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Purpose: Debridement, antibiotics, and implant retention (DAIR) is an established treatment modality in periprosthetic joint infections (PJIs), but success rates vary. This study compared the success of DAIR for PJIs after a total hip arthroplasty (THA), with or without local antibiotic delivery with CaSO4 as the carrier material. Methods: A retrospective review of DAIR for PJIs after THA performed between 2010 and 2018, including 41 patients is conducted. A total of 27 patients were treated by DAIR with local antibiotics with CaSO4 as the carrier material, and 14 patients were treated by a standard DAIR. The endpoints were treatment failure, defined as the need for a reoperation, either a second DAIR or a prosthesis removal or exchange due to persistent or recurrent infection, the initiation of a long-term suppressive antibiotic treatment, or death related to infection. Results: Considering any reoperation as an outcome, 11 of 14 cases treated without AB-CaSO4 (79 %) and 4 of the 27 cases treated with AB-CaSO4 failed (15 %). Considering revision as an outcome, 9 out of 14 cases treated without AB-CaSO4 (64 %) and 4 of the 27 cases treated with AB-CaSO4 (15 %) failed. A Kaplan–Meier survival analysis showed that local antibiotic delivery with CaSO4 as the carrier material led to a significantly longer infection-free survival, considering any surgical revision (p; hazard ratio 8.9 (95 % CI 2.8–28.2)) or revision with component exchange (p=0.0015; hazard ratio 5.6 (95 % CI 1.7–18.2)) as the endpoint. Conclusion: The addition of local antibiotics with CaSO4 as the carrier material to DAIR for PJIs after THA significantly increases success rates, such as infection-free survival, any reoperation, and revision with component exchange in particular.

Abstract Systemic sclerosis (SSc) is a severe multi-organ disease with interstitial lung disease (ILD) being the major cause of death. While targeted therapies are emerging, biomarkers for sub-stratifying patients based on individual profiles are lacking. Herein, we investigated how levels of serum metabolites correlated with different stages of SSc and SSc-ILD. Serum samples of patients with SSc without ILD, stable and progressive SSc-ILD as well as of healthy controls (HC) were analysed using liquid targeted tandem mass spectrometry. The best discriminating profile consisted of 4 amino acids (AA) and 3 purine metabolites. l-tyrosine, l-tryptophan, and 1-methyl-adenosine distinguished HC from SSc patients. l-leucine, l-isoleucine, xanthosine, and adenosine monophosphate differentiated between progressing and stable SSc-ILD. In SSc-ILD, both, l-leucine and xanthosine negatively correlated with changes in FVC% predicted. Additionally, xanthosine was negatively correlated with changes in DLco% predicted and positively with the prognostic GAP index. Validation of l-leucine and l-isoleucine by an enzymatic assay confirmed both the sub-stratification of SSc-ILD patients and correlation with lung function and prognosis score. Serum metabolites may have potential as biomarkers for discriminating SSc patients based on the presence and severity of ILD. Confirmation in larger cohorts will be needed to appreciate their value for routine clinical care.

Despite being the main drinking water resource for over 5 million people, the water balance of the Eastern Mountain Aquifer system on the western side of the Dead Sea is poorly understood. The regional aquifer consists of fractured and karstified limestone – aquifers of Cretaceous age, and it can be separated into a Cenomanian aquifer (upper aquifer) and Albian aquifer (lower aquifer). Both aquifers are exposed along the mountain ridge around Jerusalem, which is the main recharge area. From here, the recharged groundwater flows in a highly karstified aquifer system towards the east and discharges in springs in the lower Jordan Valley and Dead Sea region. We investigated the Eastern Mountain Aquifer system for groundwater flow, groundwater age and potential mixtures, and groundwater recharge. We combined 36Cl ∕ Cl, tritium, and the anthropogenic gases SF6, CFC-12 (chlorofluorocarbon) and CFC-11, while using CFC-113 as “dating” tracers to estimate the young water components inside the Eastern Mountain Aquifer system. By application of lumped parameter models, we verified young groundwater components from the last 10 to 30 years and an admixture of a groundwater component older than about 70 years. Concentrations of nitrate, simazine (pesticide), acesulfame K (ACE-K; artificial sweetener) and naproxen (NAP; drug) in the groundwater were further indications of infiltration during the last 30 years. The combination of multiple environmental tracers and lumped parameter modelling helped to understand the groundwater age distribution and to estimate recharge despite scarce data in this very complex hydrogeological setting. Our groundwater recharge rates support groundwater management of this politically difficult area and can be used to inform and calibrate ongoing groundwater flow models.

