The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens.
Ontology highlight
ABSTRACT:
SUBMITTER: Blasiak A
PROVIDER: S-EPMC9244889 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background: Current standard of care (SOC) regimens against nontuberculous mycobacteria (NTM) usually result in unsatisfactory therapeutic responses, primarily due to multi-drug resistance and antibiotic susceptibility-guided therapies. In the midst of rising incidences in NTM infections, strategies to develop NTM-specific treatments have been explored and validated. Methods: To provide an alternative approach to address NTM-specific treatment, IDentif.AI was harnessed to rapidly optimize and design effective combination therapy regimens against Mycobacterium abscessus (M. abscessus), the highly resistant and rapid growth species of NTM. IDentif.AI interrogated the drug interaction space from a pool of 6 antibiotics, and pinpointed multiple clinically actionable drug combinations. IDentif.AI-pinpointed actionable combinations were experimentally validated and their interactions were assessed using Bliss independence model and diagonal measurement of n-way drug interactions. Results: Notably, IDentfi.AI-designed 3- and 4-drug combinations demonstrated greater %Inhibition efficacy than the SOC regimens. The platform also pinpointed two unique drug interactions (Levofloxacin (LVX)/Rifabutin (RFB) and LVX/Meropenem (MEM)) that may serve as the backbone of potential 3- and 4-drug combinations like LVX/MEM/RFB, which exhibited 58.33±4.99 %Inhibition efficacy against M. abscessus. Further analysis of LVX/RFB via Bliss independence model pointed to dose-dependent synergistic interactions in clinically actionable concentrations. Conclusions: IDentif.AI-designed combinations may provide alternative regimen options to current SOC combinations that are often administered with Amikacin, which has been known to induce ototoxicity in patients. Furthermore, IDentif.AI pinpointed 2-drug interactions may also serve as the backbone for the development of other effective 3- and 4-drug combination therapies. The findings in this study suggest that this platform may contribute to NTM-specific drug development.
| S-EPMC9576615 | biostudies-literature
Project description:MotivationPlatform designs - master protocols that allow for new treatment arms to be added over time - have gained considerable attention in recent years. Between 2001 and 2019, 16 platform trials were initiated globally. The COVID-19 pandemic seems to have provided a new motivation for these designs. We conducted a rapid review to quantify and describe platform trials used in COVID-19.MethodsWe cross-referenced PubMed, ClinicalTrials.gov, and the Cytel COVID-19 Clinical Trials Tracker to identify platform trials, defined by their stated ability to add future arms.ResultsWe identified 58 COVID-19 platform trials globally registered between January 2020 and May 2021. According to trial registries, 16 trials have added new therapies (median 3, IQR 4) and 11 have dropped arms (median 3, IQR 2.5). About 50% of trials publicly share their protocol, and 31 trials (53%) intend to share trial data. Forty-nine trials (84%) explicitly report adaptive features, and 21 trials (36%) state Bayesian methods.ConclusionsDuring the pandemic, there has been a surge in the number of platform trials compared to historical use. While transparency in statistical methods and clarity of data sharing policies needs improvement, platform trials appear particularly well-suited for rapid evidence generation. Trials secured funding quickly and many succeeded in adding new therapies in a short time period, thus demonstrating the potential for these trial designs to be implemented beyond the pandemic. The evidence gathered here may provide ample insight to further inform operational, statistical, and regulatory aspects of future platform trial conduct.
| S-EPMC8591985 | biostudies-literature
Project description:The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.
| S-EPMC5287291 | biostudies-literature
Project description:Radiation therapy (RT) is widely used with curative or palliative intent in the clinical management of multiple cancers. Although mainly aimed at direct tumor cell killing, mounting evidence suggests that radiation can alter the tumor to become an immunostimulatory milieu. Data suggest that the immunogenic effects of radiation can be exploited to promote synergistic antitumor effects in combination with immunotherapeutic agents. We review concepts associated with the immunogenic consequences of RT and highlight how preclinical findings are translating into clinical benefit for patients receiving combination regimens of RT and therapeutic cancer vaccines.
