Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study.

OBJECTIVE: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. METHODS: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. RESULTS: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). CONCLUSION: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Comparative effectiveness of sotrovimab versus no treatment in non-hospitalised high-risk COVID-19 patients in north west London: a retrospective cohort study.

BACKGROUND: We assessed the effectiveness of sotrovimab vs no early COVID-19 treatment in highest-risk COVID-19 patients during Omicron predominance. METHODS: Retrospective cohort study using the Discover dataset in North West London. Included patients were non-hospitalised, aged ≥12 years and met ≥1 National Health Service highest-risk criterion for sotrovimab treatment. We used Cox proportional hazards models to compare HRs of 28-day COVID-19-related hospitalisation/death between highest-risk sotrovimab-treated and untreated patients. Age, renal disease and Omicron subvariant subgroup analyses were performed. RESULTS: We included 599 sotrovimab-treated patients and 5191 untreated patients. Compared with untreated patients, the risk of COVID-19 hospitalisation/death (HR 0.50, 95% CI 0.24, 1.06; p=0.07) and the risk of COVID-19 hospitalisation (HR 0.43, 95% CI 0.18, 1.00; p=0.051) were both lower in the sotrovimab-treated group; however, statistical significance was not reached. In the ≥65 years and renal disease subgroups, sotrovimab was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR 0.11, 95% CI 0.02, 0.82; p=0.03) and 82% (HR 0.18, 95% CI 0.05, 0.62; p=0.007), respectively. CONCLUSIONS: Risk of COVID-19 hospitalisation in sotrovimab-treated patients aged ≥65 years and with renal disease was significantly lower compared with untreated patients. Overall, risk of hospitalisation was also lower for sotrovimab-treated patients, but statistical significance was not reached.

A phase I COVID-19 vaccine trial among SARS-CoV-2 seronegative and seropositive individuals in Uganda utilizing a self-amplifying RNA vaccine platform: Screening and enrollment experiences.

We report the screening and enrollment process for a phase I vaccine trial in Masaka, Uganda that investigated the safety and immunogenicity of a self-amplifying SARS-CoV-2 RNA vaccine amongst individuals with and without antibodies to SARS-CoV-2. Participant screening and enrollment were conducted between December 2021 and April 2022. Individuals were eligible if they were aged between 18 and 45 years, healthy, and never vaccinated against COVID-19. SARS-CoV-2 antibody status was determined using two point-of-care rapid tests, i.e. Multi G (MGFT3) and Standard Q (Standard Q COVID-19 IgM/IgG Plus). Data were entered and managed in OpenClinica. Analyses were performed and presented descriptively. A total of 212 individuals were screened and 43(20.3%) enrolled. The most common reasons for exclusion were ≥ grade 1 laboratory abnormalities (39, 18.4%), followed by discordant SARS-CoV-2 antibody results (23, 10.9%). While the first 38 participants were quickly enrolled over a period of 9 weeks, it took another 9 weeks to enroll the remaining five, as antibody negative participants became scarce during the surge of the Omicron variant. The SARS-CoV-2 antibody positivity rate was determined to be 60.8% and 84.4% in each half of the 18 months of screening respectively. The mean age (±Standard Deviation, SD) of screened and enrolled participants was 27.7 (±8.1) and 30.2 (±8.3) years respectively. We demonstrated that it is feasible to successfully screen and enroll participants for COVID-19 vaccine trials in Uganda in the time of a pandemic. Our experiences may be useful for investigators planning to undertake similar work in Africa.

Progress of the COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape.

Where 2020 saw the development and testing of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented pace, the first half of 2021 has seen vaccine rollout in many countries. In this Progress article, we provide a snapshot of ongoing vaccine efficacy studies, as well as real-world data on vaccine effectiveness and the impact of virus variants of concern. Where they have been deployed in a high proportion of the adult population, the currently approved vaccines have been extremely effective in preventing COVID-19, particularly severe disease. Nonetheless, there are still significant challenges in ensuring equitable vaccine access around the globe and lessons that can be learned for controlling this pandemic and for the next pandemic.

Knowledge, Attitudes, and Practices Regarding COVID-19 among Healthcare Workers in Uganda: A Cross-Sectional Survey.

