Design of amyloidogenic peptide traps.

Segments of proteins with high ß-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in ß-strand and ß-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs bind their cognate peptides in vitro with nanomolar affinities. The crystal structure of a designed protein-peptide complex is close to the design model, and NMR characterization reveals how the peptide-binding cleft is protected in the apo state. We use the approach to design binders to the amyloid-forming proteins transthyretin, tau, serum amyloid A1 and amyloid ß1-42 (Aß42). The Aß binders block the assembly of Aß fibrils as effectively as the most potent of the clinically tested antibodies to date and protect cells from toxic Aß42 species.

Surface patches induce nonspecific binding and phase separation of antibodies.

Nonspecific interactions are a key challenge in the successful development of therapeutic antibodies. The tendency for nonspecific binding of antibodies is often difficult to reduce by rational design, and instead, it is necessary to rely on comprehensive screening campaigns. To address this issue, we performed a systematic analysis of the impact of surface patch properties on antibody nonspecificity using a designer antibody library as a model system and single-stranded DNA as a nonspecificity ligand. Using an in-solution microfluidic approach, we find that the antibodies tested bind to single-stranded DNA with affinities as high as KD = 1 µM. We show that DNA binding is driven primarily by a hydrophobic patch in the complementarity-determining regions. By quantifying the surface patches across the library, the nonspecific binding affinity is shown to correlate with a trade-off between the hydrophobic and total charged patch areas. Moreover, we show that a change in formulation conditions at low ionic strengths leads to DNA-induced antibody phase separation as a manifestation of nonspecific binding at low micromolar antibody concentrations. We highlight that phase separation is driven by a cooperative electrostatic network assembly mechanism of antibodies with DNA, which correlates with a balance between positive and negative charged patches. Importantly, our study demonstrates that both nonspecific binding and phase separation are controlled by the size of the surface patches. Taken together, these findings highlight the importance of surface patches and their role in conferring antibody nonspecificity and its macroscopic manifestation in phase separation.

Endogenously produced catecholamines improve the regulatory function of TLR9-activated B cells.

The sympathetic nervous system (SNS) contributes to immune balance by promoting anti-inflammatory B cells. However, whether B cells possess a self-regulating mechanism by which they modulate regulatory B cell (Breg) function is not well understood. In this study, we investigated the ability of B cells to synthesize their own catecholamines upon stimulation with different B cell activators and found that expression of the enzyme tyrosine hydroxylase (TH), required to generate catecholamines, is up-regulated by Toll-like receptor (TLR)9. This TLR9-dependent expression of TH correlated with up-regulation of adrenergic receptors (ADRs), enhanced interleukin (IL)-10 production, and overexpression of the co-inhibitory ligands programmed death ligand 1 (PD-L1) and Fas ligand (FasL). Moreover, concomitant stimulation of ß1-3-ADRs together with a B cell receptor (BCR)/TLR9 stimulus clearly enhances the anti-inflammatory potential of Bregs to suppress CD4 T cells, a crucial population in the pathogenesis of autoimmune diseases, like rheumatoid arthritis (RA). Furthermore, TH up-regulation was also demonstrated in B cells during the course of collagen-induced arthritis (CIA), a mouse model for the investigation of RA. In conclusion, our data show that B cells possess an autonomous mechanism to modulate their regulatory function in an autocrine and/or paracrine manner. These findings help to better understand the function of B cells in the regulation of autoimmune diseases and the interplay of SNS.

Sharp, localized phase transitions in single neuronal cells.

The origin of nonlinear responses in cells has been suggested to be crucial for various cell functions including the propagation of the nervous impulse. In physics, nonlinear behavior often originates from phase transitions. Evidence for such transitions on the single-cell level, however, has so far not been provided, leaving the field unattended by the biological community. Here, we demonstrate that single cells of a human neuronal cell line display all optical features of a sharp, highly nonlinear phase transition within their membrane. The transition is reversible and does not originate from protein denaturation. Triggered by temperature and modified by pH here, a thermodynamic approach strongly suggests that similar nonlinear state changes can be induced by other variables such as calcium or mechanical stress. At least in lipid membranes, such state changes are accompanied by significant changes in permeability, enzyme activity, elastic, and electrical properties.

EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.

OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.

Specific Regulation of Enzymatic Activity by Interface Pulses.

