The outcome of three-dimensional (3D) bioprinting heavily depends, amongst others, on the interaction between the developed bioink, the printing process, and the printing equipment. However, if this interplay is ensured, bioprinting promises unmatched possibilities in the health care area. To pave the way for comparing newly developed biomaterials, clinical studies, and medical applications (i.e. printed organs, patient-specific tissues), there is a great need for standardization of manufacturing methods in order to enable technology transfers. Despite the importance of such standardization, there is currently a tremendous lack of empirical data that examines the reproducibility and robustness of production in more than one location at a time. In this work, we present data derived from a round robin test for extrusion-based 3D printing performance comprising 12 different academic laboratories throughout Germany and analyze the respective prints using automated image analysis (IA) in three independent academic groups. The fabrication of objects from polymer solutions was standardized as much as currently possible to allow studying the comparability of results from different laboratories. This study has led to the conclusion that current standardization conditions still leave room for the intervention of operators due to missing automation of the equipment. This affects significantly the reproducibility and comparability of bioprinting experiments in multiple laboratories. Nevertheless, automated IA proved to be a suitable methodology for quality assurance as three independently developed workflows achieved similar results. Moreover, the extracted data describing geometric features showed how the function of printers affects the quality of the printed object. A significant step toward standardization of the process was made as an infrastructure for distribution of material and methods, as well as for data transfer and storage was successfully established.

We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term safety in the TACKLE adult outpatient treatment study. Participants received 600 mg AZD7442 (n = 452) or placebo (n = 451) ≤ 7days of COVID-19 symptom onset. Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo [relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7; p = 0.009] or 50.7% (95% CI 17.5, 70.5; p = 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1-2weeks. Over median safety follow-up of 170days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively. AZD7442 was well tolerated and reduced hospitalization and mortality through 6months, and symptom burden through 29days, in outpatients with mild-to-moderate COVID-19. Clinicaltrials.gov, NCT04723394. ( https://beta. gov/study/NCT04723394 ).

Efficiency improvements in heat pump can drastically reduce global energy demand. Caloric heat pumps are currently being investigated as a potentially more efficient alternative to vapor compression systems. Caloric heat pumps are driven by solid-state materials that exhibit a significant change in temperature when a field is applied, such as a magnetic or an electric field as well as mechanical stress. For most caloric materials, the phase transition results in a certain amount of power dissipation, which drastically impacts the efficiency of a caloric cooling system. The impact on the efficiency can be expressed by a figure of merit (FOM), which can directly be deduced from material properties. This FOM has been derived for 36 different magneto-, elasto-, electro and barocaloric material classes based on literature data. It is found that the best materials can theoretically attain second law efficiencies of over 90%. The FOM is analogous to the isentropic efficiency of idealized compressors of vapor compression systems. The isentropic efficiency can thus be directly linked to the theoretically achievable efficiency of a compressor-based refrigeration system for a given refrigerant. In this work a theoretical comparison is made between efficiency of caloric heat pumps and vapor compression systems based on the material losses for the caloric heat pump and the efficiency of the compressor for vapor compression systems. The effect of heat regeneration is considered in both cases. In vapor compression systems, the effect of the working fluid on the efficiency is also studied.

In an all-solid-state electrocaloric arrangement, an absolute temperature change which exceeds twice the electrocaloric adiabatic temperature change is locally realized, using just the distributed thermal capacitances and resistances and spatio-temporal distributed electric field control. First, simulations demonstrate surface temperature changes up to four times (400%) the electrocaloric adiabatic temperature change for several implementations of all-solid state distributed element configurations. Then, experimentally, an all-solid-state assembly is built from commercial electrocaloric capacitors with two independently-controlled parts, and the measured surface temperature change was 223% of the adiabatic electrocaloric temperature change, which clearly exceeds twice the adiabatic temperature change and verifies the practical feasibility of the approach. This allows a significant increase of the maximum temperature difference per stage in cascaded and thermal switch-based electrocaloric heat pumps, which was previously limited by the adiabatic electrocaloric temperature change (100%) under no-load conditions. Distributed thermal element simulations provide insight in the spatio-temporal temperatures within the all-solid-state electrocaloric element. Since only the distributed thermal capacitance and resistance is used to boost the temperature change, the maximum absolute temperature change occurs only in parts of the all-solid-state element, for example close to the surfaces. A trade-off of the approach is that the required electrocaloric capacitance increases more than the gained boost of the absolute temperature change, reducing the power density and electrical efficiency in heat pump systems. Nevertheless, the proposed approach enables to simplify electrocaloric heat pumps or to increasing the achievable temperature span, and might also improve other electrocaloric applications.

