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We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Urszula Tyrcha is the Chemical Synthesis Specialist at the company RECEPTON Sp. z o.o., Aleksandra Hec-Gałązka is the Chemical Synthesis Specialist at the company RECEPTON Sp. z o.o., Prof. Dr Tad Holak is the CSO of the company RECEPTON Sp. z o.o., Head of Drug Discovery Laboratory Dr Tomasz Sitar is the CEO of the company RECEPTON Sp. z o.o., Head of Protein Engineering Laboratory., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Newer biomarkers of Hepatitis B virus (HBV) infection and treatment response have not been well-characterized in individuals with HBV/HIV coinfection., Methods: Pre-genomic RNA (pgRNA) and quantitative HBsAg (qHBsAg) were used to evaluate the associations with baseline characteristics. Participants included two separate groups - 236 with HBV/HIV coinfection enrolled in a cross-sectional cohort in Ghana and 47 from an HBV nucleoside/nucleotide treatment trial comparing tenofovir to adefovir in the United States., Results: In both cohorts, HBe antigenemia was highly associated with pgRNA and HBV DNA levels. In the treatment cohort, pre-treatment pgRNA serum concentration was 7.0 log 10 U/mL, and mean qHBsAg was 201,297 IU/mL. The observed treatment-associated decrease in pgRNA was consistent with a biphasic decline curve that reached second-phase kinetics following treatment week 12. Changes from baseline were significantly correlated with changes in serum ALT (r = - 0.518; P = 0.023) but not with changes in HBV DNA (r = 0.132, P = NS). qHBsAg also correlated with ALT change (r = - 0.488, P = 0.034)., Conclusion: pgRNA and qHBsAg represent newer biomarkers of HBV replication that may help monitor response and treatment outcomes. HBV pgRNA is highly associated with both HBeAg and ALT and may predict both active replication from the closed circular DNA (cccDNA) template as well as hepatic injury., Competing Interests: MA, MS, and GC are employees and shareholders of Abbott Laboratories. All other authors have no conflicts of interest., (Copyright © 2024 Pathogens and Immunity.)

Biomaterials, like hydroxyapatite (HAp), are the subject of many scientific investigations. Their specific application, however, is determined by the form and some characteristic features of the resulting material. Synthesis methods and optimization procedures leading to a product of predetermined characteristics are therefore of great interest. To broaden the existing knowledge, sonoprecipitation was investigated as a potential method for the production of nanosized HAp particles. The research was carried out in a static mixer (STM) immersed in the ultrasonic bath. The influence of operating conditions, e.g., ultrasonic power P US ( ε US ), ultrasonic frequency (f US ), and unit mixing power ( ε mix ), was investigated in terms of nucleation intensity, product quality, and characteristics (particle size distribution ( PSD ), mean size, shape, etc.). As a result, the optimal conditions for the HAp nanoparticles synthesis (mean size: d ~150 nm; length: L 1 ~250 nm; width: L 2 ~80 nm) in the form of needles/whiskers/rods-similar to the shape of the HAp present in natural human bones, free from agglomerates, with negligible signs of particle destruction-were determined. The formation of HAp of smaller sizes ( d ≤ 100 nm) and more compact shapes ( L 1 ~155 nm, L 2 ~90 nm), useful in bone regeneration processes, was also discussed.