Healthcare workers (HCWs) are at high risk of COVID-19. However, data on HCWs' knowledge, attitudes, and practices (KAP) toward COVID-19 are limited. Between September and November 2020, we conducted a questionnaire-based COVID-19 KAP survey among HCWs at three hospitals in Uganda. We used Bloom's cut-off of ≥80% to determine sufficient knowledge, good attitude, and good practice, and multivariate Poisson regression with robust variance for statistical analysis. Of 717 HCWs invited to participate, 657 (91.6%) agreed and were enrolled. The mean age (standard deviation) of enrollees was 33.2 (10.2) years; most were clinical HCWs (64.7%) and had advanced secondary school/other higher-level education (57.8%). Overall, 83.9% had sufficient knowledge, 78.4% had a positive attitude, and 37.0% had good practices toward COVID-19. Factors associated with KAP were: Knowledge: being a clinical HCW (aRR: 1.12; 95% CI: 1.02-1.23) and previous participation in health research (aRR: 1.10; 95% CI: 1.04-1.17); Attitude: age > 35 years (aRR: 0.88; 95% CI: 0.79-0.98); Practice: being a clinical HCW (aRR: 1.91; 95% CI: 1.41-2.59). HCWs in Uganda have good knowledge and positive attitude but poor practices towards COVID-19. Differences in COVID-19 KAP between clinical and non-clinical HCWs could affect uptake of COVID-19 interventions including vaccination.

Willingness to participate in COVID-19 vaccine trials; a survey among a population of healthcare workers in Uganda.

BACKGROUND: Healthcare workers (HCWs) are at high risk of acquiring SARS-CoV-2 and COVID-19 and may therefore be a suitable population for COVID-19 vaccine trials. We conducted a survey to evaluate willingness-to-participate in COVID-19 vaccine trials in a population of HCWs at three hospitals in Uganda. METHODS: The survey was conducted between September and November 2020. Using a standardised questionnaire, data were collected on socio-demographics, previous participation in health research, COVID-19 information sources, underlying health conditions, and willingness-to-participate in COVID-19 vaccine trials. Data were analysed descriptively and a binomial generalised linear model with a log link function used to investigate factors associated with unwillingness to participate. RESULTS: 657 HCWs (female, 63%) were enrolled with a mean age of 33 years (Standard Deviation, 10). Overall willingness-to-participate was 70.2%. Key motivating factors for participation were: hope of being protected against COVID-19 (81.1%), altruism (73.3%), and the opportunity to get health care (26.0%). Selected hypothetical trial attributes reduced willingness-to-participate as follows: weekly-quarterly study visits over a 12-month period (70.2%-63.2%, P = 0.026); provision of approximately 50ml of blood at each study visit (70.2%-63.2%, P = 0.026); risk of mild-moderate local adverse reactions (70.2%-60.3%, P<0.001); chance of receiving candidate vaccine or placebo (70.2%-56.9%, P<0.001); and delay of pregnancy [Overall, 70.2%-57.1% P<0.001); Female, 62.8%-48.4% (P = 0.002); Male, 82.5%-71.5% (P = 0.003)]. Collectively, these attributes reduced willingness-to-participate from [70.2%-42.2% (P<0.001) overall; 82.5%-58.1% (P<0.001) in men; 62.8%-32.6% (P<0.001) in women]. Among individuals that were unwilling to participate, the commonest barriers were concerns over vaccine safety (54.6%) and fear of catching SARS-CoV-2 (31.6%). Unwillingness to participate was associated with being female (aRR 1.97, CI 1.46-2.67, P<0.001) and having university or other higher-level education (aRR 1.52, CI 1.05-2.2, P = 0.026). CONCLUSIONS: Willingness-to-participate in COVID-19 vaccine trials among HCWs in Uganda is high but may be affected by vaccine trial requirements and concerns about the safety of candidate vaccines.

Conditional Ultrasound Sensitivity of Poly[(N-isopropylacrylamide)-co-(vinyl imidazole)] Microgels for Controlled Lipase Release.

Triggering the release of cargo from a polymer network by ultrasonication as an external, noninvasive stimulus can be an interesting concept for on-demand release. Here, it is shown that, in pH- and thermosensitive microgels, the ultrasound sensitivity of the polymer network depends on the external conditions. Crosslinked poly[(N-isopropylacrylamide)-co-(vinyl imidazole)] microgels showed a volume phase transition temperature (VPTT) of 25-50 °C, which increases with decreasing pH. Above the VPTT the polymer chains are collapsed, while below VPTT they are extended. Only in the case of maximum observed swelling, where the polymer chains are expanded, the microgels are mechanically fragmented through ultrasonication. In contrast, when the polymer chains are partially collapsed it is not possible to manipulate the microgels by ultrasound. Additionally, the ultrasound-induced on-demand release of wheat germ lipase from the microgels could be demonstrated successfully. The principle of conditional ultrasound sensitivity is likely to be general and can be used for selection of matrix-cargo combinations.

