[Interventions for Escalating Crisis Situations in Inpatient Acute Psychiatric Treatment - Results of a Content Analysis of Joint Crisis Plans]. / Interventionen bei sich zuspitzenden Krisensituationen in der stationären akutpsychiatrischen Behandlung ­ Ergebnisse einer inhaltsanalytischen Auswertung von Behandlungsvereinbarungen.

OBJECTIVE: Identification of interventions to prevent coercive measures in the event of escalating crisis situations in an inpatient acute psychiatric treatment context. METHODS: Content analysis of 98 joint crisis plans (JCP) using frequency analysis (secondary data analysis). RESULTS: In over half of the joint crisis plans, withdrawal to a low-stimulation environment (64.3%), a conversation (62.2%), and a walk (57.1%) were agreed upon as intervention for escalating crisis situations. A significant difference (p=0.020) was found in relation to the intake of (on-demand) medication, which was determined exclusively by males. CONCLUSIONS: The results provide potentially helpful suggestions for escalating crisis situations and gender-specific findings with regard to the agreed interventions.

Development and validation of an ultra-performance liquid chromatography with tandem mass spectrometry method for determination of soluble repulsive guidance molecule A in human serum and cerebrospinal fluid.

Aim: Repulsive guidance molecule A (RGMa) is upregulated in neurodegenerative diseases. To assess RGMa levels in human serum and cerebrospinal fluid (CSF), a quantification method was developed and validated according to ICH M10 guideline.Methods & results: Sample preparation consisted of immunoprecipitation (IP, only for serum), digestion and purification followed by MS.Conclusion: An UPLC-MS/MS method was established and used to assess normal range of soluble RGMa levels in serum and CSF of healthy controls, and patients with mild cognitive impairment or Alzheimer's disease. The normal range was between 13.0-44.8 ng/ml (CSF) and 9.9-20.9 ng/ml (serum) in healthy controls. In the CSF of patients with mild cognitive impairment and Alzheimer's disease, total soluble RGMa was twofold lower while unchanged in serum.

[Box: see text].

BNPLA: borated plastic for 3D-printing of thermal and cold neutron shielding.

3D printing technologies such as fused filament fabrication (FFF) offer great opportunities to enable the fabrication of complex geometries without access to a workshop or knowledge of machining. By adding filler materials to the raw filaments used for FFF, the material properties of the plastic can be adapted. With the addition of neutron absorbing particles, filaments can be created that enable 3D printing of neutron shielding with arbitrary geometry. Two materials for FFF are presented with different mixing ratios of hexagonal Boron nitride (h-BN) and Polylactic acid (PLA). BNPLA25 with 25 %wt h-BN and BNPLA35 with 35 %wt h-BN are compared to the commercially available Addbor N25 material. To qualify the applicability of BNPLA25 and BNPLA35 as shielding material for neutron instrumentation, such as neutron imaging, we investigated the overall neutron attenuation, the influence of non-optimized print settings, as well as characterized the incoherent neutron scattering and the microstructure using neutron imaging, and time-of-flight small-angle-neutron-scattering. Finally, the tensile strength of the material was determined in standardized tensile tests. The measured neutron attenuation shows excellent agreement with analytical calculations, thus validating both the material composition and the calculation method. Approximately 6 mm (8 mm) BNPLA35 are needed for 1 × 10 - 3 transmission of a cold (thermal) neutron beam. Lack of extrusion due to suboptimal print settings can be compensated by increased thickness, clearly visible defects can be mitigated by 11-18% increase in thickness. Incoherent scattering is shown to be strongly reduced compared to pure PLA. The tensile strength of the material is shown not to be impacted by the h-BN filler. The good agreement between the measured attenuation and calculation, combined with the adoption of safety factor enables the quick and easy development as well as the performance estimation of shielding components. BNPLA is uniquely suited for 3D printing neutron shielding because of the combination of non-abrasive h-BN particles in standard PLA, which results in a filament that can be printed with almost any off-the-shelf printer and virtually no prior experience in 3D printing. This mitigates the slightly lower attenuation observed as compared to filaments containing B 4 C , which is highly abrasive and requires extensive additive manufacturing experience.

CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis.

Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy. However, a substantial proportion of patients either do not respond or develop resistances. This underscores a need for novel approaches and therapeutic targets as well as a better understanding of the mechanisms of melanoma pathogenesis. Long non-coding RNAs (lncRNAs) comprise a poorly characterized class of functional players and promising targets in promoting malignancy. Certain lncRNAs have been identified to play integral roles in melanoma progression and drug resistances, however systematic screens to uncover novel functional lncRNAs are scarce. Here, we profile differentially expressed lncRNAs in patient derived short-term metastatic cultures and BRAF-MEK-inhibition resistant cells. We conduct a focused growth-related CRISPR-inhibition screen of overexpressed lncRNAs, validate and functionally characterize lncRNA hits with respect to cellular growth, invasive capacities and apoptosis in vitro as well as the transcriptomic impact of our lead candidate the novel lncRNA XLOC_030781. In sum, we extend the current knowledge of ncRNAs and their potential relevance on melanoma. Significance: Previously considered as transcriptional noise, lncRNAs have emerged as novel players in regulating many cellular aspects in health and disease including melanoma. However, the number and as well as the extent of functional significance of most lncRNAs remains elusive. We provide a comprehensive strategy to identify functionally relevant lncRNAs in melanoma by combining expression profiling with CRISPR-inhibition growths screens lowering the experimental effort. We also provide a larger resource of differentially expressed lncRNAs with potential implications in melanoma growth and invasion. Our results broaden the characterized of lncRNAs as potential targets for future therapeutic applications.

Design of a pilot-scale microwave freeze dryer for in situ neutron imaging.

The gentle yet cost-effective drying of sensitive products in the food and pharmaceutical industries is becoming increasingly important. To maintain sensitive ingredients, color, structure, and viability of micro-organisms, often freeze-drying is the only possible way to preserve the product. As many products come in as bulk material, they are dried on heated shelves resulting in poor heat and mass transport through the bed. Resulting in a very time and cost intensive process. Therefore, efforts are being made to improve the mass and heat transport of the process. The outer mass transport through the bulk can be improved by continuous mixing of the pellets, facilitating the removal of water vapor from the condenser. In addition, the issue of limited heat transport can be addressed by using volumetric energy input from microwaves. This process is called dynamic microwave freeze-drying. As dynamic microwave freeze-drying is a combined drying and mixing process, with particle properties continuously changing during drying, it is necessary to gain a more detailed insight into the process. For this purpose, a drier is designed that is capable of in situ neutron imaging, a method sensitive to a material's hydrogen content. This paper presents the design of a pilot-scale microwave freeze dryer for in situ neutron imaging and shows the first images taken during the dynamic microwave freeze-drying of bulk particles at the Center for Energy Research, Budapest Neutron Center in Budapest, Hungary.

A multicentennial mode of North Atlantic climate variability throughout the Last Glacial Maximum.

Paleoclimate proxy records from the North Atlantic region reveal substantially greater multicentennial temperature variability during the Last Glacial Maximum (LGM) compared to the current interglacial. As there was no obvious change in external forcing, causes for the increased variability remain unknown. Exploiting LGM simulations with a comprehensive coupled climate model along with high-resolution proxy records, we introduce an oscillatory mode of multicentennial variability, which is associated with moderate variations in the Atlantic meridional overturning circulation and depends on the large-scale salinity distribution. This self-sustained mode is amplified by sea-ice feedbacks and induces maximum surface temperature variability in the subpolar North Atlantic region. Characterized by a distinct climatic imprint and different dynamics, the multicentennial oscillation has to be distinguished from Dansgaard-Oeschger variability and emerges only under full LGM climate forcing. The potential of multicentennial modes of variability to emerge or disappear in response to changing climate forcing may have implications for future climate change.

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

Polymer-nucleobase composites for chemotherapy drug capture.