A poled piezoelectric ceramic such as lead zirconate titanate (PZT) belongs to a C crystal class, with ten independent material constants. If we consider losses, all the material parameters can be represented in complex form as all the ten material parameters also have ten loss components associated with them. Therefore, a total of 20 independent material constants are required to obtain the entire model. In this work, we present a procedure for determining the complete reduced matrix of a piezoelectric ultrasonic disc transducer using one-dimensional resonance analysis in thickness and radial modes and parametric sweep using finite element analysis to numerically calculate the impedance while comparing it with the measured impedance. The objective is to obtain the material parameters that minimize the error between the measured impedance data and the numerical impedance curve without using any optimization techniques. We can follow the standard procedure of resonance analysis for radial and thickness modes and then conduct a sensitivity analysis using parametric sweeps in COMSOL to evaluate the unknown material values. In addition, we present the transform equations in reduced matrix form to evaluate the critically sensitive parameters concerning other consistent evaluated material constant sets. To validate the procedure, we used the impedance responses of two piezoelectric discs with diameter-to-thickness ratios of 25 and 22.5. The comparison between the numerical and experimental results shows an excellent agreement for electrical impedance curves.

Orthobiologics are increasingly used to augment healing of tissues. Despite growing demand for orthobiologic products, many health systems do not enjoy substantial savings expected with high-volume purchases. The primary goal of this study was to evaluate an institutional program designed to (1) prioritize high-value orthobiologics and (2) incentivize vendor participation in value-driven contractual programs. A three-step approach was used to reduce costs through optimization of orthobiologics supply chain. First, surgeons with orthobiologics expertise were engaged in key supply chain purchasing decisions. Second, eight orthobiologics formulary categories were defined. Capitated pricing expectations were established for each product category. Capitated pricing expectations were established for each product using institutional invoice data and market pricing data. In comparison with similar institutions, products offered by multiple vendors were priced at a lower benchmark (10th percentile of market price) than more rare products priced at the 25th percentile of the market price. Pricing expectations were transparent to vendors. Third, a competitive bidding process required vendors to submit pricing proposals for products. Clinicians and supply chain leaders jointly awarded contracts to vendors that met pricing expectations. Compared with our projected estimate of $423,946 savings using capitated product prices, our actual annual savings was $542,216. Seventy-nine percent of savings came from allograft products. Although the number of total vendors decreased from 14 to 11, each of the nine returning vendors received a larger, three-year institutional contract. Average pricing decreased across seven of the eight formulary categories. This study demonstrates a three-step replicable approach to increase institutional savings for orthobiologic products, engaging clinician experts, and strengthening relationships with select vendors. Vendor consolidation permits a symbiotic win-win relationship: Health systems achieve increased value by reducing unnecessary complexity of multiple contracts, and vendors obtain larger contracts with increased market share. Level IV study.

