Only repeatedly elevated IgG4 levels in primary sclerosing cholangitis may distinguish a particular patient phenotype.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic liver disease leading to inflammation with scaring and strictures of bile ducts, which can lead to liver cirrhosis. A subtype of PSC characterized by high serum IgG4 (sIgG4) levels has been reported to be associated with poor outcomes, but the exact role and the longitudinal development of sIgG4 levels in PSC progression remains to be clarified. The aim of this study was to investigate if subsequent analysis of sIgG4 levels allows the identification of the PSC phenotype with high sIgG4. METHODS: sIgG4 values were repeatedly analysed in a well-characterized European PSC cohort of 110 individuals. Biochemical parameters, clinical endpoints, death and liver transplantation were compared between PSC subgroups. RESULTS: 12.7% (n = 14) of PSC patients showed increased sIgG4 levels (PSC-IgG4). The values normalized in 57.1% (n = 8; PSC-IgG4norm) during follow-up measurements, whereas the values remained permanently elevated in 42.9% (n = 6; PSC-IgG4const). Serum values of AP and γGT were significantly higher in PSC-IgG4const compared to PSC-IgG4norm at final blood sampling. Furthermore, mean age at PSC diagnosis was markedly lower in PSC-IgG4const compared to PSC-IgG4norm. CONCLUSIONS: This is the first study analyzing longitudinal development of sIgG4 in PSC. Our data indicate that only sequential determination of sIgG4 levels allow to accurately distinguish between the PSC phenotype with high sIgG4 and PSC with low sIgG4.

Guest Editorial - Shifting Dynamics: ICU Admissions in Denmark during the First Wave of the COVID-19 Pandemic.

The advent of the SARS-CoV-2 pandemic brought unprecedented challenges to healthcare systems worldwide. As the virus spread across continents, hospitals faced a surge in patient admissions, particularly to intensive care units (ICUs). Understanding the impact of the pandemic on the sickest patients admitted to hospital is crucial for enhancing preparedness for future outbreaks. In this edition of the journal, authors from Denmark report on a register-based national observational study that sheds light on the changes in ICU admission rates and demographic profiles of patients during the initial phase of the pandemic.

Video Versus Nonvideo in a Rabbit Training Model for Establishing an Emergency Front of Neck Airway in Children: A Prospective Trial.

OBJECTIVES: Simulating a realistic "cannot intubate, cannot oxygenate" (CICO) situation to train an "emergency front of neck airway" is difficult. It further remains unclear if provision of regular technical refreshers improves performance in the setting of a real CICO situation. The purpose of this prospective study on an established surgical rabbit cadaver tracheostomy model was to evaluate the benefit of viewing training material shortly before performing "emergency front of neck airway." METHODS: Previously trained participants were randomized into 2 groups. The control group (video) was allowed to watch an instructional video before performing a tracheotomy on the training model, while the study group (nonvideo) was not. Queried outcomes included success rate, performance time, and severe secondary airway injuries between the 2 groups. RESULTS: In 29 tracheotomies performed by 29 participants, the overall success rate was 86% (92% video; 81% nonvideo, P = 0.4). Performance time was not different between the 2 groups (video: 80 s [IQR25-75: 53-86], nonvideo 64 s [IQR25-75: 47-102]; P = 0.93). Only in the nonvideo group, the performance time and the time between the workshops correlated positively (P = 0.048). Severe secondary injuries were noted in 4 of 29 rabbit cadavers, 2 in each group. Watching a refresher video before performing an emergency surgical tracheostomy in an infant training model did not influence the success rate and the performance time in previously trained anesthetists. CONCLUSIONS: These results highlight the ease of learning, memorization, and recall of this emergency surgical tracheostomy technique and may demonstrate its applicability in a real infant CICO situation.

Carbon ion beam dosimetry in magnetic fields using Farmer-type ionization chambers of different radii: measurements and simulations.

