Recruitment of epitope-specific T cell clones with a low-avidity threshold supports efficacy against mutational escape upon re-infection.

Repetitive pathogen exposure leads to the dominant outgrowth of T cell clones with high T cell receptor (TCR) affinity to the relevant pathogen-associated antigens. However, low-affinity clones are also known to expand and form immunological memory. While these low-affinity clones contribute less immunity to the original pathogen, their role in protection against pathogens harboring immune escape mutations remains unclear. Based on identification of the TCR repertoire and functionality landscape of naive epitope-specific CD8+ T cells, we reconstructed defined repertoires that could be followed as polyclonal populations during immune responses in vivo. We found that selective clonal expansion is governed by clear TCR avidity thresholds. Simultaneously, initial recruitment of broad TCR repertoires provided a polyclonal niche from which flexible secondary responses to mutant epitopes could be recalled. Elucidating how T cell responses develop "from scratch" is informative for the development of enhanced immunotherapies and vaccines.

Prevalence of obesity and cardiovascular disease in adults with type 2 diabetes and use of diabetes medication in Germany: A claims data study.

AIMS: To identify the prevalence of cardiovascular disease (CVD) and obesity in patients with type 2 diabetes (T2D) in Germany and to evaluate if antidiabetic treatment patterns varied by comorbidity status. MATERIALS AND METHODS: Patients with T2D (aged ≥18 years) were identified during the study period (2014-2020) from medical claims of 4.5 million publicly insured German residents and divided into different cohorts based on CVD and/or obesity diagnosis. Annual prevalence and incidence were estimated for each study year, while characteristics and treatments were assessed in 2020. Data were extrapolated to the German population by age and sex. RESULTS: The prevalence of T2D in 2020 was 11.4%. Among patients with T2D, 53.0% had CVD, 39.3% had obesity, and 20.9% had CVD and obesity. Since 2014, CVD increased by 1.4%, obesity by 4.5%, and CVD with obesity by 2.7% in patients with T2D. The incidence of T2D in 2020 was 1.0% (42.9% had CVD, 37.9% had obesity, and 15.8% had CVD and obesity). Among the prevalent T2D population in 2020, 4.9% received glucagon-like peptide-1 receptor agonists (GLP-1RAs), 9.7% received sodium-glucose cotransporter-2 (SGLT2) inhibitors, and 13.0% received GLP-1 RAs and/or SGLT2 inhibitors. Of those with CVD, 12.9% received GLP-1 RAs and/or SGLT2 inhibitors (without CVD, 13.2%). Of those with obesity, 19.4% received GLP-1RAs and/or SGLT2 inhibitors (without obesity, 9.0%). CONCLUSIONS: In this retrospective claims database study, more than two thirds of patients with T2D also had CVD, obesity, or both CVD and obesity. GLP-1 RA and SGLT2 inhibitor use remained low.

Poly(2-oxazoline)-Antibiotic Conjugates with Penicillins.

The conjugation of antibiotics with polymers is rarely done, but it might be a promising alternative to low-molecular-weight derivatization. The two penicillins penicillin G (PenG) and penicillin V (PenV) were attached to the end groups of different water-soluble poly(2-oxazoline)s (POx) via their carboxylic acid function. This ester group was shown to be more stable against hydrolysis than the ß-lactam ring of the penicillins. The conjugates are still antimicrobially active and up to 20 times more stable against penicillinase catalyzed hydrolysis. The antibiotic activity of the conjugates against Staphylococcus aureus in the presence of penicillinase is up to 350 times higher compared with the free antibiotics. Conjugates with a second antimicrobial function, a dodecyltrimethylammonium group (DDA-X), at the starting end of the PenG and PenV POx conjugates are more antimicrobially active than the conjugates without DDA-X and show high activity in the presence of penicillinase. For example, the conjugates DDA-X-PEtOx-PenG and DDA-X-PEtOx-PenV are 200 to 350 times more active against S. aureus in the presence of penicillinase and almost as effective as the penicillinase stable cloxacollin (Clox) under these conditions. These conjugates show even greater activity compared to cloxacollin without this enzyme present. Further, both conjugates kill Escherichia coli more effectively than PenG and Clox.

Evaluation of Adherence and Persistence to Triple Therapy in Patients with COPD: A German Claims Data Study.

Purpose: Triple therapy (long-acting muscarinic antagonist/long-acting ß2-agonist/inhaled corticosteroid) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence. This study assessed comparative adherence and persistence to single-inhaler triple therapy (SITT) versus MITT among patients with COPD in a real-world setting in Germany. Patients and Methods: This retrospective analysis using the WIG2 benchmark database identified patients with COPD newly initiating triple therapy with MITT or SITT (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or formoterol/beclomethasone/glycopyrronium bromide [FOR/BDP/GLY]) November 2017-June 2019. Eligible patients were ≥35 years with 1 year's continual insurance prior to triple therapy initiation and no previous record of triple therapy. Inverse probability of treatment weighting was used to balance baseline characteristics. Adherence was measured using proportion of days covered (PDC) at 6, 12, and 18 months post-treatment initiation; persistence (time until treatment discontinuation) was measured at 6, 12, and 18 months, with a gap of >30 days used to define non-persistence. Results: Of 5710 patients included in the analysis (mean age 66 years), 71.4% initiated MITT and 28.6% initiated SITT (FF/UMEC/VI: 41.4%; FOR/BDP/GLY: 58.6%). Mean PDC was higher among SITT versus MITT users at all time points; at each time point, mean PDC was highest among FF/UMEC/VI users. During the first 6 months following treatment initiation, higher adherence was exhibited by FF/UMEC/VI (29%) and FOR/BDP/GLY (19%) users versus MITT users. Over the entire observation period, FF/UMEC/VI users had the highest proportion of persistent patients; at 18 months, 16.5% of FF/UMEC/VI users were persistent versus 2.3% of MITT users. Conclusion: Patients initiating SITT in Germany had significantly higher adherence and persistence compared with patients initiating MITT over 6 to 18 months following treatment initiation. Among SITT, FF/UMEC/VI users had the highest proportion of adherence and persistence.

