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One of the most important advantages of twin-fluid atomizers over other atomizers is the opportunity of atomizing liquids in a wide range of liquid properties efficiently. Thus, the fundamentals of spray dynamics, such as spray pattern, liquid breakup length, and spatial droplet size evolution using different liquid properties need to be investigated in some detail. The purpose of this study is therefore to examine and describe the influence of the liquid viscosity and surface tension on the spray performance of prefilming air-blast atomizers. A high-speed background shadowgraphy technique associated with particle tracking and Phase Doppler Anemometry (PDA) as a non-intrusive high-resolution local measurement technique were utilized to study the atomization process regarding the influence of the liquid properties on the spray quality. Generally, the break up mechanism is considerably influenced by the liquid viscosity. The breakup length ( ) is dependent on liquid viscosity with for Pa = 0.25 and 0.6 bar air pressure, respectively. Droplet size distribution profiles of different liquids in axial and radial directions are studied. No significant influences of the surface tension and viscosity were observed on the mean droplet velocity downstream of the spray. A minor increase of the droplet mean diameter was observed with liquid viscosity variations from 22 to 111 mPas, however, the liquid surface tension was verified to play an important role in the atomization process at prefilming airblast atomizers as well. According to the available experimental data, it has subsequently been possible to develop an original and descriptive model based on a dimensional approach at different air pressure ranges.

The aim of the present work is the investigation of the turbulent flow field downstream of an axisymmetric sudden expansion with a large aspect ratio of D/d = 12,3. For the fundamentally understanding of the flow some numerical results are presented. They were achieved by using the RANS approach and SST turbulence model. The flow field is characterized by a jet-like flow near the nozzle exit and a large toroidal recirculation zone. The x-component of the velocity u was measured using one-component laser Doppler velocimetry. Axial and radial velocity distributions as well as some velocity spectra were measured. The spectra were calculated from the velocity signal using the Sample-And-Hold method together with the refinement technique. At the axial half length of the recirculation zone at the edge of the jet flow a narrow band peak was observed in spectra, suggesting the existence of large-scale fluctuations or instability of the flow field. Further investigations reveal that this effect is locally limited and shows no sensitivity against changes of the inlet conditions, e.g. the Reynolds number and velocity profile.

A bulk of a liquid dispersed into single droplets using the kinetic energy of a high-velocity gas in an air-blast atomizer is frequently employed in technical atomization processes. The atomized liquid is primary situated on a surface (prefilming surface) to form a thin liquid film before being exposed to high-velocity air flow. Moreover, the performance of spray processes is affected by the variation in the atomizer geometry, liquid physical properties and operational conditions. The purpose of this study is to examine and describe the influence of the nozzle geometry and a wide range of test conditions on the spray performance of prefilming air-blast atomizers. In order to evade the commonly complicated internal flow, an important but simple geometry was selected. Liquid break up mechanisms close to the atomizer exit were investigated using shadowgraphy associated with particle tracking. Furthermore, high-resolution local velocity and droplet size measurements were performed using phase Doppler anemometry (PDA). On the whole, the break up mechanism is considerably influenced by either air pressure and liquid flowrates or atomization edge size. Droplet size distribution profile of the different spray parameters in axial and radial directions are studied. The location of the maximum droplet mean velocity and the minimum Sauter mean diameter (SMD) within the spray are determined. The prefilming surface area and atomization edge size were observed to influence the liquid sheet breakup, droplet velocity and droplet size. With an atomization edge length increase of 5.7 mm, the global SMD increased to a maximum of 70% within different operation conditions.

Aim. The aim of the present study was to record habits and attitudes of primary school students in Greece regarding sun-protection measures. Materials and Methods. 2,163 students with an average age of 9.9 (±1.1) years, studying in 14 schools of a Greek region, constituted our sample. The SPSS 17.0 software was used for the statistical analysis and significance level was set to P≤0.05. Results. Our sample had an equal gender distribution. 16% of the students belonged to the high-risk group, 70.2% of the participants lived 0–5 km away from the sea (urban area), 84.2% of the students were Greek, and 15.8% had non-Greek nationality. Half of the participants said they wear a hat when under the sun and 72% of them said they use sunscreen. 33.1% of the students said they had a sunburn last summer. Greek students as well as those who lived near the sea had better behaviour patterns regarding sun protection. Finally, children who did not use a sunscreen systematically had suffered sunburns more often than the rest. Conclusions. Health education programmes are necessary for students and parents/teachers alike, in order to raise awareness about everyday sun protection.

Results from experiments on the atomization of printing ink for the application to a novel offset printing concept are presented and discussed. Offset printing ink is a highly viscous fluid exhibiting a complex rheology and thus difficult to disintegrate into fine droplets. Hence, a special atomization technique has been developed to coat the respective roller of the printing unit with ink. The article contains information on the rheology of printing ink, a description of the atomization experiments and their results in form of droplet size distributions in dependence of various parameters, and a dimensional analysis of the process. [ABSTRACT FROM AUTHOR]

This paper demonstrates the flora, plant communities and substrates of an old solvay process spoil tip in Upper Silesia, Poland. In an area of 15 000 m2 there are growing 136 vascular plant species. The flora is characterised by the preponderance of Asteraceae - species and long-lived perennial herbs, many of them coming from meadows and grasslands. Ninety-five percent of species are apophytes despite the anthropogenic origin of the site. A majority of species are associated with moderately dry, base-rich soils with low or moderate levels of nitrogen. The site is shown to be an important refuge for some protected species, montane species and other elements uncommon in the local flora. An analysis of a series of samples used a methodology based on the assessment of percentage cover of particular species and multivariate analysis based on TWINSPAN. Both suggested a relatively high overall similarity between the samples with minor variations associated with moister substrates.Elemental analysis and pH determinations of soil samples associated with the relevés revealed a narrow range of pH and an absence of any strong concentrations of heavy metals. A redundancy analysis of the soil-plant relationships suggested that the strongest trend of differentiation was most closely associated with a phosphate gradient, and the next strongest was pH and possibly waterlogging. The most species-rich vegetation was associated with low phosphate and high pH levels. The results could be interpreted to suggest that processes of soil development and plant succession are slow but nevertheless perceptible, with implications for future loss of diversity. The vegetation constitutes an assemblage essentially of one type showing only weak relationships with described vegetation types such as Molinio-Arrhenatheretea meadow, Festuco-Brometea grassland and Caricetalia davallianae mire. The results also suggest that the vegetation of the site is of considerable value for nature conservation. The site should be protected and be the subject of further research.

