Radioimmunotherapy with 90-yttrium-ibritumomab tiuxetan (90Y-IT) as first-line treatment in patients with follicular lymphoma (FL) demonstrated promising results with a complete remission (CR) rate of 56% and a median progression-free survival (PFS) of 26 months, when initially analyzed after a median follow-up of 30.6 months. The aim of this long-term follow-up was to investigate whether clinical benefits were maintained and new safety signals appeared. Fifty-nine patients, aged >= 50 years, with FL grade 1 to 3A in stages II to IV were treated with 90Y-IT as first-line therapy. If CR without evidence of minimal residual disease (MRD), partial response or stable disease was achieved 6 months after treatment, patients were observed without further treatment. Patients with CR but persisting MRD received consolidation therapy with rituximab. The primary endpoint was the clinical response rate. Secondary endpoints were time to progression, safety, and tolerability. After a median follow-up of 9.6 years, median PFS was 3.6 years, and 8-year PFS was 38.3%. Median overall survival (OS) was not reached during the extended follow-up, and 8-year OS amounted to 69.2%. Age 65 years and above or disease progression within 24 months of treatment were significantly associated with shorter OS. An important finding was the lack of new safety signals. In particular, no increase in secondary malignancies or transformation into aggressive lymphoma was observed compared to trials with a similar follow-up. In summary, 90Y-IT as first-line treatment demonstrates a favorable safety profile and long-term clinical activity in a substantial fraction of FL patients in need of therapy. ClinicalTrials.gov Identifier: NCT00772655.
View lessHouse dust mites and storage mites have a high allergenic potential and lead to sensitization through the formation of specific IgE antibodies. Due to their preferred stay in houses, they belong to the group of house mites, which are referred to as "domestic mites" in the English-speaking world.Their anatomy and biology justify their astonishing adaptability to changing environmental situations (e.g. temperature, humidity, food) and make it understandable that measures to reduce their frequency are usually difficult to implement in practice.
View lessHouse dust mites and storage mites are grouped together under the name "domestic mites". As a result, mites can trigger allergic diseases of the upper and lower respiratory tract as well as cross-reactions to other allergens. Sensitization to house mites is widespread in the German population. Around eleven million adults in Germany are sensitized (15.9%). Men are affected more often than women, and sensitization occurs more frequently in large cities and in those with a higher socioeconomic status. Sensitizations are less common in old age. As clinically silent sensitizations, they can lead to diagnostic problems, which is the case with about 40% of sensitizations.
View lessIntroduction In patients with pro-opiomelanocortin (POMC) or leptin receptor (LEPR) deficiency, managing obesity and hyperphagia can be burdensome for patients and caretakers. The impacts on health-related quality of life are under-recognized and are not well characterized. Methods We conducted in-depth qualitative interviews in patients with POMC (n = 3) and LEPR (n = 2) deficiencies participating in an ongoing open-label extension of phase 3 clinical trials with the melanocortin receptor 4 agonist setmelanotide to describe the patient experience of hyperphagia and characterize changes following treatment with setmelanotide. Results Prior to setmelanotide treatment, all five patients described abnormal sensations of hunger with none indicating feeling satiated after meals and also reported that the burden of hyperphagia impacted their families, emotions, and work and/or school functioning. Following setmelanotide treatment, all five patients reported consistent reductions in hunger and weight, decreased eating, and feeling satiated after meals in addition to substantial improvements in each area of functioning they had previously reported. All five patients indicated they were very satisfied with the impact of setmelanotide on their quality of life and would be upset if treatment was discontinued. Conclusions In patients with POMC or LEPR deficiency, hyperphagia and the inability to feel satiety negatively impacted quality of life. By reducing hunger and improving satiety, setmelanotide facilitated important changes in the lives of these patients. This qualitative research study suggests that the impact of setmelanotide goes beyond favorable clinical changes (e.g., weight and hunger) to also include quality of life improvements that are highly meaningful to patients.
View lessAnti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established. To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12(+) patients compared to Jo-1(+) patients, while PL-7(+) patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138(+) plasma cells and CXCL12(+)/CXCL13(+)CD20(+) B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase(+) activated mesenchymal fibroblasts and CD68(+)MHC-II(+)CD169(+) macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.