Intravenous chemotherapy (e.g., doxorubicin (DOX)) is standard treatment for many cancers but also leads to side effects due to off-target toxicity. To address this challenge, devices for removing off-target chemotherapy agents from the bloodstream have been developed, but the efficacy of such devices relies on the ability of the underlying materials to specifically sequester small-molecule drugs. Anion-exchange materials, genomic DNA, and DNA-functionalized iron oxide particles have all been explored as drug-capture materials, but cost, specificity, batch-to-batch variation, and immunogenicity concerns persist as challenges. Here, we report a new class of fully synthetic drug-capture materials. We copolymerized methacrylic acid and ethylene glycol dimethacrylate in the presence of several nucleobases and derivatives (adenine, cytosine, xanthine, and thymine) to yield a crosslinked resin with nucleobases integrated into the material. These materials demonstrated effective DOX capture: up to 27 mg of DOX per g of material over 20 minutes from a phosphate-buffered saline solution with an initial concentration of 0.05 mg mL-1 of DOX. These materials use only the individual nucleobases for DOX capture and exhibit competitive capture efficacy compared to previous materials that used genomic DNA, making this approach more cost-effective and reducing potential immunological concerns.

Individual perceptions on the relationship between migraine and neck pain.

BACKGROUND: Despite neck pain being a common complaint for people with migraine, little is known about how individuals perceive the relationship between their migraine and neck pain. Exploring their beliefs and perceptions could provide valuable understanding to improve overall management and reduce the burden of migraine and neck pain. OBJECTIVES: To investigate individual perspectives on how migraine and neck pain relate. METHODS: A retrospective qualitative study was performed. Seventy participants (mean age 39.2, 60 female) were recruited via community and social media advertisements, and interviewed by an experienced physiotherapist using a semi-structured interview framework. An Inductive thematic analysis was used to analyse the responses. RESULTS: Five themes were identified from the interviews: (i) the timing of neck pain and migraine, (ii) causality beliefs, (iii) burden of neck pain and migraine, (iv) experiences with treatment and (v) mismatched perspectives. Diverse views emerged, revealing links between the first two themes of timing and causality, showing increased burden in those suffering from both neck pain and migraine, and providing insights into apparently ineffective or even aggravating treatments. CONCLUSIONS: Valuable insights for clinicians emerged. Due to the complex relationship, clinicians should discuss the aetiology of neck pain in migraine with patients. For some individuals, neck treatment may not produce long-term relief and may even aggravate migraine, but the value of short-term relief in a chronic condition must be considered individually. Clinicians are ideally placed to have discussions with patients individually to tailor individual decisions about management.

Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2 S Donor Conjugate with Complexed Fe2.

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2 S donor conjugate, complexed with Fe2+ , termed AAN-PTC-Fe2+ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2 S, an inhibitor of catalase, an enzyme that detoxifies H2 O2 . Fe2+ and H2 S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+ , the AAN sequence, or the ability to generate H2 S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2 S-amplified, enzyme-responsive platform for synergistic cancer treatment.

Characterizing Ion-Polymer Interactions in Aqueous Environment with Electric Fields.

Polymers make the basis of highly tunable materials that could be designed and optimized for metal recovery from aqueous environments. While experimental studies show that this approach has potential, it suffers from a limited knowledge of the detailed molecular interaction between polymers and target metal ions. Here, we propose to calculate intrinsic electric fields from polarizable force field molecular dynamics simulations to characterize the driving force behind Eu3+ motion in the presence of poly(ethylenimine methylenephosphonate), a specifically designed metal chelating polymer. Focusing on the metal chelation initiation step (i.e., before binding), we can rationalize the role of each molecule on ion dynamics by projecting these electric fields along the direction of ion motion. We find that the polymer functional groups act indirectly, and the polymer-metal ion interaction is actually mediated by water. This result is consistent with the experimental observation that metal sequestration by these polymers is entropically driven. This study suggests that electric field calculations can help the design of metal chelating polymers, for example, by seeking to optimize polymer-solvent interactions rather than polymer-ion interactions.

[Long Term Evaluation of the Implementation of the Safewards Model - Results of a Follow-Up-Study Among Patients and Staff in Acute Psychiatric Wards]. / Langzeitevaluation der Implementierung des Safewards-Modells ­ Ergebnisse einer Follow-Up-Erhebung unter Patient*innen und Mitarbeitenden der Akutpsychiatrie.

OBJECTIVE: Evaluation of long-term effects of the implementation of the Safewards Model (SM) among staff and patients in acute psychiatry in Germany. METHOD: Assessment of ward atmosphere, job satisfaction, fidelity, and coercive interventions in 2 locked wards directly before and 15 months after implementation of the SM. RESULTS: Ward atmosphere was assessed significantly better after implementation, job satisfaction was still above-average at both times, coercive interventions declined significantly in one ward, fidelity and degree of implementation were still high. CONCLUSIONS: The implementing of the SM in locked wards in acute psychiatry can also have positive effects in long run.

