Background: Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) is an unexplored therapy amidst the rapidly evolving spectrum of medical therapies for COVID-19 and is expected to counter the three most lifethreatening consequences of COVID-19 including lung injury by the virus, cytokine storm and sepsis. Methods: A single center, phase I/II, randomized controlled, single-blinded trial was conducted at Dow University of Health Sciences, Karachi, Pakistan. Participants were COVID-19 infected individuals, classified as either severely or critically ill with Acute Respiratory Distress Syndrome (ARDS). Participants were randomized through parallel-group design with sequential assignment in a 4:1 allocation to either intervention group with four C-IVIG dosage arms (0.15, 0.20, 0.25, 0.30 g/kg), or control group receiving standard of care only (n = 10). Primary outcomes were 28-day mortality, patient's clinical status on ordinal scale and Horowitz index (HI), and were analysed in all randomized participants that completed the follow-up period (intentionto-treat population). The trial was registered at clinicaltrials.gov (NCT04521309). Findings: Fifty participants were enrolled in the study from June 19, 2020 to February 3, 2021 with a mean age of 56.54 §13.2 years of which 22 patients (44%) had severe and 28 patients (56%) had critical COVID-19. Mortality occurred in ten of 40 participants (25%) in intervention group compared to six of ten (60%) in control group, with relative risk reduction in intervention arm I (RR, 0.333; 95% CI, 0.087À1.272), arm II (RR, 0.5; 95% CI, 0.171À1.463), arm III (RR, 0.167; 95% CI, 0.024À1.145), and arm IV (RR, 0.667; 95% CI, 0.268À1.660). In intervention group, median HI significantly improved to 359 mmHg [interquartile range (IQR) 127À400, P = 0.009)] by outcome day, while the clinical status of intervention group also improved as compared to control group, with around 15 patients (37.5%) being discharged by 7th day with complete recovery. Additionally, resolution of chest X-rays and restoration of biomarkers to normal levels were also seen in intervention groups. No drug-related adverse events were reported during the study. Interpretation: Administration of C-IVIG in severe and critical COVID-19 patients was safe, increased the chance of survival and reduced the risk of disease progression. Funding: Higher Education Commission (HEC), Pakistan (Ref no. 20-RRG-134/RGM/R&D/HEC/2020).

Background: This study assesses the feasibility of producing hyperimmune anti-COVID-19 intravenously administrable immunoglobulin (C-IVIG) from pooled convalescent plasma (PCP) to provide a safe and effective passive immunization treatment option for COVID-19. Materials & methods: PCP was fractionated by modified caprylic acid precipitation followed by ultrafiltration/diafiltration to produce hyperimmune C-IVIG. Results: In C-IVIG, the mean SARS-CoV-2 antibody level was found to be threefold (104 ± 30 cut-off index) that of the PCP (36 ± 8.5 cut-off index) and mean protein concentration was found to be 46 ± 3.7 g/l, comprised of 89.5% immunoglobulins. Conclusion: The current method of producing C-IVIG is feasible as it uses locally available PCP and simpler technology and yields a high titer of SARS-CoV-2 antibody. The safety and efficacy of C-IVIG will be evaluated in a registered clinical trial (NCT 04521309).