View lessPurpose Traumatic brain injury (TBI) is one of the leading causes of death and disability in children. Medical therapy remains limited, and decompressive craniectomy (DC) is an established rescue therapy in case of elevated intracranial pressure (ICP). Much discussion deals with clinical outcome after severe TBI treated with DC, while data on the pediatric population is rare. We report our experience of treating severe TBI in two different treatment setups at the same academic institution. Methods Forty-eight patients (<= 16 years) were hospitalized with severe TBI (GCS <= 8 points) between 2008 and 2018 in a pediatric intensive care unit (ICU) at a specialized tertiary pediatric care center. Data on treatment, clinical status, and outcome was retrospectively analyzed. Outcome data included Glasgow Outcome Scale (GOS) at 3-, 12-, and 36-month follow-up. Data was compared to a historic cohort with 53 pediatric severe TBI patients treated at the same institution in a neurointensive care unit between 1996 and 2007. Ethical approval was granted (EA2/076/21). Results Between 2008 and 2018, 11 patients were treated with DC. Compared to the historic cohort, patients were younger and GCS was worse, while in-hospital mortality and clinical outcome remained similar. A trend towards more aggressive EVD placement and the internal paradigm change for treatment in a specialized pediatric ICU was observed. Conclusions In children with severe TBI treated over two decades, clinical outcome was comparable and mostly favorable in two different treatment setups. Consequent therapy is warranted to maintain the positive potential for favorable outcome in children with severe TBI.
View lessBackground Diabetes mellitus (DM) is a risk factor for periodontitis. Data on risk-modifying factors for periodontitis in diabetes patients are limited. Aims We tested whether sex, age, type of diabetes, metabolic state, comorbidities, complications, measures of well-being and quality of life are predicting periodontitis in a German diabetes outpatient cohort. Methods In total, 1180 out of 1293 participating DM patients completed questionnaires on quality of life, dental hygiene and health. All patients also filled out a modified version of the periodontitis risk questionnaire by the American Association for Periodontology, from which the status of "assumed periodontitis" was deducted. In a subset of participants (n = 461), we measured or inquired the most recent Community Parodontal Index (CPI), providing an objective measure for clinically diagnosed periodontitis. For all subjects, DM history and phenotype, major metabolic parameters (HbA1c, BMI, LDL and total cholesterol levels), general health risk factors, comorbidities and medication were collected. Results Clinically diagnosed (CPI > 2) and assumed periodontitis was detected in 60-67% of our patients. Male sex and oral health-related quality of life were associated with clinically diagnosed periodontitis. Male sex, age, smoking, dental hygiene, dental control and diabetes-related quality of life independently predicted assumed periodontitis. Conclusion In DM patients, quality of life and lifestyle factors which systemically alter microvascular and immunological functions seem to predict periodontitis. Further studies are needed for replication and for pathomechanistic clarification.
View lessDas Psychotherapeutengesetz von 1998 hat die Stellung der Psychotherapeutinnen und Psychotherapeuten in Deutschland gestärkt, jedoch auch dringliche Wünsche offen gelassen. Nach zehnjähriger Diskussion entstanden die ersten Entwürfe für eine grundlegende Novellierung des bestehenden Gesetzes. Das Bundesgesundheitsministerium beteiligte etwa 60 Verbände und Interessenvertretungen an der Vorbereitung eines Reformgesetzes sowie einer neuen Approbationsordnung, darunter die Bundespsychotherapeutenkammer, die Deutsche Gesellschaft für Psychologie und den Berufsverband deutscher Psychologinnen und Psychologen. Vorrangig war die Gleichstellung der Psychotherapie mit anderen akademischen Heilberufen durch Einführung einer einheitlichen Approbation für Psychotherapie nach einem B.Sc./M.Sc.-Studiengang. Dabei konkurrierten ein eher multidisziplinäres Studienmodell, das schon ab dem ersten Semester eine Ausbildung in Psychotherapie vermittelt, und ein eher disziplinär ausgerichtetes Modell, das eine Spezialisierung auf Psychotherapie im zweiten Abschnitt des Psychologiestudiums vornimmt.. Anhand von Dokumenten und Druckschriften wird die Vorgeschichte des 2019 erlassenen Reformgesetzes und der 2020 nachfolgenden Approbationsordnung rekonstruiert.