High-resolution neutron imaging of salt precipitation and water transport in zero-gap CO2 electrolysis.

The electrochemical reduction of CO2 is a pivotal technology for the defossilization of the chemical industry. Although pilot-scale electrolyzers exist, water management and salt precipitation remain a major hurdle to long-term operation. In this work, we present high-resolution neutron imaging (6 µm) of a zero-gap CO2 electrolyzer to uncover water distribution and salt precipitation under application-relevant operating conditions (200 mA cm-2 at a cell voltage of 2.8 V with a Faraday efficiency for CO of 99%). Precipitated salts penetrating the cathode gas diffusion layer can be observed, which are believed to block the CO2 gas transport and are therefore the major cause for the commonly observed decay in Faraday efficiency. Neutron imaging further shows higher salt accumulation under the cathode channel of the flow field compared to the land.

SARS-CoV-2 in dialysis patients and the impact of vaccination.

BACKGROUND: In centre haemodialysis (ICHD) patients have been identified as high risk of contracting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection due to frequent healthcare contact and poor innate and adaptive immunity. Our ICHD patients were offered immunisation from January 2021. We aimed to assess outcomes following SARS-CoV-2 infection and report on the effect of vaccination in our ICHD patients. METHODS: Demographics, SARS-CoV-2 status, hospitalisation, mortality and vaccination status were analysed. From 11th March 2020 to 31st March 2021, 662 ICHD patients were included in the study and these patients were then followed up until 31st August 2021. RESULTS: SARS-CoV-2 infection occurred in 28.4% with 51.1% of them requiring hospitalisation in contrast to community infection rates of 13.9% and hospitalisation of 9.0%. 28-day mortality was 19.2% in comparison to 1.9% of the community. Mortality increased to 34.0% over the study period. Mortality over the study period was 1.8 times in infected patients (HR 1.81 (1.32-2.49) P < 0.001) despite adjustment for age, gender and ethnicity. 91.3% of ICHD patients have now received both doses of SARS-CoV-2 vaccinations. CONCLUSIONS: ICHD patients are at increased risk of acquiring SARS-CoV-2, with increased rates of hospitalisation and mortality. The increased mortality extends well beyond the 28 days post-infection and persists in those who have recovered. Peaks and troughs in infection rates mirrored community trends. Preliminary data indicates that the SARS-CoV-2 vaccination provides protection to ICHD patients, with ICHD case rates now comparable to that of the local population.

Water management in anion-exchange membrane water electrolyzers under dry cathode operation.

Dry cathode operation is a desired operation mode in anion-exchange membrane water electrolyzers to minimize contamination of the generated hydrogen. However, water management under such operation conditions makes it challenging to maintain reliable performance and durability. Here, we utilize high-resolution in situ neutron imaging (∼6 µm effective resolution) to analyze the water content inside the membrane-electrode-assembly of an anion-exchange membrane water electrolyzer. The ion-exchange capacity (IEC) and thus hydrophilicity of the polymer binder in the cathode catalyst layer is varied to study the influence on water content in the anode (mid IEC, 1.8-2.2 meq. g-1 and high IEC, 2.3-2.6 meq. g-1). The neutron radiographies show that a higher ion-exchange capacity binder allows improved water retention, which reduces the drying-out of the cathode at high current densities. Electrochemical measurements confirm a generally better efficiency for a high IEC cell above 600 mA cm-2. At 1.5 A cm-2 the high IEC has a 100 mV lower overpotential (2.1 V vs. 2.2 V) and a lower high frequency resistance (210 mΩ cm-2 vs. 255 mΩ cm-2), which is believed to be linked to the improved cathode water retention and membrane humidification. As a consequence, the performance stability of the high IEC cell at 1 A cm-2 is also significantly better than that of the mid IEC cell (45 mV h-1 vs. 75 mV h-1).

An immuno-enrichment free, validated quantification of tau protein in human CSF by LC-MS/MS.

