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AbstractContinued advancements in the treatment of pediatric brain tumors have resulted in a growing proportion of children surviving previously incurable diagnoses. However, survivors of pediatric brain tumors show reduced Health-Related Quality of Life (HRQoL) compared to healthy populations and non-CNS childhood cancer survivors. This review systematically evaluates the existing literature on the influence of supratentorial and infratentorial brain tumor locations on Health-Related Quality of Life outcomes in survivors of pediatric brain tumors. Five electronic databases were searched for relevant articles published between their inception and January 2022. A purpose-developed evaluative tool was constructed to assess the quality of eligible studies. 16 of the 5270 identified articles were included in this review (n = 1391). This review found little evidence relating to the impact of brain tumor location on HRQoL, with only one study finding a significant difference between supratentorial and infratentorial tumor survivors. Key limitations of the current evidence include poor statistical reporting, ambiguous construct definitions, and insufficient adjustment for confounds. Findings from this review show that recovery from a pediatric brain tumor extends beyond recovery post-treatment and that further study into the factors influencing survivor HRQoL, including the influence of tumor location, is necessary.

Objective Loose bodies are free-floating tissues of cartilage and bone that can cause pain, swelling, the inability to straighten the knee, or intermittent locking of the knee. Loose bodies can arise from degenerative joint disease, flake fractures, osteochondritis dissecans, or chondromatosis. We hypothesized that loose bodies can be classified in stages with tissue characteristics similar to endochondral ossification.Design Loose bodies were harvested from patients undergoing joint replacement. Samples were processed for histology, gene expression analysis, and micro-computed tomography (µCT). Cartilage- and bone-related genes and proteins were selected for immunofluorescence stainings (collagen type I, II, and X, SOX9 [SRY-box transcription factor 9], and MMP13 [matrix metalloproteinase 13]) and gene expression analysis (FN[fibronectin], COL1A1, COL2A1, COL10A1, SOX9, MMP13, and aggrecan [ACAN]).Results Loose bodies were grouped in 4 stages: fibrous, (mineralized) cartilaginous, cartilage and bone, and bone. Hyaline-like cartilage tissue with Benninghoff arcades was present in stages 2 and 3. A transition from cartilaginous to mineralized tissue and bone trabecula was defined by an increase in COL1A1and COL10A1(stage 3 vs. 4: p= 0.047) positive area. Stage 4 showed typical trabecular bone tissue. The relative volume of calcified tissue (mineralized cartilage and bone tissue) decreased with stages (stages 1-2 vs. 3: p= 0.002; stage 1-2 vs. 4: p= 0.012). COL2A1expression and stained area decreased from stages 1-2 to 4 (p= 0.010 and p= 0.004). ACANexpression decreased from stage 1-2 to stage 3 (p= 0.049) and stage 4 (p= 0.002).Conclusion Loose bodies show tissue characteristics similar to endochondral ossification. They are probably a relevant substrate for regenerative therapeutic interventions in joint disease.

Zusammenfassung: Die Wiedereinführung des Oberflächenersatzes hat zu einer überraschend schnellen Reetablierung dieses Verfahrens nach den unbefriedigenden Ergebnissen in der Vergangenheit geführt. Die relativ hohe Rate an Frühversagern gibt jedoch noch Anlass zu Bedenken. Im Rahmen der vorliegenden Studie wurden 256 Revisionspräparate tribologisch, radiologisch, morphologisch und histologisch analysiert, um Ursachen für das Versagen bzw. die Revision zu identifizieren. Mehr als zwei Drittel der Versager wurden aufgrund einer Fraktur revidiert – Halsfrakturen traten hierbei deutlich früher auf als Fakturen innerhalb des Kopfes und Pfannenlockerungen. Die Versagensrate war innerhalb der ersten 16 Wochen nach Implantation und bei den ersten 10 Operationen eines Operateurs am höchsten. Revisionen ohne Vorliegen einer Fraktur oder Pfannenlockerung erfolgten im Durchschnitt nach 2 Jahren. Revisionen, bedingt durch femurseitige Probleme wie Notching oder überhöhte Implantationskräfte, traten vor pfannenseitigen Problemen wie Pfannenlockerung oder erhöhtem Verschleiß durch Pfannenfehlpositionierung auf. Die Anteversion der Pfanne spielt hierbei eine wichtige Rolle, die im Rahmen der Studie jedoch nicht quantifiziert werden konnte.