View lessPatients with Marfan syndrome and related disorders are at risk for aortic dissection and aortic rupture and therefore require appropriate monitoring. Computed tomography (CT) and transthoracic echocardiography (TTE) are routinely used for initial diagnosis and follow-up. The purpose of this study is to compare whole-heart CT and TTE aortic measurement for initial work-up, 2-year follow-up, and detection of progressive aortic enlargement. This retrospective study included 95 patients diagnosed with Marfan syndrome or a related disorder. All patients underwent initial work-up including aortic diameter measurement using both electrocardiography-triggered whole-heart CT and TTE. Forty-two of these patients did not undergo aortic repair after initial work-up and were monitored by follow-up imaging within 2 years. Differences between the two methods for measuring aortic diameters were compared using Bland-Altman plots. The acceptable clinical limit of agreement (acLOA) for initial work-up, follow-up, and progression within 2 years was predefined as < +/- 2 mm. Bland-Altman analysis revealed a small bias of 0.2 mm with wide limits of agreement (LOA) from + 6.3 to - 5.9 mm for the aortic sinus and a relevant bias of - 1.6 mm with wide LOA from + 5.6 to - 8.9 mm for the ascending aorta. Follow-up imaging yielded a small bias of 0.5 mm with a wide LOA from + 6.7 to - 5.8 mm for the aortic sinus and a relevant bias of 1.1 mm with wide LOA from + 8.1 to - 10.2 mm for the ascending aorta. Progressive aortic enlargement at follow-up was detected in 57% of patients using CT and 40% of patients using TTE. Measurement differences outside the acLOA were most frequently observed for the ascending aorta. Whole-heart CT and TTE measurements show good correlation, but the frequency of measurement differences outside the acLOA is high. TTE systematically overestimates aortic diameters. Therefore, whole-heart CT may be preferred for aortic monitoring of patients with Marfan syndrome and related disorders. TTE remains an indispensable imaging tool that provides additional information not available with CT.
View lessOpioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (+/-)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund's adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1 beta, TNF-alpha, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.
View lessThe temporal discrimination threshold (TDT) has been established as a biomarker of impaired temporal processing and endophenotype in various forms of focal dystonia patients, such as cervical dystonia, writer's cramp or blepharospasm. The role of TDT in musician's dystonia (MD) in contrast is less clear with preceding studies reporting inconclusive results. We therefore compared TDT between MD patients, healthy musicians and non-musician controls using a previously described visual, tactile, and visual-tactile paradigm. Additionally, we compared TDT of the dystonic and non-dystonic hand and fingers in MD patients and further characterized the biomarker regarding its potential influencing factors, i.e. musical activity, disease variables, and personality profiles. Repeated measures ANOVA and additional Bayesian analyses revealed lower TDT in healthy musicians compared to non-musicians. However, TDTs in MD patients did not differ from both healthy musicians and non-musicians, although pairwise Bayesian t-tests indicated weak evidence for group differences in both comparisons. Analyses of dystonic and non-dystonic hands and fingers revealed no differences. While in healthy musicians, age of first instrumental practice negatively correlated with visual-tactile TDTs, TDTs in MD patients did not correlate with measures of musical activity, disease variables or personality profiles. In conclusion, TDTs in MD patients cannot reliably be distinguished from healthy musicians and non-musicians and are neither influenced by dystonic manifestation, musical activity, disease variables nor personality profiles. Unlike other isolated focal dystonias, TDT seems not to be a reliable biomarker in MD.