OBJECTIVE: To investigate magnetic field effects on the dose distribution and ionization chambers response in carbon ion reference fields and determine magnetic field correction factors for chambers of different volumes. Approach: The response of six Farmer-type chambers with varying radii (1 to 6 mm, termed as R1 to R6) was measured in magnetic fields up to 1 T in 0.1 T increments using an experimental electromagnet and compared with Monte Carlo simulations. Chamber readings were measured in the entrance region of a monoenergetic carbon ion beam of 390.75 MeV/u. A lower energy of 200.28 MeV/u was applied to chamber R3 for comparison. Polarity and recombination corrections were investigated for the R3 chamber. The local dose change induced by the magnetic field was calculated by Monte Carlo, which together with change of the chamber's response, was used to calculate the final magnetic field correction factors. Main results: The dependence of the chamber response on the magnetic field was non-linear and volume-dependent. Maximum changes ranged from 0.30% (R4) to 0.62% (R5) at 0.2 T. For R3, the response for the lower energy was systematically decreased by 0.2% in the range of 0.2 T to 0.7 T. No significant effect of the magnetic field on polarity and ion recombination correction was found. The maximum variation of the local dose was found to be (0.03±0.08)% at 0.2 T for beam energy of 390.75 MeV/u. Magnetic field correction factors for the different chambers ranged from 0.28% (R4) to 0.60% (R5). Significance: This study provides the first detailed analysis of chambers' response to magnetic flux densities of up to 1 T using chambers of different radii and comparison with simulations. By combining the chamber response alterations with local dose changes magnetic field correction factors were calculated for all six chambers, including the commercial Farmer-type chamber.

Human Neutrophil Elastase: Characterization of Intra- vs. Extracellular Inhibition.

Neutrophil elastase (HNE), like other members of the so-called GASPIDs (Granule-Associated Serine Peptidases of Immune Defense), is activated during protein biosynthesis in myeloid precursors and stored enzymatically active in cytoplasmic granules of resting neutrophils until secreted at sites of host defense and inflammation. Inhibitors thus could bind to the fully formed active site of the protease intracellularly in immature progenitors, in circulating neutrophils, or to HNE secreted into the extracellular space. Here, we have compared the ability of a panel of diverse inhibitors to inhibit HNE in the U937 progenitor cell line, in human blood-derived neutrophils, and in solution. Most synthetic inhibitors and, surprisingly, even a small naturally occurring proteinaceous inhibitor inhibit HNE intracellularly, but the extent and dynamics differ markedly from classical enzyme kinetics describing extracellular inhibition. Intracellular inhibition of HNE potentially affects neutrophil functions and has side effects, but it avoids competition of inhibitors with extracellular substrates that limit its efficacy. As both intra- and extracellular inhibition have advantages and disadvantages, the quantification of intracellular inhibition, in addition to classical enzyme kinetics, will aid the design of novel, clinically applicable HNE inhibitors with targeted sites of action.

Voices of Wisdom: Geriatric Interviews on Self-Management of Type 2 Diabetes in the United States-A Systematic Review and Metasynthesis.

This review is aimed at unraveling the intricacies of diabetic self-management among geriatric people, drawing on current insights and understanding the complex paths geriatric people navigate. A wide search was conducted in health-oriented databases, including CINAHL, Embase, PsycINFO, MEDLINE, PubMed, Web of Science, and Cochrane Library, while gray literature was excluded. The search combined keywords and subject headings, focusing on the geriatric population, diabetes, self-management, and qualitative research. A three-tiered screening process was employed, with titles and then abstracts initially reviewed. Full-text analysis followed, with disagreements resolved among reviewers. In total, there were 248 participants included across these eight studies. Positive attitudes and perceptions were found to play a significant role in optimizing diabetes self-care outcomes. Support from family and friends was identified as crucial for self-care, while healthcare professionals often lacked adequate support and encouragement. Participants emphasized the importance of listening to their bodies and acknowledging hidden issues. These themes collectively highlight the multifaceted aspects of diabetes self-care and the impact of various factors on the self-management experiences of geriatric individuals with diabetes. The goal of this review is not to objectify self-management as a treatment strategy but to emphasize the importance of cultivating positive attitudes, respecting individual values, and addressing cultural and ethnic differences in healthcare practices to enhance self-management in this population. By embracing cultural diversity, understanding barriers, and respecting individual values, healthcare professionals and policymakers can improve the quality of life for the geriatric population living with diabetes.

