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Background: SARS-CoV-2 antigen rapid detection tests (RDTs) emerged as point-of-care diagnostics alongside reverse transcription polymerase chain reaction (RT-qPCR) as reference., Methods: In a prospective performance assessment from 12 November 2020 to 30 June 2023 at a single centre tertiary care hospital, the sensitivity and specificity (primary endpoints) of RDTs from three manufacturers (NADAL®, Panbio™, MEDsan®) were compared to RT-qPCR as reference standard among patients, accompanying persons and staff aged ≥ six month in large-scale, clinical screening use. Regression models were used to assess influencing factors on RDT performance (secondary endpoints)., Findings: Among 78,798 paired RDT/RT-qPCR results analysed, overall RDT sensitivity was 34.5% (695/2016; 95% CI 32.4-36.6%), specificity 99.6% (76,503/76,782; 95% CI 99.6-99.7%). Over the pandemic course, sensitivity decreased in line with a lower rate of individuals showing typical COVID-19 symptoms. The lasso regression model showed that a higher viral load and typical COVID-19 symptoms were directly significantly correlated with the likelihood of a positive RDT result in SARS-CoV-2 infection, whereas age, sex, vaccination status, and the Omicron VOC were not., Interpretation: The decline in RDT sensitivity throughout the pandemic can primarily be attributed to the reduced prevalence of symptomatic infections among vaccinated individuals and individuals infected with Omicron VOC. RDTs remain valuable for detecting SARS-CoV-2 in symptomatic individuals and offer potential for detecting other respiratory pathogens in the post-pandemic era, underscoring their importance in infection control efforts., Funding: German Federal Ministry of Education and Research (BMBF), Free State of Bavaria, Bavarian State Ministry of Health and Care., Competing Interests: Declaration of interests Daniel Zeller receives honoraria from Angelini Pharma and Novartis outside of the submitted work. Manuel Krone receives honoraria from Abbott, GSK, Pfizer, and Sanofi outside of the submitted work. None of the other authors have any conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Presence of micrometastases in the sentinel lymph node (SLN) is currently used to assess prognosis of melanoma patients. The immunoactivity within the SLN is known to be influenced by the primary tumor (PT), which may in turn impact the SLNs' metastatic state., Aim: We characterize the temporal dependence and underlying mechanisms of the immunological effects of the PT on the SLN., Methods: The prognostic value of SLN state as a function of PT removal time was evaluated. To put the results into a functional context, selected PTs and corresponding SLNs were analyzed for gene and protein expression patterns., Results: In a cohort of 202 patients with known distant metastasis and similar PT prognostic characteristics, SLNs removed before or within one week after the PT (IM-SLN) had a higher incidence of micrometastases than those removed at least one week after the PT (DEL-SLN). The immunoactivity in IM-SLN was found to be lower than in DEL-SLN. Specifically, in IM-SLNs, T helper 17 / regulatory T-cells were predominant, whereas in DEL-SLNs, cytotoxic γδT-cells were more frequent. The higher immune activity in DEL-SLNs was probably facilitated by CD209 + antigen-presenting cells. Indeed, in PT with high TGFβ expression CD209 + cells appear to be trapped and no increased immunoactivity was observed in DEL-SLN., Conclusions: Presence of micrometastases in DEL-SLNs have a higher negative prognostic value as in IM-SLNs since they indicate not only a melanoma's propensity to metastasize, but possibly also its capacity to escape immune responses., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. VKD received a research grant, honoraria for talks and travel support from SUN Pharma. CR is employed by Merck Serono. TG reports receiving speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, outside the submitted work. SH has acted as a consultant and / or received travel assistance from BMS, Kyowa Kirin. RG received honoraria as speaker from BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre, as advisory board member from BMS, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, MerckSerono, Pfizer, Immunocore, Delcath, for meeting support from SUN, Pierre-Fabre, Boehringer Ingelheim and for research projects (to institution) from Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, Kyowa-Kirin, Admiral-Hermal. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Sanofi, and Sun Pharma, is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, ICON, MerckSerono, Pfizer, and Sanofi. His group receives research grants from Merck Serono, IQVIA, and Alcedis. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Key Message: Analysis of the N-terminome of Physcomitrella reveals N-terminal monomethylation of nuclear-encoded, mitochondria-localized proteins. Post- or co-translational N-terminal modifications of proteins influence their half-life as well as mediating protein sorting to organelles via cleavable N-terminal sequences that are recognized by the respective translocation machinery. Here, we provide an overview on the current modification state of the N-termini of over 4500 proteins from the model moss Physcomitrella (Physcomitrium patens) using a compilation of 24 N-terminomics datasets. Our data reveal distinct proteoforms and modification states and confirm predicted targeting peptide cleavage sites of 1,144 proteins localized to plastids and the thylakoid lumen, to mitochondria, and to the secretory pathway. In addition, we uncover extended N-terminal methylation of mitochondrial proteins. Moreover, we identified PpNTM1 (P. patens alpha N-terminal protein methyltransferase 1) as a candidate for protein methylation in plastids, mitochondria, and the cytosol. These data can now be used to optimize computational targeting predictors, for customized protein fusions and their targeted localization in biotechnology, and offer novel insights into potential dual targeting of proteins., (© 2024. The Author(s).)

Purpose: To investigate the diagnostic performance of an automatic pipeline for detection of hydronephrosis on kidney's parenchyma on unenhanced low-dose CT of the abdomen., Methods: This retrospective study included 95 patients with confirmed unilateral hydronephrosis in an unenhanced low-dose CT of the abdomen. Data were split into training (n = 67) and test (n = 28) cohorts. Both kidneys for each case were included in further analyses, whereas the kidney without hydronephrosis was used as control. Using the training cohort, we developed a pipeline consisting of a deep-learning model for automatic segmentation (a Convolutional Neural Network based on nnU-Net architecture) of the kidney's parenchyma and a radiomics classifier to detect hydronephrosis. The models were assessed using standard classification metrics, such as area under the ROC curve (AUC), sensitivity and specificity, as well as semantic segmentation metrics, including Dice coefficient and Jaccard index., Results: Using manual segmentation of the kidney's parenchyma, hydronephrosis can be detected with an AUC of 0.84, a sensitivity of 75% and a specificity of 82%, a PPV of 81% and a NPV of 77%. Automatic kidney segmentation achieved a mean Dice score of 0.87 and 0.91 for the right and left kidney, respectively. Additionally, automatic segmentation achieved an AUC of 0.83, a sensitivity of 86%, specificity of 64%, PPV of 71%, and NPV of 82%., Conclusion: Our proposed radiomics signature using automatic kidney's parenchyma segmentation allows for accurate hydronephrosis detection on unenhanced low-dose CT scans of the abdomen independently of widened renal pelvis. This method could be used in clinical routine to highlight hydronephrosis to radiologists as well as clinicians, especially in patients with concurrent parapelvic cysts and might reduce time and costs associated with diagnosing hydronephrosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Thomas Kroencke reports financial support was provided by Siemens Healthineers. Florian Schwarz reports financial support was provided by Siemens Healthineers. Judith Becker reports financial support was provided by University Augsburg. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Glioblastoma (GBM) is the most prevalent, malignant, primary brain tumor in adults, characterized by limited treatment options, frequent relapse, and short survival after diagnosis. Until now, none of the existing therapy and treatment approaches have proven to be an effective cure. The availability of predictive human blood-tumor barrier (BTB) test systems that can mimic in-vivo pathophysiology of GBM would be of great interest in preclinical research. Here, we present the establishment of a new BTB in-vitro test system combining GBM spheroids and BBB models derived from human induced pluripotent stem cells (hiPSCs)., Methods: We co-cultured hiPSC-derived brain capillary endothelial-like cells (iBCECs) with GBM spheroids derived from U87-MG and U373-MG cell lines in a cell culture insert-based format. Spheroids were monitored over 168 hours (h) of culture, characterized for GBM-specific marker expression and treated with standard chemotherapeutics to distinguish inhibitory effects between 2D mono-culture and 3D spheroids. GBM-induced changes on iBCECs barrier integrity were verified via measurement of transendothelial electrical resistance (TEER), immunocytochemical staining of tight junction (TJ) proteins claudin-5 and occludin as well as the glucose transporter-1 (Glut-1). GBM-induced secretion of vascular endothelial growth factor (VEGF) was additionally quantified., Results: Our hypothesis was validated by reduced expression of TJ proteins, occludin and claudin-5 together with significant barrier breakdown in iBCECs after only 24 h of co-culture, demonstrated by reduction in TEER from 1313 ± 265 Ω*cm 2 to 712 ± 299 Ω*cm 2 (iBCECs + U87-MG) and 762 ± 316 Ω*cm 2 (iBCECs + U373-MG). Furthermore, 3D spheroids show more resistance to standard GBM chemotherapeutics in-vitro compared to 2D cultures., Conclusions: We demonstrate the establishment of a simplified, robust in-vitro BTB test system, with potential application in preclinical therapeutic screening and in studying GBM-induced pathological changes at the BBB., (© 2024. The Author(s).)

