Residual Humoral Immunity Sustained Over Decades in a Cohort of Vaccinia-Vaccinated Individuals.

Serological testing of Singaporeans who received childhood smallpox vaccination found anti-vaccinia IgG binding and neutralizing activity indicating long-term humoral immunity. There was correlation between IgG and neutralizing titers indicating IgG could be used as a surrogate marker for humoral immunity. In 2019, Singapore experienced a case of imported monkeypox. As with smallpox, disease can be prevented through vaccination, which was mandatory for Singaporean infants until 1981. However, the degree of residual immunity in older vaccinated Singaporeans remains unknown. Sera from individuals born 1946-1984 were therefore tested and those born prior to 1981 were found to have higher anti-vaccinia IgG and neutralizing activity titers. This suggests that protective humoral immunity remains, which could reduce disease severity in an orthopoxvirus outbreak. Correlation between IgG and neutralizing titers was observed indicating that serology could be used as a surrogate marker for immunity.

Neural stem cell therapy of foetal onset hydrocephalus using the HTx rat as experimental model.

Foetal onset hydrocephalus is a disease starting early in embryonic life; in many cases it results from a cell junction pathology of neural stem (NSC) and neural progenitor (NPC) cells forming the ventricular zone (VZ) and sub-ventricular zone (SVZ) of the developing brain. This pathology results in disassembling of VZ and loss of NSC/NPC, a phenomenon known as VZ disruption. At the cerebral aqueduct, VZ disruption triggers hydrocephalus while in the telencephalon, it results in abnormal neurogenesis. This may explain why derivative surgery does not cure hydrocephalus. NSC grafting appears as a therapeutic opportunity. The present investigation was designed to find out whether this is a likely possibility. HTx rats develop hereditary hydrocephalus; 30-40% of newborns are hydrocephalic (hyHTx) while their littermates are not (nHTx). NSC/NPC from the VZ/SVZ of nHTx rats were cultured into neurospheres that were then grafted into a lateral ventricle of 1-, 2- or 7-day-old hyHTx. Once in the cerebrospinal fluid, neurospheres disassembled and the freed NSC homed at the areas of VZ disruption. A population of homed cells generated new multiciliated ependyma at the sites where the ependyma was missing due to the inherited pathology. Another population of NSC homed at the disrupted VZ differentiated into ßIII-tubulin+ spherical cells likely corresponding to neuroblasts that progressed into the parenchyma. The final fate of these cells could not be established due to the protocol used to label the grafted cells. The functional outcomes of NSC grafting in hydrocephalus remain open. The present study establishes an experimental paradigm of NSC/NPC therapy of foetal onset hydrocephalus, at the etiologic level that needs to be further explored with more analytical methodologies.

Catchment-scale Phosphorus Export through Surface and Drainage Pathways.

The site-specific nature of P fate and transport in drained areas exemplifies the need for additional data to guide implementation of conservation practices at the catchment scale. Total P (TP), dissolved reactive P (DRP), and total suspended solids (TSS) were monitored at five sites-two streams, two tile outlets, and a grassed waterway-in three agricultural subwatersheds (221.2-822.5 ha) draining to Black Hawk Lake in western Iowa. Median TP concentrations ranged from 0.034 to 1.490 and 0.008 to 0.055 mg P L for event and baseflow samples, respectively. The majority of P and TSS export occurred during precipitation events and high-flow conditions with greater than 75% of DRP, 66% of TP, and 59% of TSS export occurring during the top 25% of flows from all sites. In one subwatershed, a single event (annual recurrence interval < 1 yr) was responsible for 46.6, 84.0, and 81.0% of the annual export of TP, DRP, and TSS, respectively, indicating that frequent, small storms have the potential to result in extreme losses. Isolated monitoring of surface and drainage transport pathways indicated significant P and TSS losses occurring through drainage; over the 2-yr study period, the drainage pathway was responsible for 69.8, 59.2, and 82.6% of the cumulative TP, DRP, and TSS export, respectively. Finally, the results provided evidence that particulate P losses in drainage were greater than dissolved P losses. Understanding relationships between flow, precipitation, transport pathway, and P fraction at the catchment scale is needed for effective conservation practice implementation.

