Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 244
Filter
1.
Cancer Research Conference: American Association for Cancer Research Annual Meeting, ACCR ; 83(7 Supplement), 2023.
Article in English | EMBASE | ID: covidwho-20245051

ABSTRACT

mRNA is a new class of drugs that has the potential to revolutionize the treatment of brain tumors. Thanks to the COVID-19 mRNA vaccines and numerous therapy-based clinical trials, it is now clear that lipid nanoparticles (LNPs) are a clinically viable means to deliver RNA therapeutics. However, LNP-mediated mRNA delivery to brain tumors remains elusive. Over the past decade, numerous studies have shown that tumor cells communicate with each other via small extracellular vesicles, which are around 100 nm in diameter and consist of lipid bilayer membrane similar to synthetic lipidbased nanocarriers. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain tumors without undue toxicity. We synthesized LNPs using four components similar to the formulation used in the mRNA COVID19 vaccines (Moderna and Pfizer): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. For the in vitro screen, we tested ten classes of helper lipids based on their abundance in extracellular vesicle membranes, commercial availability, and large-scale production feasibility while keeping rest of the LNP components unchanged. The transfection kinetics of GFP mRNA encapsulated in LNPs and doped with 16 mol% of helper lipids was tested using GL261, U87 and SIM-A9 cell lines. Several LNP formations resulted in stable transfection (upto 5 days) of GFP mRNA in all the cell lines tested in vitro. The successful LNP candidates (enabling >80% transfection efficacy) were then tested in vivo to deliver luciferase mRNA to brain tumors via intrathecal administration in a syngeneic glioblastoma (GBM) mouse model, which confirmed luciferase expression in brain tumors in the cortex. LNPs were then tested to deliver Cre recombinase mRNA in syngeneic GBM mouse model genetically modified to express tdTomato under LoxP marker cassette that enabled identification of LNP targeted cells. mRNA was successfully delivered to tumor cells (70-80% transfected) and a range of different cells in the tumor microenvironment, including tumor-associated macrophages (80-90% transfected), neurons (31- 40% transfected), neural stem cells (39-62% transfected), oligodendrocytes (70-80% transfected) and astrocytes (44-76% transfected). Then, LNP formulations were assessed for delivering Cas9 mRNA and CD81 sgRNA (model protein) in murine syngeneic GBM model to enable gene editing in brain tumor cells. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~94% of brain tumor cells in vivo. In conclusion, we have developed a library of safe LNPs that can transfect GBM cells in vivo with high efficacy. This technology can potentially be used to develop novel mRNA therapies for GBM by delivering single or multiple mRNAs and holds great potential as a tool to study brain tumor biology.

2.
Advanced Therapeutics ; 6(5) (no pagination), 2023.
Article in English | EMBASE | ID: covidwho-20244710

ABSTRACT

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

3.
Diabetic Medicine ; 40(Supplement 1):164, 2023.
Article in English | EMBASE | ID: covidwho-20244653

ABSTRACT

Objective: Semaglutide is the first glucagon-like peptide- 1 receptor agonist with oral and subcutaneous formulations. We studied patient adherence and clinical response following their prescription in a primary care setting. Method(s): We searched for patients starting semaglutide between October 2020 to November 2021 in primary care registries in Dudley, West Midlands. We tracked their collection of medications for up to six months, changes in HbA1C and weight if these data were available at 26 weeks (range 22-52 weeks), with significance tested using a t-test. Patients prescribed both formulations were excluded. Result(s): Clinical data were available in 180 of the 443 patients. Baseline HbA1c was 79.0 +/- 18.6mmol/mol (Ozempic) and 81.9 +/- 19.3mmol/mol (Rybelsus) and pre-treatment weight was 108.4 +/- 10.5 kg (Ozempic) and 104.3 +/- 26.7 kg (Rybelsus). 62.8% of patients were of non-white ethnicity and 82.8% were on >= two anti-diabetic drugs. In patients with six-month follow-up data, mean reduction in HbA1c and weight was 17.1 +/- 20.8mmol/ mol and 3.9 +/- 6.2 kg (Ozempic n = 53, p < 0.01) and 18.2 +/- 14.5mmol/mol and 5.9 +/- 4.2 kg (Rybelsus n = 5, p < 0.05). Drug continuation rates were measured in 324 patients. 3.2% and 19.0% of patients for Ozempic and Rybelsus respectively did not obtain further prescriptions after their initial script. At six months, 87.2% continued with Ozempic and 57.2% with Rybelsus. Conclusion(s): This study demonstrates similarly significant reductions in HbA1c and weight with Ozempic and Rybelsus, despite the complexity of follow-up during Covid-19 restrictions. The lower adherence to Rybelsus warrants further study.