The thermodynamic state of the interface in which an enzyme is embedded can regulate the enzymatic activity. Indeed, it has been demonstrated by others and us that close to the maximum in compressibility, the activity of the enzyme is at a maximum as well. Pulses propagating along the interface can modulate the interface state and were demonstrated to be able to modulate the activity of interface-associated acetylcholinesterase (AChE). Here, we demonstrate that enzyme activity modulation by interface pulses depends specifically on the pulse type. Using membrane-embedded enzyme phospholipase A2 (PLA2), enzyme activity can be monitored by detecting the lateral pressure without an additional assay required. We show that pulses that shift the state toward higher pressure and higher lateral density increase the enzymatic activity, while pulses that reduce the pressure induce the opposite effect. These results further support a physical mechanism for enzyme-enzyme communication where compressibility, lateral density, and pressure (thermodynamic state) and not specific molecular modifications regulate enzymatic activity.

Treat to target and shared decision-making in systemic lupus erythematosus from the patients' perspective: results from an international patient survey.

OBJECTIVES: Treat-to-target (T2T) is being recognised as a promising concept to significantly improve the outcomes of patients with systemic lupus erythematosus (SLE). Despite its success being closely tied to patients' involvement, the patients' perspective regarding T2T has not been evaluated. We aimed to investigate patients' attitude towards T2T and their involvement in treatment decisions. METHODS: We designed a 13-question online survey on T2T, examining acceptance, willingness to participate in T2T trials, and potential obstacles. This was distributed amongst Dutch, Austrian, German, and Bulgarian patient organisations. RESULTS: In total, 863 patients participated of whom 48.4% reported being in remission, while 13% were uncertain about their remission status. Regarding shared decision-making, 62.1% reported being somewhat fully involved in treatment decisions, while 20.7% felt uninvolved. Shared decision-making was associated with disease duration, Dutch origin and satisfaction with treatment and remission. As for satisfaction with their health status, 56.2% were somewhat fully satisfied, while 29.3% were unsatisfied. 65.5% were satisfied with their treatment, 14.8% were not. Leading treatment goals were quality of life (QoL) normalisation (37.4%), organ damage prevention (24.6%) and absence of disease activity (22.6%). T2T was mainly seen positive with additional doctors' visits and initiation of new immunosuppressive drugs as potential disadvantages. CONCLUSIONS: T2T was perceived as beneficial with improvement of QoL as the most important treatment goal and the possibility of additional doctors' visits and initiation of new immunosuppressive agents as potential drawbacks. Patients unsatisfied with their health status and treatment may benefit from greater involvement in treatment decisions.

Structural Analysis of Breast-Milk αS1-Casein: An α-Helical Conformation Is Required for TLR4-Stimulation.

Breast-milk αS1-casein is a Toll-like receptor 4 (TLR4) agonist, whereas phosphorylated αS1-casein does not bind TLR4. The objective of this study was to analyse the structural requirements for these effects. In silico analysis of αS1-casein indicated high α-helical content with coiled-coil characteristics. This was confirmed by CD-spectroscopy, showing the α-helical conformation to be stable between pH 2 and 7.4. After in vitro phosphorylation, the α-helical content was significantly reduced, similar to what it was after incubation at 80 °C. This conformation showed no in vitro induction of IL-8 secretion via TLR4. A synthetic peptide corresponding to V77-E92 of αS1-casein induced an IL-8 secretion of 0.95 ng/mL via TLR4. Our results indicate that αS1-casein appears in two distinct conformations, an α-helical TLR4-agonistic and a less α-helical TLR4 non-agonistic conformation induced by phosphorylation. This is to indicate that the immunomodulatory role of αS1-casein, as described before, could be regulated by conformational changes induced by phosphorylation.

[ViaCogScreen: An Efficient, Valid, and Repeatable Screening Tool for Cognitive Performance Assessment of the Elderly]. / ViaCogScreen: ein zeitökonomisches, valides und wiederholbares Screeningverfahren zum Leistungsmonitoring älterer Menschen.