Purpose: This study aims to investigate the psychological distress experienced by patients with an initial diagnosis of abnormal Pap smears or dysplastic changes of the cervix uteri. It investigated whether patients' age, education, information level and approach to information acquisition have an impact on their psychological distress., Methods: A total of 364 female patients, aged 20-80 years, referred to the special dysplasia consultation hour at the Department of Obstetrics and Gynecology, Wuerzburg, completed a questionnaire containing validated items to assess information level, information acquisition, information needs and psychological distress, including a distress thermometer. Data from questionnaires and medical reports were used for analysis., Results: The study found that 56.9% of patients experienced psychological distress before their first visit. Patients under 44 years of age, especially those with concerns about fertility and sexuality, and those with lower levels of education showed higher levels of distress (p-value = 0.018 and p-value = 0.037). 40.9% of patients felt poorly informed and 53.7% of patients wanted more information before their visit. Correlational analysis showed that the method of obtaining information correlated with the desire for more information (p-value < 0.001). Those who received information via the Internet felt less informed, wanted more information and experienced more anxiety., Conclusion: These findings highlight the need for improved patient education strategies and effective doctor-patient communication to address the knowledge gap and reduce patient distress. In addition, healthcare providers should ensure that patients have access to reliable online resources for accurate information., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The size of the human cochlear, measured by the diameter of the basal turn, varies between 7 and 11 mm. For hearing rehabilitation with cochlear implants (CI), the size of the cochlear influences the individual frequency map and the choice of electrode length. OTOPLAN® (CAScination AG [Bern, Switzerland] in cooperation with MED-EL [Innsbruck, Austria]) is a software tool with CE marking for clinical applications in CI treatment which allows for precise pre-planning based on cochlear size. This literature review aims to analyze all published data on the application of OTOPLAN®., Materials and Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to identify relevant studies published in the PubMed search engine between January 2015 and February 2023 using the search terms "otoplan" [title/abstract] OR "anatomy-based fitting" [title/abstract] OR "otological software tool" [title/abstract] OR "computed tomography-based software AND cochlear" [title/abstract]., Results: The systematic review of the literature identified 32 studies on clinical use of OTOPLAN® in CI treatment. Most studies were reported from Germany (7 out of 32), followed by Italy (5), Saudi Arabia (4), the USA (4), and Belgium (3); 2 studies each were from Austria and China, and 1 study from France, India, Norway, South Korea, and Switzerland. In the majority of studies (22), OTOPLAN® was used to assess cochlear size, followed by visualizing the electrode position using postoperative images (5), three-dimensional segmentation of temporal bone structures (4), planning the electrode insertion trajectory (3), creating a patient-specific frequency map (3), planning of a safe drilling path through the facial recess (3), and measuring of temporal bone structures (1)., Conclusion: To date, OTOPLAN® is the only DICOM viewer with CE marking in the CI field that can process pre-, intra-, and postoperative images in the abovementioned applications., (© 2024. The Author(s).)

It has long been known in historical research that the Habsburg Emperor Maximilian II (1527-1576) suffered from heart complaints throughout his life. Numerous biographers mention this fact. His medical history and even the results of the autopsy of his body have been handed down; however, it has not been sufficiently investigated how Maximilian's physicians explained his heart condition, often referred to as "tremor cordis", and what causes and triggers they held responsible for this complaint in general and in the specific case of their famous patient. This article addresses these questions, primarily on the basis of a detailed consultation by the imperial personal physician Andrea Gallo, dating from 1555. Gallo's consilium, which has been ignored by scholares so far, first summarizes the state of knowledge on heart tremors at that time. It then turns to Maximilian's case and provides revealing insights into his mental state., (© 2023. The Author(s).)

Objective: To evaluate objective and subjective hearing outcomes in experienced cochlear implant users with single sided deafness (SSD CI) who used fitting maps created via anatomy-based fitting (ABF) and clinically-based fitting (CBF)., Participants: Twelve SSD CI users with postlingual hearing loss., Intervention: OTOPLAN (Version 3. (MED-EL) was used to determine intracochlear electrode contact positions using post-operative high-resolution flat panel volume computed tomography. From these positions, the corresponding center frequencies and bandwidths were derived for each channel. These were implemented in the clinical fitting software MAESTRO to yield an ABF map individualized to each user., Main Outcome Measures: ABF and CBF maps were compared. Objective speech perception in quiet and in noise, binaural effects, and self-perceived sound quality were evaluated., Results: Significantly higher speech perception in noise scores were observed with the ABF map compared to the CBF map (mean SRT 50 : -6.49 vs. -4.8 dB SNR for the S 0 N CI configuration and - 3.85 vs. -2.75 dB SNR for the S 0 N 0 configuration). Summation and squelch effects were significantly increased with the ABF map (0.86 vs. 0.21 dB SNR for summation and 0.85 vs. -0.09 dB SNR for squelch). No improvement in speech perception in quiet or spatial release from masking were observed with the ABF map. A similar level of self-perceived sound quality was reported for each map. Upon the end of the study, all users opted to keep the ABF map. This preference was independent of the angular insertion depth of the electrode array., Conclusions: Experienced SSD CI users preferred using the ABF map, which gave them significant improvements in binaural hearing and some aspects of speech perception., (© 2024. The Author(s).)

Purpose: In cochlear implantation (CI) surgery, there are a wide variety of intraoperative tests available. However, no clear guide exists on which tests must be performed as the minimum intraoperative testing battery. Toward this end, we studied the usage patterns, recommendations, and attitudes of practitioners toward intraoperative testing., Methods: This study is a multicentric international survey of tertiary referral CI centers. A survey was developed and administered to a group of CI practitioners (n = 34) including otologists, audiologists and biomedical engineers. Thirty six participants were invited to participate in this study based on a their scientific outputs to the literature on the intraoperative testing in CI field and based on their high load of CI surgeries. Thirty four, from 15 countries have accepted the invitation to participate. The participants were asked to indicate the usage trends, perceived value, influence on decision making and duration of each intraoperative test. They were also asked to indicate which tests they believe should be included in a minimum test battery for routine cases., Results: Thirty-two (94%) experts provided responses. The most frequently recommended tests for a minimum battery were facial nerve monitoring, electrode impedance measurements, and measurements of electrically evoked compound action potentials (ECAPs). The perceived value and influence on surgical decision-making also varied, with high-resolution CT being rated the highest on both measures., Conclusion: Facial nerve monitoring, electrode impedance measurements, and ECAP measurements are currently the core tests of the intraoperative test battery for CI surgery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Precise preoperative radiological evaluation of aural atresia is of utmost importance for surgical planning. Until now, multislice computed tomography (MSCT) has been used but it cannot adequately visualize small structures such as the stapes. Flat-panel volume CT (fpVCT) with its secondary reconstructions (fpVCT SECO ) offers a high-resolution visualization of the middle ear. New otosurgical planning software also enables detailed 3D reconstruction of the middle ear anatomy., Aim of the Work: Evaluation of the use of fpVCT SECO in combination with an otosurgical planning software for a more accurate diagnosis and treatment of congenital aural atresia., Material and Methods: Seven patients with congenital aural atresia underwent preoperative MSCT (600 µm slice thickness) and corresponding fpVCT (466 µm slice thickness). In addition, fpVCT SECO (99 µm slice thickness) were reconstructed. The Jahrsdoerfer and Siegert grading scores were determined and their applicability in the abovementioned imaging modalities was evaluated. In addition, the malleus incus complex was analyzed in 3D rendering., Results: Imaging with fpVCT SECO enabled reliable visualization of the abnormalities, in particular the ossicular chain. A significant difference in the Siegert grading score was found. In addition, the malleus-incus complex could be visualized better in 3D., Discussion: The introduction of new imaging techniques and surgical planning techniques into the diagnostic concept of aural atresia facilitates the identification of malformed anatomy and enables systematic analysis. This combination can also help to more accurately classify the pathology and thus increase the safety and success of the surgical procedure., (© 2024. The Author(s).)

