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PurposeThe melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection.MethodsHearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia hearts were perfused with ramelteon (Ram) with or without the MT2 receptor inhibitor 4-phenyl-2-propionamidotetralin (4P-PDOT+Ram, 4P-PDOT). In subsequent experiments, ramelteon was administered together with the radical oxygen species (ROS) scavenger N-2-mercaptopropionylglycine (MPG+Ram). To determine whether the blockade of ramelteon-induced cardioprotection can be restored, we combined ramelteon and MPG with mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA) at different time points. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining.ResultsRamelteon-induced infarct size reduction was completely blocked by 4P-PDOT and MPG. Ramelteon and MPG combined with CsA before ischemia were not cardioprotective but CsA at the onset of reperfusion could restore infarct size reduction.ConclusionsThis study shows for the first time that despite the higher affinity to MT1 receptors, (1) ramelteon-induced cardioprotection involves MT2 receptors, (2) cardioprotection requires ROS release, and (3) inhibition of the mPTP can restore infarct size reduction.

MassIVE.quant is a repository infrastructure and data resource for reproducible quantitative mass spectrometry–based proteomics, which is compatible with all mass spectrometry data acquisition types and computational analysis tools. A branch structure enables MassIVE.quant to systematically store raw experimental data, metadata of the experimental design, scripts of the quantitative analysis workflow, intermediate input and output files, as well as alternative reanalyses of the same dataset. MassIVE.quant is a data repository and data resource for reproducible quantitative mass spectrometry–based proteomics.

Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice. To evaluate the current diagnostic practice for managing the suspicion of HIT. This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT. Suspicion of HIT. The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests. Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively. In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

ObjectivesOral and maxillofacial surgery (OMFS) has undergone pioneering progress through the development of three-dimensional (3D) printing technologies. The aim of this study was to evaluate the use of 3D printing at OMFS university and non-university hospitals and private practices in Germany.Materials and methodsFor explorative assessment, a dynamic online questionnaire containing 10–22 questions about the current use of 3D printing and the reasons behind it was sent to OMFS university and non-university hospitals and private practices in Germany by the study group from the German Association of Oral and Maxillofacial Surgery (DGMKG).ResultsIn total, 156 participants responded from university (23 [14.7%]) and non-university hospitals (19 [12.2%]) and private practices without (85 [50.5%]) and with 29 (18.6%) inpatient treatment facility. Highest applications of 3D printing were in implantology (57%), microvascular bone reconstructions (25.6%), and orthognathics (21.1%). Among the participants, 37.8% reportedly were not using 3D printing. Among the hospitals and private practices, 21.1% had their own 3D printer, and 2.5% shared it with other departments. The major reason for not having a 3D printer was poor cost efficiency (37.6%). Possessing a 3D printer was motivated by independence from external providers (91.3%) and rapid template production (82.6%). The preferred printing methods were stereolithography (69.4 %) and filament printing (44.4%).ConclusionsOMFS 3D printing is established in Germany with a wide range of applications.Clinical relevanceThe prevalence of 3D printing in hospitals and private practices is moderate. This may be enhanced by future innovations including improved cost efficiency.

Hybrid joints consisting of metals and fiber-reinforced polymer composites exhibit highly desirable properties for many lightweight design applications. This study investigates the potential of additively manufactured surface structures for enhancing the bond strength of such joints in comparison to face milled and laser structured surfaces. Titanium samples with different surface structures (as-built surface, groove-, and pin-shaped structures) were manufactured via electron beam melting and joined to carbon fiber-reinforced polyether-ether-ketone (PEEK) via adhesive bonding and thermal direct joining, respectively. Bond strength was evaluated by tensile shear testing. Samples were exposed to salt spray testing for 1000 h for studying bond stability under harsh environmental conditions. The initial tensile shear strengths of the additively manufactured samples were competitive to or in some cases even exceeded the values achieved with laser surface structuring for both investigated joining methods. The most promising results were found for pin-shaped surface structures. However, the hybrid joints with additively manufactured structures tended to be more susceptible to degradation during salt spray exposure. It is concluded that additively manufactured structures can be a viable alternative to laser surface structuring for both adhesive bonding and thermal direct joining of metal-polymer hybrid joints, thus opening up new potentials in lightweight design.