Simulated radiographic bone and joint modeling from 3D ankle MRI: feasibility and comparison with radiographs and 2D MRI.

PURPOSE: The purpose of this work is to simulate radiographs from isotropic 3D MRI data, compare relationship of angle and joint space measurements on simulated radiographs with corresponding 2D MRIs and real radiographs (XR), and compare measurement times among the three modalities. MATERIALS AND METHODS: Twenty-four consecutive ankles were included, eight males and 16 females, with a mean age of 46 years. Segmented joint models simulating radiographs were created from 3D MRI data sets. Three readers independently performed blinded angle and joint space measurements on the models, corresponding 2D MRIs, and XRs at two time points. Linear mixed models and the intraclass correlation coefficient (ICC) was ascertained, with p values less than 0.05 considered significant. RESULTS: Simulated radiograph models were successfully created in all cases. Good agreement (ICC > 0.65) was noted among all readers across all modalities and among most measurements. Absolute measurement values differed between modalities. Measurement time was significantly greater (p < 0.05) on 2D versus simulated radiographs for most measurements and on XR versus simulated radiographs (p < 0.05) for nearly half the measurements. CONCLUSIONS: Simulated radiographs can be successfully generated from 3D MRI data; however, measurements differ. Good inter-reader and moderate-to-good intra-reader reliability was observed and measurements obtained on simulated radiograph models took significantly less time compared to measurements with 2D and generally less time than XR.

Hospitalization costs for community-acquired pneumonia in Dutch elderly: an observational study.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the most common infections, especially in the elderly (≥65 years). The aim of this study was to quantify hospitalization costs for CAP in different age groups and in patients with different CAP risk profiles. Secondary objectives were to assess disease severity differences between placebo and vaccine receiving participants and identify cost driving factors of CAP in hospitalized elderly in the Netherlands. METHODS: This prospective cohort study of hospitalized CAP patients was executed in parallel to the Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA). Within the CAPiTA, a cohort of 84,496 subjects aged ≥65, all suspected CAP-episodes presenting in one of the 58 participating hospitals between September 2008 and August 2013 were included. CAP was diagnosed on clinical and radiographical criteria. Invasive pneumococcal disease (IPD) and non-IPD-CAP episodes, regardless of the causing pathogen, were evaluated separately. Costs were calculated by multiplying recorded healthcare resources with Dutch unit cost prices for the year 2012. Multivariate regression analysis was performed to identify cost drivers. RESULTS: In the sentinel hospitals 3225 suspected CAP and IPD episodes were included, of which 1933 were radiographically confirmed by chest X-ray. Analyses were conducted on confirmed CAP episodes only. Overall mean length of hospital stay was 12.1 days, the in-hospital mortality rate was 11.26 %, and mean costs were €8301 (95 % CI: €7760-€8999). When stratified in age-categories 65-74, 75-84 and ≥85, mean hospitalization costs were €8674, €8770 and €6197, respectively (p = 0.649). IPD-CAP and non-IPD-CAP mean hospitalization costs were €13,611 and €8081, respectively. Higher CURB-65 score and individuals at medium risk for developing pneumococcal disease were significantly associated with higher costs. Being male, lower age, previous admissions, lower risk, lower urbanity and higher socio-economic status were associated with lower costs. CONCLUSIONS: Mean hospitalization costs of a CAP subject were €8301 and higher for IPD-CAP compared to non-IPD-CAP cases. Medium risk patients and higher CURB-65 scores were identified as cost driving factors.

Cost-effectiveness of adult pneumococcal conjugate vaccination in the Netherlands.

The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands. Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65-74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted. The ICER for base-case was €8650 per QALY (95% CI 5750-17,100). Vaccination of high-risk individuals aged 65-74 years was cost-saving and extension to medium-risk individuals aged 65-74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100.PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries.

Semiconducting Graphene from Highly Ordered Substrate Interactions.