Objective: To investigate if preoperative ondansetron reduces postoperative nausea associated with laparoscopic gastropexy and castration in dogs., Study Design: Prospective clinical study., Animals: Twenty client-owned, healthy male dogs., Methods: Dogs were premedicated with dexmedetomidine (2-5 mcg kg -1 ) and methadone (0.2-0.5 mg kg -1 ) intramuscularly. General anesthesia was induced with propofol and maintained with an inhalant anesthetic agent. Dogs were randomized into group S (saline 0.1 mL kg -1 , intravenously) or group O (ondansetron 0.2 mg kg -1 , intravenously). Plasma and serum were collected before premedication and 3 hours postextubation to measure arginine vasopressin (AVP) and cortisol concentrations. Nausea scoring occurred before and 10 minutes after premedication, immediately after extubation, and at 1, 2 and 3 hours postextubation. Data were analyzed by mixed and split-plot anova with Bonferroni adjustment for the number of group comparisons. Significance was set at p < 0.05., Results: Nausea scores increased over time at 1 (p = 0.01) and 2 (p < 0.001) hours postextubation in both groups compared with before premedication. Median nausea score (0-100 mm) for groups S and O before premedication were 2.5 and 0.5 mm, respectively. At 1 and 2 hours postextubation, group S scored 7.5 and 4.0 mm and group O scored 6.0 and 5.0 mm, respectively. No significant differences in nausea scores within or between groups were observed before premedication and 3 hours postextubation. Cortisol concentrations increased significantly 3 hours postextubation in both groups (p < 0.001) compared with before premedication, with no differences between groups. AVP concentrations showed no significant differences within or between groups., Conclusions and Clinical Relevance: Preoperative intravenous administration of ondansetron (0.2 mg kg -1 ) did not impact postoperative nausea after laparoscopic gastropexy and castration. Investigation of higher doses of ondansetron on the incidence of postoperative nausea and vomiting in dogs after surgery is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: We conducted a multicentre real-world study to assess the outcomes of radical salvage re-irradiation for non-melanoma skin cancer (nMSC) recurrences following definitive or postoperative radiotherapy., Materials and Methods: Data on patients treated between 2006 and 2022 with re-irradiation for nMSCs were retrospectively collected from five high-volume brachytherapy centers. The primary endpoint was local control (LC). Secondary endpoints included overall survival, progression-free survival, and adverse events (AEs). The Kaplan-Meier estimator and Cox Proportional-Hazards Model were utilised in the analysis., Results: A total of 58 patients with a median age of 78.4 years with recurrences of previously irradiated nMSC in the head and neck region were included in the analysis. The majority had cutaneous basal cell carcinoma (BCC; 91.4%), and were irradiated with high-dose-rate brachytherapy (HDR-BT; 91.4%). The most common locations included the nasal region (36.2%) and external ear (18.9%). The 1-year LC was 73.1% and decreased to 41.7% at three years. The size of the re-irradiated lesion was the single independent prognostic factor in Cox analysis (per mm; HR 1.07; 95% CI 1.04-1.11; p < 0.001). Grade 3 or worse AEs were reported in 7 cases (12.1%)., Conclusion: Re-irradiation for nMSCs, predominantly administered with brachytherapy for radiorecurrent BCC, is associated with high recurrence rates, and the risk of failure significantly increases with the size of the treated lesion. Re-irradiation could be an option for selected elderly patients with small, localised, inoperable recurrences after RT to achieve local control or defer systemic treatment; however, prospective trials are necessary to confirm its safety and efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The validated HCM Risk-Kids model provides accurate individualized estimates of sudden cardiac death risk in children with hypertrophic cardiomyopathy (HCM). A second validated model, PRIMaCY, also provides individualized estimates of risk, but its performance and clinical impact has not been independently investigated. The aim of this study was to investigate the clinical impact of using the PRIMaCY sudden cardiac death (SCD) risk model in childhood HCM., Methods and Results: The estimated 5-year SCD risk was calculated for children meeting diagnostic criteria for HCM in a large single-centre cohort using PRIMaCY (clinical and genetic) and HCM Risk-Kids model, and model performance was assessed. Three hundred one patients [median age 10 (interquartile range 4-14)] were followed up for an average of 4.9 (±3.8) years, during which 30 (10.0%) reached the SCD or equivalent event endpoint. Harrell's C-statistic for the clinical and genetic models was 0.66 [95% confidence interval (CI) 0.52-0.8] and 0.66 (95% CI 0.54-0.80) with a calibration slope of 0.19 (95% CI 0.04-0.54) and 0.26 (95% CI -0.03-0.62), respectively. The number needed to treat to potentially treat one life-threatening arrhythmia for the PRIMaCY clinical, PRIMaCY genetic, and HCM Risk-Kids models was 13.7, 14.5, and 9.4, respectively., Conclusion: Although PRIMaCY has a similar discriminatory ability to that reported for HCM Risk-Kids, estimated risk estimates did not correlate well with observed risk. A higher proportion of patients met implantable cardioverter-defibrillator thresholds using PRIMaCY model compared with HCM Risk-Kids. This has important clinical implications as these patients will be exposed to a lifetime risk of complications and inappropriate therapies., Competing Interests: Conflict of interest: P.M.E. declares consultancies for Pfizer and Sarepta. J.P.K. declares consultancies for Tenaya, Cytokinetics, and DiNAQOR. The other authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The main contact lens for pediatric aphakia has historically been a silicone elastomer lens (Silsoft SuperPlus). Due to supply chain disruption, many aphakic children required an alternative lens. We performed quantitative and qualitative comparisons between Silsoft SuperPlus and alternative aphakic soft contacts., Method: Sixty-nine aphakic eyes of 49 patients wearing Silsoft SuperPlus lenses underwent the refitting process into an alternative soft contact. Data collected included lens parameters, visual acuity, keratometry, horizontal visible iris diameter, and over-refraction. A 6-question survey assessing the patients'/guardians' experience with Silsoft SuperPlus versus the alternative lens was conducted at initial fit and 1-3 months post-fit., Results: Twenty-four patients (49 %), 4(8 %), and 1(2 %) were refit into Flexlens Definitive 74, Biofinity XR, and Intelliwave Pro Toric lenses, respectively. Sixteen patients (34 %) remained in Silsoft SuperPlus due to personal lens surplus or inability to handle the new lens while 2(4 %) opted for glasses. Silsoft SuperPlus was typically successful in eyes with average keratometry (AveK) 7.4-7.6 mm. Flexlens Definitive 74 required a base curve 0.4 mm steeper than the AveK. Patients'/guardias' reported a trend toward greater comfort with handling Silsoft SuperPlus, however, patients experienced less adverse side effects with the alternative soft contact lenses., Conclusions: Flexlens Definitive 74 was an adequate alternative to Silsoft SuperPlus in aphakic children, however lens parameters must be steepened. Keratometry streamlined the contact lens fitting process. Alternative soft lenses are a cost-effective alternative to Silsoft contact lenses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The methylotrophic yeast Komagataella phaffii is considered one of the most effective producers of recombinant proteins of industrial importance. Effective producers should be characterized by the maximal reduction of degradation of the cytosolic recombinant proteins. The mechanisms of degradation of cytosolic proteins in K. phaffii have not been elucidated; however, data suggest that they are partially degraded in the autophagic pathway. To identify factors that influence this process, a developed system for the selection of recombinant strains of K. phaffii with impaired autophagic degradation of the heterologous model cytosolic protein (yeast β-galactosidase) was used for insertional tagging of the genes involved in cytosolic proteins degradation. In one of the obtained strains, the insertion cassette disrupted the open reading frame of the gene encoding β-1,6-N-acetylglucosaminyltransferase. A recombinant strain with deletion of this gene was also obtained. The rate of degradation of the β-galactosidase enzyme was two times slower in the insertion mutant and 1.5 times slower in the deletion strain as compared to the parental strain with native β-1,6-N-acetylglucosaminyltransferase. The rate of degradation of native K. phaffii cytosolic and peroxisomal enzymes, formaldehyde dehydrogenase, formate dehydrogenase, and alcohol oxidase, respectively, showed similar trends to that of β-galactosidase-slower degradation in the deletion and insertional mutants as compared to the wild-type strain, but faster protein degradation relative to the strain completely defective in autophagy. We conclude that K. phaffii gene designated ACG1, encoding β-1,6-N-acetylglucosaminyltransferase, is involved in autophagy of the cytosolic and peroxisomal proteins., (© 2023 John Wiley & Sons Ltd.)

Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six clusters and unexpectedly found that none corresponded to traditional definitions of M1 or M2 macrophages. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 (gal-3) and osteopontin ( Spp1 ). Spatial transcriptomics, computational inferences of intercellular communication, and in vitro assays indicated that macrophage-derived Spp1 regulates stromal progenitor differentiation. Gal-3 + macrophages were chronically activated in dystrophic muscle, and adoptive transfer assays showed that the gal-3 + phenotype was the dominant molecular program induced within the dystrophic milieu. Gal-3 + macrophages were also elevated in multiple human myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining their transcriptional programs and reveal Spp1 as a major regulator of macrophage and stromal progenitor interactions.