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

Abstract Background SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized double-blind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods COVID-19 pneumonia pts (N=368; Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results Pts enrolled in the study were on corticosteroids (97%) and anti-coagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates; Cox regression site-stratified, HR 0.73; 95% CI:0.50-1.06; P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67; 95% CI:0.48-0.96; P=0.027) and 60 days (HR 0.67; 95% CI:0.48-0.92; P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62; 95% CI:0.40-0.95; P=0.028), severe ARDS/PaO2/FiO2 ≤ 100 mmHg (n=98, HR 0.55; 95% CI:0.30-0.98; P=0.044) and eGFR < 60 mL/min/1.73m2 (n=108, HR 0.55; 95% CI:0.31-0.96; P=0.036). Treatment-emergent AEs were 90.9% Vilo vs 91.0% P. Infections were comparable: Vilo 62.9%, P 59.3%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. Disclosures Alexander Vlaar, MD, PhD, InflaRx GmbH: Advisor/Consultant Maria Habel, PhD, InflaRx GmbH: Stocks/Bonds Claus Thielert, PhD, InflaRx GmbH: Stocks/Bonds James Dickinson, MSc, InflaRx GmbH: Stocks/Bonds simon Rückinger, PhD, InflaRx GmbH: Advisor/Consultant Robert Zerbib, MSc, InflaRx GmbH: Stocks/Bonds Dorothee Neukirchen, PhD, InflaRx GmbH: Stocks/Bonds Korinna Pilz, MD, MSc, InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds Renfeng Guo, MD, InflaRx GmbH: Board Member|InflaRx GmbH: CSO|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds Diederik van de Beek, MD, PhD, InflaRx GmbH: Advisor/Consultant Niels Riedemann, MD, PhD, InflaRx GmbH: Board Member|InflaRx GmbH: CEO|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds.

Abstract Background Nirmatrelvir with ritonavir (nirmatrelvir/r) is an oral antiviral COVID-19 treatment. We report its efficacy to shorten time to sustained alleviation and resolution of COVID-19 signs/symptoms in nonhospitalized adults with COVID-19 at high risk of severe disease as of primary completion data cut (11 Dec 2021). Methods In this phase 2/3 double-blind study, eligible adults with confirmed SARS-CoV-2 and ≤ 5 days (d) of symptoms were randomized 1:1 to nirmatrelvir/r 300 mg/100 mg or placebo (PBO) every 12 hrs for 5 d. Pts logged presence and severity (on 3- or 4-point scales) of prespecified COVID-19 signs/symptoms daily Day 1 (pre-dose) through 28. Times to sustained alleviation and resolution of all targeted signs/symptoms were assessed, summarized with Kaplan-Meier curves, and compared by treatment by log-rank test. Individual signs/symptoms were compared with descriptive analyses. Results From Jul–Dec 2021, 2246 pts enrolled; 2085 pts (nirmatrelvir/r, n=1039; PBO, n=1046) met criteria for the mITT1 population (≤ 5 d of symptom onset, did not/not expected to receive an mAb). More pts achieved sustained alleviation or sustained resolution with nirmatrelvir/r. Shorter median times to sustained alleviation/resolution were observed with nirmatrelvir/r (13/16 d) vs PBO (15/19 d; Fig 1 & 2). Also, a shorter median time to sustained alleviation was seen in pts treated ≤ 3 d of symptoms with nirmatrelvir/r (12 d) vs PBO (15 d). The most common symptoms were cough, muscle/body aches, and headache in both groups. The median time to sustained alleviation of cough and headache was 2 d less with nirmatrelvir/r vs PBO. The median time to sustained resolution of muscle aches and shortness of breath was 3 d and 4 d less with nirmatrelvir/r. The proportion of pts with severe signs/symptoms in the nirmatrelvir/r vs PBO group was significantly higher at baseline, but significantly lower after treatment, showing nirmatrelvir/r significantly reduced symptom severity through Day 28 (Fig 3). Pts who were seronegative vs seropositive or had high vs low viral load at baseline achieved faster times to sustained alleviation with nirmatrelvir/r vs PBO. Conclusion Nirmatrelvir/r treatment reduced duration and severity of COVID-19 symptoms vs PBO in pts at high risk of progressing to severe disease. NCT04960202. Disclosures Jennifer Hammond, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Heidi Leister-Tebbe, BSN, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Annie Gardner, MPH, MSPT, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Paula Abreu, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Weihang Bao, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Wayne Wisemandle, MA, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Wajeeha Ansari, MPH, Pfizer Inc.: Stocks/Bonds Magdalena Alicja Harrington, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Jesus Abraham Simón Campos, MD, AstraZeneca: Board Member|AstraZeneca: Speaker|Eli Lilly: Board Member|Pfizer: Board Member|Roche: Board Member|Roche: Speaker Kara W. Chew, M.D., M.S., Merck Sharp & Dohme: Grant/Research Support Rienk Pypstra, MD, MBA, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds James M Rusnak, MD, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds.