While numerous methods have been proposed to produce semiconducting graphene, a significant band gap has never been demonstrated. The reason is that, regardless of the theoretical gap formation mechanism, subnanometer disorder prevents the required symmetry breaking necessary to make graphene semiconducting. In this work, we show for the first time that semiconducting graphene can be made by epitaxial growth. Using improved growth methods, we show by direct band measurements that a band gap greater than 0.5 eV can be produced in the first graphene layer grown on the SiC(0001) surface. This work demonstrates that order, a property that remains lacking in other graphene systems, is key to producing electronically viable semiconducting graphene.

The role of phage display in therapeutic antibody discovery.

Phage display involves the expression of selected proteins on the surface of filamentous phage through fusion with phage coat protein, with the genetic sequence packaged within, linking phenotype to genotype selection. When combined with antibody libraries, phage display allows for rapid in vitro selection of antigen-specific antibodies and recovery of their corresponding coding sequence. Large non-immune and synthetic human libraries have been constructed as well as smaller immune libraries based on capturing a single individual's immune repertoire. This completely in vitro process allows for isolation of antibodies against poorly immunogenic targets as well as those that cannot be obtained by animal immunization, thus further expanding the utility of the approach. Phage antibody display represents the first developed methodology for high throughput screening for human therapeutic antibody candidates. Recently, other methods have been developed for generation of fully human therapeutic antibodies, such as single B-cell screening, next-generation genome sequencing and transgenic mice with human germline B-cell genes. While each of these have their particular advantages, phage display has remained a key methodology for human antibody discovery due its in vitro process. Here, we review the continuing role of this technique alongside other developing technologies for therapeutic antibody discovery.

The bottom-up growth of edge specific graphene nanoribbons.

The discovery of ballistic transport in graphene grown on SiC(0001) sidewall trenches has sparked an intense effort to uncover the origin of this exceptional conductivity. How a ribbon's edge termination, width, and topography influence its transport is not yet understood. This work presents the first structural and electronic comparison of sidewall graphene grown with different edge terminations. We show that armchair and zigzag terminated ribbons, grown from SiC, have very different topographies and interact differently with the substrate, properties that are critical to device architecture in sidewall ribbon electronics.

Wide-gap semiconducting graphene from nitrogen-seeded SiC.

All carbon electronics based on graphene have been an elusive goal. For more than a decade, the inability to produce significant band-gaps in this material has prevented the development of graphene electronics. We demonstrate a new approach to produce semiconducting graphene that uses a submonolayer concentration of nitrogen on SiC sufficient to pin epitaxial graphene to the SiC interface as it grows. The resulting buckled graphene opens a band gap greater than 0.7 eV in the otherwise continuous metallic graphene sheet.

Novel phage display-derived mycolic acid-specific antibodies with potential for tuberculosis diagnosis.

Tuberculosis is a major cause of mortality and morbidity due to infectious disease. However, current clinical diagnostic methodologies such as PCR, sputum culture, or smear microscopy are not ideal. Antibody-based assays are a suitable alternative but require specific antibodies against a suitable biomarker. Mycolic acid, which has been found in patient sputum samples and comprises a large portion of the mycobacterial cell wall, is an ideal target. However, generating anti-lipid antibodies using traditional hybridoma methodologies is challenging and has limited the exploitation of this lipid as a diagnostic marker. We describe here the isolation and characterization of four anti-mycolic acid antibodies from a nonimmune antibody phage display library that can detect mycolic acids down to a limit of 4.5ng. All antibodies were specific for the methoxy subclass of mycolic acid with weak binding for α mycolic acid and did not show any binding to closely related lipids or other Mycobacterium tuberculosis (Mtb) derived lipids. We also determined the clinical utility of these antibodies based on their limit of detection for mycobacteria colony forming units (CFU). In combination with an optimized alkaline hydrolysis method for rapid lipid extraction, these antibodies can detect 10(5) CFU of Mycobacterium bovis BCG, a close relative of Mtb and therefore represent a novel approach for the development of diagnostic assays for lipid biomarkers.

Biodiversity offsets and the challenge of achieving no net loss.