View lessFor management of Budd-Chiari syndrome (BCS), a step-wise therapeutic approach starting with medical treatment, followed by endovascular recanalization, transjugular intrahepatic portosystemic shunt, and finally liver transplantation has been adopted. We retrospectively analyzed 51 patients with symptomatic short segment (<= 30 mm) hepatic vein (HV)-type BCS who underwent percutaneous transluminal balloon angioplasty (PTBA) with/without stenting to determine the feasibility, clinical effectiveness, and long-term outcomes. The intervention was technically successful in 94.1% of cases (48/51)-32 patients underwent PTBA and 16 patients underwent HV stenting. Procedure-related complications occurred in 14 patients (29.1%). The clinical success rate at 4 weeks was 91.7% (44/48). Nine patients underwent reintervention, six patients due to restenosis/occlusion and three patients with clinical failure. The mean primary patency duration was 64.6 +/- 19.9 months (CI, 58.5-70.8; range, 1.2-81.7 months). The cumulative 1-, 2-, and 5-year primary patency rates were 85.4, 74.5, and 58.3%, respectively. The cumulative 1-, 2-, and 5-year secondary patency rates were 93.8, 87.2, and 75%, respectively. The cumulative 1-, 2-, and 5-year survival rates were 97.9, 91.5, and 50%, respectively. Percutaneous transluminal angioplasty with and without stenting is effective and achieves excellent long-term patency and survival rates in patients with symptomatic HV-type BCS. With its lower incidence of re-occlusion and higher clinical success rate, HV angioplasty combined with stenting should be the preferred option especially in patients with segmental HV-type BCS.
View lessPassive translational tibiofemoral laxity has been extensively examined in posterior cruciate ligament (PCL) insufficient patients and belongs to the standard clinical assessment. However, objective measurements of passive rotational knee laxity, as well as range of tibiofemoral motion during active movements, are both not well understood. None of these are currently quantified in clinical evaluations of patients with PCL insufficiency. The objective of this study was to quantify passive translational and rotational knee laxity as well as range of anterior-posterior and rotational tibiofemoral motion during level walking in a PCL insufficient patient cohort as a basis for any later clinical evaluation and therapy. The laxity of 9 patient knees with isolated PCL insufficiency or additionally posterolateral corner (PLC) insufficiency (8 males, 1 female, age 36.78 +/- 7.46 years) were analysed and compared to the contralateral (CL) knees. A rotometer device with a C-arm fluoroscope was used to assess the passive tibiofemoral rotational laxity while stress radiography was used to evaluate passive translational tibiofemoral laxity. Functional gait analysis was used to examine the range of anterior-posterior and rotational tibiofemoral motion during level walking. Passive translational laxity was significantly increased in PCL insufficient knees in comparison to the CL sides (15.5 +/- 5.9 mm vs. 3.7 +/- 1.9 mm, p < 0.01). Also, passive rotational laxity was significantly higher compared to the CL knees (26.1 +/- 8.2 degrees vs. 20.6 +/- 5.6 degrees at 90 degrees knee flexion, p < 0.01; 19.0 +/- 6.9 degrees vs. 15.5 +/- 5.9 degrees at 60 degrees knee flexion, p = 0.04). No significant differences were observed for the rotational (16.3 +/- 3.7 degrees vs. 15.2 +/- 3.6 degrees, p = 0.43) and translational (17.0 +/- 5.4 mm vs. 16.1 +/- 2.8 mm, p = 0.55) range of anterior-posterior and rotational tibiofemoral motion during level walking conditions for PCL insufficient knees compared to CL knees respectively. The present study illustrates that patients with PCL insufficiency show a substantial increased passive tibiofemoral laxity, not only in tibiofemoral translation but also in tibiofemoral rotation. Our data indicate that this increased passive multiplanar knee joint laxity can be widely compensated during level walking. Further studies should investigate progressive changes in knee joint laxity and kinematics post PCL injury and reconstruction to judge the individual need for therapy and effects of physiotherapy such as quadriceps force training on gait patterns in PCL insufficient patients.