4.
International Journal of Applied Pharmaceutics ; 15(3):1-11, 2023.
Article in English | EMBASE | ID: covidwho-20242785

ABSTRACT

Recent advancements in nanotechnology have resulted in improved medicine delivery to the target site. Nanosponges are three-dimensional drug delivery systems that are nanoscale in size and created by cross-linking polymers. The introduction of Nanosponges has been a significant step toward overcoming issues such as drug toxicity, low bioavailability, and predictable medication release. Using a new way of nanotechnology, nanosponges, which are porous with small sponges (below one microm) flowing throughout the body, have demonstrated excellent results in delivering drugs. As a result, they reach the target place, attach to the skin's surface, and slowly release the medicine. Nanosponges can be used to encapsulate a wide range of medicines, including both hydrophilic and lipophilic pharmaceuticals. The medication delivery method using nanosponges is one of the most promising fields in pharmacy. It can be used as a biocatalyst carrier for vaccines, antibodies, enzymes, and proteins to be released. The existing study enlightens on the preparation method, evaluation, and prospective application in a medication delivery system and also focuses on patents filed in the field of nanosponges.Copyright © 2023 The Authors.

5.
Drug Evaluation Research ; 45(7):1426-1434, 2022.
Article in Chinese | EMBASE | ID: covidwho-20239013

ABSTRACT

In order to comprehensively understand the research hotspots and development trends of Lonicera Japonica Flos in the past 20 years, and to provide intuitive data reference and objective opinions and suggestions for subsequent related research in this field, this study collected 8 871 Chinese literature and 311 English literature related to Lonicera Japonica Flos research in the core collection databases of Wanfang Data), CNKI and Web of Science (WOS) from 2002 to 2021, and conducted bibliometric and visual analysis using vosviewer. The results showed that the research on the active components of Lonicera Japonica Flos based on phenolic acid components, the research on the mechanism of novel coronavirus pneumonia based on data mining and molecular docking technology, and the pharmacological research on the anti-inflammatory and antiviral properties of Lonicera Japonica Flos are the three hot research directions in the may become the future research direction. In this paper, we analyze the research on Lonicera Japonica Flos from five aspects: active ingredients, research methods, formulation and preparation, pharmacological effects and clinical applications, aiming to reveal the research hotspots, frontiers and development trends in this field and provide predictions and references for future research.Copyright © Drug Evaluation Research 2022.

6.
American Journal of Geriatric Psychiatry ; 29(4 Supplement):S109-S110, 2021.
Article in English | EMBASE | ID: covidwho-20238388

ABSTRACT

Introduction: There is a dearth of information on older users (65+ years) of medical cannabis, who may face unique challenges due to altered metabolism with aging, concurrent medication use, and risk of adverse effects. This observational study aimed to describe a large cohort of older medical cannabis users in Canada. Method(s): From Oct 2014 to Oct 2020, a commercial medical cannabis provider based in Canada collected anonymized data for research purposes from patient volunteers. Data included demographic, social, and health details (at intake) and cannabis products, self-perceived changes in symptoms and change in medications (at follow-up, variable duration). Cannabis products were categorized as cannabidiol (CBD) only, tetrahydocannabinol (THC) only or mixed CBD/THC. Of the mixed, formulations could be in 1:1 ratios (CBD+/THC+), predominantly CBD (CBD+/THC-) or predominantly THC (CBD-/THC+). Result(s): In total, 9766 subjects in the older cohort (65+ years old) completed the entire questionnaire (mean age (SD) = 73.6 (6.8) y, 60% female). They represented 23.1% of the total dataset (N = 42,267, mean (SD) =51.5 (16.8) y). The proportion of adults in the older cohort tended to increase over time (pre-2018: 17.6%;2018: 26.7%;2019: 31.2%;2020: 22.7%, when the overall intake decreased from 8869 to 5644). Among the older cohort, 15.5% were previous cannabis users and 67.7% were referred for chronic pain (mainly arthritis, chronic pain, lower back pain). Concomitant analgesic use was common (over-the-counter analgesics: 44.5%;opioids: 28.3%;NSAIDs: 24.5%). 7.9% of the sample (compared to 19.9% in the whole sample) were referred for psychiatric disorders, though 21.4% indicated antidepressant use and 12.3% indicated benzodiazepine use. Another 7% were referred for neurological disorders. Follow-up data were captured in visits (11,992) from 4698 older patients, averaging 2.5 visits per patient. The type of medical cannabis used changed over time, with increasing use of cannabis oil compared to herbal cannabis. In 2020, of 2478 visits, 78.9% use was cannabis oil and 6.7% was herbal forms (pre-2018: 57.6% vs 36.2%). The composition of cannabis oil demonstrated a preference for cannabinoid oil (CBD+) over tetrahydrocannabinol (THC+) in 6043 visits: 45.2% were using CBD+ preparations, only 3.2% were using THC+ preparations, and for CBD/THC combinations, CBD predominated (CBD+/THC-: 30.5%;CBD+/THC+: 16.8%;CBD-/THC+: 4.3%). Adverse-effects (7062 visits) included dry mouth (15.8%), drowsiness (8.6%), dizziness (4%) and hallucinations (0.6%). Patients reported improved pain, sleep and mood over time, though 15-20% reported no improvement or worsening. Medication use was mostly unchanged, though 40% of opioid users reported requiring reduced dosages. Conclusion(s): These data were drawn from a large convenience sample. The data suggest an increasing proportion of older users of medical cannabis, though COVID-19 may have affected recent use. Female users comprised a higher proportion, and cannabis oil containing CBD was preferred. Systematic studies of effectiveness and safety in older users of cannabinoids are needed given its increasing use. Funding(s): No funding was received for this work.Copyright © 2021