Businesses, governments, and financial institutions are increasingly adopting a policy of no net loss of biodiversity for development activities. The goal of no net loss is intended to help relieve tension between conservation and development by enabling economic gains to be achieved without concomitant biodiversity losses. biodiversity offsets represent a necessary component of a much broader mitigation strategy for achieving no net loss following prior application of avoidance, minimization, and remediation measures. However, doubts have been raised about the appropriate use of biodiversity offsets. We examined what no net loss means as a desirable conservation outcome and reviewed the conditions that determine whether, and under what circumstances, biodiversity offsets can help achieve such a goal. We propose a conceptual framework to substitute the often ad hoc approaches evident in many biodiversity offset initiatives. The relevance of biodiversity offsets to no net loss rests on 2 fundamental premises. First, offsets are rarely adequate for achieving no net loss of biodiversity alone. Second, some development effects may be too difficult or risky, or even impossible, to offset. To help to deliver no net loss through biodiversity offsets, biodiversity gains must be comparable to losses, be in addition to conservation gains that may have occurred in absence of the offset, and be lasting and protected from risk of failure. Adherence to these conditions requires consideration of the wider landscape context of development and offset activities, timing of offset delivery, measurement of biodiversity, accounting procedures and rule sets used to calculate biodiversity losses and gains and guide offset design, and approaches to managing risk. Adoption of this framework will strengthen the potential for offsets to provide an ecologically defensible mechanism that can help reconcile conservation and development. Balances de Biodiversidad y el Reto de No Obtener Pérdida Neta.

High island densities and long range repulsive interactions: Fe on epitaxial graphene.

The understanding of metal nucleation on graphene is essential for promising future applications, especially of magnetic metals which can be used in spintronics or computer storage media. A common method to study the grown morphology is to measure the nucleated island density n as a function of growth parameters. Surprisingly, the growth of Fe on graphene is found to be unusual because it does not follow classical nucleation: n is unexpectedtly high, it increases continuously with the deposited amount θ and shows no temperature dependence. These unusual results indicate the presence of long range repulsive interactions. Kinetic Monte Carlo simulations and density functional theory calculations support this conclusion. In addition to answering an outstanding question in epitaxial growth, i.e., to find systems where long range interactions are present, the high density of magnetic islands, tunable with θ, is of interest for nanomagnetism applications.

Estimate of colostral immunoglobulin G concentration using refractometry without or with caprylic acid fractionation.

Our objectives were to evaluate the use of refractometry as a means of estimating immunoglobulin G (IgG) concentration of bovine maternal colostrum (MC) and determine if fractionation of MC using caprylic acid (CA) improved estimates of IgG. Samples (n=85) of MC were collected from a single dairy in California and used to determine the method of CA fraction that produced the best prediction of IgG based on CA fractionation followed by refractometry. Subsequently, samples of MC (n=827) were collected from 67 farms in 12 states to compare refractometry with or without CA fractionation as methods to estimate IgG concentration. Samples were collected from the feeding pool and consisted of fresh (n=196), previously frozen (n=479), or refrigerated (n=152) MC. Samples were further classified by the number freeze-thaw cycles before analysis. Fractionation with CA was conducted by adding 1 mL of MC to a tube containing 75 µL of CA and 1 mL of 0.06 M acetic acid. The tube was shaken and allowed to react for 1 min. Refractive index of the IgG-rich supernatant (nDf) was determined using a digital refractometer. Whole, nonfractionated MC was analyzed for IgG by radial immunodiffusion (RID) and refractive index (nDw). The relationship between nDf and IgG (r=0.53; n=805) was weak, whereas that between nDw and IgG was stronger (r=0.73; n=823). Fresh samples analyzed by refractometry that subsequently went through 1 freeze-thaw cycle before RID analysis resulted in the strongest relationship between IgG and nDf or nDw (r=0.93 and 0.90, respectively). The MC samples collected fresh on the farm but frozen 2 or more times before analysis by refractometry or RID had low correlations between IgG and nDf and nDw (r=0.09 and 0.01). Samples refrigerated or frozen on the farm before analysis had weaker relationships between RID and nDf or nDw (r=0.38 to 0.80), regardless of the number of freeze-thaw cycles. Breed and lactation number did not affect the accuracy of either test. These results indicated that refractometry, without or with CA fractionation, was an accurate and rapid method to determine IgG concentration when samples of MC were not previously stored before refractometry and frozen only once before RID analysis.