Tau protein is a key target of interest in developing therapeutics for neurodegenerative diseases. Here, we sought to develop a method that quantifies extracellular tau protein concentrations in human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. We demonstrate that the fit-for-purpose validated method in Alzheimer's Disease CSF is limited to quasi quantitative measures of tau surrogate peptides. We also provide evidence that CSF total Tau measures by LC-MS are feasible in the presence of monoclonal therapeutic antibodies in human CSF. Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target engagement and pharmacodynamics for anti-tau antibody drug development campaigns.

Needle clogging of protein solutions in prefilled syringes: A two-stage process with various determinants.

Clogging of staked-in-needle prefilled syringes (PFS) is a sporadic and scarcely predictable event, which occurs particularly in highly concentrated protein solutions and can result in the injection of incomplete doses, especially if autoinjector devices are used for administration. A systematic screening of possible causes and triggers was performed in order to find the crucial factors of influence, the underlying mechanisms and possible measures for prevention. An essential prerequisite for the formation of a solidified clog in the needle is the ingress of liquid from the barrel, which was investigated and quantified by means of neutron imaging after storage of prefilled syringes under various conditions. The needle filling ratio increases with both the storage temperature and the storage period, as a result of atmospheric gas diffusion through the needle shield. While the air pocket in the needle is reduced by this process, diffusion of water vapor does not affect the filling ratio but instead increases the protein concentration in the needle lumen, leading to an exponential rise of the viscosity and finally to the solidification of the protein solution. Maintaining the air pocket in the needle by avoiding any diffusion promoting pressure gradient is therefore the most effective protection from clogging.

Exploring the role of polymer hydrophobicity in polymer-metal binding thermodynamics.

Metal-chelating polymers play a key role in rare-earth element (REE) extraction and separation processes. Often, these processes occur in aqueous solution, but the interactions among water, polymer, and REE are largely under-investigated in these applications. To probe these interactions, we synthesized a series of poly(amino acid acrylamide)s with systematically varied hydrophobicity around a consistent chelating group (carboxylate). We then measured the ΔH of Eu3+ chelation as a function of temperature across the polymer series using isothermal titration calorimetry (ITC) to give the change in heat capacity (ΔCP). We observed an order of magnitude variation in ΔCP (39-471 J mol1 K-1) with changes in the hydrophobicity of the polymer. Atomistic simulations of the polymer-metal-water interactions revealed greater Eu3+ and polymer desolvation when binding to the more hydrophobic polymers. These combined experimental and computational results demonstrate that metal binding in aqueous solution can be modulated not only by directly modifying the chelating groups, but also by altering the molecular environment around the chelating site, thus suggesting a new design principle for developing increasingly effective metal-chelating materials.

[DGPPN pilot study on the implementation of the S3 guideline "Prevention of coercion: prevention and therapy of aggressive behavior in adults"]. / DGPPN-Pilotstudie zur Implementierung der S3-Leitlinie "Verhinderung von Zwang: Prävention und Therapie aggressiven Verhaltens bei Erwachsenen".

OBJECTIVE: To investigate whether implementation recommendations derived from the German guidelines "Prevention of coercion" can be implemented on acute psychiatric wards by means of implementation consultants into ward work and if this contributes to an increased level of adherence to guideline intervention recommendations approved by the DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde)? MATERIAL AND METHODS: Two medical or nursing experts advised ward teams on the implementation of three individually selected recommendations from the guidelines in a structured consulting process over 6 months. The degree of implementation of the recommendations was assessed before and after the intervention by the ward teams together with the implementation consultants using a tool developed for this purpose (PreVCo rating tool). RESULTS: A total of five wards responsible for compulsorily admitted patients took part in the pilot study; three of them completed the intervention. On all three wards, implementation of the guideline recommendations improved for both selected and unselected recommendations. The strategy of using implementation consultants as well as the application of the PreVCo rating tool were well accepted and considered feasible by both the treatment teams and the implementation consultants. CONCLUSION: This pilot study showed that an implementation of recommendations on psychiatric wards derived from the German guidelines "Prevention of coercion" supported by implementation consultants is feasible, well acceptable among treatment teams and can lead to positive changes. The sample of five wards with diverse patient profiles was convincing. The efficacy in terms of reduction of coercive measures is currently being investigated in a randomized controlled trial on 55 psychiatric wards in different parts of Germany, with an intervention based on this pilot study.