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Karst groundwater-dependent ecosystems (KGDEs) in the Mediterranean region are important in terms of ecosystem services and biodiversity but are increasingly under anthropogenic pressures and climate-change constraints. For this study, the ecohydrological characteristics, threats, and protection status of 112 selected KGDEs around the Mediterranean Sea, including caves, springs, rivers and wetlands, were evaluated, based on local expert knowledge and scientific literature. Results demonstrate that KGDEs contribute considerably to regional biodiversity. The diversity of karst landscapes, combined with the groundwater emergence at springs, leads to exceptional habitat diversity, particularly in arid climates, where KGDEs serve as a refuge for species that could not thrive in the surrounding environment. The most common threats identified among the selected sites are direct human disturbances, such as mass tourism or overfishing, water-quality deterioration and water shortage from aquifer overdraft and/or climate change. Although most of the selected sites are under protection, conservation measures are frequently insufficient. Such shortcomings are often caused by poor data availability, little knowledge on conservation needs of invertebrate species, and conflicts of interest with the local population. For this purpose, it is necessary to raise environmental awareness and promote interdisciplinary research, in order to monitor water quality and quantity in addition to the status of the biocenoses.

Immunogenicity, the unwanted immune response triggered by therapeutic antibodies, poses significant challenges in biotherapeutic development. This response can lead to the production of anti-drug antibodies, potentially compromising the efficacy and safety of treatments. The internalization of therapeutic antibodies into dendritic cells (DCs) is a critical factor influencing immunogenicity. Using monoclonal antibodies, with differences in non-specific cellular uptake, as tools to explore the impact on the overall risk of immunogenicity, this study explores how internalization influences peptide presentation and subsequently T cell activation. To investigate the impact of antibody internalization on immunogenicity, untargeted toolantibodies with engineered positive or negative charge patches were utilized. Immature monocyte-derived DCs (moDCs), known for their physiologically relevant high endocytic activity, were employed for internalization assays, while mature moDCs were used for MHC-II associated peptide proteomics (MAPPs) assays. In addition to the lysosomal accumulation and peptide presentation, subsequent CD4+ T cell activation has been assessed. Consequently, a known CD4+ T cell epitope from ovalbumin was inserted into the tool antibodies to evaluate T cell activation on a single, shared epitope. Antibodies with positive charge patches exhibited higher rates of lysosomal accumulation and epitope presentation compared to those with negative charge patches or neutral surface charge. Furthermore, a direct correlation between internalization rate and presentation on MHC-II molecules could be established. To explore the link between internalization, peptide presentation and CD4+ T cell activation, tool antibodies containing the same OVA epitope were used. Previous observations were not altered by the insertion of the OVA epitope and ultimately, an enhanced CD4+ T cell response correlated with increased internalization in DCs and peptide presentation. These findings demonstrate that the biophysical properties of therapeutic antibodies, particularly surface charge, play a crucial role in their internalization into DCs. Antibodies internalized faster and processed by DCs, are also more prone to be presented on their surface leading to a higher risk of triggering an immune response. These insights underscore the importance of considering antibody surface charge and other properties that enhance cellular accumulation during the preclinical development of biotherapeutics to mitigate immunogenicity risks.

Immunogenicity refers to the ability of a substance, such as a therapeutic drug, to elicit an immune response. While beneficial in vaccine development, undesirable immunogenicity can compromise the safety and efficacy of therapeutic proteins by inducing anti-drug antibodies (ADAs). These ADAs can reduce drug bioavailability and alter pharmacokinetics, necessitating comprehensive immunogenicity risk assessments starting at early stages of drug development. Given the complexity of immunogenicity, an integrated approach is essential, as no single assay can universally recapitulate the immune response leading to the formation of anti-drug antibodies. To better understand the Dendritic Cell (DC) contribution to immunogenicity, we developed two flow cytometry-based assays: the DC internalization assay and the DC activation assay. Monocyte-derived dendritic cells (moDCs) were generated from peripheral blood mononuclear cells (PBMCs) and differentiated over a five-day period. The internalization assay measured the accumulation rate of therapeutic antibodies within moDCs, while the activation assay assessed the expression of DC activation markers such as CD40, CD80, CD86, CD83, and DC-SIGN (CD209). To characterize these two assays further, we used a set of marketed therapeutic antibodies. The study highlights that moDCs differentiated for 5 days from freshly isolated monocytes were more prone to respond to external stimuli. The internalization assay has been shown to be highly sensitive to the molecule tested, allowing the use of only 4 donors to detect small but significant differences. We also demonstrated that therapeutic antibodies were efficiently taken up by moDCs, with a strong correlation with their peptide presentation on MHC-II. On the other hand, by monitoring DC activation through a limited set of activation markers including CD40, CD83, and DC-SIGN, the DC activation assay has the potential to compare a series of compounds. These two assays provide a more comprehensive understanding of DC function in the context of immunogenicity, highlighting the importance of both internalization and activation processes in ADA development. The DC internalization and activation assays described here address key gaps in existing immunogenicity assessment methods by providing specific and reliable measures of DC function. The assays enhance our ability to pre-clinically evaluate the immunogenic potential of biotherapeutics, thereby improving their safety and efficacy. Future work should focus on further validating these assays and integrating them into a holistic immunogenicity risk assessment framework.