In the midst of the COVID-19 pandemic and the universal chaos created by it, this study explores the role of sense of coherence (Soc, Antonovsky, 1979) and how it enables coping with a stressful situation and staying well. SOC is a generalized orientation which allows one to perceive the world as comprehensible, manageable, and meaningful. In an attempt to understand ‘how does the SOC work’ we employed the salutogenic assumption that a strong SOC allows one to reach out in any given situation and find those resources appropriate to the specific stressor. Thus, we hypothesized that the positive impact of SOC on mental health outcomes would be mediated through coping resources that are particularly salient in times of crisis. One resource is related to the micro level (perceived family support) and the other concerns the macro level (trust in leaders and social-political institutions). Data collection was conducted in different countries during May–June 2020 via online platforms. The data included 7 samples of adult participants (age 18–90) from Israel (n ​= ​669), Italy (n ​= ​899), Spain (n ​= ​476), Germany (n ​= ​708), Austria (n ​= ​1026), Switzerland (n ​= ​147), and the U.S. (n ​= ​506). The questionnaires included standard tools (MHC-SF, SOC-13) as well as questionnaires of perceived family support and trust that were adapted to the pandemic context. As expected, SOC was associated with mental health in all the samples. Perceived family support and trust in leaders and social-political institutions mediated the relationships between SOC and mental health, controlling for age, gender, and level of financial risk. It appears that SOC has a universal meaning, not limited by cultural and situational characteristics. The discussion focuses on the theoretical, social, and political applications of the salutogenic model – and its core concept of SOC – in the context of coping with a global pandemic across different cultural contexts and countries.

Introduction: Local application of antibiotics provides high concentrations at the site of interest, with minimal systemic toxicity. Carrier materials might help manage dead space. Calcium sulphate (CaSO4) has a dissolution time that only slightly exceeds the usually recommended duration of systemic antibiotic treatments. This in vitro study evaluates compatibility, release kinetics and antibacterial activity of new combinations of antibiotics with CaSO4 as carrier material.Methods: CaSO4 pellets added with 8% w/w antibiotic powder were exposed once in phosphate-buffered saline (PBS) solution and once in bovine plasma, in an elution experiment run over 6 weeks at 37 °C. Antibiotic elution was examined at various time points. Concentration was measured by liquid chromatography with tandem mass spectrometry. Antimicrobial activity was checked with an agar diffusion test.Results: Piperacillin-tazobactam, ceftazidime, cefepime, and meropenem showed fast reduction of concentration and activity. Flucloxacillin and cefuroxime remained present in relevant concentrations for 4 weeks. Ciprofloxacin, levofloxacin and clindamycin lasted for 6 weeks, but also at cell toxic concentrations. Ceftriaxone showed a near-constant release with only a small reduction of concentration from 130 to 75 mg/l. Elution profiles from PBS and plasma were comparable.Conclusion: CaSO4 provides new possibilities in the local treatment of bone and joint infections. Ceftriaxone appears to be of particular interest in combination with CaSO4. Release persists at clinically promising concentrations, and appears to have a depot-like slow release from CaSO4, with only a small reduction in activity and concentration over 6 weeks. To the best of our knowledge, such a particular persistent release never was described before, for any antibiotic in combination with a carrier material for local application.

This Pilot Study aimed at improving the information on the state of the Indonesian marine environment that is gained from satellite data. More than 2000 historical and actual synthetic aperture radar (SAR) data from ENVISAT ASAR and Sentinel-1A/B C-SAR, respectively, were used to produce oil pollution density maps of two regions of interest (ROI) in Indonesian waters. The normalized spill number and the normalized mean polluted area were calculated, and our findings indicate that in general, the marine oil pollution in both ROI is of different origin: while ship traffic appears to be the main source in the Java Sea, oil production industry causes the highest pollution rates in the Strait of Makassar. In most cases hot spots of marine oil pollution were found in the open sea, and the largest number of oil spills in the Java Sea was found from March to May and from September to December, i.e., during the transition from the north-west monsoon to the south-east monsoon, and vice versa. This is when the overall wind and current patterns change, thereby making oil pollution detection with SAR sensors easier. In support of our SAR image analyses high-resolution numerical forward and backward tracer experiments were performed. Using the previously gained information we identify strongly affected coastal areas (with most oil pollution being driven onshore), but also sensitive parts of major ship traffic lanes (where any oil pollution is likely to be driven into marine protected areas). Our results demonstrate the feasibility of our approach, to combine numerical tracer modelling with (visual) SAR image analyses for an assessment of the marine environment in Indonesian waters, and they help in better understanding the observed seasonality.