The recently introduced HCM-AF Risk Calculator allows the prognosis of atrial fibrillation (AF) occurrence in hypertrophic cardiomyopathy (HCM) patients. The aim of this study was to assess the clinical application of the HCM-AF Risk Score in the prediction of the clinical outcomes of Polish patients. The study included 92 patients (50.0% female, median age 55 years), with a baseline sinus rhythm diagnosed between 2013 and 2018. The analysis involved the incidence of clinical characteristics and outcomes, total mortality, rehospitalisation, and the course of heart failure (HF). According to the HCM-AF Risk Score, the HCM population was stratified into three subgroups, with a low (13/14.2%), intermediate (30/32.6%), and high risk of AF (49/53.2%). Subgroups differed significantly: the high-risk subgroup was older, had a higher body mass index (BMI), and more advanced signs of left ventricular (LV) hypertrophy and left atrium (LA) dilatation. The registered AF incidence was 31.5% and 43.5% in the 2- and 5-year follow-ups, and it was significantly higher than in the HCM-AF Risk Score population, which had 4.6% in the 2-year follow-up, and 10.7% in the 5-year follow-up. In the whole population, the AF incidence in both the 2- and 5-year follow-ups revealed a strong correlation with the HCM-AF Risk Score (r = 0.442, p < 0.001; r = 0.346, p < 0.001, respectively). The clinical outcomes differed among the subgroups: the total mortality was 15.4% vs. 20.0% vs. 42.9% ( p < 0.05); rehospitalisation was 23.1% vs. 53.3% vs. 71.4% ( p < 0.05). The highest HF progression was in the high-risk subgroup (36.7%). Regardless of the high results of the HCM-Risk Score in Polish patients, the score underestimates the real-life high level of AF incidence. The HCM-AF Risk Score seems to be useful in the prediction of the general clinical outcomes in HCM patients.

Background: Commercial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests were developed before variants with spike protein mutations emerged, leading to concerns that these tests have reduced sensitivity for detecting antibody responses in individuals infected with Omicron subvariants. This study was performed to evaluate Abbott ARCHITECT serologic assays, AdviseDx SARS-CoV-2 IgG II, and SARS-CoV-2 IgG for the detection of spike (S) and nucleocapsid (N) IgG antibody increases in vaccinated healthcare workers infected with Omicron subvariants., Methods: During the BA.1/2 and BA.4/5 waves, 171 SARS-CoV-2-infected individuals (122 in the BA.1/2 wave, 49 in the BA.4/5 wave) were tested for S and N IgG post infection. Sequencing and SARS-CoV-2 variant confirmation were performed on nasal swab samples from individuals infected during the BA.1/2 wave., Results: Twenty-seven Omicron sequence confirmed individuals in the BA.1/2 wave and all 49 in the BA.4/5 wave had pre-infection antibody data. Compared to pre-infection levels, post-infection S IgG increased 6.6-fold from 1294 ± 302 BAU/ml (mean ± standard error measurement) to 9796 ± 1252 BAU/ml ( P < 0.001) during the BA.1/2 wave, and 3.6-fold from 1771 ± 351 BAU/ml to 8224 ± 943 BAU/ml ( P < 0.001) during the BA.4/5 wave. N IgG increased post infection 19.1-fold from 0.2 ± 0.1 to 3.7 ± 0.5 ( P < 0.001) during the BA.1/2 wave and 13.5-fold from 0.22 ± 0.1 to 3.2 ± 0.3 ( P < 0.001) during the BA.4/5 wave. Among 159 infection-naïve individuals, positive N IgG levels were detected with a sensitivity of 88% in the 87 individuals who were tested between 14 days and 60 days post infection., Conclusions: The large increases in post-infection S IgG along with the N IgG sensitivity that was comparable to previously reported N IgG sensitivity data in unvaccinated individuals after Omicron infection, support the use of Abbott SARS-CoV-2 assays for detecting increased S IgG and seroconversion of N IgG in vaccinated individuals post Omicron infection. Given that 68% of the United States population is fully vaccinated, these results are of current relevance., Competing Interests: The authors declare the following financial interests/personal relationships: MA, MR, AO, BH, MS, VH, AA, EG, TF, EA, and GC are employees and shareholders of Abbott Laboratories. This work was funded by Abbott Laboratories. AL is a consultant for Abbott Laboratories., (© 2023 The Author(s).)

Spondyloarthropathies (SpA) are a family of rheumatic disorders that could be divided into axial (axSpA) and peripheral (perSpA) sub-forms depending on the disease clinical presentation. The chronic inflammation is believed to be driven by innate immune cells such as monocytes, rather than self-reactive cells of adaptive immune system. The aim of the study was to investigate the micro-RNA (miRNA) profiles in monocyte subpopulations (classical, intermediate and non-classical subpopulations) acquired from SpA patients or healthy individuals in search for prospective disease specific and/or disease subtype differentiating miRNA markers. Several SpA-specific and axSpA/perSpA differentiating miRNAs have been identified that appear to be characteristic for specific monocyte subpopulation. For classical monocytes, upregulation of miR-567 and miR-943 was found to be SpA-specific, whereas downregulation of miR-1262 could serve as axSpA-differentiating, and the expression pattern of miR-23a, miR-34c, mi-591 and miR-630 as perSpA-differentiating markers. For intermediate monocytes, expression levels of miR-103, miR-125b, miR-140, miR-374, miR-376c and miR-1249 could be used to distinguish SpA patients from healthy donors, whereas the expression pattern of miR-155 was identified as characteristic for perSpA. For non-classical monocytes, differential expression of miR-195 was recognized as general SpA indicator, while upregulation of miR-454 and miR-487b could serve as axSpA-differentiating, and miR-1291 as perSpA-differentiating markers. Our data indicate for the first time that in different SpA subtypes, monocyte subpopulations bear disease-specific miRNA signatures that could be relevant for SpA diagnosis/differentiation process and may help to understand SpA etiopathology in the context of already known functions of monocyte subpopulations., 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 © 2023 Stec, Czepiel, Lenart, Piestrzyńska-Kajtoch, Plewka, Bieniek, Węglarczyk, Szatanek, Rutkowska-Zapała, Guła, Kluczewska, Baran, Korkosz and Siedlar.)

Background: HBV pregenomic RNA (pgRNA) is a circulating biomarker for covalently closed circular DNA activity in HBV-infected individuals and has been studied for treatment efficacy, disease staging, and off-therapy outcomes; however, data on the stability are scarce. Increasing HBV pgRNA assay sensitivity may improve its predictive value and provide additional insights at low viral levels., Methods: Modifications to a fully automated first (v1) generation HBV pgRNA assay improved sensitivity up to 15-fold over the previous assay. Flexible sample input volumes yielded lower limits of quantitation of 10 and 22 copies/mL for 0.6 and 0.2 mL assays, respectively. Results are standardized to secondary standards that are traceable to the WHO HBV DNA standard, and internal and external controls are included., Results: Comparison between v1 and modified v2 assays showed increased sensitivity from 152 copies/mL with v1 to 10 (0.6 mL) and 22 (0.2 mL) copies/mL with v2, respectively. Quantitated v2 results were indistinguishable from v1, indicating that comparisons can be made to previous studies. Single timepoint treatment-naive blood donors or longitudinal draws from patients with chronic hepatitis B on AB-729, an investigational siRNA therapy, showed improved detection and quantifiable pgRNA with v2 compared with v1. Stability testing demonstrated excellent HBV pgRNA plasma stability after 3 freeze-thaw cycles, for at least 7 days at 25-37 °C and at least 30 days at 4°C, with ≤0.25 Log U/mL decrease., Conclusion: HBV pgRNA v2 assays with increased sensitivity and flexible input volumes demonstrated increased detection and quantitation of low viral titer samples. Highly sensitive HBV pgRNA assays may be useful in refining predictive treatment outcomes based on this marker. HBV pgRNA was stable under multiple conditions, which increases the reliability of this marker., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

