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In this paper, a non-isothermal study of the calendering processes is presented using Carreau–Yasuda model along with nonlinear slip condition introduced at the upper roll surface. The flow equations for the problem are developed and converted into dimensionless form with the help of dimensionless variables and then finally simplified by a well-known lubrication approximation theory. The final equations are solved numerically using “bvp4c” to find stream function and velocity profiles, while the hybrid numerical method which is the combination of shooting and finite difference methods is used to solve the energy equation. Graphs show the impact of the concerned material parameters on various quantities of interest. The pressure distribution decreases with the increasing values of the slip parameter and Weissenberg number. The mechanical variables show an increasing trend with the increasing values of the slip parameter and Weissenberg number. The temperature distribution increases with an increase in the Brinkman number, while temperature shows declining trend near the roll surface with the increasing values of the slip parameter. The force separating the two rollers, total power input into both rolls, increase with the increasing values of the Weissenberg number and slip parameters. The results show that the Newtonian model predicts higher pressure in the nip zone than the Carreau–Yasuda model. It is interesting to note that for the case of shear thinning, the Carreau–Yasuda model predicts 30% less pressure in the nip region when compared to the Newtonian model.

Crystalline ZnO offers an excellent host matrix to create a dilute magnetic semiconductor (DMS) owing to its facile Zn-atom substitution with the transition metal dopant atom. The exchange interactions between the spin of the dopant atoms and the carriers in the ZnO matrix results in the room-temperature ferromagnetic order in the entire lattice. In this work, we report on the enhanced solubility (doping) of Fe atoms in ZnO matrix. Zn1-x FexO DMS nanoparticles were synthesized with different doping concentrations (x = 0.01, 0.05, 0.20, 0.22, and 0.25) via a modified version of co-precipitation method, in which the precursors’ solution was heated at 60 ℃ during the stirring process. Only the wurtzite phase was obtained for all Zn1-x FexO samples in X-ray diffraction, and no secondary phase was observed, which supports the idea of an enhanced solubility limit of Fe doping up to 25%. A systematic broadening of the Raman characteristic peak at 525 cm−1 associated with Fe substitution across the entire range of doping accompanied with the suppression of ZnO peak at 371cm−1 and 435 cm−1, supporting the enhanced doping effect further. The bandgap exhibited a systematic trend — it first increased from 3.13 eV for undoped to 3.23 for x = 0.1 and dropped to the value of 2.94 for the highest concentration (x = 0.25) with few in band transitions for high doping. VSM results showed magnetic behavior for all the doped samples at room temperature.

Augmenting T cell mediated tumor killing via immunogenic cancer cell death (ICD) is the cornerstone of emerging immunotherapeutic approaches. We investigated the potential of methylene blue photodynamic therapy (MB-PDT) to induce ICD in human lung cancer. Non-Small Cell Lung Cancer (NSCLC) cell lines and primary human lung cancer organoids were evaluated in co-culture killing assays with MB-PDT and light emitting diodes (LEDs). ICD was characterised using immunoblotting, immunofluorescence, flow cytometry and confocal microscopy. Phototherapy with MB treatment and low energy LEDs decreased the proliferation of NSCLC cell lines inducing early necrosis associated with reduced expression of the anti-apoptotic protein, Bcl2 and increased expression of ICD markers, calreticulin (CRT), intercellular cell-adhesion molecule-1 (ICAM-1) and major histocompatibility complex I (MHC-I) in NSCLC cells. MB-PDT also potentiated CD8+ T cell-mediated cytolysis of lung cancer via granzyme B in lung cancer cells and primary human lung cancer organoids.