Despite the immense clinical success of the antibody therapeutics that neutralize programmed death receptor ligand 1 (PD-L1) and thus resurrect T cell antitumor activity, the patient response rates remain low. In this issue of Cell Chemical Biology, Ludwig et al. 1 reveal novel topologies of multiparatopic antibodies that mediate potent PD-L1 downregulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Self-measured blood pressure monitoring (SMBP) is an important out-of-office resource that is effective in improving hypertension control. Changes in SMBP use during the Coronavirus Disease 2019 (COVID-19) pandemic have not been described previously., Methods: Behavioral Risk Factor Surveillance System (BRFSS) data were used to quantify changes in SMBP use between 2019 (prior COVID-19 pandemic) and 2021 (during the COVID-19 pandemic). Fourteen states administered the SMBP module in both years. All data were self-reported from adults who participated in the BRFSS survey. We assessed the receipt of SMBP recommendations from healthcare professionals and actual use of SMBP among those with hypertension (n = 68,820). Among those who used SMBP, we assessed SMBP use at home and sharing BP readings electronically with healthcare professionals., Results: Among adults with hypertension, there was no significant changes between 2019 and 2021 in those reporting SMBP use (57.0% vs. 55.7%) or receiving recommendations from healthcare professionals to use SMBP (66.4% vs. 66.8%). However, among those who used SMBP, there were significant increases in use at home (87.7% vs. 93.5%) and sharing BP readings electronically (8.6% vs. 13.1%) from 2019 to 2021. Differences were noted by demographic characteristics and residence state., Conclusions: Receiving a recommendation from the healthcare provider to use SMBP and actual use did not differ before and during the COVID-19 pandemic. However, among those who used SMBP, home use and sharing BP readings electronically with healthcare professional increased significantly, although overall sharing remained low (13.1%). Maximizing advances in virtual connections between clinical and community settings should be leveraged for improved hypertension management., (© Published by Oxford University Press on behalf of American Journal of Hypertension Ltd 2024.)

Aflibercept is a therapeutic recombinant fusion protein comprising extracellular domains of human vascular endothelial growth factor receptors (VEGFRs) and IgG1-Fc. It is a highly glycosylated protein with five N-glycosylation sites that might impact it structurally and/or functionally. Aflibercept is produced in mammalian cells and exhibits large glycan heterogeneity, which hampers glycan-associated investigations. Here, we report the expression of aflibercept in a plant-based system with targeted N-glycosylation profiles. Nicotiana benthamiana -based glycoengineering resulted in the production of aflibercept variants carrying designed carbohydrates, namely, N-glycans with terminal GlcNAc and sialic acid residues, herein referred to as AFLI GnGn and AFLI Sia , respectively. Both variants were transiently expressed in unusually high amounts (2 g/kg fresh leaf material) in leaves and properly assembled to dimers. Mass spectrometric site-specific glycosylation analyses of purified aflibercept showed the presence of two to four glycoforms in a consistent manner. We also demonstrate incomplete occupancy of some glycosites. Both AFLI GnGn and AFLI Sia displayed similar binding potency to VEGF 165 , with a tendency of lower binding to variants with increased sialylation. Collectively, we show the expression of functionally active aflibercept in significant amounts with controlled glycosylation. The results provide the basis for further studies in order to generate optimized products in the best-case scenario.

Introduction: Allergen-specific IgE-blocking IgG antibodies contribute to successful allergen immunotherapy (AIT), however, not much is known about their affinity. Since affinity measurements of polyclonal antibodies in serum are technically challenging we evaluated the applicability of acidic disruption of antibody-allergen complexes by a modified ELISA protocol with monoclonal antibodies (mAbs) specific for the relevant major allergens Betv1 and Mald1. Then, AIT-induced blocking and non-blocking Mald1-specific antibodies in sera from individuals with or without reduced apple allergy were compared., Methods: After testing their pH stability coated recombinant allergens were incubated with (i) mAbs diluted in PBS or human serum and (ii) sera from individuals after sublingual administration of Mald1 or Betv1 for 16 weeks. Immune complexes were exposed to buffers in the pH range of 6.4-3.4 and residual antibodies were measured. Avidity indexes (AI), defined as the pH removing 50% of antibodies, were compared to the dissociation constants (K D ) of mAbs determined by surface plasmon resonance., Results: The selected pH range was applicable to disrupt allergen complexes with highly affine mAbs without compromising allergen integrity. AIs of mAbs accorded with K D values and were unaffected by epitope specificity or the presence of serum proteins. The inter-assay variability was <4% CV. Protective Mald1-specific IgG antibodies from individuals with reduced apple allergy showed a higher collective binding strength than that of the non-protective antibodies of individuals without reduced apple allergy., Conclusion: Acidic disruption of allergen-antibody complexes may be used to estimate the net-binding force of polyclonal serum antibodies and eases the investigation of affinity-related research questions in AIT., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Lack of initiation or escalation of blood pressure (BP) lowering medication when BP is uncontrolled, termed therapeutic inertia (TI), increases with age and may be influenced by comorbidities., Methods: We examined the association of age and comorbidities with TI in 22,665 visits with a systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg among 7,415 adults age ≥65 years receiving care in clinics that implemented a hypertension quality improvement program. Generalized linear mixed models were used to determine the association of comorbidity number with TI by age group (65-74 and ≥75 years) after covariate adjustment., Results: Baseline mean age was 75.0 years (SD 7.8); 41.4% were male. TI occurred in 79.0% and 83.7% of clinic visits in age groups 65-74 and ≥75 years, respectively. In age group 65-74 years, prevalence ratio of TI with 2, 3-4, and ≥5 comorbidities compared with zero comorbidities was 1.07 (95% confidence interval [CI]: 1.04, 1.12), 1.08 (95% CI: 1.05, 1.12), and 1.15 (95% CI: 1.10, 1.20), respectively. The number of comorbidities was not associated with TI prevalence in age group ≥75 years. After implementation of the improvement program, TI declined from 80.3% to 77.2% in age group 65-74 years and from 85.0% to 82.0% in age group ≥75 years (P < 0.001 for both groups)., Conclusions: TI was common among older adults but not associated with comorbidities after age ≥75 years. A hypertension improvement program had limited impact on TI in older patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Target: BP™ is a national initiative launched by the American Heart Association and the American Medical Association in 2017 in response to the high prevalence of uncontrolled blood pressure (BP) in the United States., Target: BP™ provides support to health care organizations and health care teams, with no user fees, to improve the quality of care for adults with hypertension by providing education and resources and recognizing organizations committed to prioritizing and reporting their rate of BP control. Through Target: BP™, the American Heart Association and the American Medical Association also collaborate to align policy with evidence through federal, state, and institutional policy advocacy and raise public awareness through media campaigns. In 2022, Target: BP™ recognized 1309 health care organizations serving 8.4 million patients with hypertension for prioritizing BP control, 675 of which affirmed performance of evidence-based BP measurement activities and 551 of which reported BP control rates ≥70%. With the proportion of US adults with controlled BP falling to 48.2% from 2017 to 2020, Target: BP™ remains focused on regaining lost ground in national BP control rates by emphasizing accurate BP measurement, rapid treatment intensification, healthful lifestyle changes, and evidence-based use of self-measured BP monitoring., Target: BP™ also emphasizes adoption of team-based care models and prioritizing equitable health outcomes. More than 1.37 million unique users have visited https://targetbp.org/ and downloaded 98 341 Target: BP™ resources from 2017 to 2022., Competing Interests: Disclosures All authors have read and approved the submission of the article; the article has not been published and is not being considered for publication elsewhere, in whole or in part, in any language, except as an abstract. The findings and conclusions are those of the authors and do not necessarily represent the official position the American Medical Association.

