Recent approaches to mRNA vaccine delivery by lipid-based vectors prepared by continuous-flow microfluidic devices.

Advancements in nanotechnology have resulted in the introduction of several nonviral delivery vectors for the nontoxic, efficient delivery of encapsulated mRNA-based vaccines. Lipid- and polymer-based nanoparticles (NP) have proven to be the most potent delivery systems, providing increased delivery efficiency and protection of mRNA molecules from degradation. Here, the authors provide an overview of the recent studies carried out using lipid NPs and their functionalized forms, polymeric and lipid-polymer hybrid nanocarriers utilized mainly for the encapsulation of mRNAs for gene and immune therapeutic applications. A microfluidic system as a prevalent methodology for the preparation of NPs with continuous flow enables NP size tuning, rapid mixing and production reproducibility. Continuous-flow microfluidic devices for lipid and polymeric encapsulated RNA NP production are specifically reviewed.

Nanotechnology for ultrafast nucleic acid amplification

Nucleic acid detection has been one of the most valued tools in point-of-care diagnostics from life science, agriculture, food safety and environmental surveillance, because of its high sensitivity, great specificity and simple operation. Since polymerase chain reactions (PCR) were discovered, more and more researchers attach importance to exploring ultrafast nucleic acid amplification methods for further expediting the process of detection and curbing infectious diseases' high spread rate, especially after the coronavirus disease 2019 (COVID-19) worldwide pandemic event. Nowadays, nanotechnology as one of the most cut-ting-edge technologies has aroused growing attention. In this review, we describe new advances in na-notechnology research for ultrafast nucleic acid amplification. We have introduced commonly used nanotechnologies, namely nanofluidics, nanoporous materials, nanoparticles and so on. Recent advances in these nanotechnologies for ultrafast sample pretreatments, accelerated enzymatic amplification and rapid heating/cooling processes was summarized. Finally, challenges and perspectives for the future applications of ultrafast nucleic acid amplification are presented.(c) 2022 Elsevier Ltd. All rights reserved.

GLOBAL CAMPAIGNS TOWARDS LOCAL MANUFACTURE OF ANTI-HIV/AIDS DRUGS IN CONTINUOUS FLOW SYSTEMS

Drug shortage and inaccessibility, stemming from exorbitant pharmaceutical drug prices, is only but a fraction of the many factors affecting global health. Most recently, the world was reminded of the role of pandemics in fast tracking the above-mentioned problem. A potentially sustainable solution would entail establishing cost effective and efficient local drug manufacture capacity in different regions. Using the HIV/AIDS epidemic as a case example, efforts by various research groups towards this goal are presented herein. © 2022 TeknoScienze. All rights reserved.

Process Intensification and Increased Safety for the On-Demand Continuous Flow Synthesis of Dithiothreitol, a Crucial Component in Polymerase Chain Reaction Testing Kits

The importance of rapid access to diagnostics tools in the identification of pathogens-including their crucial component, bioreagents-was recently underscored in the COVID-19 pandemic. The currently adopted synthesis of dithiothreitol (DTT) involves four steps in batch with long reaction times and which generates a highly carcinogenic and mutagenic bis-epoxide intermediate. In this work, we have developed an intensified telescoped three-step continuous flow synthesis of DTT involving a base-mediated ring closure epoxidation, a nucleophilic epoxide opening with thioacetic acid, and an acid-mediated deacetylation. One of the key features is that the first two steps are conducted in a telescoped continuous flow fashion, allowing generation and consumption of the hazardous intermediate in situ, suppressing the need for its isolation, and improving the overall safety of the synthesis. The process is completed by an acid-catalyzed deacetylation and a subsequent recrystallization to afford the desired DTT. Flow chemistry allows here to intensify the process by using high temperatures and high pressures while minimizing the number of unit operations and improving the overall safety of the process. Our protocol permits the on-demand production of DTT in case of future outbreaks.

The Society of Thoracic Surgeons Intermacs 2022 Annual Report: Focus on 2018 Heart Transplant Allocation System.

The thirteenth annual report from The Society of Thoracic Surgeons (STS) Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) highlights outcomes for 27,314 patients receiving continuous flow durable left ventricular assist devices (LVAD) over the last decade (2012-2021). In 2021, 2,464 primary LVADs were implanted, representing a 23.5% reduction in the annual volume compared to peak implantation in 2019 and an ongoing trend from the prior year. This decline is likely a reflection of the untoward effects of the COVID-19 pandemic and the change in the US heart transplant allocation system in 2018. The last several years have been characterized by a shift in device indication and type with 81.1% of patients now implanted as destination therapy and 92.7% receiving an LVAD with full magnetic levitation in 2021. However, despite an older, more ill population being increasingly supported pre-implant with temporary circulatory devices in the recent (2017-2021) vs prior (2012-2016) eras, the 1- and 5-year survival continues to improve at 83.0% and 51.9%, respectively. The adverse events profile has also improved, with significant reduction in stroke, gastrointestinal bleeding, and hospital readmissions. Finally, we examined the impact of the change in heart transplant allocation system in 2018 on LVAD candidacy, implant strategy, and outcomes. In the competing outcomes analysis, the proportion of transplant eligible patients receiving a transplant has declined from 56.5% to 46.0% at 3 years, while the proportion remaining alive with ongoing support has improved from 24.1% to 38.1% at 3 years, underscoring the durability of the currently available technology.

