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Hypoxia-responsive prodrug of ATR inhibitor, AZD6738, selectively eradicates treatment-resistant cancer cellsTargeted therapy remains the future of anti-cancer drug development, owing to the lack of specificity of current treatments which lead to damage in healthy normal tissues. ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility. Here, ICT10336 is reported, a newly developed hypoxia-responsive prodrug of ATR inhibitor, AZD6738, which is hypoxia-activated and specifically releases AZD6738 only in hypoxic conditions, in vitro. This hypoxia-selective release of AZD6738 inhibited ATR activation (T1989 and S428 phosphorylation) and subsequently abrogated HIF1a-mediated adaptation of hypoxic cancers cells, thus selectively inducing cell death in 2D and 3D cancer models. Importantly, in normal tissues, ICT10336 is demonstrated to be metabolically stable and less toxic to normal cells than its active parent agent, AZD6738. In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor-targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index.
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Molecular basis of transport of surface functionalised gold nanoparticles to pulmonary surfactantLigands like alkanethiol (e.g. dodecanethiol, hexadecanethiol, etc.) and polymers (e.g. poly(vinyl pyrrolidone), polyethylene glycol-thiol) capped to the gold nanoparticles (AuNPs) are widely used in biomedical field as drug carriers and as promising materials for probing and manipulating cellular processes. Ligand functionalised AuNPs are known to interact with the pulmonary surfactant (PS) monolayer once reaching the alveolar region. Therefore, it is crucial to understand the interaction between AuNPs and PS monolayers. Using coarse-grained molecular dynamics simulations, the effect of ligand density, and ligand length have been studied for two classes of ligands on a PS model monolayer consisting of DPPC, POPG, cholesterol and SP-B (mini-peptide). The ligands considered in this study are alkanethiol and polyethylene glycol (PEG) thiol as examples of hydrophobic and hydrophilic ligands, respectively. It was observed that the interaction between AuNPs and PS changes the biophysical properties of PS monolayer in compressed and expanded states. The AuNPs with hydrophilic ligand, can penetrate through the monolayer more easily, while the AuNPs with hydrophobic ligand are embedded in the monolayer and participated in deforming the monolayer structure particularly the monolayer in the compressed state. The bare AuNPs hinder to lower the monolayer surface tension value at the interface, however introducing ligand to the bare AuNPs or increasing the ligand length and density have an impact of lowering of monolayer surface tension to a minor extent. The simulation results guide the design of ligand protected NPs as drug carriers and can identify the nanoparticles' potential side effects on lung surfactant.
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Structure and diffusive dynamics of aspartate α-decarboxylase (ADC) liganded with d-serine in aqueous solutionIncoherent neutron spectroscopy, in combination with dynamic light scattering, was used to investigate the effect of ligand binding on the center-of-mass self-diffusion and internal diffusive dynamics of Escherichia coli aspartate α-decarboxylase (ADC). The X-ray crystal structure of ADC in complex with the D-serine inhibitor was also determined, and molecular dynamics simulations were used to further probe the structural rearrangements that occur as a result of ligand binding. These experiments reveal that D-serine forms hydrogen bonds with some of the active site residues, that higher order oligomers of the ADC tetramer exist on ns–ms time-scales, and also show that ligand binding both affects the ADC internal diffusive dynamics and appears to further increase the size of the higher order oligomers.
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Maleimide-thiol linkages alter the biodistribution of SN38 therapeutic microbubbles compared to biotin-avidin while preserving parity in tumoral drug deliveryTherapeutic microbubbles (thMBs) contain drug-filled liposomes linked to microbubbles and targeted to vascular proteins. Upon the application of a destructive ultrasound trigger, drug uptake to tumour is improved. However, the structure of thMBs currently uses powerful non-covalent bonding of biotin with avidin-based proteins to link both the liposome to the microbubble (MB) and to bind the targeting antibody to the liposome-MB complex. This linkage is not currently FDA-approved, and therefore, an alternative, maleimide-thiol linkage, that is currently used in antibody-drug conjugates was examined. In a systematic manner, vascular endothelial growth factor receptor 2 (VEGFR2)-targeted MBs and thMBs using both types of linkages were examined for their ability to specifically bind to VEGFR2 in vitro and for their ultrasound imaging properties in vivo. Both showed equivalence in the production of the thMB structure, in vitro specificity of binding and safety profiles. In vivo imaging showed subtle differences for thMBs where biotin thMBs had a faster wash-in rate than thiol thMBs, but thiol thMBs were longer-lived. The drug delivery to tumours was also equivalent, but interestingly, thiol thMBs altered the biodistribution of delivery away from the lungs and towards the liver compared to biotin thMBs, which is an improvement in biosafety.