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with COVID-19. We hypothesised that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with anti-inflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalised with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomised controlled platform trial in hospitalised patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139+SoC vs 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc ANCOVA over days 2–7: p=0.0099 vs SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy and major organ function were evaluated. Conclusions: In COVID pneumonitis, inhaled GB013 was well-tolerated, achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04473053. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).Keywords: Covid-19; Galectin-3; GB0139

With the emergence of computation-intensive and delay-sensitive applications, such as face recognition, virtual reality, augmented reality, and Internet of Things (IoT) devices; Mobile Edge Computing (MEC) allows the IoT devices to offload their heavy computation tasks to nearby edge cloud network rather than to compute the tasks locally. Therefore, it helps to reduce the energy consumption and execution delay in the ground mobile users. Flying Unmanned Aerial Vehicles (UAVs) integrated with the MEC server play a key role in 5G and future wireless communication networks to provide spatial coverage and further computational services to the small, battery-powered and energy-constrained devices. The UAV-enabled MEC (U-MEC) system has flexible mobility and more computational capability compared to the terrestrial MEC network. They support line-of-sight (LoS) links with the users offloading their tasks to the UAVs. Hence, users can transmit more data without interference by mitigating small-scale fading and shadowing effects. UAVs resources and flight time are very limited due to size, weight, and power (SWaP) constraints. Therefore, energy-aware communication and computation resources are allocated in order to minimize energy consumption.In this paper, a brief survey on U-MEC networks is presented. It includes the brief introduction regarding UAVs and MEC technology. The basic terminologies and architectures used in U-MEC networks are also defined. Moreover, mobile edge computation offloading working, different access schemes used during computation offloading technique are explained. Resources that are needed to be optimized in U-MEC systems are depicted with different optimization problem, and solution types. Furthermore, to guide future work in this area of research, future research directions are outlined. At the end, challenges and open issues in this domain are also summarized.

Purpose The relentless rise in antimicrobial resistance is a major societal challenge and requires, as part of its solution, a better understanding of bacterial colonization and infection. To facilitate this, we developed a highly efficient no-wash red optical molecular imaging agent that enables the rapid, selective, and specific visualization of Gram-positive bacteria through a bespoke optical fiber–based delivery/imaging endoscopic device. Methods We rationally designed a no-wash, red, Gram-positive-specific molecular imaging agent (Merocy-Van) based on vancomycin and an environmental merocyanine dye. We demonstrated the specificity and utility of the imaging agent in escalating in vitro and ex vivo whole human lung models (n = 3), utilizing a bespoke fiber–based delivery and imaging device, coupled to a wide-field, two-color endomicroscopy system. Results The imaging agent (Merocy-Van) was specific to Gram-positive bacteria and enabled no-wash imaging of S. aureus within the alveolar space of whole ex vivo human lungs within 60 s of delivery into the field-of-view, using the novel imaging/delivery endomicroscopy device. Conclusion This platform enables the rapid and specific detection of Gram-positive bacteria in the human lung.

Fibroblast activation protein (FAP) is a cell surface propyl-specific serine protease involved in the regulation of extracellular matrix. Whilst expressed at low levels in healthy tissue, upregulation of FAP on fibroblasts can be found in several solid organ malignancies, including non-small cell lung cancer, and chronic inflammatory conditions such as pulmonary fibrosis and rheumatoid arthritis. Their full role remains unclear, but FAP expressing cancer associated fibroblasts (CAFs) have been found to relate to a poor prognosis with worse survival rates in breast, colorectal, pancreatic, and non-small cell lung cancer (NSCLC). Optical imaging using a FAP specific chemical probe, when combined with clinically compatible imaging systems, can provide a readout of FAP activity which could allow disease monitoring, prognostication and potentially stratify therapy. However, to derive a specific signal for FAP any sequence must retain specificity over closely related endopeptidases, such as prolyl endopeptidase (PREP), and be resistant to degradation in areas of active inflammation. We describe the iterative development of a FAP optical reporter sequence which retains FAP specificity, confers resistance to degradation in the presence of activated neutrophil proteases and demonstrates clinical tractability ex vivo in NSCLC samples with an imaging platform.