Process Intensification and Increased Safety for the On-Demand Continuous Flow Synthesis of Dithiothreitol, a Crucial Component in Polymerase Chain Reaction Testing Kits

The importance of rapid access to diagnostics tools in the identification of pathogens-including their crucial component, bioreagents-was recently underscored in the COVID-19 pandemic. The currently adopted synthesis of dithiothreitol (DTT) involves four steps in batch with long reaction times and which generates a highly carcinogenic and mutagenic bis-epoxide intermediate. In this work, we have developed an intensified telescoped three-step continuous flow synthesis of DTT involving a base-mediated ring closure epoxidation, a nucleophilic epoxide opening with thioacetic acid, and an acid-mediated deacetylation. One of the key features is that the first two steps are conducted in a telescoped continuous flow fashion, allowing generation and consumption of the hazardous intermediate in situ, suppressing the need for its isolation, and improving the overall safety of the synthesis. The process is completed by an acid-catalyzed deacetylation and a subsequent recrystallization to afford the desired DTT. Flow chemistry allows here to intensify the process by using high temperatures and high pressures while minimizing the number of unit operations and improving the overall safety of the process. Our protocol permits the on-demand production of DTT in case of future outbreaks. © 2023 American Chemical Society.

Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug

Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1, PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the amino-nitrile 10·HCl. T3P was found to be a more practical choice since the reagent promoted efficient and concomitant dehydration of the amide impurity 9 (derived from the amino-amide contaminant 8·HCl invariably present in 10·HCl) to 1. This observation allowed for the development of the second strategy, namely a continuous flow synthesis of 1 from 9 mediated by T3P. Under optimized conditions, this conversion could be achieved within 30 min in flow as opposed to 12–16 h in a traditional batch process. The final API had quality attributes comparable to those obtained in conventional flask processes.

Self-Measured Doppler Blood Pressure Readings in Continuous-Flow LVAD Patients are Reliable

Background: Blood pressure (BP) management is imperative in reducing risk of adverse events in continuous flow (CF) left ventricular assist device (LVAD) patients. The gold standard for non-invasive blood pressure (BP) measurement in these patients is Doppler ultrasound, which requires training and dexterity and is not routinely used in the outpatient setting. In the current COVID-19 pandemic era, telehealth assessment has become mandatory to assess and monitor patients. At our institution, we have issued all CF-LVAD patients with a Doppler ultrasound device and an oscillometric BP monitor, and provided training to correctly use these devices. Accuracy of BP measurements in this setting has not been confirmed. Aim: We examined whether Doppler BP obtained by CF-LVAD patients (pts) correlates to Doppler BP obtained by health care workers (HCWs). Methods: CF-LVAD pts were recruited between November 2020 and January 2022. During these routine outpatient follow-up visits, Doppler BP measurements were obtained simultaneously and independently by pts and HCW. BP was taken in a comfortable seating position following 5 minutes rest. Results: A total 223 pairs of simultaneous patient Doppler BP readings and HCW Doppler BP readings were obtained from 38 CF-LVAD patients (87% male, mean age at implant 52 + 14 years, 15 HeartMate3 and 23 HeartWare HVAD, with support duration range 28 - 3492 days). Patient Doppler BP (average 85.9 + 9.8 mmHg) correlated closely with HCW Doppler BP (average 86.1 + 9.6 mmHg), r2=0.90, p<0.0001. There was no significant difference between BP taken by the patient and HCW (p=0.4). The mean difference between the two methods was -0.17 mmHg and the standard deviation was 0.22 mmHg (figure) using Bland-Altman analysis. Conclusions: These results demonstrate that in our patient-population, Doppler-derived blood pressure measurements in CF-LVAD patients were accurate and reliable. This supports the routine use of home Doppler BP measurement and monitoring by CF-LVAD patients, especially in the telehealth era. (Figure Presented).