It has been demonstrated that after two doses, SARS-CoV-2 mRNA vaccine-induced neutralizing antibodies against Omicron subvariants are much lower than against wild type virus and a booster dose greatly increases Omicron neutralization. We compared Spike-binding IgG responses against wild type virus and four SARS-CoV-2 Omicron subvariants in infection-naïve and previously-infected (hybrid immunity) individuals after the second and the third (booster) dose of BNT162b2. In both groups of individuals, antibodies for all four Omicron subvariants were lower than wild type antibodies. Compared to infection-naïve individuals, hybrid immunity resulted in higher antibodies levels after 2 doses of vaccine but not after the booster. In both groups, antibodies for wild type and all Omicron subvariants waned over an 8-month period post second dose but rebounded after the booster. These results underscore the importance of boosters to restore diminishing antibody levels for both infection-naïve and previously-infected individuals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors M.A., M.S., and G.C. are employees and shareholders of Abbott Laboratories. A.L. has received consulting fees from Abbott Laboratories. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nano-sized radiosensitizers can be used to increase the effectiveness of radiation-based anticancer therapies. In this study, bimetallic, ~30 nm palladium-platinum nanoparticles (PdPt NPs) with different nanostructures (random nano-alloy NPs and ordered core-shell NPs) were prepared. Scanning transmission electron microscopy (STEM), selected area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDS), zeta potential measurements, and nanoparticle tracking analysis (NTA) were used to provide the physicochemical characteristics of PdPt NPs. Then, PdPt NPs were added to the cultures of colon cancer cells and normal colon epithelium cells in individually established non-toxic concentrations and irradiated with the non-harmful dose of X-rays/protons. Cell viability before and after PdPt NPs-(non) assisted X-ray/proton irradiation was evaluated by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Flow cytometry was used to assess cell apoptosis. The results showed that PdPt NPs significantly enhanced the effect of irradiation on cancer cells. It was noticed that nano-alloy PdPt NPs possess better radiosensitizing properties compared to PtPd core-shell NPs, and the combined effect against cancer cells was c.a. 10% stronger for X-ray than for proton irradiation. Thus, the radio-enhancing features of differently structured PdPt NPs indicate their potential application for the improvement of the effectiveness of radiation-based anticancer therapies.

Background: Long-term studies of vaccine recipients are necessary to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody durability and assess the impact of booster doses on antibody levels and protection from infection. The identification of vaccine breakthrough infections among fully vaccinated populations will be important in understanding vaccine efficacy and SARS-CoV-2 vaccine escape capacity., Methods: SARS-CoV-2 spike (S) receptor-binding domain and nucleocapsid (N) immunoglobulin (Ig) G levels were measured in a longitudinal study of 1000 Chicago healthcare workers who were infection naive or previously infected and then vaccinated. Changes in S and N IgG were followed up through 14 months, and vaccine breakthrough infections were identified by increasing levels of N IgG., Results: SARS-CoV-2 S IgG antibody levels among previously infected and previously noninfected individuals decreased steadily for 11 months after vaccination. Administration of a booster 8-11 months after vaccination increased S IgG levels >2-fold beyond those observed after 2 doses, resulting in S IgG levels that were indistinguishable between previously infected and uninfected individuals. Increases in N IgG identified vaccine breakthrough infections and showed >15% breakthrough infection rates during the Omicron wave starting in December 2021., Conclusions: These results demonstrate SARS-CoV-2 antibody changes after vaccination and breakthrough infections and identify high levels of vaccine breakthrough infections during the Omicron wave, based on N IgG increases., Competing Interests: Potential conflicts of interest. M. A., M. S., and G. C. are employees and shareholders of Abbott Laboratories. A. L. has received consulting fees from Abbott Laboratories. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In vaccine clinical trials, both binding antibody (bAb) levels and neutralization antibody (nAb) titers have been shown to be correlates of SARS-CoV-2 vaccine efficacy. We report a strong correlation bAb and nAb responses against the SARS-CoV-2 Omicron (BA.1) variant in infection-naïve and previously infected (convalescent) individuals after one and two doses of BNT162b2 vaccination. The vaccine-induced bAb levels against Omicron were significantly lower compared to previous variants of concern in both infection-naive and convalescent individuals, with the convalescent individuals showing significantly higher bAb compared to the naïve individuals at all timepoints. The finding that bAb highly correlated with nAb provides evidence for utilizing binding antibody assays as a surrogate for neutralizing antibody assays. Our data also revealed that after full vaccination, a higher percentage of individuals had undetectable Omicron nAb (58.6% in naive individuals, 7.4% in convalescent individuals) compared to the percentage of individuals who had negative Omicron bAb (0% in naive individuals, 0% in convalescent individuals). The discordance between bAb and nAb activities and the high degree of immune escape by Omicron may explain the high frequency of Omicron infections after vaccination.

Background: An innovative remote learning intervention, PICO Pal, was implemented with groups of undergraduate nursing students in a nursing research course to promote interactive learning, collaboration, and information literacy., Problem: Evidence-based practice (EBP) is a challenging topic to teach nursing students, especially in a remote learning environment., Approach: PICO Pal used Apple Numbers to facilitate remote group work on a PICOT poster. The approach was evaluated using pre- and posttest surveys with 50 undergraduate nursing students at a small private university in New Jersey., Outcomes: The evaluation showed positive perceptions of the assignment and gains with knowledge of EBP. However, there were no gains in the perceptions of group work., Conclusions: The assignment was effective at teaching aspects of the EBP process but should be reevaluated to maximize group work dynamics and comfort with use of technology., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The use of materials requires adjusting their features to current applications/needs. In crystallization, the production methods leading directly to the product with pre-determined characteristics are being sought. The research focuses on the abilities of "shaping" the solid product (CSD, shape, form, etc.) and is based on experimental work carried out in the ultrasound (US)-assisted Koflo static mixer (STM). As the model reaction calcium fluoride precipitation has been used as a "common denominator" that complements the previous authors' studies, providing comprehensive knowledge and a more general look at the mentioned problem. It has been shown that it is possible to obtain crystals with the desired characteristics; however, one should be aware of the used reactors' limitations. The conscious selection of operating conditions, as well as US parameters (if they are used), is also essential. It has been revealed that the introduction of US to the STM only affects the turbulence intensity, but it doesn't change the mixing profile. The kinetics of crystallization remain unchanged, but crystals are subjected to greater attrition. In the stirred tank reactors, one might significantly improve the homogeneity of the unit mixing distribution by the selection of the relative input power ε rel and, thus, affect the kinetics of crystallization.