Nationwide evaluation of quality and composition of colostrum on dairy farms in the United States.

The objective of this study was to characterize the quality of maternal colostrum (MC) fed to newborn dairy calves in the United States and identify the proportion of MC that meets industry standards for IgG concentration and total plate count (TPC). Samples of MC (n=827) were collected from 67 farms in 12 states between June and October 2010. Samples were collected from Holsteins (n=494), Jerseys (n=87), crossbred (n=7), and unidentified dairy cattle (n=239) from first (n=49), second (n=174), third or greater (n=128), and unknown (n=476) lactations. Samples were identified as fresh (n=196), refrigerated (n=152), or frozen (n=479) before collection, as well as whether the sample was from an individual cow (n=734) or pooled (n=93). Concentration of IgG in MC ranged from <1 to 200mg/mL, with a mean IgG concentration of 68.8 mg/mL (SD=32.8). Almost 30% of MC contained <50 mg of IgG/mL. The IgG concentration increased with parity (42.4, 68.6, and 95.9 mg/mL in first, second, and third and later lactations, respectively). No differences in IgG concentration were observed among breeds or storage method; however, IgG was highest in samples collected in the Midwest and lowest in samples collected in the Southwest (79.7 vs. 64.3 mg/mL). Total plate count of samples ranged from 3.0 to 6.8 log(10) cfu/mL, with a mean of 4.9 log(10) cfu/mL (SD=0.9) and was greater in samples collected in the Southeast compared with other regions of the country. Pooled samples had greater TPC than individual samples and refrigerated samples had greater TPC than frozen and fresh samples. Almost 43% of samples collected had TPC >100,000 cfu/mL, 16.9% of the samples had >1 million cfu/mL. Only 39.4% of the samples collected met industry recommendations for both IgG concentration and TPC. Almost 60% of MC on dairy farms is inadequate, and a large number of calves are at risk of failure of passive transfer or bacterial infections, or both. Also, the data indicate that regional differences exist in colostrum quality.

A 45-year-old female with hypokalemic rhabdomyolysis due to VIP-producing composite pheochromocytoma.

The watery diarrhea, hypokalemia and achlorhydria (WHDA) syndrome due to vasoactive intestinal polypeptide (VIP)-producing extra-pancreatic tumors is rare. We report on a 45-year-old woman who suffered from persistent secretory diarrhea for six years and who was admitted to hospital with complaints of muscular weakness and myalgia. Biochemical testing revealed pronounced rhabdomyolysis due to severe hypokalemia. Gastrointestinal evaluation of long-standing diarrhea including endoscopy of the upper and lower gastrointestinal tract and the small intestine did not show any pathologies. An abdominal computed tomography scan revealed a mass of 4 × 5 cm in the left adrenal gland demonstrating a strong uptake in the 123I-labelled metaiodobenzylguanidine scintigraphy. Plasma levels of chromogranin A, calcitonin, parathormone, basal renin and most prominently VIP were increased in line with a increased 24 hour urinary secretion of noradrenaline, dopamine, normetanephrine and vanillymandelic acid. A WDHA (watery diarrhea, hypokalaemia, achlorhydria) syndrome with hypokalemic rhabdomyolysis due to a VIP-producing adrenal tumor was diagnosed that was removed surgically. The histological evaluation demonstrated a composite pheochromocytoma. Diarrhea stopped immediately after surgery together with a normalization of laboratory parameters. In conclusion, this case report focuses on the rare clinical presentation of secretory diarrhea and electrolyte disturbances in combination with hypokalemic rhabdomyolysis which was caused by a VIP-producing composite pheochromocytoma.

Structural Brain Volumes of Individuals at Clinical High Risk for Psychosis: A Meta-analysis.