Zusammenfassung: Im folgenden Beitrag werden die Entstehung, Entwicklung und Außenwirkung folgender 8 diagnosespezifischer Patientengruppen seltener Netzhautdegenerationen (SND) in der Patientenorganisation PRO RETINA Deutschland e.V. beschrieben: Atrophia gyrata, Bardet-Biedl-Syndrom (BBS), Refsum-Syndrom, Usher-Syndrom, Zapfen-Stäbchen-Dystrophie (ZSD), Lebersche kongenitale Amaurose (LCA), Chorioideremie, Morbus Stargardt/juvenile Makuladegeneration. Ansätze der Patientenselbsthilfe zur geeigneten Organisation und Interaktion mit dem professionellen System wurden im Rahmen eines BMG-geförderten Projekts unterstützt, analysiert und dokumentiert. Bei SND-Gruppen mit syndromalen Formen liegt im Vergleich zu nichtsyndromalen Formen ein hoher Organisationsgrad vor (Refsum-Syndrom 25%; BBS 14%; Usher-Syndrom 8%); Patienten mit syndromalen Erkrankungen (z. B. Usher-Syndrom) arbeiten auch motivierter in der Selbsthilfe mit. Sie hängen aber mehr von der Unterstützung durch Angehörige und von Hilfsmitteln ab. Folgende Tendenzen bei der Entwicklung der SND-Gruppen waren zu erkennen:

In temperate and subtropical regions, ancient proteins are reported to survive up to about 2 million years, far beyond the known limits of ancient DNA preservation in the same areas. Accordingly, their amino acid sequences currently represent the only source of genetic information available to pursue phylogenetic inference involving species that went extinct too long ago to be amenable for ancient DNA analysis. Here we present a complete workflow, including sample preparation, mass spectrometric data acquisition and computational analysis, to recover and interpret million-year-old dental enamel protein sequences. During sample preparation, the proteolytic digestion step, usually an integral part of conventional bottom-up proteomics, is omitted to increase the recovery of the randomly degraded peptides spontaneously generated by extensive diagenetic hydrolysis of ancient proteins over geological time. Similarly, we describe other solutions we have adopted to (1) authenticate the endogenous origin of the protein traces we identify, (2) detect and validate amino acid variation in the ancient protein sequences and (3) attempt phylogenetic inference. Sample preparation and data acquisition can be completed in 3–4 working days, while subsequent data analysis usually takes 2–5 days. The workflow described requires basic expertise in ancient biomolecules analysis, mass spectrometry-based proteomics and molecular phylogeny. Finally, we describe the limits of this approach and its potential for the reconstruction of evolutionary relationships in paleontology and paleoanthropology.

Artificial intelligence (AI) can accelerate catalyst design by identifying key physicochemical descriptive parameters correlated with the underlying processes triggering, favoring, or hindering the performance. In analogy to genes in biology, these parameters might be called “materials genes” of heterogeneous catalysis. However, widely used AI methods require big data, and only the smallest part of the available data meets the quality requirement for data-efficient AI. Here, we use rigorous experimental procedures, designed to consistently take into account the kinetics of the catalyst active states formation, to measure 55 physicochemical parameters as well as the reactivity of 12 catalysts toward ethane, propane, and n-butane oxidation reactions. These materials are based on vanadium or manganese redox-active elements and present diverse phase compositions, crystallinities, and catalytic behaviors. By applying the sure-independence-screening-and-sparsifying-operator symbolic-regression approach to the consistent data set, we identify nonlinear property–function relationships depending on several key parameters and reflecting the intricate interplay of processes that govern the formation of olefins and oxygenates: local transport, site isolation, surface redox activity, adsorption, and the material dynamical restructuring under reaction conditions. These processes are captured by parameters derived from N2adsorption, X-ray photoelectron spectroscopy (XPS), and near-ambient-pressure in situ XPS. The data-centric approach indicates the most relevant characterization techniques to be used for catalyst design and provides “rules” on how the catalyst properties may be tuned in order to achieve the desired performance.

Based on the concept that most reaction steps proceed only at the surface layer of a bulk catalyst, the catalytic impact of the surface-modification with POx, BOx, and MnOxin the selective oxidation of ethane, propane, and n-butane is systematically studied. Three different promoter elements are deposited as a sub-monolayer on the surface of oxidation catalysts with high dispersion by sequential and self-limiting reactions at the solid–gas interface, using atomic layer deposition. Oxygenate and olefin selectivities are tuned by the surface deposition of POxand BOx, leading to improved product yields. The mixed metal oxide MoVTeNbOxis used as a case study to demonstrate the effect of the modification in different reactions with yield improvements of up to 24% in the propane oxidation towards acrylic acid. It is shown that the beneficial performance is related to a change in surface composition, a modification in the electronic properties of the redox active element vanadium, and a decrease in acidity. A comparative study considering several bulk catalysts and deposited elements revealed further promoting effects for different oxidation catalysts. In particular, the deposition of POxon V-containing oxides suppresses COxformation. Precisely adjusted surface modifications leading to enhanced product yields demonstrate the potential of atomic layer deposition as a powerful tool for tuning catalytic properties of bulk catalysts.

