The Delphi method, originally developed at the RAND Corporation in the early 1950s, is a structured, iterative consensus-building technique designed to elicit and aggregate expert opinion on topics where robust empirical evidence is lacking or incomplete. It relies on four core principles: anonymity of participants, iterative questioning across successive rounds, controlled feedback provided between rounds, and statistical aggregation of group responses. In the health sciences, the method has gained widespread adoption for the development of clinical guidelines and recommendation statements, particularly in contexts where randomized controlled trial evidence is unavailable or difficult to obtain. The SIOT consensus applied this methodology to NSAID prescribing in orthopedics, a field where significant variability persists in practice and adherence to existing guidelines.

The consensus process began with a scientific board of seven members—six clinicians and one methodologist—who defined the clinical questions, identified key topics, and conducted a systematic literature review using PubMed/MEDLINE. The board proposed twenty statements spanning four domains, which were then submitted to a broader expert panel of twenty-eight members for evaluation using a six-point Likert scale. Consensus was defined as at least seventy-five percent of ratings concentrating within a single tertile of ascending relevance. In the first round, held on twenty-nine October 2025, twelve statements reached consensus. Six revised statements reached consensus in the second round, held on three December 2025, while two were eliminated because of persistent opinion dispersion.

Among the most significant recommendations to emerge from the process is the endorsement of short-cycle NSAID therapy, limited to cycles of a maximum of seven to ten days, within a multimodal analgesia approach. The panel agreed that because renal, cardiovascular, and gastrointestinal risks are closely related to NSAID dose and duration of treatment, current recommendations suggest that NSAIDs may be considered relatively safe when prescribed at the lowest effective dose for a period not exceeding ten days. Multimodal analgesia combinations incorporating NSAIDs have been established as an effective pain management strategy in several studies, particularly in the perioperative setting, and the consensus reinforces this framework as the standard of care for effective and opioid-sparing pain management in orthopedics.

The consensus also supports the use of symptomatic slow-acting drugs for osteoarthritis, known as SYSADOAs, to reduce NSAID consumption in patients with osteoarthritic pain. A recent meta-analysis confirmed the efficacy of SYSADOAs in osteoarthritis, with evidence supporting their NSAID-sparing effect in this clinical context. The panel agreed that when administered as part of conservative treatment strategies for osteoarthritic pain, SYSADOAs can help reduce the use of NSAIDs, offering a pharmacological alternative that may improve long-term safety profiles for patients requiring sustained pain management. This recommendation is particularly relevant given that osteoarthritis is among the most prevalent musculoskeletal disorders worldwide and one of the leading causes of chronic pain and disability.

In the domain of traumatic pain, the consensus reached agreement on two statements with important clinical implications. The panel recommended NSAIDs perioperatively in frail fracture patients within multimodal analgesia protocols to reduce opioid intake and limit the onset of complications, including delirium. Evidence from recent randomized controlled trials supports this approach: in one trial conducted in one hundred thirty-two patients aged sixty-five years or older undergoing hip fracture surgery, the prevalence of postoperative delirium was significantly lower in the anti-inflammatory bundle group compared with the placebo group. In another trial, the combination of oral acetaminophen and intravenous ketorolac was a viable alternative to opioid-based pain management in closed tibial shaft fractures treated with intramedullary nailing, decreasing opioid consumption without affecting pain scores or union rates.

The panel also affirmed that short-term administration of an NSAID, defined as less than ten to fifteen days, in the postoperative period and upon discharge of a patient operated on for a fracture is not associated with a significant risk of pseudoarthrosis. Several studies and meta-analyses have shown that short-term NSAID use does not significantly affect bone healing rates or increase the incidence of delayed union. However, the consensus was refined in the second round to establish that regular use of NSAIDs should be limited in patients at risk of developing stress fractures. Emerging evidence suggests that NSAIDs may inhibit remodeling within cortical bone, which could lead to increased bone density with extended use in a similar fashion as antiresorptive medications, potentially increasing the risk of stress fractures in physically active populations.