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APOE genotype, eicosapentaenoic acid (EPA) supplementation and n-3 highly unsaturated fatty acid (HUFA) levels in patients with multiple colorectal polyps: A secondary analysis of the seAFOod polyp prevention trialIntroduction: We examined the relationship between Apolipoprotein E (APOE) genotype and n-3 highly unsaturated fatty acid (HUFA) levels in participants of the seAFOod trial, who were undergoing colonoscopy surveillance after removal of colorectal polyps. Methods: Baseline and on-treatment (eicosapentaenoic acid [EPA] 2 g daily or placebo for 6 months) levels of n-3 HUFAs, and plasma 18-hydroxyeicosapentaenoic acid (HEPE), were analysed according to APOE genotype (based on polymorphisms rs429358 and rs7412) in 584 participants. Results: Before treatment, APOE2/2 individuals had lower levels, and APOE4/4 participants had higher levels, of n-3 HUFAs, including EPA, than APOE3/3 counterparts (P < 0.01 for the APOE2/2 versus APOE4/4 comparison). After EPA supplementation, n-3 HUFA levels were not significantly different when stratified by APOE genotype, although APOE4 carriers displayed lower plasma 18-HEPE levels than individuals without an APOE4 allele (P = 0.002). Conclusions: APOE genotype is associated with differential n-3 HUFA and 18-HEPE levels in individuals with multiple colorectal polyps.
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Physiologically-obtainable polyphenol exposures modulate reactive oxygen and nitrogen species signaling in the C2C12 model of skeletal muscle ageingAge-related frailty is a significant health and social care burden, with limited treatment options. There is a lack of suitable cell culture model for screening large numbers of test compounds to identify those which promote healthy skeletal muscle function. This paper describes the characterization of reactive oxygen and nitrogen species (RONS) signalling changes in young and aged myoblasts and myotubes using C2C12 cells, and the application of aged cultures to assess the effect of dietary polyphenols on RONS signalling. Aged myoblasts and myotubes showed significantly increased reactive oxygen species (p < 0.01 and p < 0.001 respectively), nitric oxide (p < 0.05 for myoblasts and myotubes), and lipid peroxidation (p < 0.05 for myoblasts and myotubes). Nine polyphenols were assessed in aged myoblasts and myotubes using concentrations and incubation times consistent with known pharmacokinetic parameters for these compounds. Although several polyphenols were seen to reduce single markers of RONS signalling, only kaempferol and resveratrol significantly reduced multiple markers in both cell models. Modulation of enzymatic antioxidant activities was assessed as a possible mechanism of action, although superoxide dismutase and catalase activities were significantly reduced in aged (versus young) myotubes (p < 0.01 and p < 0.05 respectively), no effect of polyphenol treatment on these enzyme activities were observed. Overall, this research has shown the utility of the C2C12 model (myoblasts and myotubes) for screening compounds in aged muscle, and that resveratrol and kaempferol (using pharmacokinetically-informed exposures) can modulate RONS signalling in skeletal muscle cells after an acute exposure.
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Physical activity level and stroke risk in US population: A matched case–control study of 102,578 individualsBackground: Stroke has been linked to a lack of physical activity; however, the extent of the association between inactive lifestyles and stroke risk has yet to be characterized across large populations. Purpose: This study aimed to explore the association between activity-related behaviors and stroke incidence. Methods: Data from 1999 to 2018 waves of the concurrent cross-sectional National Health and Nutrition Examination Survey (NHANES) were extracted. We analyzed participants characteristics and outcomes for all participants with data on whether they had a stroke or not and assessed how different forms of physical activity affect the incidence of disease. Results: Of the 102,578 individuals included, 3851 had a history of stroke. A range of activity-related behaviors was protective against stroke, including engaging in moderate-intensity work over the last 30 days (OR = 0.8, 95% CI = 0.7–0.9; P = 0.001) and vigorous-intensity work activities over the last 30 days (OR = 0.6, 95% CI = 0.5–0.8; P < 0.001), and muscle-strengthening exercises (OR = 0.6, 95% CI = 0.5–0.8; P < 0.001). Conversely, more than 4 h of daily TV, video, or computer use was positively associated with the likelihood of stroke (OR = 11.7, 95% CI = 2.1–219.2; P = 0.022). Conclusion: Different types, frequencies, and intensities of physical activity were associated with reduced stroke incidence, implying that there is an option for everyone. Daily or every other day activities are more critical in reducing stroke than reducing sedentary behavior duration.