High numbers of membrane immunoglobulin E (IgE)-positive cells are characteristic of allergic conditions, atopic dermatitis, or IgE myeloma. Antibodies targeting the extracellular membrane-proximal domain of the membranous IgE-B-cell receptor (BCR) fragment can be used for specific depletion of IgE-BCR-positive cells. In this study, we derivatized such an antibody with a toxin and developed an antibody-drug conjugate (ADC) that showed strong cytotoxicity for an IgE-positive target cell line. Site-specific conjugation with maleimidocaproyl-valine-citrulline- p -aminobenzoyloxycarbonyl-monomethyl-auristatin E via a newly introduced single cysteine residue was used to prepare a compound with a drug-antibody ratio of 2 and favorable biophysical properties. The antibody was rapidly taken up by the target cells, showing almost complete internalization after 4 h of treatment. Its cytotoxic effect was potentiated upon cross-linking mediated by an anti-human IgG F(ab') 2 fragment. Because of its fast internalization and strict target specificity, this antibody-drug conjugate presents a valuable starting point for the further development of an anti-IgE cell-depleting agent, operating by the combined action of receptor cross-linking and toxin-mediated cytotoxicity.

Loss of function of progranulin (PGRN), encoded by the granulin ( GRN ) gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of Grn -/- mice. Recently, mice deficient in both PGRN and TMEM106B were shown to develop severe motor deficits and pathology. Here, we show that intracerebral ventricle injection of PGRN-expressing AAV1/9 viruses partially rescues motor deficits, neuronal loss, glial activation, and lysosomal abnormalities in Tmem106b -/- Grn -/- mice. Widespread expression of PGRN is detected in both the brain and spinal cord for both AAV subtypes. However, AAV9 but not AAV1-mediated expression of PGRN results in high levels of PGRN in the serum. Together, these data support using the Tmem106b -/- Grn -/- mouse strain as a robust mouse model to determine the efficacy of PGRN-elevating therapeutics., Competing Interests: The authors T.F., P.L., H.X.Q., and F.H. declare that they have no conflict of interest. M.K., A.M., G.M., G.W. J.P., K.P., A.K., H.L., and N.D. are/were employees of Alector and may have an equity interest in Alector, Inc., (© 2023 The Author(s).)

Periodontal disease in ruminants is common and occurs in farmed and wild animals. Periodontal lesions can result from the secretion of endotoxins by pathogenic bacteria and as consequences of immune system activity. Three main types of periodontitis have been described. The first is chronic inflammation involving mainly premolars and molars-periodontitis (PD). The second type is an acute inflammatory reaction occurring with calcification of the periosteum of the jawbone and swelling of the surrounding soft tissues (Cara inchada, CI-"swollen face"). Finally, a third type, similar to the first but located in the incisor area, is called "broken mouth" (BM). Etiological variation between the different types of periodontitis is indicated. This particularly manifests in the composition of the microbiome, which is characteristic of the different forms of periodontitis. The widespread detection of lesions has drawn attention to the current nature of the problem.

Objective: To explore trends in blood pressure (BP) control before and during the COVID-19 pandemic., Patients and Methods: Health systems participating in the National Patient-Centered Clinical Research Network (PCORnet) Blood Pressure Control Laboratory Surveillance System responded to data queries, producing 9 BP control metrics. Averages of the BP control metrics (weighted by numbers of observations in each health system) were calculated and compared between two 1-year measurement periods (January 1, 2019, through December 31, 2019, and January 1, 2020, through December 31, 2020)., Results: Among 1,770,547 hypertensive persons in 2019, BP control to <140/<90 mm Hg varied across 24 health systems (range, 46%-74%). Reduced BP control occurred in most health systems with onset of the COVID-19 pandemic; the weighted average BP control was 60.5% in 2019 and 53.3% in 2020. Reductions were also evident for BP control to <130/<80 mm Hg (29.9% in 2019 and 25.4% in 2020) and improvement in BP (reduction of 10 mm Hg in systolic BP or achievement of systolic BP <140 mm Hg; 29.7% in 2019 and 23.8% in 2020). Two BP control process metrics exhibited pandemic-associated disruption: repeat visit in 4 weeks after a visit with uncontrolled hypertension (36.7% in 2019 and 31.7% in 2020) and prescription of fixed-dose combination medications among those with 2 or more drug classes (24.6% in 2019 and 21.5% in 2020)., Conclusion: BP control decreased substantially during the COVID-19 pandemic, with a corresponding reduction in follow-up health care visits among persons with uncontrolled hypertension. It is unclear whether the observed decline in BP control during the pandemic will contribute to future cardiovascular events., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: We aimed to characterize seasonal variation in US population-based blood pressure (BP) control and BP-related metrics and evaluate the association between outdoor temperature and BP control variation., Methods: We queried electronic health records (EHRs) from 26 health systems, representing 21 states, to summarize BP metrics by quarters of 12-month periods from January 2017 to March 2020. Patients with at least one ambulatory visit during the measurement period and a hypertension diagnosis during the first 6 months or prior to the measurement period were included. Changes in BP control, BP improvement, medication intensification, average SBP reduction after medication intensification across quarters and association with outdoor temperature were analyzed using weighted generalized linear models with repeated measures., Results: Among 1 818 041 people with hypertension, the majority were more than 65 years of age (52.2%), female (52.1%), white non-Hispanic (69.8%) and had stage 1/2 hypertension (64.8%). Overall, BP control and process metrics were highest in quarters 2 and 3, and lowest in quarters 1 and 4. Quarter 2 had the highest percentage of improved BP (31.95 ± 0.90%) and average SBP reduction after medication intensification (16 ± 0.23 mmHg). Quarter 3 had the highest percentage of BP controlled (62.25 ± 2.55%) and lowest with medication intensification (9.73 ± 0.60%). Results were largely consistent in adjusted models. Average temperature was associated with BP control metrics in unadjusted models, but associations were attenuated following adjustment., Conclusion: In this large, national, EHR-based study, BP control and BP-related process metrics improved during spring/summer months, but outdoor temperature was not associated with performance following adjustment for potential confounders., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Attain 75% hypertension (HTN) control and improve racial equity in control with the American Medical Association Measure accurately, Act rapidly, Partner with patients blood pressure (AMA MAP BP™) quality improvement program, including a monthly dashboard and practice facilitation., Methods: Eight federally qualified health center clinics from the HopeHealth network in South Carolina participated. Clinic staff received monthly practice facilitation guided by a dashboard with process metrics (measure [repeat BP when initial systolic ≥140 or diastolic ≥90 mmHg; Act [number antihypertensive medication classes prescribed at standard dose or greater to adults with uncontrolled BP]; Partner [follow-up within 30 days of uncontrolled BP; systolic BP fall after medication added]) and outcome metric (BP <140/<90). Electronic health record data were obtained on adults ≥18 years at baseline and monthly during MAP BP. Patients with diagnosed HTN, ≥1 encounter at baseline, and ≥2 encounters during 6 months of MAP BP were included in this evaluation., Results: Among 45,498 adults with encounters during the 1-year baseline, 20,963 (46.1%) had diagnosed HTN; 12,370 (59%) met the inclusion criteria (67% black, 29% white; mean (standard deviation) age 59.5 (12.8) years; 16.3% uninsured. HTN control improved (63.6% vs. 75.1%, p <0.0001), reflecting positive changes in Measure, Act, and Partner metrics (all p <0.001), although control remained lower in non-Hispanic black than in non-Hispanic white adults (73.8% vs. 78.4%, p <0.001)., Conclusions: With MAP BP, the HTN control goal was attained among adults eligible for analysis. Ongoing efforts aim to improve program access and racial equity in control., Competing Interests: No competing financial interests exist., (© Edward M. Behling et al., 2023; Published by Mary Ann Liebert, Inc.)