A particularly notable recommendation identifies ketoprofen lysine salt as having a favorable risk-benefit profile for postdischarge pain management, especially for treatments lasting up to seven to fourteen days. The efficacy of ketoprofen for acute postoperative pain has been supported by a Cochrane review, and evidence from multiple clinical trials demonstrates that ketoprofen achieves the highest ratio between anti-inflammatory and analgesic effects among non-selective NSAIDs. A recent review outlined the advantages of ketoprofen lysine salt versus ketoprofen acid in terms of greater gastric tolerability and quicker onset of action. Furthermore, a large epidemiological study derived from a database of eight and a half million new NSAID users identified seventy-nine thousand five hundred fifty-three cases of acute myocardial infarction, finding that ketoprofen appeared to be the most widely used drug with the lowest cardiovascular risk among the NSAIDs studied.

The consensus emphasizes individualized NSAID selection based on cardiovascular, renal, and antiplatelet risk factors. The panel agreed that the presence of cardiovascular risk factors or pathology in patients with chronic orthopedic pain requires a carefully personalized choice of NSAID, and that the presence of impaired renal function requires the same individualized approach with systematic monitoring of the patient’s hydration status. Nephrotoxicity risk is elevated in elderly patients, hypovolemia, high-dose NSAID exposure, concurrent use of vasoconstrictors, and concomitant therapy with renin-angiotensin-aldosterone system inhibitors or diuretics. The panel also highlighted that the potential interference of NSAIDs with platelet aggregation processes requires particular attention in patients receiving acetylsalicylic acid therapy, as NSAIDs with long half-lives can compete with aspirin for COX-1 binding, potentially reducing its antiplatelet efficacy.

The pathophysiology underlying NSAID analgesia involves the inhibition of the cyclooxygenase family of enzymes, which are involved in the formation of prostaglandins in both the periphery and the central nervous system. Prostaglandin E2 promotes the inflammatory response in the periphery and the sensitized neuronal state in the dorsal horn of the spinal cord. At peripheral sites of inflammation, the activation of PGE2 receptors on nociceptor terminals causes neuronal depolarization and sensitization, facilitating their activation by other inflammatory mediators such as bradykinin. In response to nociceptive input, COX-2 expression is upregulated in several areas of the central nervous system, and PGE2 is released in the dorsal horn, where it acts both pre- and postsynaptically to contribute to central sensitization. Beyond cyclooxygenase inhibition, NSAIDs may also modulate additional inflammatory pathways and nociceptive processing, and there is evidence that they act centrally in structures such as the periaqueductal gray and the rostral ventromedial medulla to activate descending inhibitory pain pathways.

The SIOT consensus provides evidence-informed, clinically actionable recommendations for NSAID use across the principal orthopedic pain scenarios, aiming to improve prescribing appropriateness and patient safety in routine practice. The engagement of specialists representing diverse Italian clinical hospitals facilitated the synthesis of complementary perspectives and heterogeneous clinical experiences. The recommendations proposed through this document, founded upon scientific evidence and informed by clinical practice, constitute a resource for delivering pragmatic guidance readily translatable into routine clinical care. As the burden of musculoskeletal pain continues to grow globally, with osteoarthritis imposing an increasing cost at both individual and societal levels, consensus documents such as this one represent an important step toward standardizing care and optimizing outcomes for the millions of patients who rely on NSAIDs for pain relief every day.

Subject of Research: Use of NSAIDs in orthopedic pain management: a Delphi consensus promoted by the Italian Society of Orthopedics and Traumatology (SIOT)

Article Title: Use of NSAIDs in orthopedic pain management: a Delphi consensus promoted by the Italian Society of Orthopedics and Traumatology (SIOT)

Article References: Tranquilli Leali, P., Di Martino, A., Mercurio, M., Spinelli, M. S., Coluzzi, F., Gargano, F., Berti, L., Rivera, F., Grossi, P., Solarino, G., Urbani, A., Scaglione, F., & Randelli, P. S. (2026). Use of NSAIDs in orthopedic pain management: a Delphi consensus promoted by the Italian Society of Orthopedics and Traumatology (SIOT). Frontiers in Pain Research, 7, Article 1944515. https://doi.org/10.3389/fpain.2026.1944515

Image Credits: AI Generated

DOI: 10.3389/fpain.2026.1944515

Keywords: NSAIDs, orthopedic, pain, management, Delphi, consensus, promoted, Italian, Society, Orthopedics, Traumatology, SIOT

The researchers built their study around a well-characterized rabbit model of aqueous-deficient dry eye. They injected concanavalin A, an immune-stimulating plant protein, directly into the lacrimal glands of New Zealand white rabbits under ultrasound guidance, damaging the tear-producing glands and triggering the hallmark features of the disease. Within five days, tear break-up time collapsed by roughly 81 percent, Schirmer tear test values fell by about 51 percent, and tear osmolarity rose significantly, confirming that the animals had developed a genuine dry eye phenotype. Notably, the rabbits’ corneas also became markedly less sensitive to touch, requiring much stronger stimulation to provoke a protective blink.

