Blood Distribution of SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine in Humans.

Lipid nanoparticle mRNA vaccines are an exciting but emerging technology used in humans. There is limited understanding of the factors that influence their biodistribution and immunogenicity. Antibodies to poly(ethylene glycol) (PEG), which is on the surface of the lipid nanoparticle, are detectable in humans and boosted by human mRNA vaccination. We hypothesized that PEG-specific antibodies could increase the clearance of mRNA vaccines. To test this, we developed methods to quantify both the vaccine mRNA and ionizable lipid in frequent serial blood samples from 19 subjects receiving Moderna SPIKEVAX mRNA booster immunization. Both the vaccine mRNA and ionizable lipid peaked in blood 1-2 days post vaccination (median peak level 0.19 and 3.22 ng mL-1, respectively). The vaccine mRNA was detectable and quantifiable up to 14-15 days postvaccination in 37% of subjects. We measured the proportion of vaccine mRNA that was relatively intact in blood over time and found that the decay kinetics of the intact mRNA and ionizable lipid were identical, suggesting the intact lipid nanoparticle recirculates in blood. However, the decay rates of mRNA and ionizable lipids did not correlate with baseline levels of PEG-specific antibodies. Interestingly, the magnitude of mRNA and ionizable lipid detected in blood did correlate with the boost in the level of PEG antibodies. Furthermore, the ability of a subject's monocytes to phagocytose lipid nanoparticles was inversely related to the rise in PEG antibodies. This suggests that the circulation of mRNA lipid nanoparticles into the blood and their clearance by phagocytes influence the PEG immunogenicity of the mRNA vaccines. Overall, this work defines the pharmacokinetics of lipid nanoparticle mRNA vaccine components in human blood after intramuscular injection and the factors that influence these processes. These insights should be valuable in improving the future safety and efficacy of lipid nanoparticle mRNA vaccines and therapeutics.

Polymer-based drug-eluting stent treatment extends the time to reintervention for patients with symptomatic femoropopliteal artery disease: clinical evidence and potential economic value.

Aim: Use long-term follow-up data from the IMPERIAL study to determine whether drug-eluting polymer-based nitinol stent treatment can delay the time to repeat intervention for femoropopliteal artery disease and how such a delay may result in cost savings in a value-based episode of care. Patients & methods: The IMPERIAL randomized controlled trial was an international study of a paclitaxel-eluting polymer-coated stent (Eluvia, Boston Scientific, MA, USA) versus a polymer-free paclitaxel-coated stent (Zilver PTX, Cook Corporation, IN, USA) for treating lesions of the femoropopliteal arterial segment. Study patients (n = 465) had symptomatic lower limb ischemia. Safety and efficacy assessments were performed through 5 years. Mean time to first reintervention was calculated in post-hoc analysis for patients who underwent a clinically driven target lesion revascularization (CD-TLR) through 3 or 5 years following the index procedure. To simulate potential cost savings associated with differential CD-TLR burden over time, a cost-avoidance analysis using input parameters from IMPERIAL and US 100% Medicare standard analytical files was developed. Results: Among patients with a first CD-TLR through 3 years of follow-up, mean time to reintervention was 5.5 months longer (difference 166 days, 95% CI: 51, 282 days; p = 0.0058) for patients treated with Eluvia (n = 56) than for those treated with Zilver PTX (n = 30). Through the 5-year study follow-up period, CD-TLR rates were 29.3% (68/232) for Eluvia and 34.2% (39/114) for Zilver PTX (p = 0.3540) and mean time to first reintervention exceeded 2 years for patients treated with Eluvia at 737 days versus 645 days for the Zilver PTX group (difference 92 days, 95% CI: -85, 269 days; p = 0.3099). Simulated savings considering reinterventions occurring over 1 and 5 years following initial use of Eluvia over Zilver PTX were US $1,395,635 and US $1,531,795, respectively, when IMPERIAL CD-TLR rates were extrapolated to 1000 patients. Conclusion: IMPERIAL data suggest initial treatment with Eluvia extends the time patients spend without undergoing reintervention. This extension may be associated with cost savings in relevant time frames.