Background: Structural magnetic resonance imaging studies in individuals at clinical high risk (CHR) for psychosis have yielded conflicting results. Methods: The aims of this study were to compare intracranial and structural brain volumes and variability of CHR individuals with those of healthy control (HC) subjects and to investigate brain volume differences and variability in CHR subjects with and without transition to psychosis. The PubMed and Embase databases were searched for relevant studies published before June 1, 2020. Results: A total of 34 studies were deemed eligible, which included baseline data of 2111 CHR and 1472 HC participants. In addition, data were included for 401 CHR subjects who subsequently transitioned to psychosis and 1023 nontransitioned CHR participants. Whole-brain and left, right, and bilateral hippocampal volume were significantly smaller in CHR subjects than in HC subjects. Cerebrospinal fluid and lateral ventricle volumes were significantly larger in CHR subjects than in HC subjects. Variability was not significantly different in CHR subjects compared with HC subjects. CHR individuals with and without subsequent transition to psychosis did not show significant differences in any of the volumetric assessments or in variability. Conclusions: This meta-analysis demonstrates reduced whole-brain and hippocampal volumes and increased cerebrospinal fluid and lateral ventricle volumes in CHR individuals. However, no significant differences were observed in any of the volumetric assessments between CHR individuals with and without subsequent transition to psychosis. These findings suggest that although structural brain alterations are present before the onset of the disorder, they may not significantly contribute to the identification of CHR individuals at the highest risk for the development of psychosis.

Identifying key roles of the pharmacy technician in primary care settings.

PURPOSE: As the pharmacist's role expands, particularly in primary care practice settings, there is an opportunity for expansion of pharmacy technician duties to aid in administrative and clinical tasks that do not require the pharmacist's professional judgment. Identifying, defining, and expanding the roles of pharmacy technicians has been deemed a key part of the pharmacy practice model. These roles have been shown to enhance pharmacist efficiency and patient outreach; however, examples of the various innovative activities performed by technicians in the primary care setting are lacking in the literature. METHODS: The duties of primary care pharmacy technicians were compiled and defined in 2 different healthcare systems. The role of the technician was separately implemented at each institution, and study designs and protocols were individually created and executed. One institution utilized a 4-round consensus-building process to systematically refine and codify tasks for a dictionary of duties. The second institution utilized a free-text survey, task documentation data in the electronic medical record, and a telephone discussion with the technicians. RESULTS: Despite a lack of methods- and data-sharing between the 2 institutions, similar tasks were identified, including conducting patient outreach, assisting with medication affordability and access, providing patient education, managing referrals, and scheduling appointments. Differences in technician involvement were noted in areas such as prior authorization, care coordination meetings, and quality improvement projects. CONCLUSION: Pharmacy technicians are a helpful, yet underutilized, resource in the primary care setting. Further exploration of technician roles is needed to determine the financial and clinical impact of expanding these roles.

IDentif.AI-Omicron: Harnessing an AI-Derived and Disease-Agnostic Platform to Pinpoint Combinatorial Therapies for Clinically Actionable Anti-SARS-CoV-2 Intervention.

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested in vitro against a live B.1.1.529 (Omicron) virus first in monotherapy and then in 50 strategic combinations designed to interrogate the interaction space of 729 possible combinations. Key findings and interactions were then further explored and validated in an additional experimental round using an expanded concentration range. Overall, we found that few of the tested drugs showed moderate efficacy as monotherapies in the actionable concentration range, but combinatorial drug testing revealed significant dose-dependent drug-drug interactions, specifically between EIDD-1931 and YH-53, as well as nirmatrelvir and YH-53. Checkerboard validation analysis confirmed these synergistic interactions and also identified an interaction between EIDD-1931 and favipiravir in an expanded range. Based on the platform nature of IDentif.AI, these findings may support further explorations of the dose-dependent drug interactions between different drug classes in further pre-clinical and clinical trials as possible combinatorial therapies consisting of unmodified and nanomedicine-enabled drugs, to combat current and future COVID-19 strains and other emerging pathogens.