The incidence of acute aortic syndrome is low, but the spontaneous course is often life-threatening. Adequate ECG-gated imaging is fundamental within the diagnostic workup. We here report a case of a 53-year-old man presenting with atypical chest pain, slight increase of D dimers at admission, and extended diameter of the ascending aorta accompanied by mild aortic regurgitation. Interpretation of an initial contrast-enhanced computed tomography was false negative due to inadequate gating and motion artifacts, thereby judging a tiny contrast signal in the left anterior quadrant of the ascending aorta as a pseudointimal flap. By hazard, cardiac magnetic resonance imaging demonstrated an ulcer-like lesion superior to the aortic root, leading to aortic surgery at the last moment. As sensitivity of imaging is not 100%, this example underlines that second imaging studies might be necessary if the first imaging is negative, but the clinical suspicion still remains high.

Abstract Background In minimally invasive lateral plate osteosynthesis of the humerus (MILPOH) the plate is introduced through a deltoid split proximally and advanced through the central portion of the deltoid insertion and between bone and brachial muscle to the distal aspect of the humerus. The fracture is then indirectly reduced and bridged by the plate. Whereas it has been shown that the strong anterior and posterior parts of the distal deltoid insertion remain intact with this maneuver, its impact on deltoid muscle strength and muscular morphology remains unclear. It was the aim of this study to evaluate deltoid muscle function and MR-morphology of the deltoid muscle and its distal insertion after MILPOH. Methods Six patients (median age 63 years, range 52–69 years, f/m 5/1) who had undergone MILPOH for diaphyseal humeral fractures extending into the proximal metaphysis and head (AO 12B/C(i)) between 08/2017 and 08/2020 were included. Functional testing was performed for the injured and uninjured extremity including strength measurements for 30/60/90° shoulder abduction and flexion at least one year postoperatively. Constant-Murley-Score (CMS) including an age-and gender-adjusted version, were obtained and compared to the uninjured side. Oxford Shoulder Score (OSS) and the Disability of the Arm, Shoulder and Hand (DASH) questionnaire were acquired for the affected extremity. Quality of life was measured using the EQ visual analogue scale (EQ-5D-5 L VAS). MR imaging was performed for both shoulders accordingly at the time of follow-up to assess the integrity of the distal insertion, muscle mass and fatty degeneration of the deltoid muscle. Muscle mass was determined by measuring the area of the deltoid muscle on the axial MR image at the height of the center of the humeral head. Results Median follow-up was 29 months (range 12–48 months). Median difference of abduction strength after MILPOH was + 13% for 30°, 0% for 60° and − 22% for 90°. For flexion, the difference to the uninjured side was measured 5% for 30°, -7% for 60° and − 12% for 90°. Median CMS was 75 (66–82) for the operated extremity compared to 82 (77–90) for the uninjured side. Age- and gender-adapted CMS was calculated 88 (79–99) vs. 96 (89–107). Median OSS was 47 (40–48). DASH was 26 (15–36). EQ-5D-5 L VAS ranged from 81 to 95 with a median of 90. The median difference of the deltoid muscle area on MRI was 2% (-21% to + 53%) compared to the uninjured side. No fatty degeneration of the deltoid muscle was observed. The weaker central part of the distal deltoid insertion was exclusively perforated by the plate, leaving the strong anterior and posterior parts of the insertion intact in all patients. Conclusions MILPOH was associated with good functional and subjective outcome. Minor impairment of abduction strength was observed with increasing abduction angles. The reason for this impairment is unclear since MILPOH did not affect the structural quality of the deltoid muscle and the integrity of the strong anterior and posterior parts of its insertion remained intact. Trial registration 26/05/2023: ISRCTN51786146.

Leukemic blasts overexpress immunogenic antigens, so-called leukemia-associated antigens like the receptor for hyaluronan acid-mediated motility (RHAMM). Persistent RHAMM expression and decreasing CD8+ T-cell responses to RHAMM in the framework of allogeneic stem cell transplantation or chemotherapy alone might indicate the immune escape of leukemia cells. In the present study, we analyzed the expression of RHAMM in 48 patients suffering from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Furthermore, we correlated transcripts with the clinical course of the disease before and after treatment. Real-time quantitative reverse transcriptase polymerase chain reaction was performed from RNA of peripheral blood mononuclear cells. T cell responses against RHAMM were assessed by tetramer staining (flow cytometry) and enzyme-linked immunospot (ELISPOT) assays. Results were correlated with the clinical outcome of patients. The results of the present study showed that almost 60% of the patients were RHAMM positive; specific T-cells recognizing RHAMM could be detected, but they were nonfunctional in terms of interferon gamma or granzyme B release as demonstrated by ELISPOT assays. Immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the outcome of AML/MDS patients.