7.
Drug Delivery Letters ; 13(2):83-91, 2023.
Article in English | EMBASE | ID: covidwho-20236526

ABSTRACT

Coronavirus disease (COVID-19) is an infectious disease caused by coronavirus. Devel-oping specific drugs for inhibiting replication and viral entry is crucial. Several clinical trial studies are underway to evaluate the efficacy of anti-viral drugs for COVID-19 patients. Nanomedicine formulations can present a novel strategy for targeting the virus life cycle. Nano-drug delivery systems can modify the pharmacodynamics and pharmacokinetics properties of anti-viral drugs and reduce their adverse effects. Moreover, nanocarriers can directly exhibit anti-viral effects. A number of nanocarriers have been studied for this purpose, including liposomes, dendrimers, exosomes and decoy nanoparticles (NPs). Among them, decoy NPs have been considered more as nanodecoys can efficiently protect host cells from the infection of SARS-CoV-2. The aim of this review article is to highlight the probable nanomedicine therapeutic strategies to develop anti-viral drug delivery systems for the treatment of COVID-19.Copyright © 2023 Bentham Science Publishers.

8.
Value in Health ; 26(6 Supplement):S103, 2023.
Article in English | EMBASE | ID: covidwho-20233469

ABSTRACT

Objectives: Mucormycosis is a rare invasive fungal infection with high lethality, affecting mainly patients with hematological neoplasia, decompensated diabetes, and covid-19 infection. The aim was to perform a cost-effectiveness analysis of liposomal Amphotericin B (standard treatment) versus isavuconazole for treating mucormycosis in the consolidation phase from the perspective of the Brazilian Unified Health System. Method(s): A decision tree model was built. The analysis considered the costs of the treatment over a six-month time horizon. This included hospitalization during the entire course of treatment and the expenditures related to dialysis, complication occurring in 5% (3%-6%) of cases treated with the Amphotericin B. Appointments with specialists were included in the isavuconazole arm, and amphotericin B was used if the patient failed to respond to isavuconazole. The utility of the patient with mucormycosis, cured and with renal failure was estimated. Uncertainties were assessed through probabilistic and deterministic sensitivity analyses. Result(s): The average cost of amphotericin B and isavuconazole arm was R$1.054.874,39 and R$522.344,05, respectively. The utility was 0.479 with amphotericin B and 0.480 with isavuconazole. The ICER was R$ -684,494,237 (dominant). In deterministic sensitivity analysis, the probability of dialysis was the variable with the greatest impact. In probabilistic analysis, the ICER is distributed in the right and left lower quadrant, the acceptability curve for all the scenarios analyzed is favorable for isavuconazole. The budget impact suggests a potential savings of between R$ 350 million and R$ 415 million over five years. Conclusion(s): The treatment of mucormycosis during the consolidation phase with isavuconazole represents a lower cost, besides the convenience of oral treatment and reduced incidence of severe adverse events, with mortality similar to the Amphotericin B arm. In Brazil, the formulation of posaconazole approved is inadequate for treating mucormycosis during the consolidation phase, therefore isavuconazole is the single oral drug available.Copyright © 2023