In pediatric orthopedics, long bone lengthening procedures are routinely performed using manual, motorized or magnetically controlled implants. This study aims to prove expansion of a newly designed osmotic pump prior to long bone lengthening in living organisms and to rule out any complications related to in vivo conditions, such as congestion of the semipermeable membrane, local infection, or lack of water to drive the osmotic pump, as well as to compare in vivo and in vitro expansion data. Osmotic pumps, which were designed to distract a plate osteosynthesis, were inserted in the dorsal paraspinal musculature of four piglets. To compare the performance of the pumps in in vivo and in vitro conditions, another set of pumps was submerged in physiologic saline solution at different temperatures. The lengthening progress was measured radiographically and sonographically in the study animals. Both, in vitro and in vivo tested osmotic pumps started distraction after an intended rest phase of four days and distracted evenly over the following twelve days. No complications, clogging or damages occurred. However, we observed a temperature dependency of the distraction rate ranging from 0.98 mm/day at 39°C to 1.10 mm/day at 42°C. With a second setup, we confirmed that the distraction rate differed by 72% within a measured temperature interval of 14° C. The data presented here confirm that the novel osmotic pump showed comparable lengthening characteristics in vivo and in vitro. No complications, such as congestion of the semipermeable membrane, local infection, or lack of water to drive the osmotic pump were observed. Thus, osmotic pumps may have great potential in future applications such as long bone lengthening procedures, where continuous distraction probably provides a better bone quality than intermittent lengthening procedures. The fact that one pump failed to elongate in each condition, highlights the importance of technical improvement, but also demonstrates that this was not due to different circumstances within the in vivo or in vitro condition.

Background Patients with somatoform pain experience physical pain that cannot be attributed to any underlying medical or physiological cause, and it is often thought to be related to psychological factors. Health professionals encounter difficulties identifying this specific type of chronic pain, leading to suboptimal treatment strategies. Therefore, we aimed to describe the characteristics of patients with somatoform pain, to support the identification of affected patients. Methods We collected and analyzed a cross‐sectional survey data from 200 patients with somatoform pain admitted to one of three psychosomatic centers in Germany between August 2013 and July 2014. The survey contains 10 different categories, all of them referring to pain‐related topics. Within the survey, we analyzed validated as well as non‐validated questionnaires. Here, we present the following five: Personal data, Body: Pain perception, Cognition: Pain processing, Pain behavior, and Physical complaints. Results Our results highlight that most patients with somatoform pain experience it in several body parts and as persisting, lasting >12 h/day (50%), and constantly changing (71%). Furthermore, patients indicate feelings of helplessness, by agreeing to the expressions the pain controls me (70%). Finally, we found that pain is predominantly seen as suffering, failing to convey emotional pain, despite cognitively acknowledging the dependency of emotional and physical pain. Conclusion The study identified specific and distinctive characteristics in the emotional and behavioral responses of patients with somatoform pain, potentially distinguishing them from other patients with chronic pain. The study analyzed survey data from 200 patients with somatoform pain, finding that most experience persistent pain in multiple body parts, feel a sense of helplessness, and predominantly perceive pain as suffering rather than emotional distress, highlighting distinctive emotional and behavioral responses in this group.

(1) Background: Patients’ experiences and satisfaction with their treatment are becoming increasingly important in the context of quality assurance, but the measurement of these parameters is accompanied by several disadvantages such as poor cross-country comparability and methodological problems. The aim of this review is to describe and summarize the process of measuring, publishing, and utilizing patient experience and satisfaction data in countries with highly developed healthcare systems in Europe (Germany, Sweden, Finland, Norway, the United Kingdom) and the USA to identify possible approaches for improvement. (2) Methods: Articles published between 2000 and 2021 that address the topics described were identified. Furthermore, patient feedback in social media and the influence of sociodemographic and hospital characteristics on patient satisfaction and experience were evaluated. (3) Results: The literature reveals that all countries perform well in collecting patient satisfaction and experience data and making them publicly available. However, due to the use of various different questionnaires, comparability of the results is difficult, and consequences drawn from these data remain largely unclear. (4) Conclusions: Surveying patient experience and satisfaction with more unified as well as regularly updated questionnaires would be helpful to eliminate some of the described problems. Additionally, social media platforms must be considered as an increasingly important source to expand the range of patient feedback.