Design of Decorin-Based Peptides That Bind to Collagen†I and their Potential as Adhesion Moieties in Biomaterials.

Mimicking the binding epitopes of protein-protein interactions by using small peptides is important for generating modular biomimetic systems. A strategy is described for the design of such bioactive peptides without accessible structural data for the targeted interaction, and the effect of incorporating such adhesion peptides in complex biomaterial systems is demonstrated. The highly repetitive structure of decorin was analyzed to identify peptides that are representative of the inner and outer surface, and it was shown that only peptides based on the inner surface of decorin bind to collagen. The peptide with the highest binding affinity for collagen I, LHERHLNNN, served to slow down the diffusion of a conjugated dye in a collagen gel, while its dimer could physically crosslink collagen, thereby enhancing the elastic modulus of the gel by one order of magnitude. These results show the potential of the identified peptides for the design of biomaterials for applications in regenerative medicine.

One step creation of multifunctional 3D architectured hydrogels inducing bone regeneration.

Structured hydrogels showing form stability and elastic properties individually tailorable on different length scales are accessible in a one-step process. They support cell adhesion and differentiation and display growing pore size during degradation. In vivo experiments demonstrate their efficacy in biomaterial-induced bone regeneration, not requiring addition of cells or growth factors.

Endothelial cell response to (co)polymer nanoparticles depending on the inflammatory environment and comonomer ratio.

Endothelial cells lining the lumen of blood vessels serve as a physiological barrier controlling nanoparticle movement from the vasculature into the tissue. For exploring the effect of polymer hydrophilicity on nanoparticle interactions with human umbilical vein endothelial cells (HUVECs) in vitro, a series of monomodal poly[acrylonitrile-co-(N-vinylpyrrolidone)] model nanoparticles with increasing hydrophilicity as related to their increasing content (0-30 mol.%) of N-vinylpyrrolidone (NVP) were synthesized by miniemulsion polymerization. Nanoparticles with a low NVP content were rapidly endocytized into all cells independent from the particle dose with toxic effects only observed at high particle concentrations, while only 10-30% of the cells incorporated particles with ≥20 mol.% NVP. Since pathologies are often related to inflammation, an inflammatory HUVEC culture condition with IL-1ß stimulation has been introduced and suggested to be widely applied for studying nanocarriers, since cellular uptake in this assay was clearly increased for NVP contents ≥20 mol.%. Importantly, the secretion of functional biological mediators by HUVECs was not relevantly influenced by the nanoparticles for both homeostatic and inflammatory conditions. These findings may motivate concepts for nanocarriers specifically targeted to pathologic regions. Additionally, rapidly endocytized RhodaminB loaded particles with low NVP content may be explored for cell labeling and tracking.

Viability of human mesenchymal stem cells seeded on crosslinked entropy-elastic gelatin-based hydrogels.

Biomimetic polymer network systems with tailorable properties based on biopolymers represent a class of degradable hydrogels that provides sequences for protein adsorption and cell adhesion. Such materials show potential for in vitro MSC proliferation as well as in vivo applications and were obtained by crosslinking different concentrations of gelatin using varying amounts of ethyl lysine diisocyanate in the presence of a surfactant in pH 7.4 PBS solution. Material extracts, which were tested for cytotoxic effects using L929 mouse fibroblasts, were non-toxic. The hydrogels were seeded with human bone marrow-derived MSCs and supported viable MSCs for the incubation time of 9 d. Preadsorption of fibronectin on materials improved this biofunctionality.

Photocrosslinked co-networks from glycidylmethacrylated gelatin and poly(ethylene glycol) methacrylates.

Biopolymer-based systems with adjustable macroscopic properties that can be varied in a wide range using only small changes in chemical composition are promising candidates for biomaterial-induced autoregeneration. Glycidylmethacrylated gelatin is photopolymerized with the addition of PEG mono- or dimethacrylate to form co-networks in pH = 7.4 PBS. The degree of swelling (Q) and water uptake (H) in PBS at 37 °C are tailorable for PEGDMA co-networks (Q ≈ 250-650 vol%), while the storage modulus of swollen networks at 3 °C can be adjusted by the PEG(D)MA content (G' = 0.7-145 kPa). Indirect cytotoxicity tests on ethylene oxide sterilized films show non-toxic responses for the homonetwork and all but one PEGDMA-containing co-networks materials.