Abstract Background Outpatient treatment with SARS-CoV-2–neutralizing antibody combination AZD7442 (tixagevimab/cilgavimab) in adults with mild to moderate COVID-19 significantly reduced progression to severe disease or death through Day 29 and was well-tolerated in the Phase 3 TACKLE study primary analysis (NCT04723394). AZD7442 administered earlier in the disease course leads to more favorable outcomes and has the potential to prevent COVID-19 hospitalizations and reduce hospital burden. We report key secondary efficacy results with longer-term safety data from TACKLE over 6 months. Methods In TACKLE, non-hospitalized adults with mild to moderate COVID-19 were randomized 1:1 and dosed ≤7 days from symptom onset with a single 600-mg AZD7442 dose (2 consecutive intramuscular injections, 300 mg of each antibody; n=452) or placebo (n=451). The key secondary endpoint was death from any cause or hospitalization for COVID-19 complications or sequelae through Day 169, analyzed using a Cochran-Mantel-Haenszel test stratified by time from symptom onset and risk of severe COVID-19 progression. Results Death from any cause or hospitalization for COVID-19 complications or sequalae occurred in 20 (5.0%) versus 40 (9.8%) participants receiving AZD7442 versus placebo, respectively, translating to a relative risk reduction (RRR) of 49.1% (95% confidence interval [CI] 14.5–69.7) versus placebo (P=0.009). A sensitivity analysis excluding participants who were unblinded prior to Day 169 for consideration of vaccination yielded a similar RRR of 50.7% (95% CI 17.5–70.5; P=0.006). For baseline seronegative participants, an RRR of 58.6% (95% CI 27.6–76.4; P=0.001) was observed. The median (range) safety follow-up was 170 (1–330) days with AZD7442 and 170 (1–326) days with placebo. Adverse events occurred in 38.5% of AZD7442 participants and 43.5% of placebo participants, and were mostly mild to moderate. Conclusion A single 600-mg AZD7442 dose demonstrated statistically significant protection against death from any cause or hospitalization for COVID-19 through 6 months, and was well-tolerated. These data provide further support of AZD7442 in the COVID-19 outpatient treatment setting, with potential to reduce hospital burden. Disclosures F.D. Richard Hobbs, FMedSci, AstraZeneca: Grant/Research Support|AstraZeneca: Principal investigator|NIHR Applied Research Collaboration, Oxford Thames Valley: Director|Oxford BRC and NIHR MedTech: Investigator|UKRI and NIHR: Grant/Research Support Hugh Montgomery, MD, AstraZeneca: Advisor/Consultant|Millfield Medical Ltd: Advisor/Consultant|UK National Institute for Health Research's Comprehensive Biomedical Research Centre at University College London Hospitals: Grant/Research Support Francisco Padilla, MD, Amgen: Grant/Research Support|Amgen: Personal fees|AstraZeneca: Grant/Research Support|AstraZeneca: Personal fees|Boehringer Ingelheim: Grant/Research Support|Boehringer Ingelheim: Personal fees|Ferrer: Grant/Research Support|Ferrer: Personal fees|Kowa: Grant/Research Support|Kowa: Personal fees|Medix: Grant/Research Support|Medix: Personal fees|Merck Sharp and Dohme: Grant/Research Support|Merck Sharp and Dohme: Personal fees|Novartis: Grant/Research Support|Novartis: Personal fees|Pfizer: Grant/Research Support|Pfizer: Personal fees|Sanofi: Grant/Research Support|Sanofi: Personal fees|Servier: Grant/Research Support|Servier: Personal fees|Silanes: Grant/Research Support|Silanes: Personal fees Kenneth Kim, MD, Adagio: Funding|Eli Lilly: Funding|Merck: Funding|Pfizer: Funding|Regeneron: Speaker|Regeneron: Funding Jesus Abraham Simón Campos, MD, AstraZeneca: Board Member|AstraZeneca: Speaker|Eli Lilly: Board Member|Pfizer: Board Member|Roche: Board Member|Roche: Speaker Douglas Arbetter, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kelly W. Padilla, PharmD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Venkatesh P. Reddy, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Seth Seegobin, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Katie Streicher, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Rolando M. Viani, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Gavin CKW Koh, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Mark T. Esser, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.