Given the demographic change with an aging society in Germany, cognitive performance assessment of the elderly is of great importance. The Viacogscreen developed by us is a computer- and web-based brain performance screening for older adults that not only meets the criteria of a measurement instrument, but is also economical and repeatable. The test captures interlocking word list learning with delayed free recall and recognition, semantic word selection and fluidity, phonemic word fluidity and inverted number range, as well as incidental memory, resulting in a total of 17 performance parameters that provide a quick orientation (approximate test duration: 10-12 minutes) regarding the cognitive performance of a test subject. Three performance areas are depicted: executive functions, episodic and semantic memory. The test was standardized for 200 healthy test subjects in 6 different age groups (range: 50-85 years). For the first clinical validation, the test was used in the memory clinics in Bonn and Ulm, where 33 patients with MCI (mild cognitive impairment) and 42 patients with suspected Alzheimer's disease (VAD) were tested. A control group of 42 healthy people of approximately the same age served as the control group. With regard to the cognitive test procedure, all three groups showed significantly different results regarding the overall score (ANOVA F=73.9, p<0.001), executive functions (F=27.6 p<0.001) and semantic memory (F=54.4 p<0.001). Regarding episodic memory, both clinical groups differed significantly from the control group, but not from each other (F=48.7, p<0.001). The Viacogscreen thus produced very good results in its first validation in two memory clinics with regard to differentiation of VAD, and good results with regard to MCI. In addition to use in neurodegenerative diseases, the Viacogscreen is also suitable for other neurological and neuro-oncological diseases, as well as for use in large clinical studies since it enables electronic data collection.

De Novo Human Angiotensin-Converting Enzyme 2 Decoy NL-CVX1 Protects Mice From Severe Disease After Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.

Defining the physician global assessment threshold equivalent to remission in patients with systemic lupus erythematosus.

OBJECTIVES: The optimal threshold of the physician global assessment (PGA) for remission in SLE has never been evaluated systematically. The aim of this study was to assess the ideal PGA threshold associated with physician remission and to investigate its impact on remission rates in our Lupus cohort. METHODS: In this monocentric cross-sectional study, patients with SLE were evaluated for physician remission by asking the treating physicians if they considered their patient in remission regardless of objective remission criteria. Further, two objective remission definitions were applied: 1) DORIS remission using a PGA of < 2 (0-10) (corresponding to < 0.5 on a VAS 0-3 used in DORIS); 2) DORIS remission with omission of PGA (modDORIS). A receiver operating characteristic analysis and regression analyses were performed to assess the ideal PGA threshold and factors influencing PGA. RESULTS: Of the 233 patients included, 126 patients (54.0%) were in physician remission, 42.5% in DORIS remission and 67.0% in modDORIS remission. A PGA of < 2 NRS 0-10) had the highest sensitivity (79%) and specificity (81%) for physician remission and modDORIS (AUC 0.85 and 0.69). PGA of patients fulfilling any of the remission definitions was associated with pain and hypocomplementemia. Damage was numerically higher in patients in modDORIS only; no association between PGA and damage was found in regression analysis. CONCLUSION: Using a PGA threshold of < 2 (0-10), corresponding to < 0.6 (0-3) resulted in best prediction of physician remission. PGA levels seem to be influenced by pain and complement levels but not disease damage.

Beneficial effects associated to a healthy lifestyle in systemic lupus erythematosus: A cross-sectional study.

OBJECTIVE: To assess whether a healthy lifestyle is associated to beneficial effects on various systemic lupus erythematosus (SLE) health domains. METHODS: In a cross-sectional study, Mediterranean Diet Adherence Score (MEDAS), physical activity energy expenditure (PAEE), and smoking status were assessed by questionnaires, along with clinical parameters and various health domains including Systemic Lupus Disease Activity Score (SLEDAI), Depression Scale (CES-D), Fatigue Severity (FSS), functional status (FFbH), physical and mental quality of life (PCS, MCS). Lifestyle choices were assessed with respect to health domains by linear regression modeling. Additionally, SLE patients with a healthy lifestyle (MEDAS ≥ 4, ≥ 1 h sport per week, no smoking) were compared to those without by Wilcoxon's signed-rank test. RESULTS: 49 of 145 SLE patients (44.3 ± 31.7 years, 87.6% female) followed a healthy lifestyle and showed a higher physical quality of life (ß = 4.5 (95%-CI 1.5-7.9) p = 0.01), lower depression (ß = -5.0 (-8.2 to -0.2) p = 0.02) and lower fatigue (ß = -0.8 (-1.5 to -0.2) p = 0.01) independently of SLE disease activity. Furthermore, dsDNA-antibodies were lower (146 ± 540 vs 266 ± 146 U/mL, p = 0.049). In a more detailed analysis, physical activity had the highest impact on the various health domains when compared to smoking or diet adherence, which was consistent even after adjusting for multiple potential confounders. Each 1,000 kcal of weekly PAEE was associated to a 1.8 (0.9-2.6) point increase in the PCS (p = 0.0001), a 0.2 (0.03-0.4) point decrease in the CES-D (p = 0.01) and a 2.8 (1.2-4.4) point increase in the FFbH (p = 0.0006). CONCLUSION: A healthy lifestyle, especially physical activity is associated with beneficial effects including quality of life, depression and fatigue in SLE.