Previous reports demonstrated that severe acute respiratory syndrome coronavirus (SARS-CoV-2) binding immunoglobulin G levels did not increase significantly between the first and second doses of the BNT162b2 vaccine in previously infected individuals. We tested neutralizing antibodies (nAbs) against SARS-CoV-2 Delta and Omicron variants after the first and second doses of this vaccine in infection-naive and previously infected individuals. Delta, but not Omicron, nAb titers significantly increased from the first to the second dose in both groups of individuals. Importantly, we found that Omicron nAb titers were much lower than Delta nAb titers and that even after 2 doses of vaccine, 17 of 29 individuals in the infection-naive group and 2 of 27 in the previously infected group did not have detectable Omicron nAb titers. Infection history alone did not adequately predict whether a second dose resulted in adequate nAb. For future variants of concern, the discussion on the optimal number of vaccine doses should be based on studies testing for nAb against the specific variant., Competing Interests: Potential conflicts of interest. M. A, M. S., and G. C. are employees of Abbott Diagnostics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Due to their biocompatible and plasmonic properties, gold nanoparticles (Au NPs) are good candidates to be photosensitizers in photothermal cancer therapy (PTT)., Materials and Methods: In this paper, the dependence of the NIR-light-to-heat energy on Au NPs size was investigated. Moreover, to determine the photosensitizing properties of gold nanoparticles, PTT was conducted on two colon cell lines: SW480 and SW620 by irradiating them with two lasers having different wavelengths., Results: Transmission electron microscopy showed that the respective sizes of Au NPs were 10 nm, 12 nm and 16 nm. Moreover, local as well as global structural measurements showed that all synthesized Au NPs were crystalline and UV-Vis spectroscopy revealed that with increasing nanoparticles size the position of the surface Plasmon resonance (SPR) peaks is shifted to higher wavelengths. Decrease of cells viability was observed, when they were cultured with Au NPs and irradiated by 650 nm and 808 nm lasers. Moreover, FTIR and Raman spectra of cells, showed structural changes in DNA, phospholipids, proteins and cholesterol caused by the addition of nanoparticles and laser irradiation. The chemical changes were more pronounced in the cells cultured with Au NPs and irradiated by 650 nm lasers and these changes were dependent on the nanoparticle size. Moreover, the viability of cells investigated by the MTS assay showed, that the percentage of dead cells (∼40%) is the highest for cells cultured with 8 nm Au NPs and irradiated by the 650 nm laser. The photothermal conversion efficiency calculated from the experimental results showed a decrease of this parameter from 70% to 55% and from 61% to 48% with increasing particle size, for 650 nm and 808 nm lasers, respectively., Conclusions: The obtained results showed that the photothermal conversion efficiency of Au NPs is size-tunable, and can be correlated with the absorption/extinction ratios calculated by the Mie theory., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

Background: After the reports of severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine, patients who had received one dose of ChAdOx1-S-nCoV-19 vaccine were recommended a second dose of Pfizer's BNT162b2 vaccine. In hemodialysis patients, we compared the humoral immunogenicity and tolerability of homologous vaccination with ChAdOx1-nCoV-19/ChAdOx1-nCoV-19 (ChAd/ChAd) and BNT162b2/BNT162b2 (BNT/BNT) with heterologous vaccination of first dose of ChAdOx1-nCoV-19 and a second dose with BNT162b2 (ChAd/BNT)., Methods: In a multicenter prospective observational study, SARS-CoV-2 spike-IgG antibody levels, Nucleocapsid-protein-IgG-antibodies, and vaccine tolerability were assessed 6 weeks after second SARS-CoV-2 vaccination in 137 hemodialysis patients and 24 immunocompetent medical personnel., Results: In COVID-19-naïve hemodialysis patients, significantly higher median SARS-CoV-2-spike IgG levels were found after ChAd/BNT (N = 16) compared to BNT/BNT (N = 100) or ChAd/ChAd (N = 10) (1744 [25th-75th percentile 276-2840] BAU/mL versus 361 [25th-75th percentile 120-936] BAU/mL; p = 0.009; 1744 [25th-75th percentile 276-2840] BAU/mL versus 100 [25th-75th percentile 41-346] BAU/mL; p = 0.017, respectively). Vaccinated, COVID-19-naïve medical personnel had median SARS-CoV-2 spike-IgG levels of 650 (25th-75th percentile 217-1402) BAU/mL and vaccinated hemodialysis patients with prior COVID-19 7047 (25th-75th percentile 685-10,794) BAU/mL (N = 11). In multivariable regression analysis, heterologous vaccination (ChAd/BNT) of COVID-19-naïve hemodialysis patients was independently associated with SARS-CoV-2 spike-IgG levels. The first dose of ChAd and the second dose of BNT after the first vaccination with ChAd (heterologous vaccination, ChAd/BNT) were associated with more frequent but manageable side effects compared with homologous BNT., Conclusions: Within the limitations of this study, heterologous vaccination with ChAd/BNT appears to induce stronger humoral immunity and more frequent but manageable side effects than homologous vaccination with BNT/BNT or with ChAd/ChAd in COVID-19-naïve hemodialysis patients., (© 2022. The Author(s).)

Background: In peritoneal dialysis (PD) patients, information on the immunogenicity and tolerability of SARS-CoV-2 vaccination is still scarce. We compared the immunogenicity and tolerability of SARS-CoV-2 vaccination of PD patients with that of medical personnel., Methods: In a prospective observational cohort study, PD patients and immunocompetent medical personnel were evaluated for SARS-CoV-2 spike-IgG- and Nucleocapsid-IgG-antibody-levels before, 2 weeks after the first, and 6 weeks after the second SARS-CoV-2 vaccination and vaccine tolerability after the first and second vaccination., Results: In COVID-19-naïve PD patients (N = 19), lower SARS-CoV-2-spike-IgG-levels were found compared with COVID-19-naïve medical personnel (N = 24) 6 weeks after second vaccination (median 1438 AU/ml [25th-75th percentile 775-5261] versus 4577 [1529-9871]; p = 0.045). This finding resulted in a lower rate of strong vaccine response (spike-IgG ≥ 1000 AU/ml) of COVID-19-naïve PD patients compared with medical personnel (58% versus 92%; p = 0.013), but not for seroconversion rate (spike-IgG ≥ 50 AU/ml: 100% vs. 100%; p > 0.99). After first vaccination, COVID-naïve PD patients presented with significantly fewer side effects than medical personnel (number of any side effect: 1 [1-2] vs. 4 [1-7]; p = 0.015). A similar pattern with slightly decreased frequencies of side effects was observed for tolerability of second SARS-CoV-2 vaccination in PD patients and medical personnel (number of any side effects: 1 [1-1] vs. 2 [1-5]; p = 0.006)., Conclusions: SARS-CoV-2 vaccination in COVID-19-naïve PD patients appeared to induce a very high rate of seroconversion but a substantially lower rate of patients with a strong response compared with medical personnel. Vaccination appeared to be safe in the PD patients studied., (© 2021 The Authors. Seminars in Dialysis published by Wiley Periodicals LLC.)