Background: The planning and implementation of intervention measures against schistosomiasis, particularly mass administration, require knowledge of the current status of the infection. This is important for monitoring the impact of the intervention on disease indicators such as a decline in infection prevalence, intensity of infection, and urogenital morbidities. Following repeated rounds of mass treatment in northwestern Tanzania, the epidemiology of urogenital schistosomiasis has changed; thus, for the effective planning and allocation of resources, it is important to understand the current status of the disease in the targeted groups. Therefore, the objective of the current study was to determine the prevalence, intensity, and associated factors of Schistosoma haematobium infection and urinary tract morbidities in school-aged children from northwestern Tanzania., Materials and Methods: An analytical cross-sectional study was conducted among schoolchildren aged 5-17 years between November and December 2022. A single urine sample was collected from each child and examined for the presence of S. haematobium eggs and microhaematuria using a urine filtration technique and a urine reagent dipstick. Each child underwent an ultrasonographic examination of the urinary tract according to the World Health Organization standards (Niamey protocol) to detect S. haematobium-related morbidities., Results: Of the 3225 participants, 54.2 % were female, and the mean age was 10.9 (±1.89) years. The overall prevalence of S. haematobium was 17.7 % (95 % CI: 16.4-19.1, 572/3225). Of the 572 infected children, 81.8 % (95 % CI: 78.4-84.9, 468/572) had light-intensity infections, and 18.2 % (95 % CI: 14.9-21.4, 104/572) had heavy-intensity infections. The prevalence of macro- and microhaematuria was 2.4 % (95 % CI: 1.9-3) and 18.5 % (95 % CI: 17.2-19.8), respectively. Age (aOR: 1.2, 95 % CI: 1.0-1.5), district of residence (aOR: 2.1, 95 % CI: 1.7-2.7) and history of schistosomiasis (aOR: 2.5, 95 % CI: 1.9-3.2) were significantly associated with urinary schistosomiasis infection. However, swallowing praziquantel during the last mass drug administration was protective (aOR 0.6, 95 % CI: 0.4-0.8). The overall prevalence of ultrasound-detectable urinary tract abnormalities was 9.9 % (95 % CI: 8.9-11.1, 299/2994) and included urinary bladder abnormalities in 9.9 % (95 % CI: 8.8-11, 297/2994), ureter abnormalities in 0.2 % (95 % CI: 0.07-0.4, 6/2994), and kidney abnormalities in 0.2 % (95 % CI: 0.09-0.4, 7/2994). Calcification of the urinary bladder was observed in 0.9 % (95 % CI: 0.6-1.3, 29/2994) of the examined children., Conclusions: Schistosoma haematobium infection is still prevalent among schoolchildren in the study setting, and it causes substantial morbidity at an early age. Transmission is driven by the age of the child, district of residence, and history of schistosomiasis. However, swallowing praziquantel in rounds of mass drug administration reduces transmission. Urogenital schistosomiasis infection is associated with haematuria and ultrasound-detectable morbidities. In S. haematobium endemic areas, routine ultrasound screening for urinary tract morbidities could be considered in annual mass treatment programmes for early management. Special attention should be given to children with proteinuria, microhaematuria, and heavy infection intensities., Competing Interests: The authors declare that no competing interests exist., (© 2024 The Authors. Published by Elsevier Ltd on behalf of World Federation of Parasitologists.)

Based on the assumption that postmortem cerebrospinal fluid (CSF) is contaminated depending on the chosen sampling technique in the forensic setting resulting in bloody or at least hemolytic CSF samples, we systematically documented a total of 183 postmortem CSF samples. These samples were all assessed for their quality and color, regardless of the cause of death or the postmortem interval. The investigations were carried out through subjective assessment of color and turbidity, as well as objective measurements of the optical density (OD) of the CSF supernatants after centrifugation of each sample, with standardized photographic documentation. The observations revealed that in 28 cases the CSF was absolutely (crystal-) clear and transparent. Most of our samples showed color changes ranging from xanthrochromic to rose. Intensive staining of the supernatants was only found in a small proportion of the examined collective. We found that postmortem CSF has no uniform appearance but rather a diverse range of color spectra, and the color, as well as the OD of the CSF, correlates significantly with the postmortem interval (p < 0.001) when sampled using the proposed standard procedure., (© 2024. The Author(s).)

A significant number of prostate cancer patients are long-term survivors after primary definitive therapy, and the occurrence of late side effects, such as second primary cancers, has gained interest. The aim of this editorial is to discuss the most current evidence on second primary cancers based on six retrospective studies published in 2021-2024 using large data repositories not accounting for all possible confounding factors, such as smoking or pre-existing comorbidities. Overall, prostate cancer patients treated with curative radiotherapy have an increased risk (0.7-1%) of the development of second primary cancers compared to patients treated with surgery up to 25 years after treatment. However, current evidence suggests that the implementation of intensity modulated radiation therapy is not increasing the risk of second primary cancers compared to conformal 3D-planned radiotherapy. Furthermore, increasing evidence indicates that highly conformal radiotherapy techniques may not increase the probability of second primary cancers compared to radical prostatectomy. Consequently, future studies should consider the radiotherapy technique and other confounding factors to provide a more accurate estimation of the occurrence of second primary cancers., (© 2024. The Author(s).)

The ompD transcript, encoding an outer membrane porin in Salmonella, harbors a controlling element in its coding region that base-pairs imperfectly with a 'seed' region of the small regulatory RNA (sRNA) MicC. When tagged with the sRNA, the ompD mRNA is cleaved downstream of the pairing site by the conserved endoribonuclease RNase E, leading to transcript destruction. We observe that the sRNA-induced cleavage site is accessible to RNase E in vitro upon recruitment of ompD into the 30S translation pre-initiation complex (PIC) in the presence of the degradosome components. Evaluation of substrate accessibility suggests that the paused 30S PIC presents the mRNA for targeted recognition and degradation. Ribonuclease activity on PIC-bound ompD is critically dependent on the recruitment of RNase E into the multi-enzyme RNA degradosome, and our data suggest a process of substrate capture and handover to catalytic sites within the degradosome, in which sequential steps of seed matching and duplex remodelling contribute to cleavage efficiency. Our findings support a putative mechanism of surveillance at translation that potentially terminates gene expression efficiently and rapidly in response to signals provided by regulatory RNA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Vaccinations represent an easily accessible, safe, and important method for preventing infections. Patients with primary immunodeficiencies (PID) are more susceptible to infections and should receive an extended spectrum of immunizations in many countries., Methods: Between January 2019 and May 2020, vaccination certificates of 70 patients with PID from the regions of Würzburg and Hanover in Germany were evaluated. The patients were additionally surveyed regarding their attitude towards vaccinations and the communication with their physicians. Medical records were analyzed., Results: Of the 70 patients, 54 (77%) suffered from common variable immunodeficiency, 30 (43%) were diagnosed with accompanying autoimmunity, 62 (89%) had an increased susceptibility to infections, and 56 (80%) were on immunoglobulin substitution therapy. Seven patients (10%) had neither a vaccination certificate nor were they able to recollect of their last vaccination. Only 55 (79%) and 43 (61%) patients stated that their rheumatologist or immunologist had recommended an influenza and a pneumococcal vaccination, respectively. When asked about their overall trust in vaccinations on a scale of 0 to 10 (0 = very low, 10 = very high), the mean value was 7.8. The most common vaccination was against tetanus in 63 (90%) patients, 49 (70%) had received vaccination against pneumococci, and 39 (56%) had received an influenza vaccination. Interestingly, 26 patients (37%) were vaccinated against measles, even though this is contraindicated in most PID patients., Conclusion: Our data suggest that vaccination rates in this at-risk population are insufficient. Healthcare providers should emphasize vaccinations routinely when caring for these patients., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Cervical cancer often originates from cervical cell dysplasia. Previous studies mainly focused on surgical margins and high-risk human papillomavirus persistence as factors predicting recurrence. New research highlights the significance of positive findings from endocervical curettage (ECC) during excision treatment. However, the combined influence of surgical margin and ECC status on dysplasia recurrence risk has not been investigated., Methods: In this retrospective study, data from 404 women with high-grade squamous intraepithelial lesions (HSIL) who underwent large loop excision of the transformation zone (LLETZ) were analyzed. Records were obtained retrospectively from the hospital's patient database including information about histopathological finding from ECC, endocervical margin status with orientation of residual disease after LLETZ, recurrent/persistent dysplasia after surgical treatment and need for repeated surgery (LLETZ or hysterectomy)., Results: Patients with cranial (= endocervical) R1-resection together with cells of HSIL in the ECC experienced re-surgery 17 times. With statistical normal distribution, this would have been expected to happen 5 times (p < 0.001). The Fisher's exact test confirmed a statistically significant connection between the resection status together with the result of the ECC and the reoccurrence of dysplasia after surgery (p < 0,001). 40,6% of the patients with re-dysplasia after primary LLETZ had shown cranial R1-resection together with cells of HSIL in the ECC. Investigating the risk for a future abnormal Pap smear, patients with cranial R1-resection together with dysplastic cells in the ECC showed the greatest deviation of statistical normal distribution with SR = 2.6., Conclusion: Our results demonstrate that the future risk of re-dysplasia, re-surgery, and abnormal Pap smear for patients after LLETZ due to HSIL is highest within patients who were diagnosed with cranial (endocervical) R1-resection and with cells of HSIL in the ECC in their primary LLETZ. Consequently, the identification of patients, who could benefit of intensified observation or required intervention could be improved., (© 2024. The Author(s).)