Measuring that sensitivity required a device with a long pedigree. The team used a Cochet-Bonnet esthesiometer, an instrument descended from a design first described in 1894, which touches the central cornea with a fine nylon filament. By shortening the filament in five-millimeter steps, the examiner increases the force delivered until the animal blinks and retracts its eye; the filament length at which this occurs provides an index of corneal touch threshold. Dry eye rabbits responded only when the filament was shortened to about 3.8 centimeters, compared with 5.7 centimeters in healthy controls, mirroring the reduced corneal sensitivity documented in human patients with the disease.

Against this baseline, the effect of phosphosulindac was striking. A single 25-microliter eye drop of the compound, formulated at 0.2 percent in a Carbopol-based hydrogel, restored corneal sensitivity to normal levels within five minutes, the first time point tested. The normalization persisted for roughly 26 to 27 hours before gradually dissipating, an unusually stable response that raises the possibility of once-daily dosing. Intriguingly, a higher concentration of 0.6 percent produced a shorter effect lasting only about two and a half hours, hinting at a dose-response relationship that is far from linear.

The choice of formulation proved critical. Cyclodextrin-based solutions, in which the hydrophobic phosphosulindac molecule is shuttled inside the cup-shaped interior of cyclic glucose oligomers, and an oil-in-water emulsion also restored sensitivity in dry eyes, but their effects lasted under an hour. Polymer nanoparticles, by contrast, were ineffective. The team also uncovered a sharp pharmacological threshold: in solution, 0.05 and 0.1 percent phosphosulindac did nothing, while 0.2 percent was fully active, and an eightfold higher dose of 1.6 percent added no further benefit. In cyclodextrin formulations, activity peaked at pH 6.2, consistent with pH-dependent shifts in the stability of the drug-cyclodextrin inclusion complex.

What distinguishes phosphosulindac is the company it failed to keep. None of six structurally related compounds, including sulindac itself, aspirin derivatives and an ibuprofen derivative, reproduced the effect. Neither did cyclosporine and lifitegrast, the two pillar immunomodulatory drugs approved for dry eye, nor a commercial artificial tear. Ketorolac and bromfenac, two non-steroidal anti-inflammatory eye drops, actually further depressed corneal sensitivity in the dry eye animals, as did the anesthetics proparacaine and benoxinate, which abolished responses almost immediately. Phosphosulindac, uniquely among everything tested, pushed sensitivity in the opposite direction.

In healthy eyes, the story inverted. Applied to normal rabbit corneas, phosphosulindac suppressed sensitivity, producing a peak reduction of nearly 56 percent at 50 minutes that resolved by about 140 minutes, a slower and longer-lasting effect than lidocaine, which numbed more powerfully but faded within 30 minutes. The authors speculate that in a normal cornea, densely populated with sensory endings, the drug may depolarize or overwhelm mechanosensory and polymodal nociceptors beyond the threshold needed to propagate a blink reflex, whereas in a dry eye, where nerve endings have been lost, the same action sensitizes the surviving receptors enough to restore measurable responses.

Several features of the data argue that the effect is direct and non-anesthetic. It appeared within minutes, was fully reversible within hours, and outlasted the measurable residence of the drug in the cornea reported in earlier pharmacokinetic work, pointing to downstream changes in nerve function rather than simple tissue numbing. Crucially, phosphosulindac is not itself a classical NSAID and does not suppress prostaglandin production in the cornea; unlike ketorolac and bromfenac, which have been linked to the devastating complication of corneal melt, it inhibits matrix metalloproteinases instead. The team also confirmed the findings in pigmented Dutch-belted rabbits, ruling out melanin sequestration as a confounder.