Intracavitary Applications for CEUS in PTCD.

Intracavitary contrast-enhanced ultrasound is widely accepted as a highly informative, safe, and easily reproducible technique for the diagnosis, treatment, and follow-up of different pathologies of the biliary tree. This review article describes the diverse applications for CEUS in intracavitary biliary scenarios, supported by a literature review of the utilization of the method in indications like biliary obstruction by various etiologies, including postoperative strictures, evaluation of the biliary tree of liver donors, and evaluation of the localization of a drainage catheter. We also provide pictorial examples of the authors' personal experience with the use of intracavitary CEUS in cases of PTCD as a palliative intervention. Intracavitary CEUS brings all the positive features of US together with the virtues of contrast-enhanced imaging, providing comparable accuracy to the standard techniques for diagnosing biliary tree diseases.

Study Protocol of a Randomized, Two-Arm, Phase I/II Trial Investigating the Feasibility, Safety, and Efficacy of Local Treatment with US-Guided High-Intensity Focused Ultrasound in Combination with Palliative Chemotherapy in Inoperable Pancreatic Cancer.

BACKGROUND: Pancreatic adenocarcinoma (PaC) still has a dismal prognosis, and despite medical advances, a bleak 5-year survival rate of only 8%, largely due to late diagnosis and limited curative surgical options for most patients. Frontline palliative treatment shows some survival advantages. However, the high disease mortality is accompanied by high morbidity including cancer-related pain and additional symptoms, which strongly impair patients' quality of life (QOL). At present, there is no established strategy for local therapy for PaC primarily aiming to manage local tumor growth and alleviate associated symptoms, particularly pain. In recent years, non-invasive high-intensity focused ultrasound (HIFU) has shown promising results in reducing cancer pain and tumor mass, improving patients' QOL with few side effects. STUDY DESIGN: This is the first randomized controlled trial worldwide including 40 patients with inoperable pancreatic adenocarcinoma randomized into two groups: group A undergoing standard chemotherapy; and group B undergoing standard chemotherapy plus local HIFU treatment. This study aims to establish a robust evidence base by examining the feasibility, safety, and efficacy of US-guided HIFU in combination with standard palliative systemic therapy for unresectable PaC. Primary endpoint assessments will focus on parameters including safety issues (phase I), and local response rates (phase II).

Correlative single-molecule and structured illumination microscopy of fast dynamics at the plasma membrane.

Total internal reflection fluorescence (TIRF) microscopy offers powerful means to uncover the functional organization of proteins in the plasma membrane with very high spatial and temporal resolution. Traditional TIRF illumination, however, shows a Gaussian intensity profile, which is typically deteriorated by overlaying interference fringes hampering precise quantification of intensities-an important requisite for quantitative analyses in single-molecule localization microscopy (SMLM). Here, we combine flat-field illumination by using a standard πShaper with multi-angular TIR illumination by incorporating a spatial light modulator compatible with fast super-resolution structured illumination microscopy (SIM). This distinct combination enables quantitative multi-color SMLM with a highly homogenous illumination. By using a dual camera setup with optimized image splitting optics, we achieve a versatile combination of SMLM and SIM with up to three channels. We deploy this setup for establishing robust detection of receptor stoichiometries based on single-molecule intensity analysis and single-molecule Förster resonance energy transfer (smFRET). Homogeneous illumination furthermore enables long-term tracking and localization microscopy (TALM) of cell surface receptors identifying spatial heterogeneity of mobility and accessibility in the plasma membrane. By combination of TALM and SIM, spatially and molecularly heterogenous diffusion properties can be correlated with nanoscale cytoskeletal organization and dynamics.

[Kratom-From natural remedy to addictive drug and back]. / Kratom ­ vom natürlichen Heilmittel zur Suchtdroge und zurück.