The presence of functionally efficient cytotoxic T lymphocytes (CTL) in the Tumour nest is crucial in mediating a successful immune response to cancer. The detection and elimination of cancer cells by CTL can be impaired by cancer-mediated immune evasion. In recent years, it has become increasingly clear that not only neoplastic cells themselves, but also cells of the tumour microenvironment (TME) exert immunosuppressive functions and thereby play an integral part in the immune escape of cancer. The most abundant stromal cells of the TME, cancer associated fibroblasts (CAFs), promote tumour progression via multiple pathways and play a role in dampening the immune response to cancer. Recent research indicates that T cells react to CAF signalling and establish bidirectional crosstalk that plays a significant role in the tumour immune response. This review discusses the various mechanisms by which the CAF/T cell crosstalk may impede anti-cancer immunity.

RationaleHigh galectin-3 levels predict poor outcomes in patients with COVID-19. Galectin-3 activates monocytes and macrophages which are directly implicated in COVID-19 immunopathology and the cytokine storm. GB0139 is a potent thiodigalactoside galectin-3 inhibitor and may reduce the severe effects of the disease. We report safety and pharmacokinetics and pharmacodynamics of the inhaled galectin-3 inhibitor, GB0139, and assess clinical outcomes and key systemic inflammatory biomarkers in hospitalised patients with COVID-19 (ClinicalTrials.gov/EudraCT identifier: NCT04473053/2020-002230-32).MethodsAdults with COVID-19 requiring oxygen, and with pneumonitis on x-ray, were randomised to receive standard of care (SOC; including dexamethasone; n=21) or SOC plus 10 mg GB0139 twice daily for 48 hours, then once daily for ≤14 days (n=20).ResultsPatients aged 27–87 years were enrolled from July 2020; the final patient completed the 90-day follow-up in April 2021. GB0139+SOC was well tolerated with no treatment-related serious adverse events reported. Incidences of adverse events were similar between treatment arms (40 with GB0139+SOC vs 35 with SOC). Plasma GB0139 was measurable in all patients after inhaled exposure, with moderate interpatient variability, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc over days 2–7: p=0·0099 vs SOC). Rate of decline in fraction of inspired oxygen (%) requirement was significantly greater in the GB0139+SOC arm with a posterior mean difference of -1·51 (95% highest posterior density: -2·90, -0·189) versus SOC. Plasma levels of biomarkers associated with inflammation, coagulopathy, major organ function and fibrosis showed a downward trend versus SOC.ConclusionsGB0139+SOC was well tolerated and achieved clinically relevant plasma concentrations and target engagement. This, and the reduction in markers associated with inflammatory, coagulation, fibrosis, and reduction in inspired oxygen (%) over SOC alone, indicates the therapeutic potential for inhaled GB0139 in hospitalised patients with COVID-19.