Background Uncontrolled blood pressure (BP) remains a leading cause of death in the United States. The American Medical Association developed a quality improvement program to improve BP control, but it is unclear how to efficiently implement this program at scale across multiple health systems. Methods and Results We conducted BP MAP (Blood Pressure Measure Accurately, Act Rapidly, and Partner With Patients), a comparative effectiveness trial with clinic-level randomization to compare 2 scalable versions of the quality improvement program: Full Support (with support from quality improvement expert) and Self-Guided (using only online materials). Outcomes were clinic-level BP control (<140/90 mm Hg) and other BP-related process metrics calculated using electronic health record data. Difference-in-differences were used to compare changes in outcomes from baseline to 6 months, between intervention arms, and to a nonrandomized Usual Care arm composed of 18 health systems. A total of 24 safety-net clinics in 9 different health systems underwent randomization and then simultaneous implementation. BP control increased from 56.7% to 59.1% in the Full Support arm, and 62.0% to 63.1% in the Self-Guided arm, whereas BP control dropped slightly from 61.3% to 60.9% in the Usual Care arm. The between-group differences-in-differences were not statistically significant (Full Support versus Self-Guided=+1.2% [95% CI, -3.2% to 5.6%], P =0.59; Full Support versus Usual Care=+3.2% [-0.5% to 6.9%], P =0.09; Self-Guided versus Usual Care=+2.0% [-0.4% to 4.5%], P =0.10). Conclusions In this randomized trial, 2 methods of implementing a quality improvement intervention in 24 safety net clinics led to modest improvements in BP control that were not statistically significant. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03818659.

Antigen-binding Fc (Fcab™) fragments, where a novel antigen binding site is introduced by the mutagenesis of the C-terminal loops of the C H 3 domain, function as parts of bispecific IgG-like symmetrical antibodies when they replace their wild-type Fc. Their homodimeric structure typically leads to bivalent antigen binding. In particular, biological situations monovalent engagement, however, would be preferred, either for avoiding agonistic effects leading to safety issues, or the attractive option of combining a single chain (i.e., one half) of an Fcab fragment reactive with different antigens in one antibody. We present the strategies for construction and selection of yeast libraries displaying heterodimeric Fcab fragments and discuss the effects of altered thermostability of the basic Fc scaffold and novel library designs that lead to isolation of highly affine antigen binding clones., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Medication nonadherence of patients with chronic conditions is a complex phenomenon contributing to increased economic burden and decreased quality of life. Intervention development relies on accurately assessing adherence but no "gold standard" method currently exists., Purpose: The present scoping review aimed to: (a) review and describe current methods of assessing medication adherence (MA) in patients with chronic conditions with the highest nonadherence rates (asthma, cancer, diabetes, epilepsy, HIV/AIDS, hypertension), (b) outline and compare the evidence on the quality indicators between assessment methods (e.g., sensitivity), and (c) provide evidence-based recommendations., Methods: PubMed, PsycINFO and Scopus databases were screened, resulting in 62,592 studies of which 71 met criteria and were included., Results: Twenty-seven self-report and 10 nonself-report measures were identified. The Medication Adherence Report Scale (MARS-5) was found to be the most accurate self-report, whereas electronic monitoring devices such as Medication Event Monitoring System (MEMS) corresponded to the most accurate nonself-report. Higher MA rates were reported when assessed using self-reports compared to nonself-reports, except from pill counts., Conclusions: Professionals are advised to use a combination of self-report (like MARS-5) and nonself-report measures (like MEMS) as these were found to be the most accurate and reliable measures. This is the first review examining self and nonself-report methods for MA, across chronic conditions with the highest nonadherence rates and provides evidence-based recommendations. It highlights that MA assessment methods are understudied in certain conditions, like epilepsy. Before selecting a MA measure, professionals are advised to inspect its quality indicators. Feasibility of measures should be explored in future studies as there is presently a lack of evidence., (© Society of Behavioral Medicine 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Self-measured blood pressure (SMBP) with commercially available connected smartphone applications may help patients effectively use SMBP measurements., Objective: To determine if enhanced SMBP paired with a connected smartphone application was superior to standard SMBP for blood pressure (BP) reduction or patient satisfaction., Design, Setting, and Participants: This randomized clinical trial was conducted among 23 health systems participating in PCORnet, the National Patient-Centered Clinical Research Network, and included patients who reported having uncontrolled BP at their last clinic visit, a desire to lower their BP, and a smartphone. Enrollment and randomization occurred from August 3, 2019, to December 31, 2020, which was followed by 6 months of follow-up for each patient. Analysis commenced shortly thereafter., Interventions: Eligible participants were randomly assigned to enhanced SMBP using a device that paired with a connected smartphone application (enhanced) or a standard device (standard). Participants received their device in the mail, along with web-based educational materials and phone-based support as needed. No clinician engagement was undertaken, and the study provided no special mechanisms for delivering measurements to clinicians for use in BP management., Main Outcomes and Measures: Reduction in systolic BP, defined as the difference between clinic BP at baseline and the most recent clinic BP extracted from electronic health records at 6 months., Results: Enrolled participants (1051 enhanced [50.0%] vs 1050 standard [50.0%]; 1191 women [56.7%]) were mostly middle-aged or older (mean [SD] age, 58 [13] years), nearly a third were Black or Hispanic (645 [31%]), and most were relatively comfortable using technology (mean [SD], 4.1 [1.1] of 5). The mean (SD) change in systolic BP from baseline to 6 months was -10.8 (18) mm Hg vs -10.6 (18) mm Hg (enhanced vs standard: adjusted difference, -0.19 mm Hg; 95% CI, -1.83 to 1.44; P = .81). Secondary outcomes were mostly null, except for documented attainment of BP control to lower than 140/<90 mm Hg, which occurred in 32% enhanced vs 29% standard groups (odds ratio, 1.15; 95% CI, 1.01-1.34). Most participants were very likely to recommend their SMBP device to a friend (70% vs 69%)., Conclusions and Relevance: This randomized clinical trial found that enhanced SMBP paired with a smartphone application is not superior to standard SMBP for BP reduction or patient satisfaction., Trial Registration: ClinicalTrials.gov Identifier: NCT03796689.