Background: Immature immune systems predispose very low birth weight (VLBW) neonates to systemic infections in early life. Defective inflammasome function may increase a neonate's susceptibility to late-onset sepsis (LOS)., Methods: Blood samples were taken on the 5 th day of life (DOL) for all VLBW neonates (non-LOS and before-LOS groups; N.=76), and within 24 hours of sepsis onset (LOS group; N.=39). Monocyte (MO) subsets and intracellular interleukin-1β (IL-1β) expression were analyzed using flow cytometry. Inflammasome function, defined as level of IL-1β and interleukin-18 (IL-18) was measured with enzyme-linked immunosorbent assay. IRA B cells were reported as a fraction of all B cells., Results: Stimulation of classical MO in non-LOS cells demonstrated a higher expression of intracellular IL-1β in comparison to MO from before LOS group. Serum from the LOS group revealed a higher level of IL-18. Stimulation of mononuclear cultures from samples taken during LOS resulted in significantly increased supernatant level of IL-1β and IL-18 in comparison to samples taken on 5 th DOL. No changes in the levels of IRA B cells were detected with the onset of sepsis., Conclusions: We did not observe a difference in the functioning of the inflammasome within monocytes taken on 5 th DOL from premature VLBW neonates. Furthermore, there was no observable change in the IRA B cells of the septic and non-septic groups. The decreased expression of intracellular IL-1β within classical MO of the before-LOS group may be an independent risk factor for LOS development.

Background: We sought to determine the prevalence and sociodemographic and clinical correlates of acute and convalescent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections among emergency department (ED) patients in Baltimore., Methods: Remnant blood samples from 7450 unique patients were collected over 4 months in 2020 for SARS-CoV-2 antibody (Ab), HCV Ab, and HIV-1/2 antigen and Ab. Among them, 5012 patients were tested by polymerase chain reaction for SARS-CoV-2 based on clinical suspicion. Sociodemographics, ED clinical presentations, and outcomes associated with coinfections were assessed., Results: Overall, 729 (9.8%) patients had SARS-CoV-2 (acute or convalescent), 934 (12.5%) HCV, 372 (5.0%) HIV infection, and 211 patients (2.8%) had evidence of any coinfection (HCV/HIV, 1.5%; SARS-CoV-2/HCV, 0.7%; SARS-CoV-2/HIV, 0.3%; SARS-CoV-2/HCV/HIV, 0.3%). The prevalence of SARS-CoV-2 (acute or convalescent) was significantly higher in those with HCV or HIV vs those without (13.6% vs 9.1%, P  < .001). Key sociodemographic disparities (race, ethnicity, and poverty) and specific ED clinical characteristics were significantly correlated with having any coinfections vs no infection or individual monoinfection. Among those with HCV or HIV, aged 18-34 years, Black race, Hispanic ethnicity, and a cardiovascular-related chief complaint had a significantly higher odds of having SARS-CoV-2 (prevalence ratios: 2.02, 2.37, 5.81, and 2.07, respectively)., Conclusions: The burden of SARS-CoV-2, HCV, and HIV co-pandemics and their associations with specific sociodemographic disparities, clinical presentations, and outcomes suggest that urban EDs should consider implementing integrated screening and linkage-to-care programs for these 3 infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Globally, key subpopulations such as healthcare workers (HCW) may have a higher risk of contracting SARS-CoV-2. In Uganda, limited access to Personal Protective Equipment and lack of clarity on the extent/pattern of community spread may exacerbate this situation. The country established infection prevention/control measures such as lockdowns and proper hand hygiene. However, due to resource limitations and fatigue, compliance is low, posing continued onward transmission risk. This study aimed to describe extent of SARS-CoV-2 seroprevalence in selected populations within the Rakai region of Uganda., Methods: From 30th November 2020 to 8th January 2021, we collected venous blood from 753 HCW at twenty-six health facilities in South-Central Uganda and from 227 population-cohort participants who reported specific COVID-19 like symptoms (fever, cough, loss of taste and appetite) in a prior phone-based survey conducted (between May and August 2020) during the first national lockdown. 636 plasma specimens collected from individuals considered high risk for SARS-CoV-2 infection, prior to the first confirmed COVID-19 case in Uganda were also retrieved. Specimens were tested for antibodies to SARS-CoV-2 using the CoronaChek™ rapid COVID-19 IgM/IgG lateral flow test assay. IgM only positive samples were confirmed using a chemiluminescent microparticle immunoassay (CMIA) (Architect AdviseDx SARS-CoV-2 IgM) which targets the spike protein. SARS-CoV-2 exposure was defined as either confirmed IgM, both IgM and IgG or sole IgG positivity. Overall seroprevalence in each participant group was estimated, adjusting for test performance., Results: The seroprevalence of antibodies to SARS-CoV-2 in HCW was 26.7% [95%CI: 23.5, 29.8] with no difference by sex, age, or cadre. We observed no association between PPE use and seropositivity among exposed healthcare workers. Of the phone-based survey participants, 15.6% [95%CI: 10.9, 20.3] had antibodies to SARS-CoV-2, with no difference by HIV status, sex, age, or occupation. Among 636 plasma specimens collected prior to the first confirmed COVID-19 case, 2.3% [95%CI: 1.2, 3.5] were reactive., Conclusions: Findings suggest high seroprevalence of antibodies to SARS-CoV-2 among HCW and substantial exposure in persons presenting with specific COVID-19 like symptoms in the general population of South-Central Uganda. Based on current limitations in serological test confirmation, it remains unclear whether seroprevalence among plasma specimens collected prior to confirmation of the first COVID-19 case implies prior SARS-CoV-2 exposure in Uganda., (© 2022. The Author(s).)