9.
Economic Papers ; 2023.
Article in English | Web of Science | ID: covidwho-20232338

ABSTRACT

The COVID-19 pandemic has wreaked social and economic havoc across the globe. This article addresses an aspect of trust that has not received wide attention in the context of the pandemic: how relational trust can affect compliance behaviour with health campaigns. This article uses a unique dataset of people receiving a COVID test after suspicion of infection. We use regression analysis to study the relation between compliance with mobility restrictions and institutional and relational trust. We find that trusting that close relations will be there for you in the case of falling ill is associated with a significant increase in the probability of complying with health campaigns as is trust that public institutions will respond appropriately to the pandemic. Additionally, we find no statistical relationship between compliance and trust in media outlets nor compliance and trust that community members (neighbours, co-workers or others) will care for you. The findings suggest that enhancing trust may improve compliance with mobility restrictions, however, increasing trust in specific groups may not aid in the effectiveness of some health campaigns. Importantly, nudging people towards compliance could be achieved by emphasising in campaigns that your behaviour could influence the health of those who you care about.

10.
Saudi J Biol Sci ; 30(7): 103700, 2023 Jul.
Article in English | MEDLINE | ID: covidwho-20230942

ABSTRACT

The Siddha system of medicine is an ancient medical lineage that is practiced primarily in the southern part of India. Siddha system of medicine has been in practice for thousands of years with documented evidence dating back to the 6th century BCE. According to siddha system of medicine's basic fundamental principle, the human body is made up of 96 thathuvam (primary components), which encompass physical, physiological, psychological, and intellectual aspects. Medicine (marunthu) is classified as a wide range of internal and external medicines. The major components of its medical formulations include plant parts, minerals and animal products. Various methods were carried out for the purification process to eliminate the toxins. Choornam, Guligai, Tailam, Parpam, Chendooram, Kattu, Pasai and Poochu are the most common medicines used in Siddha system of medicine for the treatment of various diseases. The pathophysiological classification of diseases is elaborated in detail in the classical Siddha literature. Siddha system of medicine plays an important role in protecting people from diseases such as COVID-19 by providing immune-protecting and immune-boosting medicines in today's world. Mathan tailam and maha megarajanga tailam are the two unique preparations used widely for various skin diseases including chronic wounds and burns. Scientific validation of both medicines will help in understanding their effectiveness against a typical wound condition. In the present study physio-chemical and phytochemical, HPTLC, and GC-MS analyses were carried out and discussed in detail on the multifunctional properties exhibited in the patient communities.