Background: The National Health and Nutrition Examination Survey data indicate that the proportion of US adults with hypertension that had controlled blood pressure (BP) declined from 2013 to 2014 through 2017 to 2018. We analyzed data from National Health and Nutrition Examination Survey 2009 to 2012, 2013 to 2016, and 2017 to 2020 to confirm this finding., Methods: Hypertension was defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or antihypertensive medication use. BP control among those with hypertension was defined as systolic BP <140 mm Hg and diastolic BP <90 mm Hg., Results: The age-adjusted prevalence of hypertension was 31.5% (95% CI, 30.3%-32.8%), 32.0% (95% CI, 30.6%-33.3%), and 32.9% (95% CI, 31.0%-34.7%) in 2009 to 2012, 2013 to 2016, and 2017 to 2020, respectively ( P trend=0.218). The age-adjusted prevalence of hypertension increased among non-Hispanic Asian adults from 27.0% in 2011 to 2012 to 33.5% in 2017 to 2020 ( P trend=0.003). Among Hispanic adults, the age-adjusted prevalence of hypertension increased from 29.4% in 2009 to 2012 to 33.2% in 2017 to 2020 ( P trend=0.029). In 2009 to 2012, 2013 to 2016, and 2017 to 2020, 52.8% (95% CI, 50.0%-55.7%), 51.3% (95% CI, 47.9%-54.6%), and 48.2% (95% CI, 45.7%-50.8%) of US adults with hypertension had controlled BP ( P trend=0.034). Among US adults taking antihypertensive medication, 69.9% (95% CI, 67.8%-72.0%), 69.3% (95% CI, 66.6%-71.9%), and 67.7% (95% CI, 65.2%-70.3%) had controlled BP in 2009 to 2012, 2013 to 2016, and 2017 to 2020, respectively ( P trend=0.189). Among all US adults with hypertension and those taking antihypertensive medication, a decline in BP control between 2009 to 2012 and 2017 to 2020 occurred among those ≥75 years, women, and non-Hispanic black adults., Conclusions: These data confirm that the proportion of US adults with hypertension who have controlled BP has declined.

Purpose: Prediabetes is a serious public health concern, with 34.5% of US adults meeting the criteria for prediabetes. The American Diabetes Association has highlighted metformin therapy as a consideration for individuals with BMI ≥ 35 kg/m 2 , those aged < 60 years, and women with a history of gestational diabetes. We examined metformin prescription rates among a national sample of commercially insured, higher risk patients with prediabetes., Methods: We gathered 2012 to 2018 demographic, laboratory, and prescription data for 53,551 patients with prediabetes from the IBM MarketScan research database. Our primary outcome was metformin prescription rates 1 or 3 years after a laboratory confirmation of prediabetes among patients who have a BMI ≥ 35 kg/m 2 or are aged < 60 years., Results: Overall, 2.4% (n = 1,124) of patients received a metformin prescription within 1 year of a laboratory confirmed prediabetes result, including 2.4% of patients aged < 60 years and 10.4% of those with BMI ≥ 35 kg/m 2 . By a 3 year follow-up, 4.1% (n = 1901) received a metformin prescription, including 3.9% of patients aged < 60 years and 14.0% with BMI ≥ 35 kg/m 2 . Patients who developed type 2 diabetes within the 1 (n = 2,769) or 3 year (n = 7,268) follow-up periods were excluded from analysis., Conclusions: Few prediabetes patients who were either obese or aged < 60 years received a metformin prescription between 2012 and 2018. Prescription rates increased slightly between 1 and 3 years after a prediabetes diagnosis, so strategies to support timely intervention among higher risk patients with prediabetes are critically needed., Competing Interests: Conflicts of interest: None. The findings and conclusions of this report are those of the authors and do not represent the official position of the American Medical Association., (© Copyright 2022 by the American Board of Family Medicine.)

Background: Controlled blood pressure can prevent or reduce adverse health outcomes. Social and structural determinants may contribute to the disparity that despite equivalent proportions on antihypertensive medication, non-Hispanic Black (Black) adults have lower blood pressure control and more cardiovascular events than non-Hispanic White (White) adults., Methods: Data from 2013 to 2018 National Health and Nutrition Examination Survey were pooled to assess control among Black and White adults by antihypertensive medication use and selected characteristics using the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Blood Pressure Guideline definition (systolic blood pressure <130 mm Hg and diastolic blood pressure <80 mm Hg) among 4,739 adults., Results: Among those treated with antihypertensive medication, an estimated 34.9% of Black and 45.0% of White adults had controlled blood pressure. Control was lower for Black and White adults among most subgroups of age, sex, education, insurance status, usual source of care, and poverty-income ratio. Black adults had higher use of diuretics (28.5%-Black adults vs. 23.5%-White adults) and calcium channel blockers (24.2%-Black adults vs. 14.7%-White adults) compared with White adults. Control among Black adults was lower than White adults across all medication classes including diuretics (36.1%-Black adults vs. 47.3%-White adults), calcium channel blockers (30.2%-Black adults vs. 40.1%-White adults), and number of medication classes used., Conclusions: Suboptimal blood pressure control rates and disparities warrant increased efforts to improve control, which could include addressing social and structural determinants along with emphasizing implementation of the 2017 ACC/AHA Blood Pressure Guideline into clinical practice., (© Published by Oxford University Press on behalf of American Journal of Hypertension Ltd 2022.)

Introduction: Smoking is the leading cause of preventable disease and death. However, effective medicines, including prescription medications often covered by health insurance, are available to aid cessation., Methods: Trends of 7 U.S. Food and Drug Administration-approved prescription medications for smoking cessation during 2009-2019 (before and during Affordable Care Act implementation), including fill counts and spending (total and patient, adjusted to 2019 U.S. dollars), were assessed among U.S. adults aged ≥18 years. Symphony Health's Integrated Dataverse combines data on >90% of outpatient prescription fills with market purchasing data to create national estimates. Analyses were conducted in 2021., Results: Annually, total fills (spending) decreased from 3.7 million ($577 million) in 2009 to 2.5 million ($465 million) in 2013 and increased to 4.5 million ($1.279 billion) in 2019; patient spending decreased from $174 million (30% of total annual spending) in 2009 to $54 million (4%) in 2019. Comparing 2009 with 2019, the total spending per fill increased by 80% (from $157 to $282), whereas patient spending per fill decreased by 75% (from $47 to $12). The total spending per fill for branded products increased by 175% (from $166 to $459) and decreased by 41% (from $75 to $44) for generic products. Branded product percentage decreased from 89% to 57%., Conclusions: Total fills and spending decreased from 2009 to 2013 and then increased through 2019, whereas patient spending decreased. Earlier studies suggest possible reasons for these trends, such as gradual implementation of federal requirements for insurance coverage of cessation medications and reduced cost sharing and financial barriers., (Published by Elsevier Inc.)

Inhibition of complement activation via the overexpression of complement-regulatory proteins (CRPs), most notably CD46, CD55 and CD59, is an efficient mechanism of disguise of cancer cells from a host immune system. This phenomenon extends to counteract the potency of therapeutic antibodies that could lyse target cells by eliciting complement cascade. The manifold functions and ubiquitous expression of CRPs preclude their systemic specific inhibition. We selected CD59-specific Fc fragments with a novel antigen binding site (Fcabs) from yeast display libraries using recombinant antigens expressed in bacterial or mammalian cells. To produce a bispecific antibody, we endowed rituximab, a clinically applied anti-CD20 antibody, used for therapy of various lymphoid malignancies, with an anti-CD59 Fcab. This bispecific antibody was able to induce more potent complement-dependent cytotoxicity for CD20 and CD59 expressing Raji cell line measured with lactate dehydrogenase-release assay, but had no effect on the cells with lower levels of the primary CD20 antigen or CD20-negative cells. Such molecules are promising candidates for future therapeutic development as they elicit a higher specific cytotoxicity at a lower concentration and hence cause a lower exhaustion of complement components.