Survival after resection of brain metastasis: impact of synchronous versus metachronous metastatic disease.

PURPOSE: Patients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM. METHODS: Between 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors' neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis. RESULTS: Non-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p = 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5-16.5) compared to 13 months (95% CI 9.6-16.4) for patients with metachronous BM diagnosis (p = 0.97). CONCLUSIONS: The present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence.

The proneural subtype is not associated with survival benefit from bevacizumab in newly diagnosed glioblastoma: a secondary analysis of the GLARIUS trial.

PURPOSE: The AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort. METHODS: We evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models. RESULTS: Employing the Phillips classifier, bevacizumab conferred a significant PFS advantage in patients with proneural IDH wild-type tumors (10.4 vs. 6.0 months, p = 0.002), but no OS advantage (16.4 vs. 17.4 months, p = 0.6). Multivariable analysis adjusting for prognostic covariates confirmed the absence of a significant OS advantage from bevacizumab (hazard ratio, 1.05, 95% CI, 0.42 to 2.64; p = 0.14). Further, there was no interaction between the proneural subtype and treatment arm (p = 0.15). These results were confirmed in analyses of tumor subgroups according to the Verhaak classifier. CONCLUSION: In contrast to AVAglio, glioblastoma gene expression subgroups were not associated with a differential OS benefit from first-line bevacizumab in the GLARIUS trial.

Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses.

PURPOSE: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO). METHODS: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T1-enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined. RESULTS: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T1-enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm. CONCLUSION: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.

Outcome assessment of intraoperative radiotherapy for brain metastases: results of a prospective observational study with comparative matched-pair analysis.

PURPOSE: Intraoperative radiation therapy (IORT) is an emerging alternative to adjuvant stereotactic external beam radiation therapy (EBRT) following resection of brain metastases (BM). Advantages of IORT include an instant prevention of tumor regrowth, optimized dose-sparing of adjacent healthy brain tissue and immediate completion of BM treatment, allowing an earlier admission to subsequent systemic treatments. However, prospective outcome data are limited. We sought to assess long-term outcome of IORT in comparison to EBRT. METHODS: A total of 35 consecutive patients, prospectively recruited within a study registry, who received IORT following BM resection at a single neuro-oncological center were evaluated for radiation necrosis (RN) incidence rates, local control rates (LCR), distant brain progression (DBP) and overall survival (OS) as long-term outcome parameters. The 1 year-estimated OS and survival rates were compared in a balanced comparative matched-pair analysis to those of our institutional database, encompassing 388 consecutive patients who underwent adjuvant EBRT after BM resection. RESULTS: The median IORT dose was 30 Gy prescribed to the applicator surface. A 2.9% RN rate was observed. The estimated 1 year-LCR was 97.1% and the 1 year-DBP-free survival 73.5%. Median time to DBP was 6.4 (range 1.7-24) months in the subgroup of patients experiencing intracerebral progression. The median OS was 17.5 (0.5-not reached) months with a 1 year-survival rate of 61.3%, which did not not significantly differ from the comparative cohort (p = 0.55 and p = 0.82, respectively). CONCLUSION: IORT is a safe and effective fast-track approach following BM resection, with comparable long-term outcomes as adjuvant EBRT.

Intraoperative or postoperative stereotactic radiotherapy for brain metastases: time to systemic treatment onset and other patient-relevant outcomes.