Funding: This work was funded by UK Research and Innovation (UKRI) (Coronavirus Disease [COVID-19] Rapid Response Initiative; MR/V028790/1 to C.D.L., D.A.D., and J.A.H.), LifeArc (through the University of Edinburgh STOPCOVID funding award, to K.D, D.A.D., C.D.L), The Chief Scientist Office (RARC-19 Funding Call, ‘Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis; COV/EDI/20/10’ to D.A.D, C.D.L, C.D.R, J.K.B and D.J.H), and Medical Research Scotland (CVG-1722- 2020 to DAD, CDL, CDR, JKB, and DJH). C.D.L is funded by a Wellcome Trust Clinical Career Development Fellowship (206566/Z/17/Z). J.K.B. and C.D.R. are supported by the Medical Research Council (grant MC_PC_19059) as part of the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC-4C). C.D.R. is supported by an Edinburgh Clinical Academic Track (ECAT)/Wellcome Trust PhD Training Fellowship for Clinicians award (214178/Z/18/Z). J.A.H. is supported by the U.S. Food and Drug Administration (contract 75F40120C00085, Characterization of severe coronavirus infection in humans and model systems for medical countermeasure development and evaluation’). G.C.O is funded by an NRS Clinician award. N.N.G. is funded by a Pathological Society Award. A.R.A. is supported by a Cancer Research UK Clinician Scientist Fellowship award (A24867). Immunopathology occurs in the lung and spleen in fatal COVID-19, involving monocytes/macrophages and plasma cells. Anti-inflammatory therapy reduces mortality but additional therapeutic targets are required. We aimed to gain mechanistic insight into COVID-19 immunopathology by targeted proteomic analysis of pulmonary and splenic tissues. Lung parenchymal and splenic tissue was obtained from 13 post-mortem examinations of patients with fatal COVID-19. Control tissue was obtained from cancer resection samples (lung) and deceased organ donors (spleen). Protein was extracted from tissue by phenol extraction. Olink® multiplex immunoassay panels were used for protein detection and quantification. Proteins with increased abundance in the lung included MCP-3, antiviral TRIM21 and pro-thrombotic TYMP. OSM and EN-RAGE/S100A12 abundance was correlated, and associated with inflammation severity. Unsupervised clustering identified ‘early viral’ and ‘late inflammatory’ clusters with distinct protein abundance profiles, and differences in illness duration prior to death and presence of viral RNA. In the spleen, lymphocyte chemotactic factors and CD8A were decreased in abundance, and pro-apoptotic factors were increased. B-cell receptor signalling pathway components and macrophage colony stimulating factor (CSF-1) were also increased. Additional evidence for a sub-set of host factors (including DDX58, OSM, TYMP, IL-18, MCP-3 and CSF-1) was provided by overlap between (i) differential abundance in spleen and lung tissue, (ii) meta-analysis of existing datasets, and (iii) plasma proteomic data. This proteomic analysis of lung parenchymal and splenic tissue from fatal COVID-19 provides mechanistic insight into tissue anti-viral responses, inflammation and disease stages, macrophage involvement, pulmonary thrombosis, splenic B-cell activation and lymphocyte depletion. Publisher PDF

Electric power reliability is one of the most important factors in the social and economic evolution of a smart city, whereas the key factors to make a city smart are smart energy sources and intelligent electricity networks. The development of cost-effective microgrids with the added functionality of energy storage and backup generation plans has resulted from the combined impact of high energy demands from consumers and environmental concerns, which push for minimizing the energy imbalance, reducing energy losses and CO2 emissions, and improving the overall security and reliability of a power system. It is now possible to tackle the problem of growing consumer load by utilizing the recent developments in modern types of renewable energy resources (RES) and current technology. These energy alternatives do not emit greenhouse gases (GHG) like fossil fuels do, and so help to mitigate climate change. They also have in socioeconomic advantages due to long-term sustainability. Variability and intermittency are the main drawbacks of renewable energy resources (RES), which affect the consistency of electric supply. Thus, utilizing multiple optimization approaches, the energy management system determines the optimum solution for renewable energy resources (RES) and transfers it to the microgrid. Microgrids maintain the continuity of power delivery, according to the energy management system settings. In a microgrid, an energy management system (EMS) is used to decrease the system’s expenses and adverse consequences. As a result, a variety of strategies and approaches are employed in the development of an efficient energy management system. This article is intended to provide a comprehensive overview of a range of technologies and techniques, and their solutions, for managing the drawbacks of renewable energy supplies, such as variability and load fluctuations, while still matching energy demands for their integration in the microgrids of smart cities.

A probe that allows specific 'painting' of human tumours is described. Probe activation was mediated by specific matrix metalloproteinases, resulting not only in disruption of a FRET pair, but in the generation of a fragment that "fluorescently paints" human tumours. This probe demonstrated rapid and effective human tumour labelling with the potential to allow margin detection during surgical resection.

The present study aimed to explore a new source of montmorillonite and to develop an extraction and purification protocol for its isolation from raw clay samples acquired from the Koh-e-Suleiman mountain range in Pakistan. The process involved the collection of raw clay from the source, identification and quantification of montmorillonite. Granulometric extraction and purification protocols increased the montmorillonite content from 21.8–25.1% in the raw clay to 90.1–93.9% after small-scale extraction and 85.33–89.33% on a larger scale. A techno-economic analysis highlighted the practicality and economic benefits of large-scale extraction for industrial applications. This study highlights the existence of a substantial new source of this valuable clay which is currently used across multiple industries including construction, pottery making, pharmaceuticals, cosmetics and engineering. It is intuitively expected that the large-scale extraction of the material will improve the economic condition of the region by providing employment opportunities to locals and may be a valuable resource for export.