The receptor binding domain (RBD) of the SARS-CoV-2 spike (S)-protein is a prime target of virus-neutralizing antibodies present in convalescent sera of COVID-19 patients and thus is considered a key antigen for immunosurveillance studies and vaccine development. Although recombinant expression of RBD has been achieved in several eukaryotic systems, mammalian cells have proven particularly useful. The authors aimed to optimize RBD produced in HEK293-6E cells towards a stable homogeneous preparation and addressed its O-glycosylation as well as the unpaired cysteine residue 538 in the widely used RBD (319-541) sequence. The authors found that an intact O-glycosylation site at T323 is highly relevant for the expression and maintenance of RBD as a monomer. Furthermore, it was shown that deletion or substitution of the unpaired cysteine residue C538 reduces the intrinsic propensity of RBD to form oligomeric aggregates, concomitant with an increased yield of the monomeric form of the protein. Bead-based and enzyme-linked immunosorbent assays utilizing these optimized RBD variants displayed excellent performance with respect to the specific detection of even low levels of SARS-CoV-2 antibodies in convalescent sera. Hence, these RBD variants could be instrumental for the further development of serological SARS-CoV-2 tests and inform the design of RBD-based vaccine candidates., (© 2022 The Authors. Biotechnology Journal published by Wiley-VCH GmbH.)

In response to high prevalence of hypertension and suboptimal rates of blood pressure (BP) control in the United States, the Surgeon General released a Call-to-Action to Control Hypertension (Call-to-Action) in the fall of 2020 to address the negative consequences of uncontrolled BP. In addition to morbidity and mortality associated with hypertension, hypertension has an annual cost to the US healthcare system of $71 billion. The Call-to-Action makes recommendations for improving BP control, and the purpose of this review was to summarize the literature on the cost-effectiveness of these strategies. We identified a number of studies that demonstrate the cost saving or cost-effectiveness of recommendations in the Call-to-Action including strategies to promote access to and availability of physical activity opportunities and healthy food options within communities, advance the use of standardized treatment approaches and guideline-recommended care, to promote the use of healthcare teams to manage hypertension, and to empower and equip patients to use self-measured BP monitoring and medication adherence strategies. While the current review identified numerous cost-effective methods to achieve the Surgeon General's recommendations for improving BP control, future work should determine the cost-effectiveness of the 2017 American College of Cardiology and American Heart Association Hypertension guidelines, interventions to lower therapeutic inertia, and optimal team-based care strategies, among other areas of research. Economic evaluation studies should also be prioritized to generate more comprehensive data on how to provide efficient and high value care to improve BP control., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Accurate blood pressure measurement is crucial for proper screening, diagnosis, and monitoring of high blood pressure. However, providers are not aware of proper blood pressure measurement skills, do not master all the appropriate skills, or miss key steps in the process, leading to inconsistent or inaccurate readings. Training in blood pressure measurement for most providers is usually limited to a one-time brief demonstration during professional education coursework. The American Medical Association and the American Heart Association developed a 30-minute e-Learning module designed to refresh and improve existing blood pressure measurement knowledge and clinical skills among practicing providers. One hundred seventy-seven practicing providers, which included medical assistants, nurses, advanced practice providers, and physicians, participated in a multi-site randomized educational study designed to assess the effect of this e-Learning module on blood pressure measurement knowledge and skills. Participants were randomized 1:1 to either the intervention or control group. The intervention group followed a pre-post assessment approach, and the control group followed a test-retest approach. The initial assessment showed that participants in both the intervention and control groups correctly performed less than half of the 14 skills considered necessary to obtain an accurate blood pressure measurement (mean scores 5.5 and 5.9, respectively). Following the e-Learning module, the intervention group performed on average of 3.4 more skills correctly vs 1.4 in the control group (P < .01). Our findings reinforce existing evidence that errors in provider blood pressure measurements are highly prevalent and provide novel evidence that refresher training improves measurement accuracy., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Not having a healthcare visit in the past year has been associated with a higher likelihood of uncontrolled blood pressure (BP) among individuals with hypertension., Methods: We examined factors associated with not having a healthcare visit in the past year among US adults with hypertension using data from the US National Health and Nutrition Examination Survey 2013-2018 (n = 5,985). Hypertension was defined as systolic BP (SBP) ≥140 mm Hg, diastolic BP (DBP) ≥90 mm Hg, or antihypertensive medication use. Having a healthcare visit in the past year was self-reported., Results: Overall, 7.0% of US adults with hypertension reported not having a healthcare visit in the past year. Those without vs. with a healthcare visit in the past year were less likely to be aware they had hypertension (45.0% vs. 83.9%), to be taking antihypertensive medication (36.7% vs. 91.4%, among those who were aware they had hypertension), and to have controlled BP (SBP/DBP <140/90 mm Hg; 9.1% vs. 51.7%). After multivariable adjustment, not having a healthcare visit in the past year was more common among US adults without health insurance (prevalence ratio [PR]: 2.22; 95% confidence interval [CI] 1.68-2.95), without a usual source of healthcare (PR: 5.65; 95% CI 4.16-7.67), who smoked cigarettes (PR: 1.34; 95% CI 1.02-1.77), and with heavy vs. no alcohol consumption (PR: 1.55; 95% CI 1.16-2.08). Also, not having a healthcare visit in the past year was more common among those without diabetes or a history of atherosclerotic cardiovascular disease, and those not taking a statin., Conclusions: Interventions should be considered to ensure all adults with hypertension have annual healthcare visits., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Bispecific antibodies and antibody fragments are therapeutics of growing importance. They are clinically applied for effector cell engagement, enhanced targeting selectivity, addressing of multiple cellular pathways and active transfer of certain activities into difficult-to-reach compartments. These functionalities could profit from a third antigen specificity. In this work we have employed symmetrical bispecific parental antibodies of mAb 2 format, which feature a novel antigen binding site in the C H 3 domains, and engineered them with a minimal number of point mutations to guide the formation of a controlled Fab-arm exchanged trispecific antibody at a high yield after reduction and re-oxidation. Two model antibodies, one reactive with EGFR, Her2 and VEGF, and one with Fab-arms binding to Ang2 and VEGF and an Fc fragment binding to VEGF, were prepared and examined for heterodimeric status, stability, antigen binding properties and biological activity. Resulting molecules were of good biophysical characteristics and retained antigen reactivity and biological activity of the parental mAb 2 constructs., (© 2022 Veronica Natale et al., published by De Gruyter, Berlin/Boston.)