Reliability Investigation of Contact Tracing using Resource-Constrained Mobile Devices

During this pandemic time while finding the (SARS-CoV-2) infected person many of the applications got active where various nations participated actively. The main device involved in the whole process is Smartphone. The existing applications are focusing on the use of Bluetooth technology. Bluetooth is limited with the area it can cover and noise it produces to broadcast the messages to the neighbors. Also, while searching the position of the infected person one concern could be that is Position of the smartphone accurate? or for how long the tracing will happen? While tracing the position of the person whether infected or not infected, the compromise cannot be done. At the pandemic situation, the little mistake of the position will cost the life of a person and the growing number of infected persons will yield to an exponential cost. Also, the life of the smartphone to keep working needs energy through battery. Continuous localization will need continuous flow of the energy for that device. Thus, the smartphone needs to be charged after a period of time. So, when a person is in a public place, he will need his smartphone to be active. Our main concern with the whole paper is to find the solution through the simulation for the position accuracy of the smartphone as well as to manage the energy consumption. © 2022 IEEE.

Advances in Nucleic Acid Amplification-Based Microfluidic Devices for Clinical Microbial Detection

Accurate and timely detection of infectious pathogens is urgently needed for disease treatment and control of possible outbreaks worldwide. Conventional methods for pathogen detection are usually time-consuming and labor-intensive. Novel strategies for the identification of pathogenic nucleic acids are necessary for practical application. The advent of microfluidic technology and microfluidic devices has offered advanced and miniaturized tools to rapidly screen microorganisms, improving many drawbacks of conventional nucleic acid amplification-based methods. In this review, we summarize advances in the microfluidic approach to detect pathogens based on nucleic acid amplification. We survey microfluidic platforms performing two major types of nucleic acid amplification strategies, namely, polymerase chain reaction (PCR) and isothermal nucleic acid amplification. We also provide an overview of nucleic acid amplification-based platforms including studies and commercialized products for SARS-CoV-2 detection. Technologically, we focus on the design of the microfluidic devices, the selected methods for sample preparation, nucleic acid amplification techniques, and endpoint analysis. We also compare features such as analysis time, sensitivity, and specificity of different platforms. The first section of the review discusses methods used in microfluidic devices for upstream clinical sample preparation. The second section covers the design, operation, and applications of PCR-based microfluidic devices. The third section reviews two common types of isothermal nucleic acid amplification methods (loop-mediated isothermal amplification and recombinase polymerase amplification) performed in microfluidic systems. The fourth section introduces microfluidic applications for nucleic acid amplification-based detection of SARS-CoV-2. Finally, the review concludes with the importance of full integration and quantitative analysis for clinical microbial identification.

Industry Survey: The Magic Triangle of the New Normal

At year-end 2021 and in continuous flow of waves of COVID-19, Vector Consulting with IEEE Software contacted industry experts on their challenges, lessons learned, and outlook. We have been asking almost 3,000 people across different industries worldwide. With a response rate of 5.5% covering different industry domains, the survey well represents different business-to-business models and diverse regions in the world.

Continuous manufacturing technologies in upstream pharmaceutical supply chains: Combining engineering and managerial criteria

The COVID-19 pandemic exposed vulnerabilities in upstream pharmaceutical supply chains (PSC). One is that the global supply of active pharmaceutical ingredients (APIs) is overly dependent on few locations and large-scale batch manufacturing. Regulators hope to enable more dependable location decisions and improved processing quality with the adoption of advanced technologies such as process intensification through continuous manufacturing (CM). Conceptual work suggests that the benefits of shifting from batch to CM accrue end-to-end across the PSC. Yet detailed quantitative information about CM is limited at an early stage of evaluation, and too specialised to inform managerial decisions about PSC reconfiguration. Supply chain and engineering criteria are rarely combined in the early-stage evaluation of alternative CM technologies. Extant CM research typically overlooks implications for supply chain managers. To address the current gap, this article evaluates, at an early stage of adoption, alternative CM reactor technologies for the synthesis of APIs in selected therapeutic areas. With evidence from secondary data, relevant technologies and criteria are identified, and their relative importance is evaluated in a semi-quantitative fashion following analytical hierarchy process (AHP) principles, ensuring that findings are intelligible to both engineers and managers. The proposed empirical work enriches previous conceptual frameworks predicated on volume-variety considerations. Specifically, findings suggest that, all things considered, microreactor technologies outperform alternatives. However, PSC managerial considerations introduce nuances in specific therapeutic areas, for example, antivirals where a tension between complex chemistry and the need for flexibility in unit operations may favour batch manufacturing. For analgesics the need to exploit the existing manufacturing base whilst addressing inventory reduction favours technologies that incorporate elements of batch and CM. The proposed analysis is in line with real-world decisions that global medicines manufacturers are increasingly facing, as governments seek to develop local health countermeasures to the COVID-19 pandemic in the absence of detailed information.

A High-Yielding Synthesis of EIDD-2801 from Uridine.

A simple reordering of the reaction sequence allowed the improved synthesis of EIDD-2801, an antiviral drug with promising activity against the SARS-CoV-2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17 % to 61 %, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.