How would it be assessed from an ethical point of view if human wage work were replaced by artificially intelligent systems (AI) in the course of an automation process? An answer to this question has been discussed above all under the aspects of individual well-being and social justice. Although these perspectives are important, in this article, we approach the question from a different perspective: that of leading a meaningful life, as understood in analytical ethics on the basis of the so-called meaning-in-life debate. Our thesis here is that a life without wage work loses specific sources of meaning, but can still be sufficiently meaningful in certain other ways. Our starting point is John Danaher’s claim that ubiquitous automation inevitably leads to an achievement gap. Although we share this diagnosis, we reject his provocative solution according to which game-like virtual realities could be an adequate substitute source of meaning. Subsequently, we outline our own systematic alternative which we regard as a decidedly humanistic perspective. It focuses both on different kinds of social work and on rather passive forms of being related to meaningful contents. Finally, we go into the limits and unresolved points of our argumentation as part of an outlook, but we also try to defend its fundamental persuasiveness against a potential objection.

Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-β-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery.

In this observational study, we explored the humoral and cellular immune response to SARS‐CoV‐2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). Anti‐SARS‐CoV‐2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID‐19 vaccination. The spike‐specific T‐cell response was assessed using an activation‐induced marker assay (AIM) in a subset of individuals. Previous SARS‐CoV‐2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p= 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n= 85) and without immunosuppression (n= 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike‐specific T‐cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike‐specific T‐cell response. Patients with AIH show an increased SARS‐CoV‐2 infection rate as well as an impaired B‐ and T‐cell response to SARS‐CoV‐2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling–based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, −2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KITD816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3and KITmutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.

Interpreting impedance spectra of electrochemical systems using the distribution of relaxation times analysis remains an incompletely solved task. This study carefully examines various challenges related to the interpretation of resulting distributions of relaxation times using a closed-form lumped Doyle-Fuller-Newman model. First, the physical and phenomenological interpretation of peaks in the distribution of relaxation times are analyzed through a global sensitivity analysis. Second, the assignment of processes to specific ranges of time constants is investigated. Third, the use of half cells for the characterization of full cells is examined, and the clear limitations associated with the use of lithium metal counter electrodes are pointed out. Furthermore, the study provides first insights into the effects of distributed processes such as charge transfer, double-layer effects, and solid-state diffusion. Several prevailing interpretations in the literature are challenged and new insights and guidelines for interpreting distributions of relaxation times are offered.

Die Patientensicherheit zu gewährleisten ist ein zentrales Anliegen in der Gesundheitsversorgung, deren Behandlungsprozesse eine komplexe und mit vielen Risiken behaftete Aufgabe darstellt. Im Spitalalltag kommt es denn auch immer wieder zu unerwünschten, kritischen Ereignissen, die Patienten schädigen. Hierbei untersuchen die Sicherheitswissenschaften deren Entstehung, Begleitumstände und Verbesserungsmassnahmen. Dabei kommen mit Safety-I und Safety-II zwei sich ergänzende Ansätze zur Geltung. Während Safety-I darauf abzielt, unerwünschte Ereignisse zu minimieren, fokussiert der Safety-II-Ansatz auf das Verstehen des Systems als Ganzes, aus dessen Normalbetrieb gleichermaßen erwünschte und unerwünschte Ereignisse hervorgehen. Am für diese Studie ausgewählten Universitätskrankenhaus der Schweiz ist der Safety-I-Ansatz (Fokus auf Fehlleistungen und Korrekturen negativer Auswirkungen für die Patientensicherheit) durch die Implementierung des Critical Incident Report System (CIRS) ein fester Bestandteil. Gegenstand der Untersuchung ist es zu erheben, ob und inwiefern der Safety-II-Ansatz (Fokus auf dem Normalbetrieb und Verständnis der positiven Auswirkungen für die Patientensicherheit) bereits umgesetzt wird und welche Maßnahmen seine Integration im klinischen Alltag unterstützen können.