Recently published national data demonstrate inadequate and worsening control of high blood pressure (HBP) in the United States, outcomes that likely have been made even worse by the coronavirus disease 2019 (COVID-19) pandemic. This major public health crisis exposes shortcomings of the US health care delivery system and creates an urgent opportunity to reduce mortality, major cardiovascular events, and costs for 115 million Americans. Ending this crisis will require a more coherent and systemic change to traditional patterns of care. The authors present an evidence-based Blueprint for Change for comprehensive health delivery system redesign based on current national clinical practice guidelines and quality measures. This innovative model includes a systems-based approach to ensuring proper BP measurement, assessment of cardiovascular risk, effective patient-centered team-based care, addressing social determinants of health, and shared decision-making. The authors also propose building on current national quality improvement initiatives designed to better control HBP., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Over the last two decades, yeast display methodology has served as a popular tool for discovery, humanization, stability improvement, and affinity maturation of antibodies and antibody fragments, but also for development of diverse non-antibody protein scaffolds towards the ability of antigen recognition. Yeast display is particularly well suited for multiparametric analysis of properties of derivatized proteins, allowing the evolution of most diverse protein structures into antigen binding entities with favorable expression, stability, and folding properties. Here we present the methodological basics of a novel yeast display-based approach for the functionalization of the large extracellular loop of CD81 into a de novo antigen binding unit. CD81 is intrinsically overrepresented on the surface of extracellular vesicles (EVs), naturally occurring nanoparticle units that act as cell-to-cell messengers by delivering their intracellular cargo from the source cell into a recipient cell. This amazing feature makes them of highest biotechnological interest, yet methods for their targeted delivery are still in their infancy. As a novel approach for introducing EV surface modifications enabling specific target cell recognition and internalization, we have prepared yeast display libraries of CD81 large extracellular loop mutants, which are selected towards specific antigen binding and resulting mutants conveniently clicked into the full-length EV surface protein. Resulting EVs display wild-type-like characteristics regarding the expression level and distribution of recombinant proteins and are hence promising therapeutic tools., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

[Figure: see text].

Background: Hypertension is a major risk factor for cardiovascular disease. Achieving hypertension control requires multiple supportive inventions, including self-measured blood pressure (SMBP) monitoring. The objective of this study is to report the use of SMBP among US adults., Methods: Behavioral Risk Factor Surveillance System data were used for this study. The 2019 survey included, for the first time, an optional SMBP module. Twenty states and the District of Columbia (N = 159,536) opted to include the module, which assessed whether participants were advised by a healthcare professional to use SMBP, and if they used SMBP monitoring. Among those using SMBP, additional questions assessed the location of SMBP monitoring and whether SMBP readings were shared with a healthcare professional., Results: Among adults in the study population, 33.9% (95% confidence interval 33.4%-34.5%) reported having hypertension (N = 66,869). Among them, nearly 70% were recommended to use SMBP by their healthcare professional and approximately 61% reported SMBP use regardless of recommendation. The most common location of SMBP was the home (85.6%). Overall, >80% shared their SMBP reading with their healthcare professional, 74% and 7% were shared in person and via the internet or email, respectively. There were differences in healthcare professional recommendations, use of SMBP, and SMBP information sharing across demographic characteristics and state of residency., Conclusions: SMBP recommendation was common practice among healthcare professionals, as reported by US adults with hypertension. Data from this study can be used to guide interventions to promote hypertension self-management and control., (© Published by Oxford University Press on behalf of American Journal of Hypertension Ltd 2021.)

Background The National Patient-Centered Clinical Research Network Blood Pressure Control Laboratory Surveillance System was established to identify opportunities for blood pressure (BP) control improvement and to provide a mechanism for tracking improvement longitudinally. Methods and Results We conducted a serial cross-sectional study with queries against standardized electronic health record data in the National Patient-Centered Clinical Research Network (PCORnet) common data model returned by 25 participating US health systems. Queries produced BP control metrics for adults with well-documented hypertension and a recent encounter at the health system for a series of 1-year measurement periods for each quarter of available data from January 2017 to March 2020. Aggregate weighted results are presented overall and by race and ethnicity. The most recent measurement period includes data from 1 737 995 patients, and 11 956 509 patient-years were included in the trend analysis. Overall, 15% were Black, 52% women, and 28% had diabetes. BP control (<140/90 mm Hg) was observed in 62% (range, 44%-74%) but varied by race and ethnicity, with the lowest BP control among Black patients at 57% (odds ratio, 0.79; 95% CI, 0.66-0.94). A new class of antihypertensive medication (medication intensification) was prescribed in just 12% (range, 0.6%-25%) of patient visits where BP was uncontrolled. However, when medication intensification occurred, there was a large decrease in systolic BP (≈15 mm Hg; range, 5-18 mm Hg). Conclusions Major opportunities exist for improving BP control and reducing disparities, especially through consistent medication intensification when BP is uncontrolled. These data demonstrate substantial room for improvement and opportunities to close health equity gaps.

The increased incidence of allergies and asthma has sparked interest in IgE, the central player in the allergic response. Interaction with its high-affinity receptor FcεRI leads to sensitization and allergen presentation, extracellular membrane-proximal domain in membrane IgE can act as an antigen receptor on B cells, and the interaction with low-affinity IgE receptor CD23 additionally influences its homeostatic range. Therapeutic anti-IgE antibodies act by the inhibition of IgE functions by interfering with its receptor binding or by the obliteration of IgE-B cells, causing a reduction of serum IgE levels. Fusion proteins of antibody fragments that can act as bispecific T-cell engagers have proven very potent in eliciting cytotoxic T-lymphocyte-mediated killing. We have tested five anti-IgE Fc antibodies, recognizing different epitopes on the membrane-expressed IgE, for the ability to elicit specific T-cell activation when expressed as single-chain Fv fragments fused with anti-CD3ε single-chain antibody. All candidates could specifically stain the cell line, expressing the membrane-bound IgE-Fc and bind to CD3-positive Jurkat cells, and the specific activation of engineered CD3-overexpressing Jurkat cells and non-stimulated CD8-positive cells was demonstrated for 8D6- and ligelizumab-based bispecific antibodies. Thus, such anti-IgE antibodies have the potential to be developed into agents that reduce the serum IgE concentration by lowering the numbers of IgE-secreting cells.

The overexpression of tyrosine kinase HER2 in numerous cancers, connected with fierce signaling and uncontrolled proliferation, makes it a suitable target for immunotherapy. The acquisition of resistance to currently used compounds and the multiplicity of signaling pathways involved prompted research into the discovery of novel binders as well as treatment options with multiple targeting and multispecific agents. Here we constructed an anti-HER2 tetravalent and biparatopic symmetrical IgG-like molecule by combining the Fab of pertuzumab with a HER2-specific Fcab (Fc fragment with antigen binding), which recognizes an epitope overlapping with trastuzumab. In the strongly HER2-positive cell line SK-BR-3, the molecule induced a rapid and efficient reduction in surface HER2 levels. A potent anti-proliferative effect, specific for the HER2-positive cell line, was observed in vitro, following the induction of apoptosis, and this could not be achieved with treatment with the mixture of pertuzumab and the parental Fcab. The inhibitory cytotoxic effect of our antibody as a single agent makes it a promising contribution to the armory of anti-cancer molecules directed against HER2-addicted cells.