Background Clinical samples are irreplaceable, and their transformation into searchable and reusable digital biobanks is critical for conducting statistically empowered retrospective and integrative research studies. Currently, mainly data-independent acquisition strategies are employed to digitize clinical sample cohorts comprehensively. However, the sensitivity of DIA is limited, which is why selected marker candidates are often additionally measured targeted by parallel reaction monitoring. Methods Here, we applied the recently co-developed hybrid-PRM/DIA technology as a new intelligent data acquisition strategy that allows for the comprehensive digitization of rare clinical samples at the proteotype level. Hybrid-PRM/DIA enables enhanced measurement sensitivity for a specific set of analytes of current clinical interest by the intelligent triggering of multiplexed parallel reaction monitoring (MSxPRM) in combination with the discovery-driven digitization of the clinical biospecimen using DIA. Heavy-labeled reference peptides were utilized as triggers for MSxPRM and monitoring of endogenous peptides. Results We first evaluated hybrid-PRM/DIA in a clinical context on a pool of 185 selected proteotypic peptides for tumor-associated antigens derived from 64 annotated human protein groups. We demonstrated improved reproducibility and sensitivity for the detection of endogenous peptides, even at lower concentrations near the detection limit. Up to 179 MSxPRM scans were shown not to affect the overall DIA performance. Next, we applied hybrid-PRM/DIA for the integrated digitization of biobanked melanoma samples using a set of 30 AQUA peptides against 28 biomarker candidates with relevance in molecular tumor board evaluations of melanoma patients. Within the DIA-detected approximately 6500 protein groups, the selected marker candidates such as UFO, CDK4, NF1, and PMEL could be monitored consistently and quantitatively using MSxPRM scans, providing additional confidence for supporting future clinical decision-making. Conclusions Combining PRM and DIA measurements provides a new strategy for the sensitive and reproducible detection of protein markers from patients currently being discussed in molecular tumor boards in combination with the opportunity to discover new biomarker candidates.

Purpose The aim of the study was to get a cross-sectional overview of the current status of specific organizational procedures, quality control systems, and standard operating procedures for the use of three-dimensional (3D) printing to assist in-house workflow using additive manufacturing in oral and maxillofacial surgery (OMFS) in Germany. Methods An online questionnaire including dynamic components containing 16–29 questions regarding specific organizational aspects, process workflows, quality controls, documentation, and the respective backgrounds in 3D printing was sent to OMF surgeons in university and non-university hospitals as well as private practices with and without inpatient treatment facilities. Participants were recruited from a former study population regarding 3D printing; all participants owned a 3D printer and were registered with the German Association of Oral and Maxillofacial Surgery. Results Sixty-seven participants answered the questionnaires. Of those, 20 participants ran a 3D printer in-unit. Quality assurance measures were performed by 13 participants and underlying processes by 8 participants, respectively. Standard operating procedures regarding computer-aided design and manufacturing, post-processing, use, or storage of printed goods were non-existent in most printing units. Data segmentation as well as computer-aided design and manufacturing were conducted by a medical doctor in most cases ( n  = 19, n  = 18, n  = 8, respectively). Most participants ( n  = 8) stated that “medical device regulations did not have any influence yet, but an adaptation of the processes is planned for the future.” Conclusion The findings demonstrated significant differences in 3D printing management in OMFS, especially concerning process workflows, quality control, and documentation. Considering the ever-increasing regulations for medical devices, there might be a necessity for standardized 3D printing recommendations and regulations in OMFS.

We synthesize reaction rims between thermodynamically incompatible phases in the system MgO-Al 2 O 3 -SiO 2 applying uniaxial load using a creep apparatus. Synthesis experiments are done in the MgO-SiO 2 and in the MgO-Al 2 O 3 subsystems at temperatures ranging from 1150 to 1350 °C imposing vertical stresses of 1.2 to 29 MPa at ambient pressure and under a constant flow of dry argon. Single crystals of synthetic and natural quartz and forsterite, synthetic periclase and synthetic corundum polycrystals are used as starting materials. We produce enstatite rims at forsterite-quartz contacts, enstatite-forsterite double rims at periclase-quartz contacts and spinel rims at periclase-corundum contacts. We find that rim growth under the “dry” conditions of our experiments is sluggish compared to what has been found previously in nominally “dry” piston cylinder experiments. We further observe that the nature of starting material, synthetic or natural, has a major influence on rim growth rates, where natural samples are more reactive than synthetic ones. At a given temperature the effect of stress variation is larger than what is anticipated from the modification of the thermodynamic driving force for reaction due to the storage of elastic strain energy in the reactant phases. We speculate that this may be due to modification of the physical properties of the polycrystals that constitute the reaction rims or by deformation under the imposed load. In our experiments rim growth is very sluggish at forsterite-quartz interfaces. Rim growth is more rapid at periclase-quartz contacts. The spinel rims that are produced at periclase-corundum interfaces show parabolic growth indicating that reaction rim growth is essentially diffusion controlled. From the analysis of time series done in the MgO-Al 2 O 3 subsystem we derive effective diffusivities for the Al 2 O 3 and the MgO components in a spinel polycrystal as  m 2 /s and  m 2 /s for T = 1350 °C and a vertical stress of 2.9 MPa.