BACKGROUND: Kratom/ketum is a psychoactive herbal preparation that has been used for a long time as a remedy and performance-enhancing substance in Southeast Asia. The advancement of globalization is making kratom increasingly more available in the western world, where it is becoming increasingly more used. OBJECTIVE: The current research on kratom and its ingredients is presented. MATERIAL AND METHODS: An overview of the use and effects of kratom is exemplary given on the basis of reports. The instrumentalization of the drug and its consequences up to the development of addiction are discussed. RESULTS: Consumption is accompanied by several instrumentalizeable effects so that kratom is used as a therapeutic substance in the self-management of pain, anxiety and depression as well as other substance addictions. Another benefit comes from the performance-enhancing effects on physical work and in a social context. Consumption is usually well controlled, rarely escalates and has few and mostly mild aversive side effects. The danger arises from consumption particularly when there is an escalation of the dose and from mixed consumption with other psychoactive substances. The main alkaloid mitragynine and the more potent 7­hydroxy-mitragynine are considered mainly responsible for the effect. Both have a complex pharmacology that involves partial µ­opioid receptor agonism. DISCUSSION: Epidemiological, clinical and neurochemical studies have shown that kratom only has a limited addictive drug profile, which might suggest a medical use as a remedy or substitute in addiction treatment.

Primary sclerosing cholangitis with IgG4-positive plasma cells in bile duct biopsies - Frequency and characterization.

OBJECTIVES: Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis. METHODS: Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations. RESULTS: Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients. CONCLUSIONS: IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype.

Imaging of Chromophobe Renal Cell Carcinoma with 99mTc-Sestamibi SPECT/CT: Considerations Regarding Risk Stratification and Histologic Reclassification.

PURPOSE: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. 99mTc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify oncocytomas and oncocytic renal neoplasms, including a subset of chromophobe renal cell carcinomas (chRCCs), which are viewed as false-positive. PROCEDURE: Patients imaged with renal sestamibi scans between 2014 and 2023 were reviewed. Those patients with solitary tumors that were originally classified as chRCC were included in the analysis. Imaging with SPECT/CT from the liver dome down had been carried out 75 min after the administration of 925 MBq of 99mTc-sestamibi. All available H&E and immunostained slides were re-reviewed and classified according to WHO 2022 criteria. Confirmatory immunohistochemical stains were performed in tumors considered morphologically suspicious for non-chRCC entities. RESULT: A total of 18 patients with solitary tumors were included in the final analysis. 13/18 (72.2%) tumors in this cohort remained classified as chRCC, with 4/18 (22.2%) being eosinophilic-variant chRCC. The reclassified tumors (5/18 [27.8%]) included 2/18 (11.1%) low-grade oncocytic tumor (LOT), 1/18 (5.5%) eosinophilic vacuolated tumor (EVT), and 2/18 (11.1%) unclassified low-grade oncocytic neoplasms. As such, only 2/9 (22.2%) qualitatively "hot" tumors were chRCC other than eosinophilic-variant and only 1/9 (11.1%) "cold" tumors was a histology other than chRCC. CONCLUSION: Based on current histopathologic classification methods, it is likely that the "false-positive" rate of uptake on renal sestamibi scans with chRCC has been over-stated. Further study is warranted to better refine the optimal utility of renal sestamibi scans for non-invasive risk stratification of indeterminate renal masses.

A Characterization of the Cardiac Physiology and Aortic Pulse Wave Properties of Artistic Swimmers Across Competitive Levels.