Rationale and Objectives: This study investigates the dose burden of photon-counting detector (PCD) lung CT with ultra-high-resolution (UHR) and standard mode using organ-based tube current modulation (OBTCM)., Materials and Methods: An anthropomorphic Alderson-Rando phantom was scanned in UHR and standard mode with and without OBTCM on three dose levels (IQ 5, 20, 50). Effective radiation dose was determined by thermoluminescent dosimetry in 13 measurement sites and compared with the calculated effective dose derived from the dose-length product. Image quality was evaluated subjectively by six radiologists using an equidistant 7-point scale and objectively by means of modulation transfer function analysis., Results: Measured effective radiation exposure was lower in UHR and OBTCM studies than in standard mode (IQ 5: 0.34-0.36, IQ 20: 1.57-1.70, IQ 50: 3.76-3.99 mSv). Compared with the calculated effective dose, the radiation exposure measured with thermoluminescence dosimetry was 131-170% higher. Noise in UHR mode was rated lower than in standard (all p ≤ 0.042) and OBTCM images (all p ≤ 0.028) for all dose levels, while image sharpness was deemed highest for UHR protocols (all p ≤ 0.042). The use of OBTCM had no significant effect on either dimension of subjective image quality (all p ≥ 0.999). Modulation transfer function analysis confirmed the highest spatial frequency in UHR datasets (all p ≤ 0.016)., Conclusion: In PCD-CT of the lung, full field-of-view UHR imaging entails no dose disadvantage over standard mode despite superior image quality. OBTCM possesses moderate dose saving potential. Thermoluminescence dosimetry yielded considerably higher effective doses than those calculated from dose-length products., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jan-Peter Grunz [grant number Z-3BC/02] and Philipp Gruschwitz [Z-02CSP/18] are financially supported by the Interdisciplinary Center of Clinical Research Würzburg. Andreas Kunz, Thorsten Bley, and Jan-Peter Grunz report a relationship with Siemens Healthineers that includes consulting or advisory and paid expert testimony. The Department of Diagnostic and Interventional Radiology receives ongoing research funding by Siemens Healthineers outside of the presented work., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Glycoprotein VI (GPVI) is a platelet collagen/fibrin(ogen) receptor and an emerging pharmacological target for the treatment of thrombotic and thrombo-inflammatory diseases, notably ischaemic stroke. A first anti-human GPVI (hGPVI) antibody Fab-fragment (ACT017/glenzocimab, KD: 4.1 nM) recently passed a clinical phase 1b/2a study in patients with acute ischaemic stroke and was found to be well tolerated, safe, and potentially beneficial. In this study, a novel humanized anti-GPVI antibody Fab-fragment (EMA601; KD: 0.195 nM) was developed that inhibits hGPVI function with very high potency in vitro and in vivo., Methods: Fab-fragments of the mouse anti-hGPVI IgG Emf6.1 were tested for functional GPVI inhibition in human platelets and in hGPVI expressing (hGP6tg/tg) mouse platelets. The in vivo effect of Emf6.1Fab was assessed in a tail bleeding assay, an arterial thrombosis model and the transient middle cerebral artery occlusion (tMCAO) model of ischaemic stroke. Using complementary-determining region grafting, a humanized version of Emf6.1Fab (EMA601) was generated. Emf6.1Fab/EMA601 interaction with hGPVI was mapped in array format and kinetics and quantified by bio-layer interferometry., Results: Emf6.1Fab (KD: 0.427 nM) blocked GPVI function in human and hGP6tg/tg mouse platelets in multiple assays in vitro at concentrations ≥5 µg/mL. Emf6.1Fab (4 mg/kg)-treated hGP6tg/tg mice showed potent hGPVI inhibition ex vivo and were profoundly protected from arterial thrombosis as well as from cerebral infarct growth after tMCAO, whereas tail-bleeding times remained unaffected. Emf6.1Fab binds to a so far undescribed membrane proximal epitope in GPVI. The humanized variant EMA601 displayed further increased affinity for hGPVI (KD: 0.195 nM) and fully inhibited the receptor at 0.5 µg/mL, corresponding to a >50-fold potency compared with ACT017., Conclusions: EMA601 is a conceptually novel and promising anti-platelet agent to efficiently prevent or treat arterial thrombosis and thrombo-inflammatory pathologies in humans at risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Deep brain stimulation (DBS) has emerged as a revolutionary technique for accessing and modulating brain circuits. DBS is used to treat dysfunctional neuronal circuits in neurological and psychiatric disorders. Despite over two decades of clinical application, the fundamental mechanisms underlying DBS are still not well understood. One reason is the complexity of in vivo electrical manipulation of the central nervous system, particularly in rodent models. DBS-devices for freely moving rodents are typically custom-designed and not commercially available, thus making it difficult to perform experimental DBS according to common standards. Addressing these challenges, we have developed a novel wireless microstimulation system for deep brain stimulation (wDBS) tailored for rodents. We demonstrate the efficacy of this device for the restoration of behavioral impairments in hemiparkinsonian mice through unilateral wDBS of the subthalamic nucleus. Moreover, we introduce a standardized and innovative pipeline, integrating machine learning techniques to analyze Parkinson's disease-like and DBS-induced gait changes., (© 2024. The Author(s).)

Movement disorders, such as Parkinson's disease, essential tremor, and dystonia, are characterized by their predominant motor symptoms, yet diseases causing abnormal movement also encompass several other symptoms, including non-motor symptoms. Here we review recent advances from studies of brain lesions, neuroimaging, and neuromodulation that provide converging evidence on symptom-specific brain networks in movement disorders. Although movement disorders have traditionally been conceptualized as disorders of the basal ganglia, cumulative data from brain lesions causing parkinsonism, tremor and dystonia have now demonstrated that this view is incomplete. Several recent studies have shown that lesions causing a given movement disorder occur in heterogeneous brain locations, but disrupt common brain networks, which appear to be specific to each motor phenotype. In addition, findings from structural and functional neuroimaging in movement disorders have demonstrated that brain abnormalities extend far beyond the brain networks associated with the motor symptoms. In fact, neuroimaging findings in each movement disorder are strongly influenced by the constellation of patients' symptoms that also seem to map to specific networks rather than individual anatomical structures or single neurotransmitters. Finally, observations from deep brain stimulation have demonstrated that clinical changes, including both symptom improvement and side effects, are dependent on the modulation of large-scale networks instead of purely local effects of the neuromodulation. Combined, this multimodal evidence suggests that symptoms in movement disorders arise from distinct brain networks, encouraging multimodal imaging studies to better characterize the underlying symptom-specific mechanisms and individually tailor treatment approaches., (© 2024. The Author(s).)

Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Physical activity referral schemes (PARS) are composed of various components, such as a written prescription or a person-centered approach. The role of these components in their effectiveness is yet to be understood. Therefore, we aimed to explore the relationships between PARS components and physical activity, scheme uptake, and adherence rate; and to estimate the effect of PARS., Methods: We searched Scopus, PubMed, Web of Science, CINAHL, ScienceDirect, SpringerLink, HTA, Wiley Online Library, SAGE Journals, Taylor & Francis, Google Scholar, OpenGrey, and CORE. Eligible studies were published between 1990 and November 2023 in English or German, investigated PARS with participants aged ≥ 16 years, and reported physical activity, scheme uptake, or scheme adherence. Separate random-effects meta-analysis by comparison group were conducted for physical activity. Scheme uptake and adherence rates were pooled using proportional meta-analysis. The components were analyzed via univariate meta-regression. We rated the risk of bias using RoB2 and ROBINS-I, and the certainty of evidence using GRADE., Results: Fifty-two studies were included. PARS were more effective in increasing physical activity than usual care (k = 11, n = 5046, Hedges' g = 0.18, 95%CI 0.12 to 0.25; high certainty of evidence). When PARS were compared with physical activity advice or enhanced scheme versions, the pooled Hedges' g values for physical activity were -0.06 (k = 5, n = 1082, 95%CI -0.21 to 0.10; low certainty of evidence), and 0.07 (k = 9, n = 2647, 95%CI -0.03 to 0.18; low certainty of evidence) respectively. Scheme uptake was 87% (95%CI 77% to 94%, k = 14, n = 5000) across experimental studies and 68% (95%CI 51% to 83%, k = 14, n = 25,048) across non-experimental studies. Pooled scheme adherence was 68% (95%CI 55% to 80%, k = 16, n = 3939) and 53% (95%CI 42% to 63%, k = 18, n = 14,605). The meta-regression did not detect any significant relationships between components and physical activity or scheme uptake. A person-centered approach, screening, and brief advice were positively associated with scheme adherence, while physical activity sessions were negatively associated., Conclusion: PARS are more effective in increasing physical activity than usual care only. We did not identify any components as significant predictors of physical activity and scheme uptake. Four components predicted scheme adherence, indicating that the component-effectiveness relationship warrants further research., (© 2024. The Author(s).)

Cone-beam computed tomography (CBCT)-based online adaptation is increasingly being introduced into many clinics. Upon implementation of a new treatment technique, a prospective risk analysis is required and enhances workflow safety. We conducted a risk analysis using Failure Mode and Effects Analysis (FMEA) upon the introduction of an online adaptive treatment programme (Wegener et al., Z Med Phys. 2022). A prospective risk analysis, lacking in-depth clinical experience with a treatment modality or treatment machine, relies on imagination and estimates of the occurrence of different failure modes. Therefore, we systematically documented all irregularities during the first year of online adaptation, namely all cases in which quality assurance detected undesired states potentially leading to negative consequences. Additionally, the quality of automatic contouring was evaluated. Based on those quantitative data, the risk analysis was updated by an interprofessional team. Furthermore, a hypothetical radiation therapist-only workflow during adaptive sessions was included in the prospective analysis, as opposed to the involvement of an interprofessional team performing each adaptive treatment. A total of 126 irregularities were recorded during the first year. During that time period, many of the previously anticipated failure modes (almost) occurred, indicating that the initial prospective risk analysis captured relevant failure modes. However, some scenarios were not anticipated, emphasizing the limits of a prospective risk analysis. This underscores the need for regular updates to the risk analysis. The most critical failure modes are presented together with possible mitigation strategies. It was further noted that almost half of the reported irregularities applied to the non-adaptive treatments on this treatment machine, primarily due to a manual plan import step implemented in the institution's workflow., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeard to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Purpose: In craniofacial surgery, the stable fixation of transposed bone segments is crucial in order to ensure good long-term results. The use of absorbable material in fixation avoids the need for a second surgery, which would otherwise be required to remove osteosynthesis material. The authors of the present manuscript have already demonstrated that absorbable sutures ensure the stable fixation of bone segments in patients up to 24 months of age. However, it has thus far remained unclear whether stable fixation is possible in older patients by using only absorbable sutures due to the slower bone remodelling and prolonged healing time in this cohort., Method: For the present study, osteosynthesis was performed in 50 patients ranging from 25.7 to 192.1 months of age (mean, 61.4 ± 21.7 months) using solely absorbable sutures (PDS II ® , Ethicon, Germany). Post-operative stability and possible restrictions-such as foreign body reactions-were evaluated within clinical and radiological routine follow-ups., Results: All children demonstrated clinically and radiologically stable osteosynthesis both directly post-operatively and in follow-ups. No significant foreign body reaction could be seen., Conclusion: The present study demonstrates-for the first time-that absorbable sutures with a longer absorption period are also very well suited for the fixation of bone segments in patients over 24 months of age. The sole use of absorbable sutures in children over 24 months of age is a safe procedure with nearly no foreign body reactions. The procedure enables stable and highly cost-effective osteosynthesis without altering the osteotomy design., (© 2024. The Author(s).)

Purpose: Malignant intracranial germ cell tumors (GCTs) are rare diseases in Western countries. They arise in midline structures and diagnosis is often delayed. We evaluated imaging characteristics and early tumor signs of suprasellar and bifocal GCT on MRI., Methods: Patients with the diagnosis of a germinoma or non-germinomatous GCT (NGGCT) who received non-contrast sagittal T1WI on MRI pre-therapy were included. Loss of the posterior pituitary bright spot (PPBS), the expansion and size of the tumor, and the expansion and infiltration of surrounding structures were evaluated. Group comparison for histologies and localizations was performed., Results: A total of 102 GCT patients (median age at diagnosis 12.3 years, range 4.4-33.8; 57 males; 67 in suprasellar localization) were enrolled in the study. In the suprasellar cohort, NGGCTs (n = 20) were noticeably larger than germinomas (n = 47; p < .001). Each tumor showed involvement of the posterior lobe or pituitary stalk. A PPBS loss (total n = 98) was observed for each localization and entity in more than 90% and was related to diabetes insipidus. Osseous infiltration was observed exclusively in suprasellar GCT (significantly more frequent in NGGCT; p = .004). Time between the first MRI and therapy start was significantly longer in the suprasellar cohort (p = .005), with an even greater delay in germinoma compared to NGGCT (p = .002). The longest interval to treatment had circumscribed suprasellar germinomas (median 312 days)., Conclusion: A loss of the PPBS is a hint of tumor origin revealing small tumors in the neurohypophysis. Using this sign in children with diabetes insipidus avoids a delay in diagnosis., (© 2024. The Author(s).)

Blood vessels in tumors are often dysfunctional. This impairs the delivery of therapeutic agents to and distribution among the cancer cells. Subsequently, treatment efficacy is reduced, and dose escalation can increase adverse effects on non-malignant tissues. The dysfunctional vessel phenotypes are attributed to aberrant pro-angiogenic signaling, and anti-angiogenic agents can ameliorate traits of vessel dysfunctionality. However, they simultaneously reduce vessel density and thereby impede drug delivery and distribution. Exploring possibilities to improve vessel functionality without compromising vessel density in the tumor microenvironment, we evaluated transcription factors (TFs) involved in epithelial-mesenchymal transition (EMT) as potential targets. Based on similarities between EMT and angiogenic activation of endothelial cells, we hypothesized that these TFs, Snai1 in particular, might serve as key regulators of vessel dysfunctionality. In vitro, experiments demonstrated that Snai1 (similarly Slug and Twist1) regulates endothelial permeability, permissiveness for tumor cell transmigration, and tip/stalk cell formation. Endothelial-specific, heterozygous knock-down of Snai1 in mice improved vascular quality in implanted tumors. This resulted in better oxygenation and reduced metastasis. Notably, the tumors in Snai1KD mice responded significantly better to chemotherapeutics as drugs were transported into the tumors at strongly increased rates and more homogeneously distributed. Thus, we demonstrate that restoring vessel homeostasis without affecting vessel density is feasible in malignant tumors. Combining such vessel re-engineering with anti-cancer drugs allows for strategic treatment approaches that reduce treatment toxicity on non-malignant tissues., (© 2024. The Author(s).)