| S-EPMC4258617 | biostudies-other
Project description:Oral feeding competency is a major determinant of length of stay in the neonatal intensive care unit. An infant must be able to consistently demonstrate the ability to take all required enteral nutrition by mouth before discharge home. Most infants born prematurely (<37?weeks) will require days, if not weeks, to master this oral feeding competency skill. Inappropriately timed feeding attempts can lead to acute and long-term morbidities, prolonged hospitalizations, and increased health-care costs. Previously, a panel of five genes involved in essential developmental pathways including sensory integration (nephronophthisis 4, Plexin A1), hunger signaling [neuropeptide Y2 receptor (NPY2R), adenosine-monophosphate-activated protein kinase (AMPK)], and facial development (wingless-type MMTV integration site family, member 3) required for oral feeding success were identified in neonatal saliva. This study aimed to translate these five transcriptomic biomarkers into a rapid proteomic platform to provide objective, real-time assessment of oral feeding skills, to better inform care, and to improve neonatal outcomes. Total protein was extracted from saliva of 10 feeding-successful and 10 feeding-unsuccessful infants matched for age, sex, and post-conceptional age. Development of immunoassays was attempted for five oral feeding biomarkers and two reference biomarkers (GAPDH and YWHAZ) to normalize for starting protein concentrations. Normalized protein concentrations were correlated to both feeding status at time of sample collection and previously described gene expression profiles. Only the reference proteins and those involved in hunger signaling were detected in neonatal saliva at measurable levels. Expression patterns for NPY2R and AMPK correlated with the gene expression patterns previously seen between successful and unsuccessful feeders and predicted feeding outcome. Salivary proteins associated with hunger signaling are readily quantifiable in neonatal saliva and may be utilized to assess oral feeding readiness in the newborn. This study lays the foundation for the development of an informative, rapid, proteomic platform to assess neonatal oral feeding maturation.
| S-EPMC5733069 | biostudies-literature
Project description:The unsatisfactory outcomes of typical multiple cytotoxic chemotherapeutic combination therapies used to treat patients have fostered a need for new unconventional combinations of therapeutic agents. Among the candidates, siRNA has been widely discussed and tested. However, the right time right place codelivery of siRNA with other types of active ingredients is challenging because of the possible differences among their physiochemical and pharmacodynamics properties. To accomplish a synergistic cytotoxic effect, a nanoassembly is thus designed to codeliver siRNA with other therapeutic agents. A siRNA, targeting prosurvival gene for the p75 neurotrophin receptor, and an organelle-fusing peptide, targeting mitochondria, are layered onto a nanotemplate by charge-charge interaction, followed by a layer of CD44 targeting ligand. The formulated triple-functional nanomedicine is efficiently internalized by the CD44 expressing triple-negative breast cancer cells. The encapsulated siRNA and the pro-apoptotic peptide are released inside cells, silencing the intended prosurvival gene, and inducing apoptosis by fusing the mitochondrial membrane, respectively. A synergistic effect is achieved by this three-agent combination. The design of the developed multifunctional nanomedicine can be generalized to deliver other siRNA and drugs for a maximum therapeutic combination with minimal off-targeting effects.
| S-EPMC5310967 | biostudies-literature
Project description:Combination therapy, where two or more therapeutic agents are combined to target different cellular pathways, is an effective tool in cancer treatment but often difficult to execute. Here we present the collagen peptide-based platform that allows for synchronous and colocalized cellular delivery of three different agents. The peptide is a hybrid between collagen and cell penetrating peptide (CPP) that assembles into a heterotrimer helix and forms fully organic, high aspect ratio nanoparticles. The validity of the approach was tested with three chemically different agents (Paclitaxel, Doxorubicin, and 5-Fluorouracil; a combination used in clinical treatment of (ER)-positive and (PR)-positive breast cancer) conjugated to N-terminus of the peptide. The design of this peptide-based drug delivery system provides several advantages: it avoids drug loading problems; removes the need for orthogonal synthesis; and allows for colocalized delivery of up to three drugs (which leads to the same biodistribution for each drug). In addition, hybrid collagen/CPP peptides are known to enhance cellular uptake and improve solubility of drugs. The synergistic effect, in terms of enhanced efficacy, of the Paclitaxel-Doxorubicin-5-Fluorouracil combination was also calculated. We envision self-assembling peptides as a platform for drug codelivery that can be expanded into a library of personalized combinations that may also include other functionalities like targeting or imaging.