PURPOSE: The distinct physical and environmental stressors of artistic swimming (previously termed synchronized swimming) result in unique hemodynamic stimuli. Given that the hemodynamic stress associated with participation in an exercise modality drives adaptation of the heart and central vasculature, artistic swimming may produce a distinct cardiovascular phenotype. Presumably, athletes competing at the highest levels also have greater training exposure and, thus, exhibit more adaptation. The purpose of this study was to characterize cardiovascular form and function across the competitive spectrum of artistic swimmers. METHODS: Cardiovascular structure and function were compared in a cross-sectional study of healthy controls, varsity, and elite artistic swimmers, using pulse wave analysis, pulse wave velocity, and echocardiographic images both at rest and during isometric handgrip exercise. RESULTS: Aortic stiffness was similar across all groups, as were characteristics of the decomposed aortic pressure waveform. At rest, both varsity and elite swimmers demonstrated similar systolic function compared to controls. However, peak left ventricular twist was greater in varsity and elites (controls: 8.0 ± 3.9, varsity: 12.8 ± 8.6, elites: 13.4 ± 3.9; both p < 0.02). Furthermore, elites demonstrated greater peak left ventricular radial strain (controls: 29.2 ± 9.9, varsity: 32.5 ± 10.3, elites: 53.9 ± 15.1; both p < 0.001) and longitudinal strain (controls: -16.9 ± 1.6, varsity: -16.5 ± 1.8, elites: -19.5 ± 3.2; both p < 0.04). In contrast to controls, both varsity and elite artistic swimmers demonstrated no change in peak late diastolic transmitral filling velocity (controls: Δ0.2 ± 0.04 m/s, varsity: Δ0.06 ± 0.04 m/s, elites: Δ0.05 ± 0.04 m/s) during isometric handgrip exercise (both p > 0.05), with elites demonstrating lower peak velocity than varsity swimmers, (p = 0.048) indicating preservation of diastolic function. CONCLUSIONS: Artistic swimmers demonstrate distinct cardiac physiology at rest and during isometric handgrip, with a greater extent of distinguishing features observed in those competing at the highest level of competition.

Neonatal Sepsis Episodes and Retinopathy of Prematurity in Very Preterm Infants.

Importance: Retinopathy of prematurity (ROP) is a major morbidity of preterm infants causing visual impairment, including blindness, for which timely treatment is vital and prevention is key. Increasing evidence suggests that exposure to neonatal sepsis contributes to ROP development. Objective: To investigate the association between neonatal sepsis and ROP in 2 large-scale cohorts of preterm infants born at less than 29 weeks' gestation. Design, Setting, and Participants: This retrospective cohort study was conducted using data from the German Neonatal Network (GNN) and Norwegian Neonatal Network (NNN). The GNN involves 68 and the NNN includes 21 level III neonatal intensive care units. Participants were infants born at a gestation of 22 weeks and 0 days to 28 weeks and 6 days and enrolled in the GNN between January 1, 2009, and December 31, 2022, and NNN between January 1, 2009, and December 31, 2018. Data were analyzed from February through September 2023. Exposure: Single or multiple episodes of culture-proven sepsis. Main Outcomes and Measures: Any ROP and treatment-warranted ROP. Results: Among 12 794 infants in the GNN (6043 female [47.2%] and 6751 male [52.8%]; mean [SD] gestational age, 26.4 [1.5] weeks) and 1844 infants in the NNN (866 female [47.0%] and 978 male [53.0%]; mean [SD] gestational age, 25.6 [1.5] weeks), the mean (SD) birth weight was 848 (229) g and 807 (215) g, respectively. Any ROP was present in 6370 infants (49.8%) in GNN and 620 infants (33.6%) in NNN, and treatment-warranted ROP was present in 840 infants (6.6%) in GNN and 140 infants (7.6%) in NNN. In both cohorts, there were increasing rates of treatment-warranted ROP with each sepsis episode (no sepsis: 572 of 10 658 infants [5.4%] in GNN and 85 of 1492 infants (5.7%) in NNN; 1 episode: 190 of 1738 infants in GNN [10.9%] and 29 of 293 infants [9.9%] in NNN; 2 episodes: 53 of 314 infants in GNN [16.9%] and 13 of 49 infants [26.5%] in NNN; 3 episodes: 25 of 84 infants [29.8%] in GNN and 3 of 10 infants [30.0%] in NNN). After adjusting for multiple confounders in the GNN dataset, the number of sepsis episodes was associated with ROP and treatment-warranted ROP compared with 0 episodes (1 episode: adjusted odds ratio [aOR], 1.44 [95% CI, 1.27-1.63]; P < .001 and OR, 1.60 [95% CI, 1.31-1.96]; P < .001, respectively; 2 episodes: OR, 1.81 [95% CI, 1.35-2.42]; P < .001 and OR, 2.38 [95% CI, 1.68-3.37]; P < .001, respectively; 3 episodes: OR, 4.39 [95% CI, 2.19-8.78]; P < .001 and OR, 3.88 [95% CI, 2.29-6.55]; P < .001, respectively). These associations were confirmed for any ROP by propensity score matching (for example, the aOR with propensity score matching was 1.76 [95% CI, 1.54-2.02]; P < .001 for 1 episode vs 0 episodes and 1.58 [95% CI, 1.12-2.22]; P = .007 for 3 episodes vs 0 or 1 episode). In the NNN dataset, surgical NEC was associated with treatment-warranted ROP (multivariable analysis: aOR, 3.37 [95% CI, 1.78-6.37]; P < .001). Conclusions and Relevance: This study found that in the large-scale GNN cohort, recurrent culture-proven sepsis was associated with ROP and treatment-warranted ROP in infants born at less than 29 weeks.