11.
Clinical Journal of Sport Medicine ; 33(3):e95, 2023.
Article in English | EMBASE | ID: covidwho-2322715

ABSTRACT

History: Twenty-two year old male basic trainee was brought to the ED after collapsing during a routine ruck march. At mile 8/12, soldier was noted to develop an unsteady gate and had witnessed loss of consciousness. A rectal core temperature was obtained and noted to be >107degreeF. Cooling initiated with ice sheets and EMS was activated. On arrival to the ED, patient demonstrated confusion and persistently elevated core temperatures despite ice sheeting, chilled saline and cold water bladder lavage. Cooling measures were discontinued after patient achieved euthermia in the ED;however, his temperatures subsequently spiked>103degreeF. Given rebound hyperthermia, an endovascular cooling (EVC) device was placed in the right femoral vein and patient was transferred to the ICU. Multiple attempts to place EVC device on standby were unsuccessful with subsequent rebound hyperthermia. Prolonged cooling was required. Physical Exam: VS: HR 121, BP 85/68, RR 22 SpO2 100% RA, Temp 102.4degreeF Gen: young adult male, NAD, shivering, A&Ox2 (person and place only) HEENT: Scleral anicteric, conjunctiva non-injected, moist mucus membranes Neck: Supple, no LAD Chest: CTAB, no wheezes/rales/rhonchi CV: tachycardia, regular rhythm, normal S1, S2 without murmurs, rubs, gallops ABD: NABS, soft/non-distended, no guarding or rebound EXT: No LE edema, tenderness SKIN: blisters with broad erythematous bases on bilateral heels Neuro: CN II-XII grossly intact, 5/5 strength in all extremities. Differential Diagnosis: 216. Septic Shock 217. Hypothalamic Stroke 218. Exertional Heat Stroke (EHS) 219. Neuroleptic Malignant Syndrome 220. Thyroid Storm Test Results: CBC: 18.2>14.5/40.6<167 CMP: 128/3.5 88/1831/2.7<104, AST 264, ALT 80, Ca 8.8 Lactate: 7.1 CK: 11 460 Myoglobin: 18 017 TSH: 3.16 CXR: No acute cardiopulmonary process Blood Cx: negative x2 CSF Cx: Negative COVID/Influenza/EBV: Negative Brain MRI: wnl. Final Diagnosis: Exertional Heat Stroke. Discussion(s): No EVC protocols exist for the management of EHS or rebound/refractory hyperthermia. As a result, the protocol used for this patient was adapted from post-cardiac arrest cooling protocols. It is unclear if this adapted protocol contributed to his delayed cooling and rebound hyperthermia as it was not intended for this patient demographic/ pathophysiology. Furthermore, despite initiating empiric antibiotics upon admission, delayed recognition and tailored therapy for his bilateral ankle cellulitis may have contributed to the difficulty in achieving euthermia. In summary, more research needs to be done to evaluate and develop an EVC protocol for EHS. Outcome(s): Euthermia was achieved and maintained after 36 hours of continuous EVC, at which point it was discontinued. His CK, AST/ALT, creatinine and sodium down-trended after discontinuation of EVC. Patient's antibiotics were transitioned to an oral formulation for treatment of ankle cellulitis and he was prepared for discharge. He was discharged with regular follow-up with the Fort Benning Heat Clinic. Follow-Up: After discharge, patient had regularly scheduled visits with the Fort Benning Heat Clinic. His typical lab markers for exertional heat stroke were regularly monitored. He had continued resolution of his Rhabdomyolysis, acute kidney injury and hyponatremia with typical treatment. Soldier returned to duty after 10 weeks of close monitoring and rehabilitation.

12.
Clin Pharmacol Drug Dev ; 12(5): 484-492, 2023 05.
Article in English | MEDLINE | ID: covidwho-2323614

ABSTRACT

Asciminib, a first-in-class allosteric BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP) is used in the treatment of chronic myeloid leukemia. We describe a randomized, single-dose, open-label, four-period crossover study in healthy adult participants (N = 24) which evaluated the relative bioavailability of a single 40-mg dose of asciminib in pediatric formulation (1-mg mini-tablets) compared with the reference adult tablet under fasted conditions. Additionally, the effect of food on the bioavailability of the mini-tablet formulation was evaluated. Under fasted conditions, asciminib exposure was similar for both formulations (geometric mean [Gmean ] area under the concentration-time curve from time 0 to infinity [AUCinf ] 5970 and 5700 ng ×h/mL, respectively). Food decreased the AUCinf and maximum plasma concentration (Cmax ) of the asciminib mini-tablets; this effect was more pronounced with a high-fat meal (Gmean ratios [90% confidence interval]: fasted/low-fat meal, 0.42 [0.38-047], 0.32 [0.28-0.37], respectively; fasted/high-fat meal, 0.30 [0.27-0.34], 0.22 [0.19-0.25], respectively). The mini-tablets were assessed to be easy to ingest with good palatability. Asciminib doses for a pivotal pediatric clinical trial will be defined using physiologically based pharmacokinetic modeling, which will consider the age and the higher food effect observed with the mini-tablets.


Subject(s)
Pyrazoles , Humans , Adult , Child , Biological Availability , Cross-Over Studies , Pyrazoles/pharmacokinetics , Tablets
13.
Respirology ; 28(Supplement 2):235, 2023.
Article in English | EMBASE | ID: covidwho-2318848