| S-EPMC10247525 | biostudies-literature
Project description:A key public health question during any disease outbreak when limited vaccine is available is who should be prioritized for early vaccination. Most vaccine prioritization analyses only consider variation in risk of infection and death by a single risk factor, such as age. We provide a more granular approach with stratification by demographics, risk factors, and location. We use this approach to compare the impact of different COVID-19 vaccine prioritization strategies on COVID-19 cases, deaths and disability-adjusted life years (DALYs) over the first 6 months of vaccine rollout, using California as a case example. We estimate the proportion of cases, deaths and DALYs averted relative to no vaccination for strategies prioritizing vaccination by a single risk factor and by multiple risk factors (e.g. age, location). When targeting by a single risk factor, we find that age-based targeting averts the most deaths (62% for 5 million individuals vaccinated) and DALYs (38%) and targeting essential workers averts the least deaths (31%) and DALYs (24%) over the first 6 months of rollout. However, targeting by two or more risk factors simultaneously averts up to 40% more DALYs. Our findings highlight the potential value of multiple-risk-factor targeting of vaccination against COVID-19 and other infectious diseases, but must be balanced with feasibility for policy.
| S-EPMC8866501 | biostudies-literature
Project description:The worldwide impact of the coronavirus disease 2019 (COVID-19) pandemic is unprecedented. Among the aerosol generating procedures, bronchoscopy in particular is an indispensable diagnostic and therapeutic tool that comes with a high risk of infection. Therefore, national societies have issued guidance statements. However, the individual ability of bronchoscopy units to follow these recommendations is largely unknown. We conducted a nationwide survey from 1 April 2020 to 7 April 2020 to which 218 German endoscopy units, 105 solely bronchoscopy and 113 interdisciplinary, responded. The survey was distributed electronically via the German Respiratory Society. While 17% of units did not cancel any interventions, 16% cancelled >80% of their interventions. 73% were unable to completely separate high-risk patients. Most procedural measures, such as risk stratification in patients (95%), training to handle COVID-19 patients and personal protective equipment (PPE) (91%), risk adapted use of PPE (85%) and self-monitoring for staff (84%) were adopted well. Unit managers expected shortages in PPE (74%), staff shortages (68%) and severe financial losses (63%). In the short-term, PPE shortages are perceived to be the most imminent threat to bronchoscopic activity as a whole. In this era of uncertainty, sound evidence to guide bronchoscopy units and an international concerted effort are urgently needed to formulate recommendations on facts and adapted to local conditions as described in this study.
| S-EPMC7456647 | biostudies-literature
Project description:BackgroundThe novel coronavirus disease (COVID-19) is a life-threatening illness, which represents a challenge to all health care workers. Neurosurgeons worldwide are affected in different ways.ObjectiveThis is the first study regarding the readiness of neurosurgery residents for the COVID-19 pandemic and its impact. The aim is to identify the level of knowledge and readiness and the impact of this virus among neurosurgery residents in different programs.MethodsA cross-sectional analysis was performed in which 52 neurosurgery residents from different centers were selected to complete a questionnaire-based survey. The questionnaire comprised 3 sections and 27 questions that ranged from knowledge to impact of the pandemic on various features.ResultsThe median knowledge score was 4 out of 5. The proportion of participants with a satisfactory level of knowledge was 60%. There was a statistically significant difference between the knowledge score and location of the program. Around 48% of the neurosurgery residents dealt directly with patients with COVID-19. Receiving a session about personal protective equipment was reported by 57.7%. Neurosurgery training at the hospital was affected. About 90% believed that this pandemic had influenced their mental health.ConclusionsNeurosurgery residents have a relatively good knowledge about COVID-19. The location of the program was associated with knowledge level. Most participants did not receive sufficient training about personal protective equipment. Almost all responders agreed that their training at the hospital had been affected. Further studies are needed to study the impact of this pandemic on neurosurgery residents.
| S-EPMC7229445 | biostudies-literature