NaV1.8/NaV1.9 double deletion mildly affects acute pain responses in mice.

ABSTRACT: The 2 tetrodotoxin-resistant (TTXr) voltage-gated sodium channel subtypes NaV1.8 and NaV1.9 are important for peripheral pain signaling. As determinants of sensory neuron excitability, they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and the release of neurotransmitters from sensory neuron terminals. NaV1.8 and NaV1.9, which are encoded by SCN10A and SCN11A, respectively, are predominantly expressed in pain-sensitive (nociceptive) neurons localized in the dorsal root ganglia (DRG) along the spinal cord and in the trigeminal ganglia. Mutations in these genes cause various pain disorders in humans. Gain-of-function missense variants in SCN10A result in small fiber neuropathy, while distinct SCN11A mutations cause, i. a., congenital insensitivity to pain, episodic pain, painful neuropathy, and cold-induced pain. To determine the impact of loss-of-function of both channels, we generated NaV1.8/NaV1.9 double knockout (DKO) mice using clustered regularly interspaced short palindromic repeats/Cas-mediated gene editing to achieve simultaneous gene disruption. Successful knockout of both channels was verified by whole-cell recordings demonstrating the absence of NaV1.8- and NaV1.9-mediated Na+ currents in NaV1.8/NaV1.9 DKO DRG neurons. Global RNA sequencing identified significant deregulation of C-LTMR marker genes as well as of pain-modulating neuropeptides in NaV1.8/NaV1.9 DKO DRG neurons, which fits to the overall only moderately impaired acute pain behavior observed in DKO mice. Besides addressing the function of both sodium channels in pain perception, we further demonstrate that the null-background is a very valuable tool for investigations on the functional properties of individual human disease-causing variants in NaV1.8 or NaV1.9 in their native physiological environment.

Finding the rhythm: Humans exploit nonlinear intrinsic dynamics of compliant systems in periodic interaction tasks.

Activities like ball bouncing and trampoline jumping showcase the human ability to intuitively tune to system dynamics and excite motions that the system prefers intrinsically. This human sensitivity to resonance has been experimentally supported for interactions with simple linear systems but remains a challenge to validate in more complex scenarios where nonlinear dynamics cannot be predicted analytically. However, it has been found that many nonlinear systems exhibit periodic orbits similar to the eigenmodes of linear systems. These nonlinear normal modes (NNM) are computable with a recently developed numerical mode tool. Using this tool, the present resarch compared the motions that humans excite in nonlinear systems with the predicted NNM of the energy-conservative systems. In a user study consisting of three experiment parts, participants commanded differently configured virtual double pendula with joint compliance through a haptic joystick. The task was to alternately hit two targets, which were either aligned with the NNM (Experiments 1 and 2) or purposefully arranged offset (Experiment 3). In all tested experiment variations, participants intuitively applied a control strategy that excited the resonance and stabilized an orbit close to the ideal NNM of the conservative systems. Even for increased task accuracy (Experiment 2) and targets located away from the NNM (Experiment 3), participants could successfully accomplish the task, likely by adjusting their arm stiffness to alter the system dynamics to better align the resonant motions to the task. Consequently, our experiments extend the existing research on human resonance sensitivity with data-based evidence to nonlinear systems. Our findings emphasize the human capabilities to apply control strategies to excite and exploit resonant motions in dynamic object interactions, including possibly shaping the dynamics through changes in muscle stiffness.

The Halogen Bond to Ethers - Prototypic Molecules and Experimental Electron Density.

