Design and synthesis of novel di‐ and triblock amphiphilic polyelectrolytes:Improving salt‐induced viscosity reduction of water solutions for potential application in enhanced oil recovery

In the present study, three different block copolymers based on styrene, tert‐butyl methacrylate, and glycidyl methacrylate (GMA) were synthesized via sequential atom transfer radical polymerization. The addition of the GMA block was found to be best performed at 60°C. The polymers were then hydrolyzed and neutralized, to afford amphiphilic block copolymers, and the rheological properties of their aqueous solutions were measured, in order to investigate solution properties relevant for enhanced oil recovery, as a function of the polymer structure. It was observed that these polymers behave as thickening agents with shear thinning behavior. As expected, the polymers were sensitive to the presence of salt, as lower viscosities were recorded in saline water. However, the viscosity is less affected by high salinity, when compared to previously studied analogous diblock systems. In the best case, the viscosity only decreased by a factor of 1.8 upon salt addition whereas it decreased by a factor of 10 in previously reported non‐GMA containing polymers. Finally, thermo‐responsive behavior was found for one of the synthesized polymers. In particular, a hydrolyzed triblock poly[styrene‐b‐tert‐butyl methacrylate‐b‐glycidyl methacrylate], which synthesis is reported here for the first time, showed a thermothickening behavior, promising for the intended application in oil recovery

Sex- and age specific association of new-onset atrial fibrillation with in-hospital mortality in hospitalised COVID-19 patients

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a systemic disease with cardiovascular involvement, including cardiac arrhythmias. Notably, new-onset atrial fibrillation (AF) and atrial flutter (AFL) during hospitalisation in COVID-19 patients has been associated with increased mortality. However, how this risk is impacted by age and sex is still poorly understood. METHODS: For this multicentre cohort study, we extracted demographics, medical history, occurrence of electrical disorders and in-hospital mortality from the large international patient registry CAPACITY-COVID. For each electrical disorder, prevalence during hospitalisation was calculated. Subsequently, we analysed the incremental prognostic effect of developing AF/AFL on in-hospital mortality, using multivariable logistic regression analyses, stratified for sex and age. RESULTS: In total, 5782 patients (64% male; median age 67) were included. Of all patients 11.0% (95% CI 10.2–11.8) experienced AF and 1.6% (95% CI 1.3–1.9) experienced AFL during hospitalisation. Ventricular arrhythmias were rare (<0.8% (95% CI 0.6–1.0)) and a conduction disorder was observed in 6.3% (95% CI 5.7–7.0). An event of AF/AFL appeared to occur more often in patients with pre-existing heart failure. After multivariable adjustment for age and sex, new-onset AF/AFL was significantly associated with a poorer prognosis, exemplified by a two- to three-fold increased risk of in-hospital mortality in males aged 60–72 years, whereas this effect was largely attenuated in older male patients and not observed in female patients. CONCLUSION: In this large COVID-19 cohort, new-onset AF/AFL was associated with increased in-hospital mortality, yet this increased risk was restricted to males aged 60–72 years

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study

Purpose: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. Methods: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment (“watch and wait”), chlorambucil treatment only, and patients with other treatment(s). Results: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. Conclusions: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment

Activation of NK Cells by an Endocytosed Receptor for Soluble HLA-G

Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4–containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy

Sex- and age specific association of new-onset atrial fibrillation with in-hospital mortality in hospitalised COVID-19 patients

Background: Coronavirus disease 2019 (COVID-19) is a systemic disease with cardiovascular involvement, including cardiac arrhythmias. Notably, new-onset atrial fibrillation (AF) and atrial flutter (AFL) during hospitalisation in COVID-19 patients has been associated with increased mortality. However, how this risk is impacted by age and sex is still poorly understood. Methods: For this multicentre cohort study, we extracted demographics, medical history, occurrence of electrical disorders and in-hospital mortality from the large international patient registry CAPACITY-COVID. For each electrical disorder, prevalence during hospitalisation was calculated. Subsequently, we analysed the incremental prognostic effect of developing AF/AFL on in-hospital mortality, using multivariable logistic regression analyses, stratified for sex and age. Results: In total, 5782 patients (64% male; median age 67) were included. Of all patients 11.0% (95% CI 10.2–11.8) experienced AF and 1.6% (95% CI 1.3–1.9) experienced AFL during hospitalisation. Ventricular arrhythmias were rare (<0.8% (95% CI 0.6–1.0)) and a conduction disorder was observed in 6.3% (95% CI 5.7–7.0). An event of AF/AFL appeared to occur more often in patients with pre-existing heart failure. After multivariable adjustment for age and sex, new-onset AF/AFL was significantly associated with a poorer prognosis, exemplified by a two- to three-fold increased risk of in-hospital mortality in males aged 60–72 years, whereas this effect was largely attenuated in older male patients and not observed in female patients. Conclusion: In this large COVID-19 cohort, new-onset AF/AFL was associated with increased in-hospital mortality, yet this increased risk was restricted to males aged 60–72 years

Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders

For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs

Complement Activation in the Disease Course of Coronavirus Disease 2019 and Its Effects on Clinical Outcomes

Background: Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications, and mortality rate. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown. Methods: A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. Results: Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (P<.05). These complement factors were especially elevated in intensive care unit patients during the entire disease course (P<.005 for C3a and TCC). More intense complement activation was observed in patients who died and in those with thromboembolic events. Conclusions: Patients with COVID-19 demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated proinflammatory response associated with increased mortality rate and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19