Microplastics in urban runoff: Global occurrence and fate.

Public concerns on microplastic (MP) pollution and its prevalence in urban runoff have grown exponentially. Huge amounts of MPs are transported from urban environments via surface runoff to different environment compartments, including rivers, lakes, reservoirs, estuaries, and oceans. The global concentrations of MPs in urban runoff range from 0 to 8580 particles/L. Understanding the sources, abundance, composition and characteristics of MPs in urban runoff on a global scale is a critical challenge because of the existence of multiple sources and spatiotemporal heterogeneity. Additionally, dynamic processes in the mobilization, aging, fragmentation, transport, and retention of MPs in urban runoff have been largely overlooked. Furthermore, the MP flux through urban runoff into rivers, lakes and even oceans is largely unknown, which is very important for better understanding the fate and transport of MPs in urban environments. Here, we provide a critical review of the global occurrence, transport, retention process, and sinks of MPs in urban runoff. Relevant policies, regulations and measures are put forward. Future global investigations and mitigation efforts will require us to address this issue cautiously, cooperating globally, nationally and regionally, and acting locally.

Real-time Monitoring of Aerosol Generating Dental Procedures.

OBJECTIVE: We aimed to quantify aerosol concentrations produced during different dental procedures under different mitigation processes. METHOD: Aerosol concentrations were measured by the Optical Particle Sensor (OPS) and Wideband Integrated Bioaerosol Sensor (WIBS) during routine, time-recorded dental procedures on a manikin head in a partitioned enclosure. Four different, standardised dental procedures were repeated in triplicate for three different mitigation measures. RESULT: Both high-volume evacuation (HVE) and HVE plus local exhaust ventilation (LEV) eradicated all procedure-related aerosols, and the enclosure stopped procedure-related aerosols escaping. Aerosols recorded by the OPS and WIBS were 84 and 16-fold higher than background levels during tooth 16 FDI notation (UR6) drilling, and 11 and 24-fold higher during tooth 46 FDI notation (LR6) drilling, respectively. Ultrasonic scaling around the full lower arch (CL) or the full upper arch (CU) did not generate detectable aerosols with mitigation applied. Without mitigation the largest concentration of inhalable particles during procedures observed by the WIBS and OPS was during LR6 (139/cm3) and UR6 (28/cm3) drilling, respectively. Brief aerosol bursts were recorded during drilling procedures with HVE, these did not occur with LEV, suggesting LEV provides protection against operator errors. Variation was observed in necessary fallow times (49 - 280 minutes) without mitigation, while no particles remained airborne when mitigation was utilised. CONCLUSION: This data demonstrates that correctly positioned HVE or LEV is effective in preventing airborne spread and persistence of inhalable particles originating from dental AGPs. Additionally, a simple enclosure restricts the spread of aerosols outside of the operating area. CLINICAL SIGNIFICANCE: Employing correctly positioned HVE and LEV in non-mechanically ventilated clinics can prevent the dispersal and persistence of inhalable airborne particles during dental AGPs. Moreover, using enclosures have the additive effect of restricting aerosol spread outside of an operating area.

Experience with a modified composite sequential bypass technique for limb-threatening ischemia.

BACKGROUND: Composite sequential femoro-popliteal-distal bypass is a valuable option for treatment of critical limb ischemia when autogenous vein is limited and an isolated popliteal or distal arterial segment exists. We report a modified technique for composite sequential bypass and the results with its use over a 14-year period. METHODS: Twenty-five modified composite sequential bypass procedures were performed on 24 patients to treat gangrene, ischemic ulceration, and severe rest pain. Vein grafts were anastomosed from blind popliteal or blind distal arterial segments above-knee (7) or below-knee (18) to a distal outflow vessel including the below-knee popliteal (1), posterior tibial (5), anterior tibial (7), or peroneal (12) artery. Polytetrafluoroethylene bypass grafts were then placed from a suitable inflow artery to the proximal hood of the vein graft. RESULTS: Cumulative primary patency rates were 80% at 3 years, and 65% at 5 years. The limb-salvage rate was 85% at 4 years. Occlusion of the prosthetic segment with a patent distal vein segment was recognized in two patients who presented with less severe recurrent ischemia. Limb-salvage in these patients was achieved by a secondary prosthetic graft to the patent vein graft. CONCLUSION: Our modified configuration of the prosthetic-vein anastomosis for composite sequential bypass is an alternative to the conventional procedure and may help preserve vein graft patency should the polytetrafluoroethylene graft thrombose.