The therapeutic implications are twofold. For dry eye disease, where nearly all symptoms are mediated through the nerves of the ocular surface, a drug that both treats the underlying inflammation, as the team’s earlier rabbit work demonstrated by normalizing tear break-up time, osmolarity and lactoferrin, and rapidly restores sensory function could address both signs and symptoms in a way current medications, whose benefits often take weeks to appear, do not. For normal eyes, the numbing effect suggests a potential role in managing acute ocular pain, for example after cataract surgery, though the authors stress that any anesthetic-like use would demand careful safety evaluation.

Important caveats remain. The work was conducted in rabbits with an induced, aqueous-deficient form of the disease, whereas most human dry eye is evaporative in origin, and whether the striking dichotomy between normal and dry corneas translates to patients is unknown. Confirming the proposed mechanism, a direct action on mechanosensory and polymodal corneal nociceptors, will require electrophysiological, immunohistochemical and molecular studies. Still, with dry eye affecting a substantial share of the adult population and its neuropathic pain increasingly recognized as under-treated, a small molecule that can flip corneal sensitivity back on within minutes, safely and reversibly, is a result that both neuroscientists and ophthalmologists will be watching closely.

Subject of Research: Restoration of corneal sensitivity in dry eye disease by topical phosphosulindac in a rabbit model

Article Title: Phosphosulindac (OXT-328) restores the suppressed corneal sensitivity in rabbits with dry eye disease: therapeutic implications

Article References: Huang, W., Wen, Z., Tourmouzis, K., Huang, L., Goldstein, S. M., Natke, E., Honkanen, R., & Rigas, B. (2026). Phosphosulindac (OXT-328) restores the suppressed corneal sensitivity in rabbits with dry eye disease: therapeutic implications. Frontiers in Drug Delivery, 6, Article 1778440. https://doi.org/10.3389/fddev.2026.1778440

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1778440

Keywords: dry eye disease, phosphosulindac, OXT-328, corneal sensitivity, corneal nerves, rabbit model, ophthalmic drug delivery, cyclodextrin, hydrogel, NSAIDs, esthesiometry, ocular pain

The significance of this work lies in the growing crisis surrounding non-tuberculous mycobacteria, or NTM. Unlike Mycobacterium tuberculosis, NTM are ubiquitous environmental organisms that can colonise the lungs of patients with pre-existing structural damage, such as bronchiectasis or chronic obstructive pulmonary disease, and of those who are immunosuppressed. Their incidence is rising worldwide, and they are notoriously difficult to treat because of intrinsic resistance to broad classes of antibiotics. M. kansasii, in particular, is considered a relatively virulent pulmonary pathogen whose management typically requires prolonged multidrug regimens anchored by rifampicin. Diagnosis is complicated by nonspecific clinical presentations and by the slow, sometimes unreliable nature of culture-based detection. For many patients, the therapeutic window is narrow, tolerability is poor, and outcomes are variable, which makes the discovery of a new, selectively active chemotype both timely and clinically meaningful.

The researchers built on a strategy that has become one of the most productive in modern infectious-disease pharmacology: drug repurposing. Rather than searching for new molecules from scratch, repurposing examines approved drugs and established scaffolds for previously unrecognised antimicrobial properties. Because such molecules already possess well-characterised safety, pharmacokinetic, and toxicological profiles, early-stage development can proceed more rapidly than with entirely novel chemical entities. Non-steroidal anti-inflammatory drugs have proven particularly fertile ground. Several members of this class exhibit direct antibacterial, anti-biofilm, or antibiotic-potentiating effects, and linezolid, originally developed as an antibacterial agent, has in fact found its way into the treatment of NTM infections. Diflunisal, a difluorophenyl derivative of salicylic acid, had previously been shown to modulate virulence in Staphylococcus aureus, reduce biofilm formation, and inhibit tuberculosis bacilli in vitro with minimum inhibitory concentrations in the range of 25 to 50 micromolar, hinting that its biphenyl skeleton could be a versatile starting point.