PURPOSE: Intraoperative radiotherapy (IORT) has become a viable treatment option for resectable brain metastases (BMs). As data on local control and radiation necrosis rates are maturing, we focus on meaningful secondary endpoints such as time to next treatment (TTNT), duration of postoperative corticosteroid treatment, and in-hospital time. METHODS: Patients prospectively recruited within an IORT study registry between November 2020 and June 2023 were compared with consecutive patients receiving adjuvant stereotactic radiotherapy (SRT) of the resection cavity within the same time frame. TTNT was defined as the number of days between BM resection and start of the next extracranial oncological therapy (systemic treatment, surgery, or radiotherapy) for each of the groups. RESULTS: Of 95 BM patients screened, IORT was feasible in 84 cases (88%) and ultimately performed in 64 (67%). The control collective consisted of 53 SRT patients. There were no relevant differences in clinical baseline features. Mean TTNT (range) was 36 (9 - 94) days for IORT patients versus 52 (11 - 126) days for SRT patients (p = 0.01). Mean duration of postoperative corticosteroid treatment was similar (8 days; p = 0.83), as was mean postoperative in-hospital time (11 versus 12 days; p = 0.97). Mean total in-hospital time for BM treatment (in- and out-patient days) was 11 days for IORT versus 19 days for SRT patients (p < 0.001). CONCLUSION: IORT for BMs results in faster completion of interdisciplinary treatment when compared to adjuvant SRT, without increasing corticosteroid intake or prolonging in-hospital times. A randomised phase III trial will determine the clinical effects of shorter TTNT.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Modification of 3D-Printed PLA Structures Using Photo-Iniferter Polymerization: Toward On-Demand Antimicrobial Water Filters.

Water filtration is an important application to ensure the accessibility of clean drinking water. As requirements and contaminants vary on a local level, adjustable filter devices and their evaluation with contaminants are required. Within this work, modular filter devices are designed featuring an adjustable surface functionalization. For this purpose, 3D-printed structures are created consisting of bio-based poly(lactic acid) (PLA) that are manufactured by extrusion printing. The surface of PLA is activated with amino groups that are used to install xanthates as chain transfer agents. Subsequently, photo-iniferter (PI) polymerization is used to create cationic polymer brushes on the surface of PLA substrates. Multiple surface characterization techniques are employed to prove successful growth of polymer brushes on PLA. After initial optimization studies on flat surfaces, filter devices are printed, functionalized, and used to remove bacteria from contaminated water. Significant reduction of the number of microorganisms is detected after filtration (single filtration or cycling) and contaminating organism can also be removed from freshwater samples by simple incubation with a 3D-printed filter. The herein developed setup for producing functional filter devices and probing their performance in affinity filtration is a useful platform technology, enabling the rapid testing of polymer brushes for such applications.

Myocardial Recovery, Metabolism, and Structure after Cardiac Arrest with Cardioplexol.

OBJECTIVES: Clinical studies indicate encouraging cardioprotective potential for Cardioplexol. Its cardioprotective capacities during 45 minutes of ischemia compared with pure no-flow ischemia or during 90 minutes of ischemia compared with Calafiore cardioplegia were investigated experimentally. METHODS: Forty-four rat hearts were isolated and inserted into a blood-perfused pressure-controlled Langendorff apparatus. In a first step, cardiac arrest was induced by Cardioplexol or pure no-flow ischemia lasting 45 minutes. In a second step, cardiac arrest was induced by Cardioplexol or Calafiore cardioplegia lasting 90 minutes. For both experimental steps, cardiac function, metabolic parameters, and troponin I levels were evaluated during 90 minutes of reperfusion. At the end of reperfusion, hearts were fixed, and ultrastructural integrity was examined by electron microscopy. RESULTS: Step 1: after 90 minutes of reperfusion, hearts exposed to Cardioplexol had significantly higher left ventricular developed pressure (CP-45': 74%BL vs. no-flow-45': 45%BL; p = 0.046) and significantly better maximal left ventricular relaxation (CP-45': 84%BL vs. no-flow-45': 51%BL; p = 0.012). Oxygen consumption, lactate production, and troponin levels were similar in both groups. Step 2: left ventricular developed pressure was lower (22 vs. 48% of BL; p = 0.001) and coronary flow was lower (24 vs. 53% of BL; p = 0.002) when Cardioplexol was used compared with Calafiore cardioplegia. Troponin I levels were significantly higher under Cardioplexol (358.9 vs. 106.1 ng/mL; p = 0.016). CONCLUSION: Cardioplexol significantly improves functional recovery after 45 minutes of ischemia compared with pure ischemia. However, Cardioplexol protects the myocardium from ischemia/reperfusion-related damage after 90 minutes of ischemia worse than Calafiore cardioplegia.