BackgroundMitochondrial dysfunction is discussed as a key factor in pathogenesis of Huntington's Disease. 13C-methionine breath test has been established for non-invasive and easy to perform quantification of hepatic mitochondrial function.AimAim of this pilot study was to investigate if there is evidence for subclinic hepatic mitochondrial dysfunction in manifest and/or premanifest Huntington's Disease mutation carriers using the 13C-methionine breath test.Methods13C-methionine breath test was performed within a group of 21 early manifest Huntington's Disease patients without medication, 30 premanifest mutation carriers as well as 36 healthy controls. All HD participants were scored according to the Unified Huntington's Disease Rating Scale, premanifest mutation carriers were stratified into the two groups preHD-A (further from predicted onset) and preHD-B (nearer) based on a calculation of the probability of estimated disease onset within 5years. 13C-methionine breath test was performed after an overnight fasting, breath samples were analysed by non-dispersive isotope-selective infrared spectroscopy and results expressed as percentage dose recovered after 90min of testing time. In 25 preHD participants a longtudinal follow-up investigation after 14.5month was possible. Statistical analysis comprised ANCOVA and post hoc t-tests.ResultsManifest Huntington's Disease patients and mutation carriers from our PreHD-B group revealed a significant lower amount of exhaled 13CO2 compared to healthy controls (p<0.001; p=0.017 respectively). In a stepwise linear regression model breath test results correlate significant to functional and cognitive scores of the Unified Huntington's Disease Rating Scale in manifest and also in premanifest Huntington's Disease. For all mutation carriers together there was a weak, but significant correlation of breath test results to ratio caudate volume/total intracranial volume. PreHD-B (nearer) mutation cariers showed a significant lower amount of exhaled 13CO2 after 14.5month.ConclusionsThis study clearly demonstrates for the first time in vivo a subclinical, progredient hepatic involvement in manifest and premanifest Huntington's Disease.

BackgroundMitochondrial dysfunction is discussed as a key factor in pathogenesis of Huntington's Disease. 13C-methionine breath test has been established for non-invasive and easy to perform quantification of hepatic mitochondrial function.AimAim of this pilot study was to investigate if there is evidence for subclinic hepatic mitochondrial dysfunction in manifest and/or premanifest Huntington's Disease mutation carriers using the 13C-methionine breath test.Methods13C-methionine breath test was performed within a group of 21 early manifest Huntington's Disease patients without medication, 30 premanifest mutation carriers as well as 36 healthy controls. All HD participants were scored according to the Unified Huntington's Disease Rating Scale, premanifest mutation carriers were stratified into the two groups preHD-A (further from predicted onset) and preHD-B (nearer) based on a calculation of the probability of estimated disease onset within 5 years. 13C-methionine breath test was performed after an overnight fasting, breath samples were analysed by non-dispersive isotope-selective infrared spectroscopy and results expressed as percentage dose recovered after 90 min of testing time. In 25 preHD participants a longtudinal follow-up investigation after 14.5 month was possible. Statistical analysis comprised ANCOVA and post hoc t-tests.ResultsManifest Huntington's Disease patients and mutation carriers from our PreHD-B group revealed a significant lower amount of exhaled 13CO2 compared to healthy controls (p<0.001; p=0.017 respectively). In a stepwise linear regression model breath test results correlate significant to functional and cognitive scores of the Unified Huntington's Disease Rating Scale in manifest and also in premanifest Huntington's Disease. For all mutation carriers together there was a weak, but significant correlation of breath test results to ratio caudate volume/total intracranial volume. PreHD-B (nearer) mutation cariers showed a significant lower amount of exhaled 13CO2 after 14.5 month.ConclusionsThis study clearly demonstrates for the first time in vivo a subclinical, progredient hepatic involvement in manifest and premanifest Huntington's Disease.