Halogen bonds to dialkyl ether molecules have remained largely unexplored. We here address the synthesis and the structural chemistry of the first halogen-bonded noncyclic alkyl ethers, combining 1,4-diiodotetrafluorobenzene and the prototypic or commonly used ethers dimethyl ether, tetrahydrofuran, and methyl-tert-butyl ether as halogen acceptors. Two different structural motifs based on moderately strong halogen bonds were obtained: Discrete trimolecular aggregates are formed, and unexpected halogen-bonded supramolecular chain adducts feature oxygen-bifurcated halogen bonds with 1:1 donor:acceptor ratio. Both structure types may be selectively obtained even for the same ether by adjusting the stoichiometry in the crystallization experiments. The geometric features of the etheric oxygen center were found to be flexible, in contrast to the almost linear geometry about the halogen donor atom. A high-resolution X-ray diffraction experiment on the extended adduct of dimethyl ether allowed us to study the electronic details of the acceptor-bifurcated I···O···I halogen bonds. The electron density in the bond critical points and derived properties such as the Laplacian indicate essentially electrostatic interactions and explain the geometrical flexibility of ethers in halogen bonds. Our studies demonstrate the great versatility of ethers as halogen bond acceptors, that can occur in many geometrical arrangements and whose contribution to nature's structural designs should not be underestimated.

Crystal structure and Hirshfeld surface analysis of dimeth-yl(phen-yl)phosphine sulfide.

The title compound, C8H11PS, which melts below room temperature, was crystallized at low temperature. The P-S bond length is 1.9623 (5) Šand the major contributors to the Hirshfeld surface are H⋯H (58.1%), S⋯H/H⋯S (13.4%) and C⋯H/H⋯C contacts (11.7%).

Clinical and genomic features of Mycobacterium avium complex: a multi-national European study.

BACKGROUND: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. METHODS: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. RESULTS: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%). CONCLUSIONS: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

Evaluation of AAV Capsids and Delivery Approaches for Hereditary Hemorrhagic Telangiectasia Gene Therapy.

Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous (i.v.) delivery of soluble Feline McDonough Sarcoma (FMS)-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84, and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered i.v. or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1f/f mice through i.v. followed by bAVM induction. Transduced cells in organs, vessel density, abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain endothelial cells (ECs) and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. The delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.

Evaluation of Aav Capsids and Delivery Approaches for Hereditary Hemorrhagic Telangiectasia Gene Therapy.

Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous delivery of soluble FMS-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84 and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered intravenously (i.v.) or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1 f/f mice through i.v. injection followed by brain AVM induction. Transduced cells in different organs, vessel density and abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain ECs and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and skeletal muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. Delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1 f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.

The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities.

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.

Stereoselective Entry into α,α'-C-Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain-Release C-Septanosylation Strategy.

The utility of unconventional noncovalent interactions (NCIs) such as chalcogen bonding has lately emerged as a robust platform to access synthetically difficult glycosides stereoselectively. Herein, we disclose the versatility of a phosphonochalcogenide (PCH) catalyst to facilitate access into the challenging, but biologically interesting 7-membered ring α,α'-C-disubstituted oxepane core through an α-selective strain-release C-glycosylation. Methodically, this strategy represents a switch from more common but entropically less desired macrocyclizations to a thermodynamically favored ring-expansion approach. In light of the general lack of stereoselective methods to access C-septanosides, a remarkable palette of silyl-based nucleophiles can be reliably employed in our method. This include a broad variety of useful synthons, such as easily available silyl-allyl, silyl-enol ether, silyl-ketene acetal, vinylogous silyl-ketene acetal, silyl-alkyne and silylazide reagents. Mechanistic investigations suggest that a mechanistic shift towards an intramolecular aglycone transposition involving a pentacoordinate silicon intermediate is likely responsible in steering the stereoselectivity.

Habitat modification by marram grass negatively affects recruitment of conspecifics.