ABSTRACT

Introduction/Aim: The development of safe and effective vaccines is crucial to conquering the COVID-19 pandemic. Recombinant proteins represent the best understood and reliable approach to pandemic vaccine delivery with well-established safety;however, they face challenges in design, structural characterisation, manufacture, potency testing and ensuring adequate immunogenicity. Method(s): Our team used in silico structural modelling to design a vaccine based on a stabilised spike protein extracellular domain (ECD). The insect cell expressed recombinant spike ECD was formulated with Vaxine's proprietary Advax-CpG55.2 adjuvant. Result(s): The vaccine known as Covax-19 or SpikoGen induced high titers of antibody and memory T-cells which translated to protection against SARS-CoV-2 infection in hamsters, ferrets, and aged monkeys. Despite numerous challenges along the journey, clinical trials in Iran during a major wave of delta variant infection confirmed SpikoGen vaccine was 78% effective in reducing risk of severe disease and with no evidence of vaccine-associated thrombosis, myocarditis, or sudden death, receiving marketing approval under emergency use authorisation in Iran on 6 October 2021. This made it the first recombinant spike-protein vaccine in the world to be approved, and the first Australian-developed human vaccine to receive marketing approval in four decades. Since approval millions of doses have been administered and additional trials in Australia and Iran have confirmed its effectiveness as a booster to prevent waning immunity, as well as its safety and effectiveness in children from the age of 5 years. The ongoing Australian and overseas clinical trial program is focussed on gaining better understanding the effect of dosing intervals on vaccine immunogenicity, gathering additional data on use as a booster, and development of new variant formulations. Conclusion(s): Covax-19/Spikogen is safe and effective adjuvanted recombinant protein vaccine.

14.
Journal of Cystic Fibrosis ; 21(Supplement 2):S339, 2022.
Article in English | EMBASE | ID: covidwho-2315958

ABSTRACT

Background: Next-generation SARS-CoV-2 vaccines demonstrated that nanoparticle messenger ribonucleic acid (mRNA) delivery is effective and safe for in vivo delivery in humans. Current treatments for cystic fibrosis (CF) primarily focus on modulator drug therapies designed to correct malfunctioning CF transmembrane conductance regulator (CFTR) protein, but these modulators are ineffective for the 10% of people with CF with variants that do not allow protein production. Among these is the splice variant 3120 + 1G >A, the most common CF-causing mutation in native Africans. Gene editing would allow production of CFTR protein and enhancement of function using available CFTR modulators. We have demonstrated that electroporation of a modified CRISPR-Cas9 base editor to primary human bronchial epithelial cells carrying 3120 + 1G >A and F508del mutant alleles achieved 75% genome editing of the splice variant, resulting in approximately 40% wild-type (WT) CFTR function [1]. Here,we evaluate the effectiveness of several new nanoparticle formulations at delivering green fluorescent protein (GFP) mRNA to CF bronchial epithelial (CFBE41o-) cells. Using the optimal formulation,we then tested the efficacy correction of the 3120 + 1G >Avariant in a CFTR expression minigene (EMG) integrated into the genome of isogenic CFBE cells using mRNA and plasmid deoxyribonucleic acid (DNA) encoding adenine base editor (ABE) and guide (g)RNA. Method(s): GFP served as a reporter to evaluate transfection efficiency, cell viability, and mean fluorescence intensity (MFI) for three dosages (150, 75, 32.5 ng of mRNA), four polymer-to-mRNA to weight (w/w) ratios (60, 40, 30, 20), and four polymers (R, Y, G, B). 7-AAD served as a live/dead stain to quantify viability, with flow cytometry results analyzed using FlowJo software. CFBE cells stably expressing the 3120 + 1G >A EMG were transfected with the optimized nanoparticle formulation to deliver ABE and gRNA at two dosages (150, 75 ng) of mRNA and DNA. CFTR function in CFBE cellswas measured by short circuit current, forskolin stimulation, and inh-172 inhibition as a measure of editing efficiency. Result(s): Flow cytometry showed that polymer R achieved more than 85% GFP transfection, compared with a maximum of approximately 35% for the other three polymers at the maximum 150-ng dose, with approximately 80% viability normalized to untreated cells. In addition, polymer R achieved GFP MFI more than one order of magnitude as high as other formulations (~30 000 vs 2700 MFI) for the other three polymers at 150-ng dose and 40 w/w ratio. CFBE cells transfected with polymer R nanoparticles containing ABE and guide RNA at 75 ng and 150 ng showed mean CFTR function increase to 10 muA 6 (standard error of the mean [SEM] 1.1 muA) (~10% of WT) and 6.3 muA (SEM 0.9 muA) (~6% of WT), respectively. Greater toxicity at the higher dose could explain the larger increase in CFTR current at the lower dose. DNA-encoded ABE plasmid and gRNA showed a less robust increase in CFTR function (2.9 muA [SEM 0.4 muA] for 75-ng dose;3.0 muA [SEM 0.4 muA] for 150-ng dose), which was probably a result of the nanoparticle formulation being optimized for RNA instead of DNA cargo or the additional intracellular barriers that must be overcome for successful DNA delivery. Conclusion(s): We demonstrated that an optimized nanoparticle formulation containing ABE and gRNA can correct splicing of isogenic cells bearing the 3120 + 1G >A CFTR variant, resulting in recovery of CFTR function. In ongoing work, we are adapting these nanoparticles for RNA- and DNAencoded ABE and gRNA delivery to primary human bronchial epithelial cells.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