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Genetically engineered multicistronic allele of Pmel yielding highly specific CreERT2-mediated recombination in the melanocyte lineageGenetic approaches that allow lineage tracing are essential to our future understanding of melanocytes and melanoma. To date, the approaches used to label melanocytes in mice have relied on random integration of transgenes driven by the promoters of the Tyrosinase and Dopachrome tautomerase genes, knock-in to the Dopachrome tautomerase locus or knock-in to the Mlana locus in a bacterial artificial chromosome. These strategies result in expression in other tissues such as telencephalon and other cell types such as nerves. Here we used homologous recombination in mouse embryonic stem cells to generate a targeted multicistronic allele of the Pmel locus that drives melanocyte-specific expression of CreERT2, nuclear localised H2B-Cerulean and membrane localised marcks-mKate2 allowing live imaging of melanocytes and activation of other conditional alleles. We combined this allele with R26R-EYFP mice allowing induction of EYFP expression on administration of tamoxifen or its metabolite 4-OHT. The fluorescent proteins H2B-Cerulean and marcks-mKate2 label the cell nucleus and plasma membrane respectively allowing live imaging and FACS isolation of melanoblasts and melanocytes as well as serving to provide an internal control allowing estimation of recombination efficiency after administration of tamoxifen. We demonstrate the utility of the transgene in embryonic and adult tissues.
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Artificial Interpretation: An investigation into the feasibility of archaeologically focused seismic interpretation via machine learningThe value of artificial intelligence and machine learning applications for use in heritage research is increasingly appreciated. In specific areas, notably remote sensing, datasets have increased in extent and resolution to the point that manual interpretation is problematic and the availability of skilled interpreters to undertake such work is limited. Interpretation of the geophysical datasets associated with prehistoric submerged landscapes is particularly challenging. Following the Last Glacial Maximum, sea levels rose by 120 m globally, and vast, habitable landscapes were lost to the sea. These landscapes were inaccessible until extensive remote sensing datasets were provided by the offshore energy sector. In this paper, we provide the results of a research programme centred on AI applications using data from the southern North Sea. Here, an area of c. 188,000 km2 of habitable terrestrial land was inundated between c. 20,000 BP and 7000 BP, along with the cultural heritage it contained. As part of this project, machine learning tools were applied to detect and interpret features with potential archaeological significance from shallow seismic data. The output provides a proof-of-concept model demonstrating verifiable results and the potential for a further, more complex, leveraging of AI interpretation for the study of submarine palaeolandscapes.
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Modelling the Logistics of MantzikertThe Battle of Mantzikert had profound consequences for both Byzantine and Turkish history, yet the historical sources for this campaign contain significant gaps. This book presents the results of a project that seeks to demonstrate the important role computer simulation can play in the analysis of pre-modern military logistics. In AD 1071, the Byzantine Emperor, Romanos IV Diogenes, set out from Constantinople for the eastern borders of his Empire with an army described as “more numerous than the sands of the sea”. His military campaign culminated in defeat by the Seljuk Sultan Alp Arslan at the Battle of Mantzikert. This defeat was to have profound consequences for both Byzantine and Turkish history and is still commemorated in the modern state of Turkey. Yet the historical sources for this campaign contain significant gaps and we know more about the political intrigues surrounding the emperor than we do about how the army moved and fed itself. The ‘Medieval Warfare on the Grid’ project (2007-2011) was funded by an AHRC-EPSRC-Jisc e-Science grant and set out to use computer simulation to shed new light on the Mantzikert campaign. In this book we present the results of the project and demonstrate that computer simulation has an important role to play in the analysis of pre-modern military logistics. It can give new context to historical sources, present new options for the interpretation of past events and enable questions of greater complexity to be asked of historical military campaigns. It can also highlight the similarities that exist across time and space when armies need to be mobilised, moved and fed.