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has demonstrated a survival benefit and reduces heart failure hospitalization in patients with heart failure with reduced left ventricular ejection fraction (HFrEF); however, our experience in this field is limited. This study aimed to summarize a real clinical practice of the use of ARNI in HFrEF patients hospitalized due to HFrEF in the era before the 2021 ESC HF recommendations, as well as assess their clinical outcome with regard to ARNI administration., Methods and Materials: Overall, 613 patients with HFrEF hospitalized in 2018-2020 were enrolled into a retrospective one-centre cross-sectional analysis. The study population was categorized into patients receiving (82/13.4%) and not-receiving (531/82.6%) ARNI. Clinical outcomes defined as rehospitalization, number of rehospitalizations, time to the first rehospitalization and death from any cause were analysed in the 1-2 year follow-up in the ARNI and non-ARNI groups, matched as to age and LVEF., Results: Clinical characteristics revealed the following differences between ARNI and non-ARNI groups: A higher percentage of cardiovascular implantable electronic devices (CIED) ( p = 0.014) and defibrillators with cardiac resynchronization therapy (CRT-D) ( p = 0.038), higher frequency of atrial fibrillation ( p = 0.002) and history of stroke ( p = 0.024) were in the ARNI group. The percentage of patients with HFrEF NYHA III/IV presented an increasing trend to be higher in the ARNI (64.1%) as compared to the non-ARNI group (51.5%, p = 0.154). Incidence of rehospitalization, number of rehospitalizations and time to the first rehospitalization were comparable between the groups. There were no differences between the numbers of deaths of any cause in the ARNI (28%) and non-ARNI (28%) groups. The independent negative predictor of death in the whole population of ARNI and non-ARNI groups was the coexistence of coronary artery disease (CAD) (beta= -0.924, HR 0.806, p = 0.011)., Conclusions: Our current positive experience in ARNI therapy is limited to extremely severe patients with HFrEF. Regardless of the more advanced HF and HF comorbidities, the patients treated with ARNI presented similar mortality and rehospitalizations as the patients treated by standard therapy.

Background and Objectives: Regardless of the improvement in key recommendations in non-ST-elevation myocardial infarction (NSTEMI), the prevalence of total occlusion (TO) of infarct-related artery (IRA), and the impact of TO of IRA on outcomes in patients with NSTEMI, remain unclear. Aim: The study aimed to assess the incidence and predictors of TO of IRA in patients with NSTEMI, and its clinical significance. Material and Methods: The study was a single-center retrospective cohort analysis of 399 consecutive patients with NSTEMI (293 male, mean age: 71 ± 10.1 years) undergoing percutaneous coronary intervention. The study population was categorized into patients with TO and non-TO of IRA on coronary angiography. In-hospital and one-year mortality were analyzed. Results: TO of IRA in the NSTEMI population occurred in 138 (34.6%) patients. Multivariate analysis identified the following independent predictors of TO of IRA: left ventricular ejection fraction (odds ratio (OR) 0.949, p < 0.001); family history of coronary artery disease (CAD) (OR 2.652, p < 0.001); and high-density lipoprotein (HDL) level (OR 0.972, p = 0.002). In-hospital and one-year mortality were significantly higher in the TO group than the non-TO group (2.8% vs. 1.1%, p = 0.007 and 18.1% vs. 6.5%, p < 0.001, respectively). The independent predictors of in-hospital mortality were: left ventricular ejection fraction (LVEF) at admission (OR 0.768, p = 0.004); and TO of IRA (OR 1.863, p = 0.005). Conclusions: In the population of patients with NSTEMI, TO of IRA represents a considerably frequent phenomenon, and corresponds with impaired outcomes. Therefore, the utmost caution should be paid to prevent delay of coronary angiography in NSTEMI patients with impaired left ventricular systolic function, metabolic disturbances, and a family history of CAD, who are at increased risk of TO of IRA.

Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1ɑ1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity., Competing Interests: Declaration of interests S.K., M.S., and N.K. are employees and shareholders of Regeneron Pharmaceuticals. J.L.R. is a consultant for Bayer AG., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Noble metal nanoparticles, such as gold (Au NPs), platinum (Pt NPs), or palladium (Pd NPs), due to their highly developed surface, stability, and radiosensitizing properties, can be applied to support proton therapy (PT) of cancer. In this paper, we investigated the potential of bimetallic, c.a. 30 nm PtAu and PdAu nanocomplexes, synthesized by the green chemistry method and not used previously as radiosensitizers, to enhance the effect of colorectal cancer PT in vitro. The obtained nanomaterials were characterized by scanning transmission electron microscopy (STEM), selected area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDS), UV-Vis spectroscopy, and zeta potential measurements. The effect of PtAu and PdAu NPs in PT was investigated on colon cancer cell lines (SW480, SW620, and HCT116), as well as normal colon epithelium cell line (FHC). These cells were cultured with both types of NPs and then irradiated by proton beam with a total dose of 15 Gy. The results of the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) test showed that the NPs-assisted PT resulted in a better anticancer effect than PT used alone; however, there was no significant difference in the radiosensitizing properties between tested nanocomplexes. The MTS results were further verified by defining the cell death as apoptosis (Annexin V binding assay). Furthermore, the data showed that such a treatment was more selective for cancer cells, as normal cell viability was only slightly affected.

Objective: Axial spondyloarthritis (SpA) is a chronic autoinflammatory disease with new bone formation, which is controlled by Wnt/β-catenin signaling. Dkk-1 is an inhibitor of the Wnt pathway, and in humans, platelets represent a major source of Dkk-1. This study was undertaken to investigate whether levels of Dkk-1 in serum and platelet expression of DKK1 messenger RNA (mRNA) and Dkk-1 protein are affected in patients with axial SpA compared to healthy controls., Methods: Forty-one patients with axial SpA and 35 healthy controls were enrolled in the study. Total serum Dkk-1 levels in all patients and healthy controls were measured by quantitative enzyme-linked immunosorbent assay. Platelet DKK1 mRNA was analyzed by quantitative reverse transcriptase-polymerase chain reaction in 20 patients with axial SpA and 20 controls, and Dkk-1 protein levels were measured by immunoblotting in 20 patients with axial SpA and 18 controls., Results: We found a lower concentration of Dkk-1 in the serum from patients with axial SpA compared to the serum from healthy controls (P < 0.0001). Furthermore, the expression of Dkk-1 was significantly reduced both at the transcriptional level (P < 0.04) and at the protein level (P < 0.007) in platelets isolated from the blood of patients with axial SpA., Conclusion: Our preliminary observations suggest that dysfunction of the megakaryocyte/platelet axis might be responsible for reduced serum Dkk-1 levels in patients with axial SpA. Dkk-1 is down-regulated in the platelets of patients with axial SpA, a mechanism that might play a role in new bone formation., (© 2021, American College of Rheumatology.)