Strategies for the production of long-acting therapeutics and efficient drug delivery for cancer treatment.

Protein therapeutics play a significant role in treating many diseases. They, however, suffer from patient's proteases degradation and antibody neutralization which lead to short plasma half-lives. One of the ways to overcome these pitfalls is the frequent injection of the drug albeit at the cost of patient compliance which affects the quality of life of patients. There are several techniques available to extend the half-life of therapeutics. Two of the most common protocols are PEGylation and fusion with human serum albumin. These two techniques improve stability, reduce immunogenicity, and increase drug resistance to proteases. These factors lead to the reduction of injection frequency which increases patient compliance and improve quality of life. Both techniques have already been used in many FDA approved drugs. This review describes many technologies to produce long-acting drugs with the attention of PEGylation and the genetic fusion with human serum albumin. The report also discusses the latest modified therapeutics in the field and their application in cancer therapy. We compare the modification methods and discuss the pitfalls of these modified drugs.

Microplastics undergo accelerated vertical migration in sand soil due to small size and wet-dry cycles.

Microplastics (MPs) are an emerging concern and potential risk to marine and terrestrial environments. Surface soils are reported to act as a sink. However, MP vertical mobility in the subsurface remains uncertain due to a lack of scientific data. This study focused on MP penetration in sand soil column experiments. Here we report the mobility of five different MPs, which consisted of polyethylene (PE) and polypropylene (PP) particles of various sizes and densities. We observed that the smallest sized PE MPs (21 µm) had the greatest movement potential. Moreover, it was found that when these MPs were subjected to greater numbers of wet-dry cycles, the penetration depth significantly increased, with an apparent linear relationship between depth and wet-dry cycle number (r2 = 0.817). In comparison, increasing the volume of infiltration liquid or the surface MP concentration had only negligible or weak effects on migration depth (r2 = 0.169 and 0.312, respectively). Based on the observed wet-dry cycle trend, we forecast 100-year penetration depths using weather data for 347 cities across China. The average penetration depth was calculated as 5.24 m (95% CI = 2.78-7.70 m), with Beijing Municipality and Hebei, Henan and Hubei provinces being the most vulnerable to MP vertical dispersion. Our results suggest that soils may not only represent a sink for MPs, but also a feasible entryway to subsurface receptors, such as subterranean fauna or aquifers. Finally, research gaps are identified and suggested research directions are put forward to garner a better understanding MP vertical migration in soil.

Oropharyngeal mucosal transmission of Zika virus in rhesus macaques.

Zika virus is present in urine, saliva, tears, and breast milk, but the transmission risk associated with these body fluids is currently unknown. Here we evaluate the risk of Zika virus transmission through mucosal contact in rhesus macaques. Application of high-dose Zika virus directly to the tonsils of three rhesus macaques results in detectable plasma viremia in all animals by 2 days post-exposure; virus replication kinetics are similar to those observed in animals infected subcutaneously. Three additional macaques inoculated subcutaneously with Zika virus served as saliva donors to assess the transmission risk from contact with oral secretions from an infected individual. Seven naive animals repeatedly exposed to donor saliva via the conjunctivae, tonsils, or nostrils did not become infected. Our results suggest that there is a risk of Zika virus transmission via the mucosal route, but that the risk posed by oral secretions from individuals with a typical course of Zika virus infection is low.Zika virus (ZIKV) is present in body fluids, including saliva, but transmission risk through mucosal contact is not well known. Here, the authors show that oropharyngeal mucosal infection of macaques with a high ZIKV dose results in viremia, but that transmission risk from saliva of infected animals is low.