To unlock that potential, the team systematically redesigned the diflunisal scaffold. The carboxylic acid group was esterified to boost lipophilicity, a physicochemical property frequently associated with improved antimycobacterial activity, while the phenolic hydroxyl was replaced with an amino group to enable the installation of urea moieties, a pharmacophore with a strong track record in antimycobacterial drug discovery. The urea N-substituents were chosen to probe chain length, lipophilicity, and topology, spanning short ethyl chains, longer hexyl and dodecyl chains, a cyclic cyclohexyl group, and aromatic phenyl, benzyl, and phenethyl variants. The synthetic route began with a palladium-catalysed Suzuki–Miyaura cross-coupling between commercially available (2,4-difluorophenyl)boronic acid and methyl 5-bromoanthranilate, executed at 90 degrees Celsius with tetrakis(triphenylphosphine)palladium(0) and potassium carbonate, which delivered the key aminobiphenyl intermediate in an excellent 89 percent yield. Reaction of this intermediate with various isocyanates furnished the asymmetric ureas in yields ranging from 28 to 97 percent, with the ethyl derivative proving especially difficult because of the volatility of ethyl isocyanate and the formation of a diethylurea side product.

The biological screening revealed a selectivity profile that surprised even the researchers. Against Mycobacterium tuberculosis H37Ra, the rapidly growing M. smegmatis and M. aurum, and even M. avium, the new derivatives showed little or no relevant inhibition. But against M. kansasii the results were dramatic. The ethyl-substituted urea inhibited the reference strain at 0.06 micrograms per millilitre and the hexyl analogue at 0.03 micrograms per millilitre, corresponding to micromolar potencies of just 0.18 and 0.077 respectively. The dodecyl and phenyl derivatives retained strong activity at 0.20 and 0.78 micrograms per millilitre, while diflunisal itself required 125 micrograms per millilitre to achieve the same effect against this organism. In matched comparisons, the most active analogues were therefore more than 4000-fold more potent than the parent drug against M. kansasii, and outperformed isoniazid and ciprofloxacin while at least matching rifampicin in the same assay.

Perhaps the most instructive structure–activity lesson came from a near-identical pair of compounds. The linear n-hexyl urea and its cyclohexyl counterpart differ only modestly in calculated lipophilicity, with clogP values of 6.47 and 5.85 respectively, yet constraining the flexible alkyl chain into a rigid ring abolished activity by more than 4000-fold. Similarly, inserting a methylene or ethylene spacer between the urea nitrogen and a phenyl ring, as in the benzyl and phenethyl analogues, was markedly detrimental. The authors concluded that substituent topology and conformational properties, rather than lipophilicity alone, are the critical determinants of activity, a finding that strongly implies a specific molecular interaction rather than a nonspecific membrane-disruptive effect. Supporting this interpretation, an isosteric butyramide analogue was completely inactive, and carbamate isosteres generally underperformed their urea counterparts, underscoring the importance of the two hydrogen-bond-donating NH groups of the urea linkage, although the cyclohexyl carbamate did retain moderate dual activity against both M. tuberculosis and M. kansasii.

Importantly, the two most active ureas did not lose their edge when tested against M. kansasii 6509/96, a clinical isolate resistant to isoniazid. Both compounds maintained a minimum inhibitory concentration of 0.125 micromolar at readout points after 7, 14, and 21 days of continuous exposure, indicating sustained growth inhibition without delayed regrowth. The potency also compares favourably with previously reported antimycobacterial ureas: sulfamethoxazole-based ureas active against M. kansasii typically reached low micromolar values of at least 4 micromolar, and recent thioureas achieved a best median inhibitory concentration of 1.5 micromolar against the same reference strain. Against the panel of Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, the soluble derivatives were entirely inactive, as they were against eight fungal pathogens spanning Candida, Aspergillus, and dermatophyte species, confirming an exquisitely narrow species selectivity.

Safety signals in the preliminary screens were equally encouraging. When evaluated against MonoMac-6 human monocytic cells, a model relevant to the intracellular niche that pathogenic mycobacteria occupy, and against HepG2 hepatic cells, a metabolically active surrogate for systemic drug exposure, none of the urea, amide, or carbamate derivatives showed any cytostatic effect at concentrations up to 250 micromolar. Given that the hexyl urea kills M. kansasii at approximately 0.077 micromolar, this translates into a selectivity index exceeding 3250, meaning the antimicrobial effect is over three thousand times more potent than any measurable toxicity toward mammalian cells. The researchers are careful to note that the cytostatic assay used uninfected cells and therefore cannot confirm intracellular antimycobacterial efficacy, and that mechanism-of-action work remains outstanding, but the preliminary safety profile is nonetheless exceptional for an early-stage hit series.