Objective A patient-centered approach to the management of acromegaly includes disease activity control, shared decision-making and identification of comorbidities. The Acromegaly Disease Activity Tool (ACRODAT ® ) is intended to assist physicians in providing such holistic management. The present study investigated this claim using the simulated person (SP) approach. Methods We studied patient-doctor interaction via online video consultation in a randomized prospective study design with SPs trained to simulate a specific acromegaly profile. We analyzed the proportion of conversation time devoted to health content and the specific acromegaly and comorbidity relevant categories mentioned in the conversation. We collected physicians’ feedback on the usefulness of ACRODAT ® , SPs subjective perception of the quality of the conversation and compared consultations with and without ACRODAT ® using a qualitative approach. Results The sample ( N  = 30) consisted of endocrinologists treating patients with acromegaly in Germany. For SP-physician interactions ( N  = 60), the proportion of time spent on conversation content (e.g. IGF-I, quality of life) was distributed according to the focus of the patient profile. Comorbidities were less well identified than the need for a change in therapy. Only 18.3% of the SPs were actively asked to participate in the decision-making process. ACRODAT ® did not lead to any significant differences in the course of the discussion. Conclusions Shared decision-making was underrepresented in this SP-physician interaction in acromegaly management. Physicians adapted the content of the discussion to the SP’s needs, but did not adequately address comorbidities. According to the analysis criteria used, ACRODAT ® did not contribute to a more holistic patient management in the present study.

Objective Because of its high prognostic value, neuropsychological assessment plays a crucial role in the neuro‐oncology setting. Subjective and objective cognitive performance correlate only to a limited extent, and subjective cognitive performance is strongly dependent on emotional state. We postulate that the relation of subjective and objective cognitive performance depends on tumor laterality. Methods In this prospective study, N = 63 patients with brain tumors underwent a neuropsychological test battery, including assessment of subjective cognitive function (attention, memory, executive), and symptoms of depression and anxiety before surgery. Patients with psychiatric comorbidity or severe neurological conditions were excluded. Results There were no significant differences in subjective and objective cognitive function, symptoms of depression and anxiety between left (N = 37) and right (N = 26) hemisphere tumors. All measures of subjective cognitive function correlated highly significantly with symptoms of depression and anxiety in left hemisphere tumor patients (all r ≥ 0.470). In right hemisphere tumor patients, there was no relation between subjective cognitive function and emotional state. Significant laterality differences for correlations of subjective and objective cognitive function were not found and were not significant within the two groups. Conclusions Even when unbiased by symptoms of anxiety and depression, right hemisphere tumor patients show the same discrepancy in subjective and objective cognitive function as left hemisphere tumor patients. This discrepancy may be based on a different mechanism in right hemisphere tumor patients.

Dedifferentiated vascular smooth muscle cells (vSMCs) play an essential role in neointima formation, and we now aim to investigate the role of the bone morphogenetic protein (BMP) modulator BMPER (BMP endothelial cell precursor-derived regulator) in neointima formation. To assess BMPER expression in arterial restenosis, we used a mouse carotid ligation model with perivascular cuff placement. Overall BMPER expression after vessel injury was increased; however, expression in the tunica media was decreased compared to untreated control. Consistently, BMPER expression was decreased in proliferative, dedifferentiated vSMC in vitro. C57BL/6_Bmper+/− mice displayed increased neointima formation 21 days after carotid ligation and enhanced expression of Col3A1, MMP2, and MMP9. Silencing of BMPER increased the proliferation and migration capacity of primary vSMCs, as well as reduced contractibility and expression of contractile markers, whereas stimulation with recombinant BMPER protein had the opposite effect. Mechanistically, we showed that BMPER binds insulin-like growth factor-binding protein 4 (IGFBP4), resulting in the modulation of IGF signaling. Furthermore, perivascular application of recombinant BMPER protein prevented neointima formation and ECM deposition in C57BL/6N mice after carotid ligation. Our data demonstrate that BMPER stimulation causes a contractile vSMC phenotype and suggest that BMPER has the potential for a future therapeutic agent in occlusive cardiovascular diseases.

Purpose To improve the understanding of adherence as one major factor of disease control in acromegaly patients, we systematically assessed patients’ motivations to adhere to advised follow-up schedules and recommended medication for acromegaly. Methods Cross-sectional, postal questionnaire study on adult patients with acromegaly, operated upon a growth hormone producing pituitary adenoma more than 1 year ago in two tertiary treatment centers. We assessed demographic and clinical characteristics, disease status, adherence to acromegaly medication and/or aftercare, and the five dimensions defined by the World Health Organization influencing adherence. Wherever applicable, we included validated short scales. The answers of 63 patients (33 f, 30 m; mean age 56.1 y) were analyzed. Results Patients with problems in adherence to aftercare had a significantly lower subjective symptomload than those adherent to aftercare (p = 0.026) and a lower perceived need for treatment (p = 0.045). Patients with adherence problems to medication had a higher subjective symptomload than those without (p = 0.056). They also tended to have shorter consultations, were significantly more often dissatisfied with the duration of their medical consultations (42% vs 4.8%, p = 0.019) and tended to find that their physician explained potential difficulties with adherence less well than patients without adherence problems (p = 0.089). Conclusions To our knowledge, this is the first study which explored adherence to medication and aftercare in patients with acromegaly, taking into account potential influencing factors from all areas defined by the WHO model of adherence. Of the modifiable factors of adherence, patient–doctor relationship seemed to play a crucial role and could be one leverage point to improve adherence.