Ecosystem engineers alter their environment often benefiting their own survival and growth yielding self-reinforcing feedbacks. Moreover, these habitat modifications have been found to facilitate recruitment of conspecifics for some species, while for others engineering inhibits recruitment. Whether dune grasses facilitate or inhibit recruitment of conspecifics is yet unknown. Here, we investigated how habitat modification by European marram grass (Ammophila arenaria) through embryonic dune development affects recruitment from seeds and marine dispersed rhizome fragments. Specifically, we tested at three locations with different dune morphologies how habitat modification affected natural seed and rhizome presence and shoot emergence from plots in which seeds or rhizome fragments were added. In addition, we investigated how sediment burial (i.e., the main effect of habitat modification by dune grasses) affected germination and emergence in a controlled experiment. Results show that regardless of habitat modification or beach width, seeds and rhizomes were absent in natural conditions. Habitat modification negatively affected shoot emergence from seeds (8 × less) and rhizomes (4 × less) and was negatively related to sediment dynamics. Furthermore, fewer seedlings were found with higher elevations. In controlled laboratory conditions, the highest seedling emergence was found with slight burial (0.5-3 cm); both germination and seedling emergence decreased as seeds were buried deeper or shallower. Overall, habitat modification by marram grass negatively affects recruitment of conspecifics through increased sediment dynamics and elevation. Consequently, storm events or eradication programs that include removal of adult vegetation-which leads to an unmodified system-might benefit new recruitment from seeds or clonal fragments.

Enantioselective Synthesis of Phosphine Boranes via Crystallization-Induced Dynamic Resolution of Lithiated Intermediate by Understanding the Underlying Epimerization Process.

Described herein is the successful crystallization-induced dynamic resolution (CIDR) of an α-lithiated phosphine borane utilizing the easily accessible and inexpensive ligand (R,R)-TMCDA. Starting from the essential P-prochiral building block dimethyl phenyl phosphine borane we were able to obtain phosphine boranes in yields up to 80 % and e.r. up to 98 : 2 by crystallization of the lithiated intermediate prior to the trapping reaction. NMR-based deuterium labeling experiments indicate that the epimerization in solution is based on the intermolecular proton transfer between nonlithiated phosphine borane and the corresponding lithiated intermediate, rendering the presence of the remaining starting compound in an optimized solvent mixture the main factor for successful enantioselective synthesis. Quantum chemical calculations using different model systems based on solid state structures confirm these experimental results. By gaining insights into the epimerization mechanism, essential principles for CIDR of lithiated phosphine boranes are elucidated that may be expanded to other important P-stereogenic compounds and simple chiral amines.

Crystal structure and Hirshfeld surface analysis of 2-picolyllithium·3thf.

In the title compound, (2-methyl-idene-1,2-di-hydro-pyridinium-κN)tris-(tetra-hydro-furan-κO)lithium, [Li(C6H6N)(C4H8O)3], the lithium ion adopts a distorted LiNO3 tetra-hedral coordination geometry and the 2-picolyl anion adopts its enamido form with the lithium ion lying close to the plane of the pyridine ring. A methyl-ene group of one of the thf ligands is disordered over two orientations. In the crystal, a weak C-H⋯O inter-action generates inversion dimers. A Hirshfeld surface analysis shows that H⋯H contacts dominate the packing (86%) followed by O⋯H/H⋯O and C⋯H/H⋯C contacts, which contribute 3% and 10.4%, respectively.

The Proteomic Composition and Organization of Constitutive Heterochromatin in Mouse Tissues.

Pericentric heterochromatin (PCH) forms spatio-temporarily distinct compartments and affects chromosome organization and stability. Albeit some of its components are known, an elucidation of its proteome and how it differs between tissues in vivo is lacking. Here, we find that PCH compartments are dynamically organized in a tissue-specific manner, possibly reflecting compositional differences. As the mouse brain and liver exhibit very different PCH architecture, we isolated native PCH fractions from these tissues, analyzed their protein compositions using quantitative mass spectrometry, and compared them to identify common and tissue-specific PCH proteins. In addition to heterochromatin-enriched proteins, the PCH proteome includes RNA/transcription and membrane-related proteins, which showed lower abundance than PCH-enriched proteins. Thus, we applied a cut-off of PCH-unspecific candidates based on their abundance and validated PCH-enriched proteins. Amongst the hits, MeCP2 was classified into brain PCH-enriched proteins, while linker histone H1 was not. We found that H1 and MeCP2 compete to bind to PCH and regulate PCH organization in opposite ways. Altogether, our workflow of unbiased PCH isolation, quantitative mass spectrometry, and validation-based analysis allowed the identification of proteins that are common and tissue-specifically enriched at PCH. Further investigation of selected hits revealed their opposing role in heterochromatin higher-order architecture in vivo.