Irritant contact dermatitis is a wide spread occupational skin condition. In addition to generalized protection and teaching schemes, a knowledge about individual risk might add to an improved awareness for hazards. Here, we report on a novel candidate biomarker, which might stage individual susceptibility to irritant skin damage. Subclinical sensitivity was proven in recent studies. As a nano-anatomical measure, it works non-invasively on corneocytes from tape strips. Here, we report on a 7-day course after exposure to sodium lauryl sulphate and compare the novel cell texture index with the classical markers water loss (transepidermal water loss) and natural moisturizing factor. All parameters show a high degree of correlation.

Babesia bovisparasites present a serious and significant health concern for the beef and dairy industries in many parts of the world. Difficulties associated with the current diagnostic techniques include the following: they are prone to human error (microscopy) or expensive and time-consuming (polymerase chain reaction) to perform. Little is known about the biochemical changes in blood that are associated with Babesiainfections. The discovery of new biomarkers will lead to improved diagnostic outcomes for the cattle industry. Vibrational spectroscopic technologies can record a chemical snapshot of the entire organism and the surrounding cell thereby providing a phenotype of the organism and the host infected cell. Here, we demonstrate the applicability of vibrational spectroscopic imaging techniques including Atomic Force Microscopy Infrared (AFM-IR) and confocal Raman microscopy to discover new biomarkers for B. bovisinfections. Furthermore, we applied Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) to detect B. bovisin red blood cells (RBCs). Based on changes in the IR spectral bands, with ATR-FTIR in combination with Partial Least Squares-Discriminant Analysis we were able to discriminate infected samples from controls with a sensitivity and specificity of 92.0% and 91.7%, respectively, in less than 2 min, excluding sample extraction and preparation. The proposed method utilized a lysis approach to remove hemoglobin from the suspension of infected and uninfected cells, which significantly increased the sensitivity and specificity compared to measurements performed on intact infected red blood cells (intact infected RBC, 77.3% and 79.2%). This work represents a holistic spectroscopic study from the level of the single infected RBC using AFM-IR and confocal Raman to the detection of the parasite in a cell population using ATR-FTIR for a babesiosis diagnostic.

Vinyl chloride is one of the world’s most important industrially synthesized substances, but due to its physicochemical nature, comparably little is known about its thermodynamic behavior. Accurate density and thermodynamic speed of sound data of vinyl chloride in the liquid state are measured along nine isotherms, covering the temperature range from 283 to 362 K up to a pressure of 91 MPa. Data are presented with a maximum expanded uncertainty (k= 2) of 0.15% for the density and 0.16% for the speed of sound. They are compared with all available literature sources and a preliminary equation of state. Present density data are in good agreement with the literature data and have a maximum deviation of 1.5% from the equation of state. However, no experimental speed of sound data are available in the literature for comparison and the equation of state diverges up to −12.4% from the present data.

Orbitrap Exploris 480 MS with FAIMS Pro provides fast, sensitive and robust profiling of proteomes when combined with Evosep One. The combination of Data Independent Acquisition (DIA) and FAIMS with single compensation voltages enables analysis of up to 2000 peptides per LC gradient minute and more than 5000 protein groups in twenty minutes. DIA-FAIMS based label-free quantitation achieves similar depth and quantitative accuracy as the well-established isobaric labelling approaches, but with less LC-MS measurement time, making it a good choice for large cohort of samples.

The rapid cost-reductions expected to result from volume production of lithium-ion (Li) batteries are progressively enabling electrochemical energy storage to play a key role in the economics of energy markets worldwide. Battery Energy Storage Systems (BESS) can play several roles, offering voltage and frequency support, tariff arbitrage, peak shaving, and increased reliability. The stacking of these benefits is necessary to justify the still high costs of storage. Due to the high tariffs spread through the day, shifting the load from peak hours is currently the main BESS application in many energy markets, especially for medium voltage consumers. The deployment of other functions, such as peak shaving, can contribute to more revenue sources, maximizing the project's financial return and adding more value to the product in a commercial approach. We propose a method to evaluate these stacked benefits in a techno-economic analysis of a BESS operating in Brazil. The BESS analyzed in the case study has been running for more than two years in a shopping mall connected to the medium voltage utility distribution network, with a dedicated Energy Management System (EMS) that allows the transition between the different operation modes, optimizing the system's performance. The load-shifting function represented over 97 % of the revenue share, highlighting this feature as the most important for economic viability. Peak shaving, despite being important to avoid demand trespassing fines, was not a relevant contribution of the BESS due to a well-balanced load management and demand contract.