Objectives The aim of this trial is to investigate the safety and clinical efficacy of passive immunization therapy through Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG: 5% liquid formulation), on severe and critically ill patients with COVID-19. Trial design This is a phase I/II single centre, randomised controlled, single-blinded, superiority trial, through parallel-group design with sequential assignment. Participants will be randomised either to receive both C-IVIG and standard care or only standard care (4:1). Participants The study is mono-centric with the participants including COVID19 infected individuals (positive SARS-CoV-2 PCR on nasopharyngeal and/or oropharyngeal swabs) admitted in institute affiliated with Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan. Consenting patients above 18 years that are classified by the treating physician as severely ill i.e. showing symptoms of COVID-19 pneumonia; dyspnea, respiratory rate ≥30/min, blood oxygen saturation ≤93%, PaO2/FiO2 <300, and lung infiltrates >50% on CXR; or critically ill i.e. respiratory failure, septic shock, and multiple organ dysfunction or failure. Patients with reported IgA deficiency, autoimmune disorder, thromboembolic disorder, and allergic reaction to immunoglobulin treatment were excluded from study. Similarly, pregnant females, patients requiring two or more inotropic agents to maintain blood pressure and patients with acute or chronic kidney injury/failure, were also excluded from the study. Intervention and comparator The study consists of four interventions and one comparator arm. All participants receive standard hospital care which includes airway support, anti-viral medication, antibiotics, fluid resuscitation, hemodynamic support, steroids, painkillers, and anti-pyretics. Randomised test patients will receive single dose of C-IVIG in following four dosage groups: Group 1: 0.15g/Kg with standard hospital care Group 2: 0.2g/Kg with standard hospital care Group 3: 0.25g/Kg with standard hospital care Group 4: 0.3g/Kg with standard hospital care Group 5 (comparator) will receive standard hospital care only Main outcomes The primary outcomes are assessment and follow-up of participants to observe 28-day mortality and, • the level and duration of assisted ventilation during hospital stay, • number of days to step down (shifting from ICU to isolation ward), • number of days to hospital discharge, • adverse events (Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)) during hospital stay, • change in C-Reactive Protein (CRP) levels, • change in neutrophil lymphocyte ratio to monitor inflammation. Randomisation Consenting participants who fulfill the criteria are allocated to either intervention or comparator arm with a ratio of 4:1, using sequentially numbered opaque sealed envelope simple randomization method. The participant allocated for intervention will be sequentially assigned dosage group 1-4 in ascending order. Participants will not be recruited in the next dosage group before a set number of participants in one group (10) are achieved. Blinding (masking) Single blinded study, with participants blinded to allocation. Numbers to be randomised (sample size) Total 50 patients are randomised. The intervention arms consist of 40 participants divided in four groups of 10 participants while the comparator group consists of 10 patients. Trial Status Current version of the protocol is “Version 2” dated 29th September, 2020. Participants are being recruited. Recruitment started on June, 2020 and is estimated to primarily end on January, 2021. Trial registration This trial was registered at ClinicalTrials.gov, NCT04521309 on 20 August 2020 and is retrospectively registered. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).

Not only weighty energy usage pose issues for the environment, but it also raises server maintenance costs in data centers. The massive task with the various power control functions in computer components was made to minimize energy consumption. Increasing consumption of energy in data server environments means that data centers will have high maintenance costs. Various geo-distributed data centers are starting to grow in an age of data proliferation and information growth. Energy management for servers is now demanded for technological, environmental, and economic reasons. In this environment, the main memory is a major energy consumer, not less than the processor. At the same time, an energy-efficient task scheduling strategy is a viable way to meet these goals. Unfortunately, mapping Virtual Machine (VM) resources to the Main Memory (MM) demands to achieve good performance by minimizing the energy consumption within a certain limit is a huge challenge. This paper simulates energy-efficient task scheduling algorithms in a heterogeneous virtualized environment using real-time virtual machine scheduling to resolve the issue of energy consumption. Using a simulator Real-Time system SIMulator (RTSIM), several hardwarebased scheduling algorithms are implemented to observe VM memory scheduling efficiency to save memory energy. The simulation results show that, compared to current energy-efficient scheduling methods Rate Monotonic (RM), Earliest-Deadline-First (EDF), and Least-Laxity-First (LLF), helps to reduce energy consumption and improve performance. It is also observed that memory-aware energy management architecture reduces energy and memory consumption efficiently by using EDF scheduling algorithms. In particular, EDF saves approximately 58.3 percent of memory energy than conventional systems that cannot benefit from memory-aware energy management algorithms. The energy efficiency of the algorithms continues to improve as the level of server consolidation rises. We also implemented the EDF scheduling algorithm in Xen's Credit scheduler to see if the simulation outcomes can be simulated on physical systems. Results of simulation and deployment are equated, and comparable outcomes are achieved. We also identified that shared memory between virtual machines deliberately affects memory's energy consumption based on the implementation.

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