Increased Collagen I/Collagen III Ratio Is Associated with Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse.

Background: The increase in the collagen I (COL I)/COL III ratio enhances vessel wall stiffness and renders vessels less resistant to blood flow and pressure changes. Activated microglia enhance inflammation-induced fibrosis. Hypotheses: The COL I/COL III ratio in human and mouse brain arteriovenous malformations (bAVMs) is associated with bAVM hemorrhage, and the depletion of microglia decreases the COL I/COL III ratio and hemorrhage. Method: COL I, COL III, and hemorrhages were analyzed in 12 human bAVMs and 6 control brains, and mouse bAVMs induced in three mouse lines with activin receptor-like kinase 1 (n = 7) or endoglin (n = 7) deleted in the endothelial cells or brain focally (n = 5). The controls for the mouse study were no-gene-deleted litter mates. Mouse bAVMs were used to test the relationships between the Col I/Col III ratio and hemorrhage and whether the transient depletion of microglia reduces the Col I/Col III ratio and hemorrhage. Results: The COL I/COL III ratio was higher in the human and mouse bAVMs than in controls. The microhemorrhage in mouse bAVMs was positively correlated with the Col I/Col III ratio. Transient depletion of microglia reduced the Col I/Col III ratio and microhemorrhage. Conclusions: The COL I/COL III ratio in the bAVMs was associated with bAVM hemorrhage. The depletion of microglia reduced the bAVM Col I/Col III ratio and hemorrhage.

Protein Level Quantification Across Fluorescence-based Platforms.

Biological processes are dependent on protein concentration and there is an inherent variability among cells even in environment-controlled conditions. Determining the amount of protein of interest in a cell is relevant to quantitatively relate it with the cells (patho)physiology. Previous studies used either western blot to determine the average amount of protein per cell in a population or fluorescence intensity to provide a relative amount of protein. This method combines both techniques. First, the protein of interest is purified, and its concentration determined. Next, cells containing the protein of interest with a fluorescent tag are sorted into different levels of intensity using fluorescence-activated cell sorting, and the amount of protein for each intensity category is calculated using the purified protein as calibration. Lastly, a calibration curve allows the direct relation of the amount of protein to the intensity levels determined with any instrument able to measure intensity levels. Once a fluorescence-based instrument is calibrated, it is possible to determine protein concentrations based on intensity. Key features • This method allows the evaluation and comparison of protein concentration in cells based on fluorescence intensity. • Requires protein purification and fluorescence-activated cell sorting. • Once calibrated for one protein, it allows determination of the levels of this protein using any fluorescence-based instrument. • Allows to determine subcellular local protein concentration based on combining volumetric and intensity measurements.

Development of prevalence and incidence of non-tuberculous mycobacteria in German laboratories from 2016 to 2020.

Numbers of non-tuberculous mycobacteria (NTM) pulmonary diseases (PD) have been repeatedly reported as increasing over the last decades, particularly in Europe. Sound epidemiological data are however missing for most European regions. This study calculated prevalence and incidence of NTM recovered from patients' lungs in Germany, the largest Central European country, over a five-year period. It furthermore determined regional particularities of NTM species and results from susceptibility testing. 22 German NTM laboratories provided their mycobacteriological diagnostic data of 11,430 NTM isolates recovered from 5998 pulmonary patients representing 30% of all notified NTM-PD cases of Germany from 2016 to 2020. NTM incidence and prevalence were calculated for every study year. The presented epidemiological indicators are particularly reliant as TB surveillance data were used as a reference and TB notification reaches almost 100% in Germany. Laboratory incidence and prevalence of NTM recovered from respiratory samples ranged from 4.5-4.9 and from 5.3-5.8/100,000 for the population of Germany, respectively, and did not change over the five-year study period. Prevalence and incidence were stable also when stratifying for facultative pathogenic NTM, M. avium/intracellulare complex (MAIC), and M. abscessus/chelonae complex (MABSC). The proportion of NTM with drug susceptibility testing (DST) increased from 27.3% (2016) to 43.8% (2020). The unchanging laboratory NTM prevalence/incidence in Germany represents a "ceiling" of possible NTM-PD notification when diagnostic strategies do not change in the coming years. A notable increase in NTM-DST may indicate better notification of NTM-PD and/or awareness of new clinical guidelines but still remains below clinical needs.