African montane forests harbor some of the greatest biodiversity worldwide, with high levels of species endemism. However, the loss of these forests through fragmentation, deforestation and climate change has been rapidly increasing in recent years. Montane forests in Africa are more susceptible to changes in climate than their lowland counterparts, yet their ecological value is still underrepresented. These montane forests have recently been highlighted as a major aboveground carbon (C) stock. The estimated 149.4 Mg C ha−1 from aboveground live trees surpasses estimates from the Intergovernmental Panel on Climate Change for these endangered forests, and exceeds reported values for neotropical montane and lowland forests by up to 70%. Despite the tremendous implications of these findings, coordinated and available research on the C storage potential of the other share of African montane forest biomass, that is in tree roots, is largely missing. Broadly estimated from the allometry of aboveground C stocks and from root:shoot ratios in lowland forests, more than 60 Mg C ha−1 can be stored in African montane forest roots, about 40% more than previously determined. While this broad estimation points at the potential importance of root C stocks in African montane forests, it also unveils a far-reaching knowledge gap. Here, we advocate for a more quantitative representation of the root C stock from dominant forest tree species of African tropical montane forests and ultimately for a better grasp on tree C stocks from this endangered ecosystem.

Airborne imaging differential optical absorption spectroscopy (DOAS), ground-based stationary DOAS, and car DOAS measurements were conducted during the S5P-VAL-DE-Ruhr campaign in September 2020. The campaign area is located in the Rhine-Ruhr region of North Rhine-Westphalia, western Germany, which is a pollution hotspot in Europe comprising urban and large industrial sources. The DOAS measurements are used to validate spaceborne NO2 tropospheric vertical column density (VCD) data products from the Sentinel-5 Precursor (S5P) TROPOspheric Monitoring Instrument (TROPOMI). Seven flights were performed with the airborne imaging DOAS instrument for measurements of atmospheric pollution (AirMAP), providing measurements that were used to create continuous maps of NO2 in the layer below the aircraft. These flights cover many S5P ground pixels within an area of 30 km × 35 km and were accompanied by ground-based stationary measurements and three mobile car DOAS instruments. Stationary measurements were conducted by two Pandora, two Zenith-DOAS, and two MAX-DOAS instruments. Ground-based stationary and car DOAS measurements are used to evaluate the AirMAP tropospheric NO2 VCDs and show high Pearson correlation coefficients of 0.88 and 0.89 and slopes of 0.90 ± 0.09 and 0.89 ± 0.02 for the stationary and car DOAS, respectively. Having a spatial resolution of about 100 m × 30 m, the AirMAP tropospheric NO2 VCD data create a link between the ground-based and the TROPOMI measurements with a nadir resolution of 3.5 km × 5.5 km and are therefore well suited to validate the TROPOMI tropospheric NO2 VCD. The observations on the 7 flight days show strong NO2 variability, which is dependent on the three target areas, the day of the week, and the meteorological conditions. The AirMAP campaign data set is compared to the TROPOMI NO2 operational offline (OFFL) V01.03.02 data product, the reprocessed NO2 data using the V02.03.01 of the official level-2 processor provided by the Product Algorithm Laboratory (PAL), and several scientific TROPOMI NO2 data products. The AirMAP and TROPOMI OFFL V01.03.02 data are highly correlated (r=0.87) but show an underestimation of the TROPOMI data with a slope of 0.38 ± 0.02 and a median relative difference of −9 %. With the modifications in the NO2 retrieval implemented in the PAL V02.03.01 product, the slope and median relative difference increased to 0.83 ± 0.06 and +20 %. However, the modifications resulted in larger scatter and the correlation decreased significantly to r=0.72. The results can be improved by not applying a cloud correction for the TROPOMI data in conditions with high aerosol load and when cloud pressures are retrieved close to the surface. The influence of spatially more highly resolved a priori NO2 vertical profiles and surface reflectivity are investigated using scientific TROPOMI tropospheric NO2 VCD data products. The comparison of the AirMAP campaign data set to the scientific data products shows that the choice of surface reflectivity database has a minor impact on the tropospheric NO2 VCD retrieval in the campaign region and season. In comparison, the replacement of the a priori NO2 profile in combination with the improvements in the retrieval of the PAL V02.03.01 product regarding cloud heights can further increase the tropospheric NO2 VCDs. This study demonstrates that the underestimation of the TROPOMI tropospheric NO2 VCD product with respect to the validation data set has been and can be further significantly improved.