What could explain such dramatic specificity for a single mycobacterial species? The authors propose that M. kansasii differs from M. tuberculosis and from rapidly growing mycobacteria in the composition and organisation of its cell-envelope lipids, including its distinctive lipooligosaccharides, which may alter the permeability, partitioning, or intracellular retention of amphiphilic fluorinated biphenyl derivatives. Interspecies variation in efflux pump capacity, drug-inactivating enzymes, and target susceptibility could further shape intracellular exposure. Whether the compounds act through preferential accumulation, through interaction with a species-dependent molecular target, or through interference with a resistance determinant cannot yet be distinguished with the available data. The team suggests that whole-genome sequencing of resistant mutants, combined with target-identification and uptake studies, could resolve the question in future work.

Fluorinated biphenyl ureas thus emerge from this study as a previously unrecognised chemotype for attacking M. kansasii, one that warrants systematic expansion. The path forward, as the researchers outline, involves broadening the structure–activity analysis, testing a larger panel of clinical isolates, establishing efficacy in intracellular infection models, and identifying the molecular basis of the species selectivity that makes these molecules so unusual. An unexpected synthetic bonus also came out of the work: during carbamate preparation, a side reaction yielded cyclic benzoxazine-dione scaffolds in just two steps, a shortcut to structures that normally require three-step routes. It is a fitting coda for a study built on repurposing, demonstrating that even the chemistry of an old painkiller can still yield surprises with the potential to reshape how we fight stubborn lung infections.

Subject of Research: Design of diflunisal-derived fluorinated biphenyl urea and carbamate derivatives with selective antimycobacterial activity against Mycobacterium kansasii

Article Title: Diflunisal-derived fluorinated biphenyl urea and carbamate derivatives with selective activity against Mycobacterium kansasii

Article References: Pflégr, V., Janďourek, O., Šikorová, E., Konečná, K., Bősze, S., & Krátký, M. (2026). Diflunisal-derived fluorinated biphenyl urea and carbamate derivatives with selective activity against Mycobacterium kansasii. Results in Chemistry, 31, Article 103965. https://doi.org/10.1016/j.rechem.2026.103965

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103965

Keywords: diflunisal, Mycobacterium kansasii, non-tuberculous mycobacteria, drug repurposing, urea derivatives, antimycobacterial agents, structure-activity relationships, NSAIDs, fluorinated biphenyls, antimicrobial resistance, medicinal chemistry, selectivity index

The research team designed ten new naproxen derivatives, labeled ND1 through ND10, by replacing the drug’s terminal carboxylic acid with an amide linkage attached to a variety of aromatic, heterocyclic, and aliphatic fragments. The naphthalene methoxy backbone that the cyclooxygenase enzymes recognize was left untouched, preserving the pharmacophore responsible for anti-inflammatory action. The logic is rooted in well-established medicinal chemistry: the acidic group anchors classical NSAIDs inside the COX channel through a salt bridge with the conserved Arg120 residue, but that same ionizable acid undergoes ion trapping in the acidic gastric lumen, directly irritates the epithelial barrier, and inhibits mitochondrial oxidative phosphorylation in stomach lining cells. Swapping the acid for a neutral amide could, in principle, keep the anchoring interactions while eliminating the gastric toxicity, and the amide’s terminal fragment could even reach into the less conserved side pocket that distinguishes COX-2 from COX-1, a strategy long used to convert non-selective NSAIDs into COX-2-preferring inhibitors.