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.

Crystal structure and Hirshfeld analysis of trans-di-iodido-bis-[(methyl-sulfan-yl)benzene-κS]platinum(II).

The title complex, [PtI2(C7H8I2)2], represents a further example of a square-planar PtII-di-thio-ether complex. It crystallizes in the monoclinic space group P21/c. Additional Hirshfeld analyses indicate a C-H⋯π inter-action along the [010] axis to be the most important packing factor.

[Home-care services in the first two waves of the COVID-19 pandemic: challenges for staff and care recipients]. / Ambulante Pflege in den ersten beiden Wellen der COVID-19-Pandemie: Herausforderungen für Personal und Pflegebedürftige.

INTRODUCTION: During the COVID-19 pandemic, people in need of long-term care were among the most vulnerable population groups. Home-care services were under exceptional strain, especially at the beginning of the pandemic. The aim of this study is to examine the situation and problems of care services and the people in need of care during the first two waves of the pandemic in Germany. METHODS: Two cross-sectional studies were conducted during the first two COVID-19 waves (first survey 28 April to 12 May 2020, second survey 12 January to 7 February 2021). In total, data from N = 1029 outpatient care services were included in the analysis. Descriptive measures were used for the analysis. RESULTS: The clients of home-care services were severely burdened in the first two waves of the pandemic. This can be seen on the one hand in an increased risk of illness and increased mortality, and on the other in the loss of various care and support services. The latter also has negative effects on the psychosocial condition of those in need of care, for example. Care services were affected by high staff absenteeism and additional work due to protective measures. DISCUSSION: The COVID-19 pandemic led to immense burdens for people in need of care and home-care services and to a reduction in care services. The deterioration of care provision met with an already tense situation. It has become clear that the provision of care for those in need of care by outpatient care services is not crisis-proof, and that additional challenges such as a pandemic can have dramatic consequences. For the future, reliable structures and readily available emergency plans should be established with concrete instructions for action.

[The situation of informal caregivers of working age in the COVID-19 pandemic-results of an online survey in Germany]. / Die Situation pflegender Angehöriger im erwerbsfähigen Alter in der COVID-19-Pandemie ­ Ergebnisse einer Onlinebefragung in Deutschland.

BACKGROUND: The consequences of the COVID-19 pandemic have posed major challenges to different groups. One of these are informal caregivers. This study investigates the changes the pandemic has caused for informal caregivers and the extent to which quality of life and burden of care have changed for specific subgroups. METHODS: Data for this cross-sectional study was gathered in the summer of 2020 in a convenient sample of informal caregivers (< 67 years of age, N = 1143). In addition to sociodemographic data, information on the care situation, compatibility of care and work, as well as stress and quality of life was collected in an online survey. The analysis of care situations and compatibility of care and work is done descriptively. Logistic regression models are used for a subgroup analysis of quality of life and care burden. RESULTS: The care situation has changed for 54.7% of participants and has become more time consuming. For 70.8% of respondents, the COVID-19 pandemic has made it even more difficult to balance care-giving and work. However, most respondents were satisfied with their employers' pandemic management (65.9%). A sharp decline in the quality of life and an increase in the burden of care for informal caregivers was ascertained. Both developments are stronger for young and female caregivers and for those caring for people with a greater need of support. DISCUSSION: The results indicate that living situations worsened for a substantial proportion of informal caregivers during the COVID-19 pandemic. Policymakers should recognize additional challenges that informal caregivers have faced since the outbreak of the COVID-19 pandemic and how they vary by subgroups. It is important to include home-based informal care as well as other care settings in future pandemic concepts.