Implications of MHC-restricted immunopeptidome in transplantation.

The peptide presentation by donor and recipient major histocompatibility complex (MHC) molecules is the major driver of T-cell responses in transplantation. In this review, we address an emerging area of interest, the application of immunopeptidome in transplantation, and describe the potential opportunities that exist to use peptides for targeting alloreactive T cells. The immunopeptidome, the set of peptides presented on an individual's MHC, plays a key role in immune surveillance. In transplantation, the immunopeptidome is heavily influenced by MHC-derived peptides, delineating a key subset of the diverse peptide repertoire implicated in alloreactivity. A better understanding of the immunopeptidome in transplantation has the potential to open up new approaches to identify, characterize, longitudinally quantify, and therapeutically target donor-specific T cells and ultimately support more personalized immunotherapies to prevent rejection and promote allograft tolerance.

Combining poly-epitope MoonTags and labeled nanobodies for signal amplification in cell-specific PET imaging in vivo.

Immunorecognition provides an excellent basis for targeted imaging techniques covering a wide range from basic research to diagnostics and from single cells to whole organisms. Fluorescence- or radioisotope-labeled antibodies, antibody fragments or nanobodies enable a direct signal readout upon binding and allow for versatile imaging from microscopy to whole-body imaging. However, as the signal intensity directly correlates with the number of labeled antibodies bound to their epitopes (1:1 binding), sensitivity for low-expressing epitopes can be limiting for visualization. For the first time, we developed poly-epitope tags with multiple copies (1 to 7) of a short peptide epitope, specifically the MoonTag, that are recognized by a labeled nanobody and aimed at signal amplification in microscopy and cell-specific PET imaging. In transiently transfected HeLa cells or stably transduced A4573 cells we characterized complex formation and in vitro signal amplification. Indeed, using fluorescently and radioactively labeled nanobodies we found an approximately linear signal amplification with increasing numbers of epitope copies in vitro. To test the poly-epitope approach in vivo, A4573 tumor cells were injected subcutaneously into the shoulder of NSG mice, with A4573 tumor cells expressing a poly-epitope of 7 MoonTags on one side and WT cells on the other side. Using a [68Ga]-labeled NODAGA-conjugated MoonTag nanobody, we performed PET/CT imaging at day 8-9 after tumor implantation. Specific binding of a [68Ga]-labeled NODAGA-conjugated MoonTag nanobody was observed in 7xMoonTag tumors (1.7 ± 0.5%ID/mL) by PET imaging, showing significantly higher radiotracer accumulation compared to the WT tumors (1.1 ± 0.3%ID/mL; p < 0.01). Ex vivo gamma counter measurements confirmed significantly higher uptake in 7xMoonTag tumors compared to WT tumors (p < 0.001). In addition, MoonTag nanobody binding was detected by autoradiography which was spatially matched with histological analysis of the tumor tissues. In conclusion, we expect nanobody-based poly-epitope tag strategies to be widely applicable for multimodal imaging techniques given the advantageous properties of nanobodies and their amenability to genetic and chemical engineering.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

MAGEL2 (patho-)physiology and Schaaf-Yang syndrome.

Schaaf-Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader-Willi syndrome (PWS) locus on chromosome 15. In this review, we consolidate decades of research on MAGEL2 to elucidate its physiological functions. Moreover, we synthesize current knowledge on SYS, suggesting that while MAGEL2 loss-of-function seems to underlie several SYS and PWS phenotypes, additional pathomechanisms probably contribute to the distinct and severe phenotype observed in SYS. In addition, we highlight recent therapeutic advances and identify promising avenues for future investigation.