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Polymer Conformation Determination by NMR Spectroscopy: Comparative Diffusion Ordered 1H-NMR Spectroscopy of Poly(2-Ethyl-2-Oxazoline)s and Poly(Ethylene Glycol) in D2ODiffusion ordered 1H-NMR spectroscopy (DOSY) is a useful, non-destructive technique for analysing polymer hydrodynamic size and intrinsic/solution viscosity. However, to date there has been no investigation of DOSY under variable temperature conditions that allow trends in polymer conformation to be determined. Poly(2-ethyl-2-oxazoline) (P(EtOx)) is a hydrophilic polymer that has the potential to replace poly(ethylene glycol) (PEG) in biomedical applications. Applying DOSY to a series of narrow-distribution P(EtOx) revealed that the apparent hydrodynamic radii scaled with molecular weight as expected. By altering the temperature of the solution the trends in Flory-type exponents were determined, enabling the determination of the power laws related to the coil-globule conformation of linear polymers directly from NMR data. These measurements were complicated by the onset of convection currents at higher temperatures, which impose a limit to the effective measurement range of ca. 10–35 °C. It was revealed that P(EtOx) had a more expanded random coil conformation than PEG, and it trended towards θ conditions at the lower critical solution temperature. In comparison, PEG was approximately in θ-conditions at room-temperature. This shows the use, and limitations of DOSY in polymer conformation analysis, and applies it to P(EtOx), a polymer which has not been analysed in this manner before.
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A Method for Estimation of Plasma Protein Binding Using Diffusion Ordered NMR Spectroscopy (DOSY)The plasma protein binding (PPB) of a drug plays a key role in both its pharmacokinetic and pharmacodynamic properties. During lead optimisation, medium and high throughput methods for the early determination of PPB can provide important information about potential PKPD profile within a chemotype or between different chemotype series. Diffusion ordered spectroscopy (DOSY) is an NMR spectroscopic technique that measures the diffusion of a molecule via applying varying magnetic field gradients, where the diffusion is primarily affected by its molecular size/weight and solution viscosity. Here, we describe the use of DOSY for a rapid and straight forward method to evaluate the PPB of drug molecules, using their binding to bovine serum albumin (BSA) as a model.
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Effect of high-fat diet on isometric, concentric and eccentric contractile performance of skeletal muscle isolated from female CD-1 miceDespite evidence inferring muscle and contractile mode-specific effects of high-fat diet (HFD), no study has yet considered the impact of HFD directly on eccentric muscle function. The present work uniquely examined the effect of 20-week HFD on the isometric, concentric and eccentric muscle function of isolated mouse soleus (SOL) and extensor digitorum longus (EDL) muscles. CD-1 female mice were randomly split into a control (n = 16) or HFD (n = 17) group and for 20 weeks consumed standard lab chow or HFD. Following this period, SOL and EDL muscles were isolated and assessments of maximal isometric force and concentric work loop (WL) power were performed. Each muscle was then subjected to either multiple concentric or eccentric WL activations. Post-fatigue recovery, as an indicator of incurred damage, was measured via assessment of concentric WL power. In the EDL, absolute concentric power and concentric power normalised to muscle mass were reduced in the HFD group (P < 0.038). HFD resulted in faster concentric fatigue and reduced eccentric activity-induced muscle damage (P < 0.05). For the SOL, maximal isometric force was increased, and maximal eccentric power normalised to muscle mass and concentric fatigue were reduced in the HFD group (P < 0.05). HFD effects on eccentric muscle function are muscle-specific and have little relationship with changes in isometric or concentric function. HFD has the potential to negatively affect the intrinsic concentric and eccentric power-producing capacity of skeletal muscle, but a lack of a within-muscle uniform response indicates disparate mechanisms of action which require further investigation.
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The Effects of Muscle Starting Length on Work Loop Power Output of Isolated Mouse Soleus and Extensor Digitorum Longus MuscleForce–length relationships derived from isometric activations may not directly apply to muscle force production during dynamic contractions. As such, different muscle starting lengths between isometric and dynamic conditions could be required to achieve maximal force and power. Therefore, this study examined the effects of starting length [±5–10% of length corresponding to maximal twitch force (L0)] on work loop (WL) power output (PO), across a range of cycle frequencies, of the soleus (SOL) and extensor digitorum longus muscle (EDL; N=8–10) isolated from ∼8 week old C57 mice. Furthermore, passive work was examined at a fixed cycle frequency to determine the association of passive work and active net work. Starting length affected maximal WL PO of the SOL and EDL across evaluated cycle frequencies (P0.494). For the SOL, PO produced at −5% L0 was greater than that at most starting lengths (P0.6), except −10% L0 (P=0.135, d1.08), except versus −5% L0 (P=0.124, d0.163, d<1.04). For the SOL, higher passive work was associated with reduced PO (Spearman's r=0.709, P<0.001), but no relationship was observed between passive work and PO of the EDL (Pearson's r=0.191, r2=0.04, P=0.184). This study suggests that starting length should be optimised for both static and dynamic contractions and confirms that the force–length curve during dynamic contractions is muscle specific.
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Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment EfficacyMetastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-β signalling. In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-β pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.