Demonstrating the influence of water on shape-memory polymer networks based on poly[(rac-lactide)-co-glycolide] segments in vitro.

Thermally-responsive shape-memory polymers (SMP) are highly promising implant materials for applications in minimally-invasive surgery since the shape-memory effect (SME) enables the implantation of a bulky device in a compressed temporary state through a small incision. When heated to a temperature exceeding the material switching temperature (Tsw), the device recovers its original bulky shape. Therefore, SMP implants with Tsw ~ 37 °C are required for such applications because the body cannot withstand excessive applications of heat. Here, Tsw of networks based on poly[(rac-lactide)-co-glycolide] star-shaped macrotriol or macrotetrols with 19-22 wt% glycolide content, varying oligomer molecular weight (Mn = 3000-10000 g·mol-1), and netpoint functionality (f = 3 or 4) were lowered from 55-66 °C to below body temperature via the uptake of water, which also induced SME at body temperature. Programmed samples kept their temporary shape at room temperature in water as well as at 37 °C under dry conditions but recovered in 37 °C water. Water uptake/swelling studies and FTIR analysis indicated that the mechanism of solvent-induced SME involved the plasticization of water in switching domains as opposed to changes in swelling or hydrogen bonding. This indirect actuation of SME by using a combination of solvent and heat could be exploited in easy-to-handle shape-memory implant with slower degradation kinetics.

A molecular dynamic analysis of gelatin as an amorphous material: prediction of mechanical properties of gelatin systems.

Biomaterials are used in regenerative medicine for induced autoregeneration and tissue engineering. This is often challenging, however, due to difficulties in tailoring and controlling the respective material properties. Since functionalization is expected to offer better control, in this study gelatin chains were modified with physically interacting groups based on tyrosine with the aim of causing the formation of physical crosslinks. This method permits application-specific properties like swelling and better tailoring of mechanical properties. The design of the crosslink strategy was supported by molecular dynamic (MD) simulations of amorphous bulk models for gelatin and functionalized gelatins at different water contents (0.8 and 25 wt.-%). The results permitted predictions to be formulated about the expected crosslink density and its influence on equilibrium swelling behavior and on elastic material properties. The models of pure gelatin were used to validate the strategy by comparison between simulated and experimental data such as density, backbone conformation angle distribution, and X-ray scattering spectra. A key result of the simulations was the prediction that increasing the number of aromatic functions attached to the gelatin chain leads to an increase in the number of physical netpoints observed in the simulated bulk packing models. By comparison with the Flory-Rehner model, this suggested reduced equilibrium swelling of the functionalized materials in water, a prediction that was subsequently confirmed by our experimental work. The reduction and control of the equilibrium degree of swelling in water is a key criterion for the applicability of functionalized gelatins when used, for example, as matrices for induced autoregeneration of tissues.

Influence of tyrosine-derived moieties and drying conditions on the formation of helices in gelatin.

The single and triple helical organization of protein chains strongly influences the mechanical properties of gelatin-based materials. A chemical method for obtaining different degrees of helical organization in gelatin is covalent functionalization, while a physical method for achieving the same goal is the variation of the drying conditions of gelatin solutions. Here we explored how the introduction of desaminotyrosine (DAT) and desaminotyrosyl tyrosine (DATT) linked to lysine residues of gelatin influenced the kinetics and thermodynamic equilibrium of the helicalization process of single and triple helices following different drying conditions. Drying at a temperature above the helix-to-coil transition temperature of gelatin (T > T(c), called v(short)) generally resulted in gelatins with relatively lower triple helical content (X(c,t) = 1-2%) than lower temperature drying (T < T(c), called v(long)) (X(c,t) = 8-10%), where the DAT(T) functional groups generally disrupted helix formation. While different helical contents affected the thermal transition temperatures only slightly, the mechanical properties were strongly affected for swollen hydrogels (E = 4-13 kPa for samples treated by v(long) and E = 120-700 kPa for samples treated by v(short)). This study shows that side group functionalization and different drying conditions are viable options to control the helicalization and macroscopic properties of gelatin-based materials.