Preeclampsia is a disorder of pregnancy characterized by endothelial dysfunction, abnormal placentation, systemic inflammation, and altered immune reaction. The aim of this study was to investigate the immune checkpoint molecules TIM-3 and Gal-9 on macrophages and Hofbauer cells (HBC) in the placenta of preeclampsia patients. Immunohistochemistry and Immunofluorescence was used to characterize the expression of the macrophage markers CD68 and CD163, CK7 and the proteins TIM-3 and Gal-9 in the placentas of preeclampsia patients comparing it to the placentas of healthy pregnancies. Double immunofluorescence staining (TIM-3 with CD3/CD19/CD56) was used to analyze the TIM-3 expression on other immune cells (T cells, B cells, NK cells) within the chorionic villi. The expression of TIM-3 on decidual macrophages did not significantly differ between the preeclamptic and the control group (p = 0.487). When looking at the different offspring we saw an upregulation of TIM-3 expression on decidual macrophages in preeclamptic placentas with female offspring (p = 0.049). On Hofbauer cells within the chorionic villi, the TIM-3 expression was significantly downregulated in preeclamptic cases without a sex-specific difference (p < 0.001). Looking at the protein Gal-9 the expression was proven to be downregulated both, on decidual macrophages (p = 0.003) and on Hofbauer cells (p = 0.002) within preeclamptic placentas compared to healthy controls. This was only significant in male offspring (p < 0.001 and p = 0.013) but not in female offspring (p = 0.360 and p = 0.068). While TIM-3 expression within the extravillious trophoblast and the syncytiotrophoblast was significantly downregulated (p < 0.001 and p = 0.012) in preeclampsia, the expression of Gal-9 was upregulated in (p < 0.001 and p < 0.001) compared to healthy controls. The local variations of the immune checkpoint molecules TIM-3 and Gal-9 in the placenta may contribute to the inflammation observed in preeclamptic patients. It could therefore contribute to the pathogenesis and be an important target in the treatment of preeclampsia., Competing Interests: Declaration of Competing Interest N.D. reports funding from MSD, Novartis, Pfizer, Roche, AstraZeneca, TEVA, Mentor, and MCI Healthcare. U.J. received travel money from pfm. C.D. is funded by Roche, AstraZeneca, TEVA, Mentor, and MCI Healthcare. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Preterm born individuals have an increased risk for mental health problems. Participation in club sport is associated with better mental health but the causal direction is unclear. It is not known whether this association could also be found in preterm children. Data from term born (N = 10,368), late preterm (N = 630), and very to moderately preterm born (N = 243) children from the Millennium Cohort Study at the ages of 3, 5, 7, 11, and 14 years were used. Longitudinal associations between the parent-reported Strengths and Difficulties questionnaire (SDQ) and club sport participation (days per week) were analysed using multigroup structural equation modelling, adjusting for gender, maternal depression, parental education; motor problems and attrition were controlled for. Multi-group structural equation modelling showed that children with more peer relationship problems, emotional symptoms, conduct problems or hyperactivity-inattention were less likely to participate in club sport at subsequent assessment time points. More days with club sport participation was associated with lower levels of emotional symptoms and peer relationship problems but not conduct problems or hyperactivity-inattention at subsequent ages. Results were similar in all gestational age groups. Club sport participation predicts lower levels of peer relationship and emotional problems in subsequent waves while it is also predicted by lower levels of emotional problems, peer relationship problems, conduct problems and hyperactivity-inattention in preceding waves. Since no differences in the relationship between SDQ subscales and club sport participation were seen with regard to gestational age groups, club sport should be encouraged in all children., (© 2024. The Author(s).)

Background: 3D printing holds great potential of improving examination, diagnosis and treatment planning as well as interprofessional communication in the field of gynecological oncology. In the current manuscript we evaluated five individualized, patient-specific models of cervical cancer FIGO Stage I-III, created with 3D printing, concerning their value for translational oncology., Methods: Magnetic resonance imaging (MRI) of the pelvis was performed on a 3.0 Tesla MRI, including a T2-weighted isotropic 3D sequence. The MRI images were segmented and transferred to virtual 3D models via a custom-built 3D-model generation pipeline and printed by material extrusion. The 3D models were evaluated by all medical specialties involved in patient care of cervical cancer, namely surgeons, radiologists, pathologists and radiation oncologists. Information was obtained from evaluated profession-specific questionnaires which were filled out after inspecting all five models. The questionnaires included multiple-select questions, questions based on Likert scales (1 = "strongly disagree " or "not at all useful " up to 5 = "strongly agree " or "extremely useful ") and dichotomous questions ("Yes" or "No")., Results: Surgeons rated the models as useful during surgery (4.0 out of 5) and for patient communication (4.7 out of 5). Furthermore, they believed that the models had the potential to revise the patients' treatment plan (3.7 out of 5). Pathologists evaluated with mean ratings of 3.0 out of 5 for the usefulness of the models in diagnostic reporting and macroscopic evaluation. Radiologist acknowledged the possibility of providing additional information compared to imaging alone (3.7 out of 5). Radiation oncologists strongly supported the concept by rating the models highly for understanding patient-specific pathological characteristics (4.3 out of 5), assisting interprofessional communication (mean 4.3 out of 5) and communication with patients (4.7 out of 5). They also found the models useful for improving radiotherapy treatment planning (4.3 out of 5)., Conclusion: The study revealed that the 3D printed models were generally well-received by all medical disciplines, with radiation oncologists showing particularly strong support. Addressing the concerns and tailoring the use of 3D models to the specific needs of each medical speciality will be essential for realizing their full potential in clinical practice., (© 2024. The Author(s).)

Plasminogen activator inhibitor-1 (PAI-1/Serpin E1) is classically known for its antifibrinolytic activity via inhibiting uPA and tPA of the fibrinolytic pathway. PAI-1 has a paradoxical role in tumor progression, and its molecular functions are poorly understood. PAI-1 is a widely accepted secretory protease inhibitor, however, a study suggested the localization of PAI-1 in the cytoplasm and the nucleus. Besides the plethora of its biological functions as a secretory protein, intracellular localization, and functions of PAI-1 remain unexplored at the molecular level. In this study, using various in silico approaches, we showed that PAI-1 possesses a nuclear export signal. Using the CRM1-specific inhibitor leptomycin B, we demonstrated that PAI-1 has a functional CRM1-dependent NES, indicating the possibility of its nuclear localization. Further, we confirm that PAI-1 is localized in the nucleus of endothelial cells using fluorescence microscopy and immunoprecipitation. Notably, we identified an unconventional distribution of PAI-1 in the PML bodies of the nucleus of normal endothelial cells, while the protein was restricted in the cytoplasm of slow-growing cells. The data showed that the localization of PAI-1 in PML bodies is highly correlated with the growth potential of endothelial cells. This conditional nucleocytoplasmic shuttling of PAI-1 during the aging of cells could impart a strong link to its age-related functions and tumor progression. Together, this study identifies the novel behavior of PAI-1 that might be linked with cell aging and may be able to unveil the elusive role of PAI-1 in tumor progression., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Post-COVID syndrome (PCS) describes a persistent complex of symptoms following a COVID-19 episode, lasting at least 4 to 12 weeks, depending on the specific criteria used for its definition. It is often associated with moderate to severe impairments of daily life and represents a major burden for many people worldwide. However, especially during the first two years of the COVID-19 pandemic, therapeutic and diagnostic uncertainties were prominent due to the novelty of the disease and non-specific definitions that overlooked functional deficits and lacked objective assessment. The present work comprehensively examines the status of PCS definitions as depicted in recent reviews and meta-analyses, alongside exploring associated symptoms and functional impairments. We searched the database Pubmed for reviews and meta-analysis evaluating PCS in the period between May 31, 2022, to December 31, 2023. Out of 95 studies, 33 were selected for inclusion in our analyses. Furthermore, we extended upon prior research by systematically recording the symptoms linked with PCS as identified in the studies. We found that fatigue, neurological complaints, and exercise intolerance were the most frequently reported symptoms. In conclusion, over the past eighteen months, there has been a notable increase in quantity and quality of research studies on PCS. However, there still remains a clear need for improvement, particularly with regard to the definition of the symptoms necessary for diagnosing this syndrome. Enhancing this aspect will render future research more comparable and precise, thereby advancing and understanding PCS., (© 2024. The Author(s).)

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD. AVLX-144-based probes were labeled with the radioisotopes fluorine-18 and tritium, as well as a fluorescent tag. Tracer binding showed saturable, displaceable, and uneven distribution in rat brain slices, proving effective in quantitative autoradiography and cell imaging studies. Notably, we observed diminished tracer binding in human post-mortem Parkinson's disease (PD) brain slices, suggesting postsynaptic impairment in PD. We thus offer a suite of translational probes for visualizing and understanding PSD-related pathologies.

Background: Given the shortage and unequal distribution of physicians across specialties, we aimed to evaluate factors associated with medical students' career choices, including background, personality traits, educational experience, personal interests, lifestyle considerations, and the awareness of work requirements., Methods: We conducted multiple cross-sectional surveys of students; a 159-item online questionnaire was designed and students from three different stages of the six-year medical degree course (outset, clinical phase, and on graduation) were invited to complete the survey. Data were collected between May 2021 and April 2023., Results: The questionnaire was sent to 1406 students, of whom 683 replied (49%); 481 respondents were female (70%). The top specialty choices across the respondents were internal medicine, surgery, and general practice, with anaesthesiology, paediatric and adolescent medicine (ranging 11-15%), and obstetrics and gynaecology also receiving interest, with 6% undecided. In particular, female students lost interest in surgery during the course of study in favour of the other options. The choice of general practice was associated with more vocational training, prior positive experiences with the specialty, and lower grades in the university entry examination. Clinical clerkships in a specific (freely chosen) specialty aligned with career choice, while the final practical year did not have an impact on career decision-making. All students highly desired regulated working hours and work-life-balance; however, students choosing surgery rated these items as less important. Willingness to work in a hospital environment was highly associated with choosing anaesthesiology and surgery, whereas rural areas and practices were associated with general practice. Higher scores at agreeableness were associated with choosing paediatric and adolescent medicine by more female students, whereas lower neuroticism values were associated with the choice of anaesthesiology., Conclusions: The results highlight the intricate nature of decision-making and shed light on various aspects that contribute to the process of selecting a specialty. By identifying and addressing influencing factors, we can develop targeted interventions and policies to enhance diversity and distribution across medical specialisations and to aim for high-quality and equitable healthcare that matches the specific needs of both individuals and the population as a whole., (© 2024. The Author(s).)