The monovalent cations sodium and potassium are crucial for the proper functioning of excitable cells, but, in addition, other monovalent alkali metal ions such as cesium and lithium can also affect neuronal physiology. For instance, there have been recent reports of adverse effects resulting from self-administered high concentrations of cesium in disease conditions, prompting the Food and Drug Administration (FDA) to issue an alert concerning cesium chloride. As we recently found that the monovalent cation NH4+ activates glycine receptors (GlyRs), we investigated the effects of alkali metal ions on the function of the GlyR, which belongs to one of the most widely distributed neurotransmitter receptors in the peripheral and central nervous systems. Whole-cell voltage clamp electrophysiology was performed with HEK293T cells transiently expressing different splice and RNA-edited variants of GlyR α2 and α3 homopentameric channels. By examining the influence of various milli- and sub-millimolar concentrations of lithium, sodium, potassium, and cesium on these GlyRs in comparison to its natural ligand glycine (0.1 mM), we could show that cesium activates GlyRs in a concentration- and post-transcriptional-dependent way. Additionally, we conducted atomistic molecular dynamic simulations on GlyR α3 embedded in a membrane bilayer with potassium and cesium, respectively. The simulations revealed slightly different GlyR-ion binding profiles for potassium and cesium, identifying interactions near the glycine binding pocket (potassium and cesium) and close to the RNA-edited site (cesium) in the extracellular GlyR domain. Together, these findings show that cesium acts as an agonist of GlyRs.

Zebrafish have an impressive capacity to regenerate neurons in the central nervous system. However, regeneration of the principal neuron of the evolutionary conserved cerebellum, the Purkinje cell (PC), is believed to be limited to developmental stages based on invasive lesions. In contrast, non-invasive cell type-specific ablation by induced apoptosis closely represents a process of neurodegeneration. We demonstrate that the ablated larval PC population entirely recovers in number, quickly reestablishes electrophysiological properties, and properly integrates into circuits to regulate cerebellum-controlled behavior. PC progenitors are present in larvae and adults, and PC ablation in adult cerebelli results in an impressive PC regeneration of different PC subtypes able to restore behavioral impairments. Interestingly, caudal PCs are more resistant to ablation and regenerate more efficiently, suggesting a rostro-caudal pattern of de- and regeneration properties. These findings demonstrate that the zebrafish cerebellum is able to regenerate functional PCs during all stages of the animal’s life.

IntroductionThe cerebellum is organized into functional regions each dedicated to process different motor or sensory inputs for controlling different locomotor behaviors. This functional regionalization is prominent in the evolutionary conserved single-cell layered Purkinje cell (PC) population. Fragmented gene expression domains suggest a genetic organization of PC layer regionalization during cerebellum development. However, the establishment of such functionally specific domains during PC differentiation remained elusive.Methods and resultsWe show the progressive emergence of functional regionalization of PCs from broad responses to spatially restricted regions in zebrafish by means of in vivo Ca2+-imaging during stereotypic locomotive behavior. Moreover, we reveal that formation of new dendritic spines during cerebellar development using in vivo imaging parallels the time course of functional domain development. Pharmacological as well as cell-type specific optogenetic inhibition of PC neuronal activity results in reduced PC dendritic spine density and an altered stagnant pattern of functional domain formation in the PC layer.DiscussionHence, our study suggests that functional regionalization of the PC layer is driven by physiological activity of maturing PCs themselves.

The presently known ecological valences and requirements of recent species of pill-clams (Pisidium C. Pfeiffer) in Central Europe are briefly reviewed. Species of low indicator value (e. g. P. subtruncatum, milium) are contrasted with those having a high indicator value (e. g. P. supinum, lilljeborgii). The necessity of taking into account the abundance of species, rather than merely their presence, is emphasized.

Abstract Introduction Alzheimer's disease (AD) is characterized by neurotoxic immuno‐inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small‐molecule therapeutics for AD. Results In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon “self” neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐AD molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD's complex immunopathic–proteopathic pathogenesis. Discussion Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.