15.
Topics in Antiviral Medicine ; 31(2):148, 2023.
Article in English | EMBASE | ID: covidwho-2314215

ABSTRACT

Background: COVID-19 vaccines that expand immunity against emerging variants of concern (VOC) are needed to protect against ongoing viral evolution. We investigated the impact of boosting nonhuman primates pre-immune to the original WA-1 strain with updated VOC vaccines on the breadth and magnitude of mucosal and systemic antibody (Ab) and T cell (Tc) responses. Method(s): Cynomolgus macaques were primed with 2 doses of WA-1 Spike protein encoded by either an IL-12 adjuvanted DNA vaccine administered by gene gun (GG) or a self-amplifying RNA vaccine (repRNA) delivered intramuscularly (IM) with a cationic nanocarrier (LIONTM/IM, HDT Bio) or by GG (FIG 1). A booster dose was administered at week 17 with DNA or repRNA vaccines expressing B.1.351 (Beta) and B.1.617 (Delta) Spike receptor-binding domains (RBDs) fused to influenza HA2 stem domain (SHARP, designed by AIR/ JP) followed by a final Beta + Delta + WA-1 SHARP boost at week 34. Blood and bronchoalveolar lavages (BAL) were collected before and after each dose. Binding and neutralizing Ab to VOCs, including Omicron strains, were measured by ELISA and pseudovirus neutralization assays. Tc responses to Spike protein (WA-1 peptides) were measured by ELISpot. Immune responses were compared between groups and between blood vs lung using non-parametric statistical tests. Result(s): Two doses of WA-1 DNA or repRNA vaccines induced broad Ab against all VOC with the repRNA vaccine inducing the highest titers. Boosting with VOC SHARP significantly increased mucosal and systemic Ab responses against all VOCs tested including Omicron. After final boost, all groups had comparable binding and neutralization Ab titers and Tc responses regardless of method of delivery (GG or LIONTM/IM) or formulation (DNA or repRNA). Tc responses were significantly higher in the BAL vs PBMC after WA-1 Spike doses (p=0.0420) and VOC SHARP boosters (p=0.0009). Conclusion(s): The WA-1 strain primed for broad responses against VOCs that were significantly boosted with updated SHARP vaccines including responses against Omicron, even though this strain was not included in any dose. This suggests that sequential immunization with updated vaccines may broaden mucosal and systemic immunity against future VOCs. The repRNA vaccine initially induced the strongest responses, but there were no differences between RNA and DNA following additional booster doses, a result that supports development of a more cost-effective, room temperature stable DNA vaccine for worldwide boosters. (Figure Presented).

16.
European Journal of Operational Research ; 304(1):353-365, 2023.
Article in English | Web of Science | ID: covidwho-2309551

ABSTRACT

In this paper, a comprehensive production planning problem under uncertain demand is investigated. The problem intertwines two NP-hard optimization problems: an assembly line balancing problem and a capacitated lot-sizing problem. The problem is modelled as a two-stage stochastic program assuming a risk-averse decision maker. Efficient solution procedures are proposed for tackling the problem. A case study related to mask production is presented. Several insights are provided stemming from the COVID-19 pandemic. Finally, the results of a series of computational tests are reported. (c) 2021 Elsevier B.V. All rights reserved.