View lessWe aimed to develop and test a novel metric for the relative performance of blood pressure estimation systems (B-Score). The B-Score sets absolute blood pressure estimation model performance in contrast to the dataset the model is tested upon. We calculate the B-Score based on inter- and intrapersonal variabilities within the dataset. To test the B-Score for reliable results and desired properties, we designed generic datasets with differing inter- and intrapersonal blood pressure variability. We then tested the B-Score's real-world functionality with a small, published dataset and the largest available blood pressure dataset (MIMIC IV). The B-Score demonstrated reliable and desired properties. The real-world test provided allowed the direct comparison of different datasets and revealed insights hidden from absolute performance measures. The B-Score is a functional, novel, and easy to interpret measure of relative blood pressure estimation system performance. It is easily calculated for any dataset and enables the direct comparison of various systems tested on different datasets. We created a metric for direct blood pressure estimation system performance. The B-Score allows researchers to detect promising trends quickly and reliably in the scientific literature. It further allows researchers and engineers to quickly assess and compare performances of various systems and algorithms, even when tested on different datasets.
View lessNematodes belonging to the genus Oesophagostomum frequently infect wild chimpanzees (Pan troglodytes) across widely separated field sites. Nodular lesions (granulomas) containing Oesophagostomum are commonly seen in the abdomen of infected chimpanzees post-mortem. At Taï National Park, Côte d'Ivoire, previous studies have identified larvae of a variety of Oesophagostomum spp. in wild chimpanzee stool, based on sequencing of larval DNA, and nodular lesions associated with Oesophagostomum, identified morphologically to the genus level but not sequenced. Here we present three recent cases of parasitic granulomas found post-mortem in chimpanzees at Taï. We complement descriptions of gross pathology, histopathology and parasitology with PCR and sequencing of DNA isolated from the parasitic nodules and from adult worms found inside the nodules. In all three cases, we identify Oesophagostomum stephanostomum as the causative agent. The sequences from this study were identical to the only other published sequences from nodules in nonhuman primates—those from the wild chimpanzees of Gombe, Tanzania.
View lessComorbidity scores are important predictors of in-hospital mortality after traumatic spinal cord injury (tSCI), but the impact of specific pre-existing diseases is unknown. This retrospective cohort study aims at identifying relevant comorbidities and explores the influence of end-of-life decisions. In-hospital mortality of all patients admitted to the study center after acute tSCI from 2011 to 2017 was assessed. A conditional inference tree analysis including baseline data, injury characteristics, and Charlson Comorbidity Index items was used to identify crucial predictors. End-of-life decisions were recorded. Three-hundred-twenty-one patients were consecutively enrolled. The median length of stay was 95.7 days (IQR 56.8-156.0). During inpatient care, 20 patients (6.2%) died. These patients were older (median: 79.0 (IQR 74.7-83.2) vs. 55.5 (IQR 41.4-72.3) years) and had a higher Charlson Comorbidity Index score (median: 4.0 (IQR 1.75-5.50) vs. 0.0 (IQR 0.00-1.00)) compared to survivors. Pre-existing kidney or liver disease were identified as relevant predictors of in-hospital mortality. End-of-life decisions were observed in 14 (70.0%) cases. The identified impairment of kidney and liver, important for drug metabolism and elimination, points to the need of careful decisions on pharmaceutical treatment regimens after tSCI. Appropriate reporting of end-of-life decisions is required for upcoming studies.
View lessThe ability to track minute changes of a single amino acid residue in a cellular environment is causing a paradigm shift in the attempt to fully understand the responses of biomolecules that are highly sensitive to their environment. Detecting early protein dynamics in living cells is crucial to understanding their mechanisms, such as those of photosynthetic proteins. Here, we elucidate the light response of the microbial chloride pump NmHR from the marine bacterium Nonlabens marinus, located in the membrane of living Escherichia coli cells, using nanosecond time-resolved UV/vis and IR absorption spectroscopy over the time range from nanoseconds to seconds. Transient structural changes of the retinal cofactor and the surrounding apoprotein are recorded using light-induced time-resolved UV/vis and IR difference spectroscopy. Of particular note, we have resolved the kinetics of the transient deprotonation of a single cysteine residue during the photocycle of NmHR out of the manifold of molecular vibrations of the cells. These findings are of high general relevance, given the successful development of optogenetic tools from photoreceptors to interfere with enzymatic and neuronal pathways in living organisms using light pulses as a noninvasive trigger.
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