arthroplasty: a subgroup analysis of 860 shoulders

BACKGROUND: Acromion stress fractures (ASF) or scapular spine fractures (SSF) following reverse total shoulder arthroplasty (RTSA) are common complications with impaired clinical outcome. The underlying biomechanical factors remain unclear. The aim of this study was to evaluate basic demographic and radiographic parameters predicting occurrence of different types of ASF/SSF in a large single-center study cohort. METHODS: A total of 860 RTSA (805 patients) with available minimum follow-up of 2 years were implanted between 2005 and 2018 at a tertiary academic center. All RTSA with subsequent ASF/SSF (n = 45 in 43 shoulders [42 patients, 5%]) were identified and classified as Levy I to III. Predictive demographic, surgical, and radiographic factors were evaluated for each subtype and compared to the control group (817 RTSA, 763 patients). The radiographic analysis included critical shoulder angle, lateralization shoulder angle (LSA), distalization shoulder angle (DSA), acromio-humeral distance (ACHD), acromial thickness, deltoid tuberosity index, deltoid length, and center of rotation. RESULTS: Of the 45 ASF/SSF in 42 patients, 8 were classified as Levy I, 21 as Levy II, and 16 as Levy III. Demographic analysis revealed indication as risk factor for Levy I fractures, higher American Society of Anesthesiologists score as risk for Levy type II fractures and higher age as risk factor for Levy type III fractures. None of the measured radiographic parameters were predictive for occurrence of Levy type I and Levy type II ASF. However, analysis of Levy III SSF revealed a higher postoperative LSA (89° ± 10° vs. 83° ± 9°, P = .015), a lower postoperative DSA (45° ± 8° vs. 53° ± 12°, P = .002), less distalization (ACHD of 33 ± 8 mm vs. 38 ± 10 mm, P = .049), and a more medial center of rotation preoperatively (COR-LA 16 ± 8 mm vs. 12 ± 7 mm, P = .048) as predictive radiographic factors. CONCLUSION: The present analysis showed a significant association of higher postoperative LSA, lower DSA, a lower ACHD, and higher age as predictive factor only for Levy type III fractures. Some of these factors can be surgically influenced and this knowledge can be of value for preoperative planning and surgical execution to avoid these complications

Incidence, radiographic predictors and clinical outcome for acromial stress reaction and acromial fractures in reverse total shoulder arthroplasty

INTRODUCTION Acromial and scapular spine fractures (ASF) are known complications following implantation of Reverse Total Shoulder Arthroplasty (RTSA). The entity of acromial stress reaction (ASR) without fracture has recently been described. The purpose of this study was to analyze the incidence, radiographic predictors, treatment options, healing rate and clinical outcome of ASF and ASR compared to a control group. METHODS A total of 854 primary RTSAs were implanted between 2005 and 2018 in a single shoulder unit of a tertiary referral hospital and retrospectively reviewed for the incidence of ASF and ASR. ASR was defined as pain at the acromion or scapular spine after fracture exclusion on CT scans. The ASF group was matched to a control group. Preoperative and postoperative radiographs were analyzed for radiographic predictors of ASF or ASR. The impact of ASF and ASR, operative versus non-operative treatment and fracture union on clinical outcome (Constant-Murley Score, Subjective Shoulder Value and range of motion) with minimum follow-up of 2 years was analyzed. RESULTS A total of 46 ASF (5.4 %) in 44 patients and 44 ASR (5.2%) in 43 patients were detected at a mean of 16 ± 24 months and 20±23 months postoperative, respectively. Predictive radiographic factors were an increased critical shoulder angle (CSA) and lateralization shoulder angle (LSA). The overall union rate was 55% (22/40) but significantly higher following operative treatment (9/11, 82%) compared to non-operative treatment (13/29, 45%). Patients with ASF/ASR demonstrated inferior clinical outcome (CS 44 ± 21 and 48 ± 18; SSV 52 ± 25 and 57 ± 27) compared to the control group (CS 66 ± 14; SSV: 82 ± 22) independent of bony union or treatment at mean of 59 ± 33 months (ASF) and 61 ± 38 months (ASR). CONCLUSION ASF and ASR are frequent complications following RTSA implantation with similar poor clinical outcome measures. The healing rate was shown to be much higher with a surgical approach. Nevertheless, fracture consolidation does not result in better clinical outcomes compared with nonunion

No clinical consequence of liner malseating in dual-mobility THAs at short term: a systematic review