17.
Animal Production Science ; 2023.
Article in English | Web of Science | ID: covidwho-2308858

ABSTRACT

Context. Roots and leaves have potential as feed ingredients for poultry, but antinutritional factors (ANFs), high fibre and low energy may limit their efficient utilisation. There is need to improve processing methods and diet formulation for maximum utilisation of these readily available resources and reduce feed cost. Aim. To investigate the replacement of maize with cassava root, moringa leaf meal and vegetable oil blend in finisher broiler diets. Methods. In total, 160 male broiler chickens aged 30 days were weighed and allotted randomly to 20 deep litter pens containing eight birds of similar individual weight (1500 g +/- 16.11). Four broiler finisher iso-energetic and isonitrogenous diets were formulated for the experiment. Diet 1 was based on maize and in Diets 2, 3 and 4, 15%, 30% and 45% of maize was replaced respectively, by a concentrate of cassava root meal, moringa leaf meal and vegetable oil combination (CMOC). Each diet was given to five pens in a completely randomised design for a period of 12 days. Key results. There were no significant differences in the growth parameters of birds among treatments. Except for drumsticks of birds on the 30% CMOC diet, there were no significant effects of diet on carcass components or digestive organ weights (P > 0.05). Gizzard pH was higher in the control birds than in the test groups. Feed cost per kilogram of carcass weight was significantly (P < 0.05) lower with the dietary inclusion of CMOC. Conclusion. Replacing up to 30% of the maize with CMOC is beneficial and replacement up to 45% is not detrimental. However, the economic benefits of maize replacement with CMOC need to be re-evaluated with ingredient costings less affected by the present COVID-19 pandemic. Implications. Maximum utilisation of cassava root and moringa leaf meal in the diet will reduce cost and improve income of small-to medium-holder broiler producers.

18.
Transportation Research Record ; 2023.
Article in English | Web of Science | ID: covidwho-2311549

ABSTRACT

In China, a developing country, the car ownership level is much lower than that in developed countries, but transportation policies have been implemented to discourage car ownership and mitigate traffic congestion. However, car ownership (considered as car availability in this paper, meaning that an individual has access to a household private car) may influence travelers' well-being. To highlight the interrelation between car ownership and travelers' well-being, this paper develops a probit-based discrete-continuous model to analyze the relationship between car ownership and the duration of commuters' three major non-work outdoor activities (Act1: shopping and dining;Act2: leisure and entertainment;and Act3: visiting relatives or friends) in Xiaoshan District, Hangzhou, China. Empirical results indicate strong effects of individual and household socio-demographics, built environment attributes, and work-related characteristics on the car ownership decision and the duration of three non-work activities. The analysis shows positive correlations in unobserved factors between the car ownership decision and the duration of Acts1-3, indicating a mutually promotive relationship. Similarly, negative correlations among the duration of Acts1-3 show that non-work activities' duration is mutually substitutive. These findings will help to better understand commuters' car ownership decisions and non-work outdoor activity behavior restricted by fixed work schedules in developing countries, which can, in turn, better evaluate the impact of transportation policies (such as car ownership restriction) on travel demand as well as well-being, and provide decision support for the formulation of transportation policies.

19.
Pharmaceutical Technology ; 47(1):26-29 and 35, 2023.
Article in English | EMBASE | ID: covidwho-2293103
20.
Allergy: European Journal of Allergy and Clinical Immunology ; 78(Supplement 111):306, 2023.
Article in English | EMBASE | ID: covidwho-2293006

ABSTRACT

Background: Trometamol is an excipient present in radiological contrast media, antibiotic drugs such as fosfomycin, and some NSAIDs formulations (namely ketorolac and desketoprofen). Patients with previous hypersensitivity reactions to these drugs could be at a higher risk after the administration of a SARS-CoV- 2 vaccine formulation including trometamol (SARS/Trometamol vaccine) Method: Patients with a previous history of hypersensitivity reactions to drugs including trometamol as excipient, were sent to our Department for assessment, before receiving a SARS/Trometamol vaccine from December 2021 to January 2022 Allergic study included prick-tests with SARS/Trometamol vaccine and trometamol. According to skin-tests results, a controlled administration of SARS/ Trometamol vaccine was performed. Result(s): A total of 59 patients, 42 women (71.2%) and 17 men (28.8%), were included in our study, with a mean age of 57.3 years. Nineteen patients (32.2%) reported a previous history of hypersensitivity reactions to radiological contrast media, thirty-five patients (59.3%) had reacted to NSAIDS, and five patients had suffered reactions to both drug groups (8.5%) None of the studied patients showed a positive skin-test to neither SARS/Trometamol vaccine nor trometamol. Corresponding SARS/Trometamol vaccine doses were administered to all the patients, and no hypersensitivity reactions were observed. Conclusion(s): According to our results, a previous history of hypersensitivity reactions to drugs including trometamol does not seem to increase the allergic risk after the administration of a SARS-CoV- 2 vaccine formulation containing trometamol. Thus, it would not be necessary to perform an allergic study routinely previous to the vaccination of this kind of patients. However, since trometamol allergy is rather rare, more patients should be studied before this conclusion can be generalized.

SELECTION OF CITATIONS
SEARCH DETAIL