Background: Work on the Act on the Profession of Physiotherapist had been conducted since the 1990s. However, it was not until October 2015 that the legal regulations were eventually introduced, following which physiotherapists gained professional independence and became a profession of public trust. The aim of the study was to assess the factors influencing the knowledge of these legal regulations among physiotherapists., Material and Methods: The study involved 399 physiotherapists and physiotherapy students (28.8±5.9 years old) who completed an anonymous questionnaire, in the form of a knowledge test, consisting of 24 questions on the general aspects of the reference Act., Results: Overall, 30.3% of the respondents proved to have a significant knowledge about the rights and obligations resulting from the Act. The physiotherapists who were entered into the National Register of Physiotherapists (2.6 times) and residents of large cities (1.8 times) had a greater knowledge of the Act. There was a correlation between seniority and gender, and the knowledge of legal regulations., Conclusions: The main factors influencing the state of knowledge about the Act are the entry to the National Register of Physiotherapists, the place of residence and seniority. This proves better access to up-to-date information in cities and a greater interest in the Act among those people who have obtained the right to practice their profession. Med Pr. 2021;72(4):407-14., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.

Spondyloarthritis (SpA) is characterized by chronic inflammation and structural damage involving spine and peripheral joints. Monocytes, as part of innate immune system, following migration into affected tissue, may play a role in the pathogenesis of SpA. Here, potential associations between osteogenesis-linked gene expression profile in particular monocyte subpopulations and clinical signs of SpA were investigated. The 20 patients with axial and 16 with peripheral SpA were enrolled in the study. Monocyte subpopulations (classical-CD14 ++ CD16 - , intermediate-CD14 ++ CD16 +  and non-classical-CD14 + CD16 ++ ) were isolated from blood using flow cytometry and gene expression analysis was performed using real-time PCR method and TaqMan Array, Human Osteogenesis, Fast 96-well plates. Next, the characteristic clinical features shared by axial and peripheral SpA were analyzed in the context of the expression of selected genes in the three subpopulations of monocytes. We demonstrated that expression of VEGFA in classical and MSX2 in non-classical monocytes were associated with the number of swollen and painful peripheral joints of SpA patients. We conclude that monocytes may contribute to the development of peripheral arthritis in SpA patients. This might be possible through subpopulation specific effects, linking number of inflamed joints with expression of VEGFA in classical monocytes and MSX2 in non-classical monocytes.

Obesity in the United States is pervasive and associated with morbidity, mortality, and increased health care costs. For women, obesity may affect stages of life including early menarche, fertility, pregnancy, and menopause as a result of hormonal imbalances and insulin resistance. The insulin-carbohydrate model of obesity has been proposed as an explanation for growing obesity rates and can be used to target weight loss strategies by increasing insulin sensitivity. Together, low-carbohydrate dietary patterns along with intermittent fasting may help individuals with insulin resistance not only lose weight but also increase their insulin sensitivity. The purpose of this article is to review the epidemiology and physiology of obesity and the indicators for health while outlining strategies for nurses and other clinicians to use when counseling women who are following a low-carbohydrate or ketogenic diet with intermittent fasting for weight management., (Copyright © 2021 AWHONN. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the impact of concussion on pupillary function in children by examining pupillometric parameters and assessing for differences in children reporting photosensitivity., Methods: Retrospective chart review was performed of pediatric patients referred for visual symptoms after concussion from 2017 to 2018 seen in a single academic outpatient clinic. Pupillometry data of 92 patients were included. Outcomes were compared to normative pediatric data from the same institution by 2-sample t tests. The association between photosensitivity and each outcome was assessed by use of linear mixed models with photosensitivity as a fixed effect and random patient effect., Results: Outcomes of 181 eyes in 92 concussion patients were averaged by patient and compared to normative values in scotopic conditions. Concussion patients had an average age of 13.8 ± 2.64 years. Average constriction velocity ( P = .0008), maximum constriction velocity ( P = .0012), and average dilation velocity ( P = .0034) were faster in concussion patients, whereas 75% recovery times ( P = .0027) was increased. Photosensitivity did not significantly affect measured pupillary responses., Conclusion: Dynamic pupillary responses may be increased in pediatric concussion. Pupillometry may provide insight into the complex pathophysiological changes underlying pediatric concussion.

Enhancing the effectiveness of colorectal cancer treatment is highly desirable. Radiation-based anticancer therapy-such as proton therapy (PT)-can be used to shrink tumors before subsequent surgical intervention; therefore, improving the effectiveness of this treatment is crucial. The addition of noble metal nanoparticles (NPs), acting as radiosensitizers, increases the PT therapeutic effect. Thus, in this paper, the effect of novel, gold-platinum nanocauliflowers (AuPt NCs) on PT efficiency is determined. For this purpose, crystalline, 66-nm fancy shaped, bimetallic AuPt NCs were synthesized using green chemistry method. Then, physicochemical characterization of the obtained AuPt NCs by transmission electron microscopy (TEM), selected area electron diffraction (SAED), energy dispersive X-ray spectroscopy (EDS), and UV-Vis spectra measurements was carried out. Fully characterized AuPt NCs were placed into a cell culture of colon cancer cell lines (HCT116, SW480, and SW620) and a normal colon cell line (FHC) and subsequently subjected to proton irradiation with a total dose of 15 Gy. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test, performed after 18-h incubation of the irradiated cell culture with AuPt NCs, showed a significant reduction in cancer cell viability compared to normal cells. Thus, the radio-enhancing features of AuPt NCs indicate their potential application for the improvement in effectiveness of anticancer proton therapy.

Immune checkpoint blockade is one of the most promising strategies of cancer immunotherapy. However, unlike classical targeted therapies, it is currently solely based on expensive monoclonal antibodies, which often inflict immune-related adverse events. Herein, we propose a novel small-molecule inhibitor targeted at the most clinically relevant immune checkpoint, PD-1/PD-L1. The compound is capable of disrupting the PD-1/PD-L1 complex by antagonizing PD-L1 and, therefore, restores activation of T cells similarly to the antibodies, while being cheap in production and possibly nonimmunogenic. The final compound is significantly smaller than others reported in the literature while being nontoxic to cells even at high concentrations. The scaffold was designed using a structure-activity relationship screening cascade based on a new antagonist-induced dissociation NMR assay, called the weak-AIDA-NMR. Weak-AIDA-NMR finds true inhibitors, as opposed to only binders to the target protein, in early steps of lead compound development, and this process makes it less time and cost consuming.