Viruses often pose a significant threat to the host through the exploitation of cellular machineries for their own benefit. In the context of immune responses, myriad host factors are deployed to target viral RNAs and inhibit viral protein translation, ultimately hampering viral replication. Understanding how "non-self" RNAs interact with the host translation machinery and trigger immune responses would help in the development of treatment strategies for viral infections. In this review, we explore how interferon-stimulated gene products interact with viral RNA and the translation machinery in order to induce either global or targeted translation inhibition., Competing Interests: The authors declare no conflicts of interest.

Purpose: Postoperative hypotony following PRESERFLO MicroShunt (PMS) implantation is a frequent cause of complications such as choroidal detachment and hypotony maculopathy. This study aims at evaluating the impact of intraluminal stenting of the PMS during the early postoperative period., Methods: We retrospectively analyzed the data of 97 patients who underwent PMS implantation with intraoperative placement of a Nylon 10-0 suture as intraluminal stent (PStent) and compared the outcomes to those of an existing database of the traditional MicroShunt implantation technique (PTrad, n = 120). The primary outcome measure was the intraocular pressure (IOP) at one week postoperatively. As a secondary outcome measure, adverse hypotony, defined as an IOP ≤ 5 mmHg with significant choroidal effusion and/or anterior chamber shallowing or the presence of macular folds was also assessed. Additionally, the time to stent removal and the IOP one week after stent removal were reported., Results: Preoperative median IOP was 25.0 (20.5-30.3) mmHg in PStent and 25.0 (19.3-32.0) mmHg in PTrad (p = 0.62). One week after surgery, the median IOP dropped to 10.0 (8.0-13.0) mmHg in PStent and 7.0 (5.0-9.0) in PTrad (p < 0.01). At one month, the IOP was 12.0 (10.0-14.0) mmHg in PStent and 10.0 (8.0-11.0) mmHg in PTrad (p < 0.01). After 3 months, both groups showed similar median IOP levels of 11.0 (8.0-13.5) mmHg and 10.0 (9.75-13.0) mmHg in PStent and PTrad, respectively (p = 0.66). The presence of adverse hypotony was significantly lower in PStent compared to PTrad (6.2% vs 15.8%, p < 0.05). In PStent the stent was removed after 30.0 (21.0-42.5) days. One week after stent removal the mean IOP drop was 6.1 ± 0.5 mmHg (p < 0.01)., Conclusion: In the early follow-up period, intraluminal stenting of the PMS appears to be safe and effective in controlling the IOP while reducing early postoperative hypotony. Surgical success is not compromised by stent placement. Based on our data, it is recommended to remove the suture two to six weeks after surgery for most patients with uncomplicated postoperative clinical findings., (© 2024. The Author(s).)

Introduction: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them., Methods: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment., Perspective: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed., Trial Registration: The study is registered at ClinicalTrails.gov; NCT06418646., (© 2024. The Author(s).)

Approximately 2% of the German population suffer from psoriasis. HybridVITA has developed a mobile application (app) that enables psoriasis patients to independently document the progression of the disease and the current psychological stress at home. The HybridVITA app was created in close collaboration with user groups to ensure optimal adaptation to their needs. Two interactive workshops were held with the user groups and the technical developers of the app as a core element of the developmental process. The workshops identified the needs and suggestions for improvement of the various user groups and formulated user stories for the further development of the app using the Scrum method. The participatory approach of the workshop enabled the project team to gather valuable practical knowledge at an early stage of development. The team's awareness of potential obstacles during the early stages of the project enabled them to proactively identify and address these issues prior to implementing the app in dermatological care. We are confident that a patient-centered and participatory approach to health app development can provide valuable insights for developers., (© 2024. The Author(s).)

Telepathology facilitates histological diagnoses through sharing expertise between pathologists. However, the associated costs are high and frequently prohibitive, especially in low-resource settings, where telepathology would paradoxically be of paramount importance due to a paucity of pathologists.We have constructed a telepathology system (TelePi) with a budget of < €120 using the small, single-board computer Raspberry Pi Zero and its High-Quality Camera Module in conjunction with a standard microscope and open-source software. The system requires no maintenance costs or service contracts, has a small footprint, can be moved and shared across several microscopes, and is independent from other computer operating systems. TelePi uses a responsive and high-resolution web-based live stream which allows remote consultation between two or more locations. TelePi can serve as a telepathology system for remote diagnostics of frozen sections. Additionally, it can be used as a standard microscope camera for teaching of medical students and for basic research. The quality of the TelePi system compared favorable to a commercially available telepathology system that exceed its cost by more than 125-fold. Additionally, still images are of publication quality equal to that of a whole slide scanner that costs 800 times more.In summary, TelePi is an affordable, versatile, and inexpensive camera system that potentially enables telepathology in low-resource settings without sacrificing image quality., (© 2023. The Author(s).)

Studying people in real-life situations, such as making music in a vocal group, requires flexible and integrative measurement technology. Therefore, a digital browser-based survey instrument was developed for this study. It was designed to seamlessly introduce questions on participants' mobile devices through external control immediately after relevant events, aiming to achieve high accuracy in self-administered situational questions. In addition, chronological synchronization with supplementary measurements (here eye-tracking and audio recording) was incorporated. Digital features of this web app offer convenient integration into everyday situations, synchronous interviewing of multiple people, and gathering time-based data. Due to the numerous possibilities of the browser-based development interface, various other application areas can be opened up. The contribution of this article is:-App - explanation and offer for use-Feasibility report on the implementation of the app in an eye-tracking study with vocal groups., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: The size of the human cochlear, measured by the diameter of the basal turn, varies between 7 and 11 mm. For hearing rehabilitation with cochlear implants (CI), the size of the cochlear influences the individual frequency map and the choice of electrode length. OTOPLAN® (CAScination AG [Bern, Switzerland] in cooperation with MED-EL [Innsbruck, Austria]) is a software tool with CE marking for clinical applications in CI treatment which allows for precise pre-planning based on cochlear size. This literature review aims to analyze all published data on the application of OTOPLAN®., Materials and Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to identify relevant studies published in the PubMed search engine between January 2015 and February 2023 using the search terms "otoplan" [title/abstract] OR "anatomy-based fitting" [title/abstract] OR "otological software tool" [title/abstract] OR "computed tomography-based software AND cochlear" [title/abstract]., Results: The systematic review of the literature identified 32 studies on clinical use of OTOPLAN® in CI treatment. Most studies were reported from Germany (7 out of 32), followed by Italy (5), Saudi Arabia (4), the USA (4), and Belgium (3); 2 studies each were from Austria and China, and 1 study from France, India, Norway, South Korea, and Switzerland. In the majority of studies (22), OTOPLAN® was used to assess cochlear size, followed by visualizing the electrode position using postoperative images (5), three-dimensional segmentation of temporal bone structures (4), planning the electrode insertion trajectory (3), creating a patient-specific frequency map (3), planning of a safe drilling path through the facial recess (3), and measuring of temporal bone structures (1)., Conclusion: To date, OTOPLAN® is the only DICOM viewer with CE marking in the CI field that can process pre-, intra-, and postoperative images in the abovementioned applications., (© 2024. The Author(s).)

In recent years, a novel treatment method for cancer has emerged, which is based on the starvation of tumors of amino acids like arginine. The deprivation of arginine in serum is based on enzymatic degradation and can be realized by arginine deaminases like the l-amino acid oxidase found in the ink toxin of the sea hare Aplysia punctata . Previously isolated from the ink, the l-amino acid oxidase was described to oxidate the essential amino acids l-lysine and l-arginine to their corresponding deaminated alpha-keto acids. Here, we present the recombinant production and functionalization of the amino acid oxidase Aplysia punctata ink toxin (APIT). PEGylated APIT (APIT-PEG) increased the blood circulation time. APIT-PEG treatment of patient-derived xenografted mice shows a significant dose-dependent reduction of tumor growth over time mediated by amino acid starvation of the tumor. Treatment of mice with APIT-PEG, which led to deprivation of arginine, was well tolerated.