Acoustically Induced Vocal Training for Individuals With Impaired Hearing.

OBJECTIVES/HYPOTHESIS: Articulation, phonation, and resonance disorders in the speech of hearing-impaired-speakers reduces intelligibility. The study focusses on (1) whether nonacoustic feedback may facilitate the adjustment of the vocal tract, leading to increased vocal tract resonance, and (2) whether training with the feedback would be helpful for the subsequent formation of vowels. STUDY DESIGN: Prospective. METHODS: Seven profoundly hearing-impaired participants used acoustic sound waves in the frequency range of the first two vocal tract resonances applied in front of the open mouth at intensities above 1 Pa. They were asked to amplify the sound via adjusting the vocal tract. The sound waves corresponded to the first and second resonance frequencies of the vowels [u], [o], and [a]. The self-assessment of the participants and a software-based/auditory analysis was reported. RESULTS: The participants were able to enhance the acoustic signal by adjusting the vocal tract shape. The self-perception of the participants, the auditory voice analysis, and the acoustic analysis of vowels were consistent with each other. While the maximum sound pressure levels were constant, the mean sound pressure levels increased. Breathiness and hoarseness declined during the exercises. Resonance/harmonic-to-noise ratio increased, especially for the vowels [u], [o], [a]. Furthermore, the positively connoted feedback from the participants indicated easier sound production. CONCLUSION: Nonauditory feedback, based on acoustic waves, could be suitable for improving the formation of vowels. The findings are in accordance with a reduction of acoustic losses within the vocal tract.

Adjustment of Vocal Tract Shape via Biofeedback: Influence on Vowels.

The study assessed 30 nonprofessional singers to evaluate the effects of vocal tract shape adjustment via increased resonance toward an externally applied sinusoidal frequency of 900 Hz without phonation. The amplification of the sound wave was used as biofeedback signal and the intensity and the formant position of the basic vowels /a/, /e/, /i/, /o/, and /u/ were compared before and after a vocal tract adjustment period. After the adjustment period, the intensities for all vowels increased and the measured changes correlated with the participants' self-perception.The diferences between the second formant position of the vowels and the applied frequency influences the changes in amplitude and in formant frequencies. The most significant changes in formant frequency occurred with vowels that did not include a formant frequency of 900 Hz, while the increase in amplitude was the strongest for vowels with a formant frequency of about 900 Hz.

Telechelic, Antimicrobial Hydrophilic Polycations with Two Modes of Action.

Telechelic antimicrobial poly(2-oxazoline)s with quaternary ammonium (quat) end groups are shown to be potent antimicrobial polymers against Gram-positive bacterial strains. In this study, the activity against the Gram-negative bacterium Escherichia coli is additionally implemented by hydrolyzing the poly(2-methyl-2-oxazoline) with two quart end groups to poly(ethylene imine) (PEI). The resulting telechelic polycations are active against Staphylococcus aureus and E. coli. The contribution of the PEI backbone is determined by measuring the antimicrobial activity in the presence of calcium ions. The influence of PEI on the overall activity strongly depends on the molecular weight and increases with higher mass. The PEI dominates the activity against E. coli at lower masses than against S. aureus. The quart end groups require an alkyl substituent of dodecyl or longer to dominate the antimicrobial activity. Additionally, PEI and quart end groups act synergistically.

Production, deformation and mechanical investigation of magnetic alginate capsules.

In this article we investigated the deformation of alginate capsules in magnetic fields. The sensitivity to magnetic forces was realised by encapsulating an oil in water emulsion, where the oil droplets contained dispersed magnetic nanoparticles. We solved calcium ions in the aqueous emulsion phase, which act as crosslinking compounds for forming thin layers of alginate membranes. This encapsulating technique allows the production of flexible capsules with an emulsion as the capsule core. It is important to mention that the magnetic nanoparticles were stable and dispersed throughout the complete process, which is an important difference to most magnetic alginate-based materials. In a series of experiments, we used spinning drop techniques, capsule squeezing experiments and interfacial shear rheology in order to determine the surface Young moduli, the surface Poisson ratios and the surface shear moduli of the magnetically sensitive alginate capsules. In additional experiments, we analysed the capsule deformation in magnetic fields. In spinning drop and capsule squeezing experiments, water droplets were pressed out of the capsules at elevated values of the mechanical load. This phenomenon might be used for the mechanically triggered release of water-soluble ingredients. After drying the emulsion-filled capsules, we produced capsules, which only contained a homogeneous oil phase with stable suspended magnetic nanoparticles (organic ferrofluid). In the dried state, the thin alginate membranes of these particles were rather rigid. These dehydrated capsules could be stored at ambient conditions for several months without changing their properties. After exposure to water, the alginate membranes rehydrated and became flexible and deformable again. During this swelling process, water diffused back in the capsule. This long-term stability and rehydration offers a great spectrum of different applications as sensors, soft actuators, artificial muscles or drug delivery systems.