The application of recombinant antibodies for the analysis of foods and food contaminants is now a major focus, given their capacity to be engineered to tailor their specificity, enhance their stability, and modify their structural formats to fit the desired analytical platform. In this study, human scFv antibody fragments generated against aflatoxin B1 (AFB1) were selected as the model antibody to explore the effect of antibody formats on their binding activity and to evaluate their potential use as immunoreagents for food contaminant analysis. Four human scFv antibody fragments against aflatoxin B1 (AFB1), previously isolated and engineered by chain shuffling, were converted into various formats, that is, scFv-AP fusions, scFv-Fc, and whole IgG molecules. The result indicated that the effects of the antibody format on the binding property varied, depending on the sequence of scFv. For all of the scFv clones, the scFv-AP fusion format showed the highest sensitivity by competitive ELISA, while the effects on the binding activity after conversion to scFv-Fc or IgG format varied, depending on the amino acid sequence of the antibodies. The sAFH-3e3 antibodies that showed the best performance by competitive ELISA were selected for further investigation. The sAFH-3e3 was converted to the scFv-GFP format and tested by fluorescence-linked immunosorbent assay (FLISA), which showed that its binding property was equivalent to those of scFv-Fc and IgG formats. The potential applications of the sAFH-3e3 in a rapid test kit format based on ELISA (scFv-AP) and in a lateral flow immunochromatography assay (LFIA) (IgG) were demonstrated. A comparison of methods for the extraction of AFB1 from matrices for use with these assay formats indicated that PBS and TBST are better than 70% methanol., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Optimal therapeutic strategy in low advanced papillary thyroid carcinoma (PTC) is still a matter of debate. The management differs depending on the country. A prospective non-randomized study was performed to evaluate whether less extensive surgery could be a safe, acceptable, and sufficient therapeutic option in PTC cT1N0M0 patients. The present paper summarizes the results of over a 5-year follow-up., Material: Our prospective group (PG) treated between 2011 and 2015 consisted of 139 patients with cT1aN0M0 PTC who underwent lobectomy (LT) as initial surgical treatment (PGcT1aN0M0 group) and 102 cT1bN0M0 patients in whom total thyroidectomy (TT) with unilateral central neck dissection (CND) was performed (PGcT1bN0M0). PG was compared with the retrospective group (RG) of patients who underwent TT with bilateral CND between 2004 and 2006: 103 cT1aN0M0 patients (RGcT1aN0M0) and 91cT1bN0M0 (RGcT1bN0M0). The risks of reoperation, cancer relapse and postoperative complications were analyzed., Results: Only 12 cT1aN0M0 patients (7.6%) withdrew from the trial and underwent TT with bilateral CND. Over 90% of patients accepted less extensive surgery. In 4 cT1aN0M0 cases, TT with CND was performed due to lymph node metastases found intraoperatively. The initial clinical stage according to the TNM/AJCC 7 th edition was confirmed histologically in 77% of cases in PGT1aN0M0 and in 72% in PGT1bN0M0, respectively. 24 PGcT1aN0M0 patients were reoperated on. In this group, cancer lesions in the postoperative histological specimens were found in 8 cases (32%). Five-year disease-free survival (DFS) was excellent. However, no statistically significant differences were found between PG and RG groups (99.3% in PGcT1aN0M0 and 99.0%, in RGcT1aN0M0; p = 0.41 and 98%, in PGcT1bN0M0 and 94.4% in RGcT1bN0M0; p=0.19). No significant differences were observed in the incidence of early paresis of the recurrent laryngeal nerves between PG and RG. However, as predicted, LT completely eliminated the risk of postoperative hypoparathyroidism., Summary: The results of the prospective clinical trial confirm that less extensive surgery in adequately selected low-advanced PTC patients is both safe and sufficient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Czarniecka, Zeman, Wozniak, Maciejewski, Stobiecka, Chmielik, Oczko-Wojciechowska, Krajewska, Handkiewicz-Junak and Jarzab.)

The research of extracellular vesicles (EVs) has boomed in the last decade, with the promise of them functioning as target-directed drug delivery vehicles, able to modulate proliferation, migration, differentiation, and other properties of the recipient cell that are vital for health of the host organism. To enhance the ability of their targeted delivery, we employed an intrinsically overrepresented protein, CD81, to serve for recognition of the desired target antigen. Yeast libraries displaying mutant variants of the large extracellular loop of CD81 have been selected for binders to human placental laminin as an example target. Their specific interaction with laminin was confirmed in a mammalian display system. Derived sequences were reformatted to full-length CD81 and expressed in EVs produced by HeLa cells. These EVs were examined for the presence of the recombinant protein and were shown to exhibit an enhanced uptake into laminin-secreting mammalian cell lines. For the best candidate, the specificity of antigen interaction was demonstrated with a competition experiment. To our knowledge, this is the first example of harnessing an EV membrane protein as mediator of de novo target antigen recognition via in vitro molecular evolution, opening horizons to a broad range of applications in various therapeutic settings., (© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Objective: Determine sex differences in hypertension control by age group in a diverse cohort of adults age 45-84 years at baseline followed for an average of 12 years., Methods: The Multi-Ethnic Study of Atherosclerosis enrolled 3213 men and 3601 women from six communities in the U.S. during years 2000-2002 with follow-up exams completed approximately every two years. At each exam, resting blood pressure (BP) was measured in triplicate, and the last two values were averaged. Hypertension was defined as a BP ≥ 140/90 mmHg and/or use of antihypertensive medications. Hypertension control was defined as a BP < 140/90 mmHg and in separate analyses as < 130/90 mmHg. Generalized linear mixed effects models with a binomial function were used to calculate the odds of hypertension control by age group (45-64,75-74, 75+) at a given exam and by sex, while accounting for the intra-individual correlation, and adjustment for demographics, co-morbidities, smoking, alcohol use, education and site among participants with hypertension at any of the first five exams., Results: At baseline, mean age was 64.1 (9.1 [SD]) years, 48.0% were men, and race/ethnicity was Non-Hispanic white in 34.1%, 10.1% Chinese, 35.1% Non-Hispanic Black and 20.7% Hispanic. Average SBP was lower while average DBP was higher among men vs. women at each exam. Adjusted odds ratios of hypertension control defined as BP < 140/90 mmHg among men vs. women was 0.89 (95% CI 0.67, 1.19) for age 45-64 years, 1.37 (95% CI 1.04, 1.81) for age 65-74 years and 2.08 (95% CI 1.43, 3.02) for age 75+ years. When defined as < 130/80 mmHg, adjusted odds of hypertension control among men vs. women was 0.60 (OR 0.60; 95% CI 0.46, 0.79) at age 45-64 years, 1.01 (OR 1.01; 95% CI 0.77, 1.31) at age 65-74 years and 1.71 (95% CI 1.19, 2.45) at age 75+ years., Conclusion: Sex disparities in hypertension control increase with advancing age and are greatest among adults age 75+ years., Competing Interests: Brent Egan, Michael Rakotz, and Gregory Wozniak are employed by Target BP. All other authors have no disclosures to report., (© 2021 The Authors. Published by Elsevier B.V.)