We determined antibiotic susceptibility and employed Oxford Nanopore whole-genome sequencing to explore strain diversity, resistance, and virulence gene carriage among methicillin-resistant Staphylococcus aureus (MRSA) strains from different infection sites and timepoints in a tertiary Kenyan hospital. Ninety-six nonduplicate clinical isolates recovered between 2010 and 2023, identified and tested for antibiotic susceptibility on the VITEK ID/AST platform, were sequenced. Molecular typing, antibiotic resistance, and virulence determinant screening were performed using the relevant bioinformatics tools. The strains, alongside those from previous studies, were stratified into two periods covering 2010-2017 and 2018-2023 and comparisons were made. Mirroring phenotypic profiles, aac(6 ' )-aph(2 ″ ) [aminoglycosides]; gyrA (S84L) and grlA (S80Y) [fluoroquinolones]; dfrG [anti-folates]; and tet(K) [tetracycline] resistance determinants dominated the collection. While the proportion of ST239/241-t037-SCCmec III among MRSA reduced from 37.7% to 0% over the investigated period, ST4803-t1476-SCCmec IV and ST152-t355-SCCmec IV were pre-eminent. The prevalence of Panton-Valentine leucocidin (PVL) and arginine catabolic mobile element (ACME) genes was 38% (33/87) and 6.8% (6/87), respectively. We observed the displacement of HA-MRSA ST239/241-t037-SCCmec III with the emergence of ST152-t355-SCCmec IV and a greater clonal heterogeneity. The occurrence of PVL+/ACME+ CA-MRSA in recent years warrants further investigations into their role in the CA-MRSA virulence landscape, in a setting of high PVL prevalence.

The MYCN oncoprotein binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3'-5' exoribonuclease complex, suggesting a function in RNA metabolism. Here, we show that MYCN forms stable high-molecular-weight complexes with the exosome and multiple RNA-binding proteins. MYCN binds RNA in vitro and in cells via a conserved sequence termed MYCBoxI. In cells, MYCN associates with thousands of intronic transcripts together with the ZCCHC8 subunit of the nuclear exosome targeting complex and enhances their processing. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. On chromatin, MYCN is then replaced by the MNT(MXD6) repressor protein, inhibiting MYCN-dependent transcription. RNA-binding-deficient alleles show that RNA-binding limits MYCN's ability to activate cell growth-related genes but is required for MYCN's ability to promote progression through S phase and enhance the stress resilience of neuroblastoma cells., Competing Interests: Declaration of interests M.E. is a founder of and shareholder of Tucana Biosciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nasal xenobiotic metabolizing enzymes (XMEs) are important for the sense of smell because they influence odorant availability and quality. Since the major part of the human nasal cavity is lined by a respiratory mucosa, we hypothesized that this tissue contributed to nasal odorant metabolism through XME activity. Thus, we built human respiratory tissue models and characterized the XME profiles using single-cell RNA sequencing. We focused on the XMEs dicarbonyl and l-xylulose reductase, aldehyde dehydrogenase (ALDH) 1A1, and ALDH3A1, which play a role in food odorant metabolism. We demonstrated protein abundance and localization in the tissue models and showed the metabolic activity of the corresponding enzyme families by exposing the models to the odorants 3,4-hexandione and benzaldehyde. Using gas chromatography coupled with mass spectrometry, we observed, for example, a significantly higher formation of the corresponding metabolites 4-hydroxy-3-hexanone (39.03 ± 1.5%, p = 0.0022), benzyl alcohol (10.05 ± 0.88%, p = 0.0008), and benzoic acid (8.49 ± 0.57%, p = 0.0004) in odorant-treated tissue models compared to untreated controls (0 ± 0, 0.12 ± 0.12, and 0.18 ± 0.18%, respectively). This is the first study that reveals the XME profile of tissue-engineered human respiratory mucosa models and demonstrates their suitability to study nasal odorant metabolism.

Objectives: Preeclampsia (PE) is a major cause of maternal and fetal mortality, and preterm birth. Previous studies indicate that lipid-apheresis may prolong pregnancy, namely heparin-mediated extracorporeal LDL-precipitation (HELP)- and dextran sulfate cellulose (DSC)-apheresis. We now report on double membrane plasmapheresis (DFPP) in early-onset preeclampsia (eoPE)., Study Design: Open pilot study assessing the prolongation of pregnancy in PE by lipoprotein-apheresis (DRKS00004527). Two women with eoPE were treated by DFPP and compared to a historical cohort of 6 patients with eoPE treated by HELP-apheresis (NCT01967355)., Main Outcome Measures: Clinical outcome of mothers and babies and prolongation of pregnancies (time of admission to birth)., Results: Patient 1 (33y; 22 + 5/7GW) received 4 DFPP. Delivery day 19; birthweight 270 g; weight at discharge 2134 g on day 132. Patient 2 (35y; 21 + 4/7GW) received 2 DFPP. Delivery day 19; birthweight 465 g; weight at discharge 2540 g on day 104. DFPP was well tolerated by both patients., Conclusions: DFPP proved to be save and pregnancies remained stable as long as 19 days. Although babies were born very preterm both babies could finally be dismissed from hospital. No relevant clinical differences between DFPP and HELP-apheresis could be observed. Therefore, DFPP may extend the range of available apheresis techniques to prolong pregnancies in early-onset preeclampsia. However, further studies are necessary to gain more information. REGISTER: (DRKS00004527)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patients with axial spondyloarthritis (axSpA) benefit from regular home-based exercise (HbE). In spite of recommendations, a relevant proportion of German axSpA patients does not adhere to recommended HbE practices. To enhance HbE care, we developed the novel digital therapeutic (DTx) "Axia" compliant with the European medical device regulation (MDR). Axia offers a modern app-based HbE solution with patient educative content and further integrated features., Objective: We aimed to assess Axia's efficacy, attractiveness, and functionality through a survey among axSpA-patients involved in the first user tests., Methods: A mixed-method online questionnaire with 38 items was administered to 37 axSpA volunteers after using Axia. Numeric rating scales (NRS) and likelihood scales were primarily used., Results: HbE frequency significantly increased from a median of 1 day/week to 6 days/week (p < 0.001) by using Axia. Existing HbE practitioners also increased their frequency (median of 4 days/week before, 6 days/week with Axia, p < 0.05). Axia received a median rating of 5 out of 5 stars. On NRS scales, Axia scored a median of 9 for intuitiveness and design, and a median of 8 for entertainment. 64.9% reported improved range of motion, 43.2% reported reduced pain, and 93.6% enhanced disease-specific knowledge. All users recommended Axia to other patients., Conclusion: Axia increases axSpA patients HbE frequency, possibly due to its good intuitiveness and design, leading to reduction in pain and subjective improvement of range of motion. This warrants further investigation in large randomized controlled interventional trials to establish its efficacy conclusively and patients adherence to HbE., (© 2024. The Author(s).)

Introduction: The aim of the study was to investigate the impact of different aminopenicillin administration routes on the antimicrobial effects of platelet-rich fibrin (PRF)., Methods: We enrolled patients undergoing treatment with amoxicillin/clavulanic acid (AMC) orally or ampicillin/sulbactam (SAM) intravenously. AMC was applied in a single oral dose (875/125 mg), or in a double oral dose (1750/250 mg), and SAM in a dose of 2000/1000 mg. Blood was obtained one hour after the intake of AMC or 15 min after the infusion of SAM ended. Antimicrobial effects were investigated in agar diffusion tests with fresh PRF, PRF stored for 24, and PRF stored for 48 h. Agar diffusion tests were performed with Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Porphyromonas gingivalis. Inhibition zones (IZs) around a 6 mm PRF disc were measured after 24 h., Results: IZs for fresh PRF and the single oral dose of AMC were 0.0, 4.7, 15.2, 2.3, and 0.9 mm (E. coli, S. aureus, S. pneumoniae, H. influenzae, and P. gingivalis, respectively). For the double oral dose, these values were 0.0, 11.4, 20.0, 8.1, and 7.4 mm. IZs for SAM were 11.9, 18.2, 24.7, 20.3, and 22.1 mm. Differences between parenteral and oral application as well as between different oral doses were significant (p<0.0001, one-way ANOVA)., Discussion: The results of our study demonstrate that oral administration is a suitable route to load PRF with these drugs. This could expand the scope of PRF application to prevent infections at the surgical site, especially in an outpatient setting in which drugs are normally applied orally., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)