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The Galaxy platform for accessible, reproducible, and collaborative data analyses: 2024 updateGalaxy (https://galaxyproject.org) is deployed globally, predominantly through free-to-use services, supporting user-driven research that broadens in scope each year. Users are attracted to public Galaxy services by platform stability, tool and reference dataset diversity, training, support and integration, which enables complex, reproducible, shareable data analysis. Applying the principles of user experience design (UXD), has driven improvements in accessibility, tool discoverability through Galaxy Labs/subdomains, and a redesigned Galaxy ToolShed. Galaxy tool capabilities are progressing in two strategic directions: integrating general purpose graphical processing units (GPGPU) access for cutting-edge methods, and licensed tool support. Engagement with global research consortia is being increased by developing more workflows in Galaxy and by resourcing the public Galaxy services to run them. The Galaxy Training Network (GTN) portfolio has grown in both size, and accessibility, through learning paths and direct integration with Galaxy tools that feature in training courses. Code development continues in line with the Galaxy Project roadmap, with improvements to job scheduling and the user interface. Environmental impact assessment is also helping engage users and developers, reminding them of their role in sustainability, by displaying estimated CO2 emissions generated by each Galaxy job.
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Proportion of Antipsychotics with CYP2D6 Pharmacogenetic (PGx) Associations Prescribed in an Early Intervention in Psychosis (EIP) Cohort: A Cross-Sectional StudyBackground: Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual’s genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual’s genetics, particularly psychosis drugs with known variable response due to CYP2D6 gene variants (‘CYP2D6-PGx antipsychotics’). Aims: This study aims to investigate differences between demographic groups prescribed ‘CYP2D6-PGx antipsychotics’ and estimate the proportion of patients eligible for PGx testing based on current pharmacogenomics guidance. Methods: A cross-sectional study took place extracting data from 243 patients’ medical records to explore psychosis drug prescribing, including drug transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the proportion of ‘CYP2D6-PGx antipsychotic’ prescribing and the nature of transitions. We used logistic regression analysis to investigate associations between demographic variables and prescription of ‘CYP2D6-PGx antipsychotic’ versus ‘non-CYP2D6-PGx antipsychotic’. Results: Two-thirds (164) of patients had been prescribed a ‘CYP2D6-PGx antipsychotic’ (aripiprazole, risperidone, haloperidol or zuclopenthixol). Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically significant differences between age, sex, or ethnicity in the likelihood of being prescribed a ‘CYP2D6-PGx antipsychotic’. Conclusions: This study demonstrated high rates of prescribing ‘CYP2D6-PGx-antipsychotics’ in an EIP cohort, providing
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A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose-response literatureBackground: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. Methods: We used data from two dose–response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal.
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The contradictory role of febuxostat in ABCG2 expression and potentiating hypericin‐mediated photodynamic therapy in colorectal cancersPhotodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.
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Medicines Shortages Reporting Systems (MSRS): An exploratory review of access and sustainabilityBackground: The efficacy of medicines depends on their accessibility and availability. Dedicated medicine shortage reporting systems (MSRS) have been set up in different countries, either mandatory or voluntary, following the recommendations of the World Health Organisation to ensure these. Objectives: To explore how the Medicine Shortages Reporting System (MSRS) can tackle medicine shortages through improved access and sustainability. Methods: Personnel directly involved in the reporting mechanisms for medicine shortages in eight (8) countries participated in semi-structured interviews. An interview protocol based on the Dynamic Capabilities View and Organisational Information Processing Theory (OIPT) was developed. It contained questions related to participant's views on the process involved in MSRS and how it was used to tackle shortages. Data were thematically analysed. Results: Three core elements were identified to influence MSRS's ability to tackle shortages and ensure sustainability; (1) the ability to identify what information requirements the reporting system needs, (2) identify information processing capabilities, and (3) the ability to match requirements and information processing capabilities through a dynamic capability decision-making process. The dynamic decision-making process involves reiteratively sensing shortages by understanding and validating information received. Conclusion: Building MSRS to tackle shortages for accessibility and sustainability is a systemic process that entails understanding the various elements and processes of MSRS. It includes defining medicine shortages, reconfiguring resources, defining accessibility and ensuring the system's sustainability. Our study provides insights into MSRS developed for mitigating medicine shortages and provides a framework for a sustainable MSRS. The findings extend the literature on medicine shortage management by identifying the various elements required to set up an MSRS. It also provides practical implications for countries that seek to establish MSRS to mitigate medicine shortages. Further studies could extend the number of participating countries to provide a clearer picture of the MSRS and how it can reduce medicine shortages.