A key method of reducing energy usage and bills is collaborative demand management of buildings, and smart distribution networks using local renewable energy integrated sources. Emerging technologies such as the IOT (internet of things) can be integrated with grids, allowing bidirectional communication between customers and suppliers, while supporting remote management and monitoring of live energy usage. These systems create opportunities to deal with the distributed aggregation and control of distributed energy resources (DERs). Investigating how DERs are used at residential level in buildings such as smart houses reveal new possibilities relating to how the demand side can be made more efficient. In the long term, reducing energy demand during onpeak hours is a step towards creating a clean energy future. The primary goal of this paper is to observe and investigate how specific DSM strategies minimize energy consumption while maximizing efficiency with the use of new emerging technologies. A software called ETAP is used to analyse the integration of distributed generation such as renewable energy sources (RES) to utilize local power storage. In short, this is useful in providing flexibility to consumers. A PV system was also tested with an individual domestic load using an energy management system. This test examined how appliance energy usage can be reduced and shows why a management system is required to optimally utilize a PV system.

The success of immune checkpoint therapy shows tumour-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumour micro-environment (TME). Cancer Associated Fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localise with T cells in non-small cell lung cancer. We demonstrate the bi-directional nature of CAF / T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bi-directional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells.

BackgroundVentilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP.MethodsWe conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies.ResultsWe identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none.ConclusionsNearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used.

IntroductionCOVID-19 (Coronavirus Disease 2019) is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). At present there are few proven effective treatments. This early phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients.Methods and analysisDEFINE is an ongoing exploratory multicentre platform, open label, randomised study. COVID-19 positive patients will be recruited from the following cohorts; a) community cases b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised patients requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action.The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19.Safety will be assessed usingHaematological and biochemical safety laboratory investigations.Physical examinationVital signs (blood pressure/heart rate/temperature and respiratory rate)Daily electrocardiogram (ECG) readingsAdverse eventsThe analysis population will consist of (i) all patients randomised to a treatment arm who receive any dose of the study drug and (ii) all patients randomised to the control arm who would also have been eligible to receive a study drug.Secondary analysis will assess the following variables during treatment period 1) the response of key exploratory biomarkers 2) change in WHO ordinal scale and NEWS2 score 3) oxygen requirements 4) viral load 5) duration of hospital stay 6) PK/PD and 7) changes in key coagulation pathways.Ethics and disseminationThe DEFINE trial platform and its initial two treatment and standard of care arms have received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian and NHS Greater Glasgow and Clyde.The results of each study arm will be published as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including RECOVERY, and to other partners for rapid roll out in larger patient cohorts.Registration detailsThe DEFINE protocol has been registered on ISRCTN (https://www.isrctn.com/) and Clinicaltrials.gov(https://www.clinicaltrials.gov/).ClinicalTrials.gov Identifier: NCT04473053ISRCTN Identifier: ISRCTN14212905Strengths and limitations of this studyThe trial is as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges.The team are collecting real world data of medications at an early stage of their use in COVID-19 across the full spectrum of disease; allowing the administration of different treatment formulations (inhaled vs oral vs intravenous).The simultaneous collection of clinical outcomes as well as exploratory endpoints including clinical biomarkers, flow cytometry, PK/PD and thromboelastography allows further characterisation and elucidation of the temporal immuno-inflammatory cascade in COVID-19 to inform on future therapy selection.This is a Phase 1b/IIa platform study and thus the primary end point is clinical safety therefore our anticipated numbers will be too small to allow for definitive data on efficacy.DEFINE is an experimental medicine platform, currently restricted to three clinical sites and so the generation of data will be slower than that of larger platforms with access to a greater number of patients.

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry.MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load.ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups.ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.