BACKGROUND: Liner malseating is well described in ceramic-on-ceramic total hip arthroplasties (THAs). However, limited information is known on this complication among dual-mobility articulations. As such, this systematic review analyzed liner malseating in dual-mobility THAs concerning prevalence, clinical implications, and associated risk factors. METHODS: A PRISMA criteria-based systematic review was performed, and PubMed, Web of Science, MEDLINE, and Cochrane used as data bases. All original studies from 1980 to 2022 were considered eligible for inclusion, and Methodological Index for Nonrandomized Studies (MINORS) used for quality assessment. RESULTS: In total, five retrospective cohort studies with 2330 patients (2673 dual-mobility THAs) were included. Mean age was 66.9 years, mean BMI was 29.8 kg/m2, and 35% of patients were female. Rates of malseating ranged from 0.15% to 5.8%, with a total of 53 malseated liners identified throughout all studies (1.98%). Based on THA manufacturer, malseating occurred in 48 Stryker (1.96%) and 5 Biomet Zimmer (2.14%) THAs. Mean clinical follow-up was 2.2 years (mean range, 1.3 to 6.4 years). Except one patient reporting of pain at 2 years, no revision or negative clinical implication was noted in any of the malseated liners, including normal ranged metal ions measured in four cases. A smaller acetabular component size was identified as a statistically significant risk factor for malseating in one study. Mean MINORS score was 9.8. CONCLUSIONS: Liner malseating is a rare finding in patients undergoing THAs with dual-mobility articulations. While prelim results demonstrate no negative clinical consequences to date, existing studies are limited, refer to short-term outcomes only, and do not prospectively follow-up affected patients. LEVEL OF EVIDENCE: IV

Primary reverse total shoulder arthroplasty in patients older than 80 years: clinical and radiologic outcome measures

BACKGROUND The use of reverse total shoulder arthroplasty (RTSA) has spread worldwide as a result of an expansion of indications and an aging society. However, the value of RTSA for very old patients is rarely analyzed. This study was conducted to investigate the outcome of primary RTSA in patients older than 80 years. METHODS We identified 171 shoulders (159 patients) treated with RTSA at an age of more than 80 years between January 2005 and March 2018. The primary outcome parameters were Subjective Shoulder Value (SSV) and the Constant-Murley score, mortality, complications, and reoperation rates. Secondary outcomes were adverse radiographic outcomes. A minimum follow-up of 1 year was accepted in 14 patients (8%) because of these patients' older age. RESULTS We included 171 cases (159 patients; 120 female) with a mean age of 84 ± 3 years (range 80.1-94). The main indication for RTSA was cuff tear arthropathy (43%), isolated rotator cuff tear (22%), and fracture (21%). A total of 136 patients (79%) were eligible for physical examination with a mean follow-up of 41 ± 25 months (12-121). Relative Constant-Murley scores improved significantly from 39% ± 19% to 77% ± 16% and SSV from 31% ± 18% to 74% ± 22%. The range of motion and force improved significantly as well. The surgical site complication rate was 30%, with a reoperation rate of 8% (13 patients) mainly due to fracture and glenoid loosening. The overall mortality was 16% with a mean time to death of 53 ± 31 months (95% confidence interval 15, 120), thereby no higher than the age-adjusted, expected mortality rate without this procedure. CONCLUSION Despite a quite high postoperative complication rate, RTSA is a valid therapeutic option in patients older than 80 years, with an unexpectedly low medical complication rate and good to excellent improvement of shoulder function and pain

Reverse Total Shoulder Arthroplasty for Proximal Humeral Fractures and Sequalae Compared to Non-Fracture Indications: A Matched Cohort Analysis of Outcome and Complications

BACKGROUND: With the increase in utility and popularity of the reverse total shoulder arthroplasty (RTSA) within the last decades, indications for RTSA have expanded. As well as the established indications such as cuff tear arthropathy and massive irreparable rotator cuff tears, RTSA for complex proximal humeral fractures in elderly patients has been proven to be a reliable treatment option. METHODS: A prospectively enrolled RTSA database of 1457 RTSAs implanted between September 2005 and November 2020 was reviewed. Patients treated with RTSA for a complex proximal humerus fracture and fracture sequalae (F-RTSA) were 1:1 matched with a group of patients who were treated electively with RTSA for indications other than a fracture (E-RTSA). Matching criteria included sex, age, length of follow-up and body mass index. Evaluation after a minimum of 2 years follow-up included evaluation of the absolute and relative Constant-Murley score (aCS; rCS), subjective shoulder value (SSV), range of motion (ROM) assessment and complications. RESULTS: Each of the matched cohorts comprised 134 patients with a mean follow-up of 58 ± 41 months for the fracture group and 58 ± 36 months for the elective group. The mean age for both groups was 69 ± 11 years in the F-RTSA and 70 ± 9 years for the E-RTSA group. There were no significant differences in clinical outcome measures including aCS, rCS and SSV (p > 0.05). There was a significant difference in mean active external rotation with 20° ± 18° in the F-RTSA group compared with 25° ± 19° in the E-RTSA group (p = 0.017). The complication rate was not significantly different, with 41 complications in 36 shoulders in the F-RTSA and 40 complications in 32 shoulders in the E-RTSA group (p = 0.73). The main complication for the F-RTSA group was dislocation of the greater tuberosity (6%), whereas acromial fractures (9%) were the leading complication in the E-RTSA group. There was also no significant difference in revision rate comparing F-RTSA with E-RTSA (10% vs. 14%; p = 0.25). CONCLUSIONS: RTSA for complex proximal humeral fractures and its sequalae leads to a comparable clinical outcome as that for patients treated electively with RTSA for indications other than fracture. There was, however, a significant difference in active external rotation, with inferior rotation in patients undergoing RTSA for fracture. This valuable information can help in requesting informed consent of patients with proximal humeral fractures