To test this idea without synthesizing a single molecule, the researchers deployed a multi-layered computational pipeline. Density functional theory calculations at the B3LYP/6-31+G(d,p) level probed the electronic character of each derivative, yielding frontier molecular orbital energies, chemical hardness, softness, electronegativity, and electrophilicity. The results were striking: derivatives ND1 and ND4 showed the smallest HOMO-LUMO energy gaps, around 0.30 and 0.31 electron volts, compared with 0.87 electron volts for naproxen itself, indicating far greater electronic softness and reactivity. Soft molecules polarize more readily, which favors effective dispersion forces and electronic redistribution during non-covalent binding within the hydrophobic COX-2 pocket. ND2, meanwhile, posted the highest dipole moment at over 30 Debye, suggesting the strongest potential for polar interactions with the receptor. Molecular electrostatic potential mapping reinforced the picture, revealing that the high-polarization derivatives, including ND1, ND4, ND5, ND6, and ND9, retained sharply localized electron-rich and electron-poor regions capable of directional hydrogen bonding, effectively replacing the electrostatic role of the discarded carboxylic acid.

Before any binding predictions could be trusted, the docking protocol itself had to be validated. The researchers re-docked the co-crystallized ligands into the active sites of COX-1 and COX-2, using crystal structures 3KK6 and 3NT1 from the Protein Data Bank, and obtained root-mean-square deviations of 1.48 and 0.936 angstroms respectively, well within accepted thresholds. With the protocol confirmed, all ten derivatives were docked against both enzymes using AutoDock Vina and AutoDock4, alongside reference drugs including diclofenac, aspirin, mefenamic acid, and indomethacin. Every single derivative outperformed the parent drug. Naproxen scored roughly minus 7.5 kilocalories per mole against COX-2, while the derivatives ranged from minus 8.3 to minus 10.1 kilocalories per mole under Vina scoring. ND10, bearing an aminomethyl benzoic acid terminus, achieved the most favorable AutoDock4 score of minus 11.49 kilocalories per mole, driven largely by superior van der Waals contacts, while ND5’s bulky cycloheptylethyl group delivered a minus 10.43 kilocalories per mole result.

The docking poses revealed how the amide modification preserves potency through a clever molecular sleight of hand. Although converting the carboxylate into an amide removes the classical ionic salt bridge with Arg120, the amide carbonyl steps in as an alternative hydrogen-bond partner for the Arg120 guanidinium group in complexes ND3, ND5, and ND10. This neutral interaction, combined with deep penetration of the derivatives into the hydrophobic core near GLY526 and ALA527, provides a rational basis for COX-2 selectivity. Several complexes, including ND2, ND4, ND5, ND6, ND7, ND9, and ND10, reproduced the essential binding pattern of naproxen through pi-pi stacking with aromatic residues such as PHE381, TYR385, and TRP387, while ND4, ND6, and ND10 added hydrogen bonds and pi-sigma interactions with TYR385. By replacing the ionic anchor essential for COX-1 recognition with amide-based hydrogen bonding and expanded aromatic stacking, the derivatives exploit the larger active-site volume of COX-2 while potentially reducing the COX-1-mediated gastrointestinal harm of the parent acid.

Pharmacokinetic profiling through SwissADME and ProTox 3.0 added a crucial safety dimension. All ten derivatives fell safely below the 500 grams per mole Lipinski ceiling, satisfied hydrogen-bond donor and acceptor limits, and showed topological polar surface areas between 38 and 76 square angstroms, comfortably within the threshold for passive oral absorption. Predicted gastrointestinal absorption was high across the series, and all compounds were predicted non-cardiotoxic. The toxicity results were particularly encouraging: naproxen showed an LD50 of 248 milligrams per kilogram in toxicity class 3, whereas ND1 and ND8 exhibited LD50 values of 4000 and 5000 milligrams per kilogram in the far safer class 5. ND1, ND8, and ND10 were additionally predicted to be non-neurotoxic, and nearly all compounds showed inactive nephrotoxicity predictions, in contrast to active nephrotoxicity for naproxen itself. Caveats remain, however, as several analogues were predicted to inhibit multiple cytochrome P450 isoforms, flagging a potential risk of drug-drug interactions that will require experimental confirmation.

The three most promising candidates, ND2, ND4, and ND10, were then subjected to 100-nanosecond molecular dynamics simulations in GROMACS using the CHARMM36 force field, solvated in explicit water with physiological ion concentrations. The trajectories told a dramatic story. Naproxen repeatedly dissociated and rebounded at three distinct binding-site regions over the simulation, maintaining only intermittent hydrogen bonding of zero to two bonds and showing the highest conformational fluctuation of any system studied. ND4, by contrast, locked into its binding pose almost immediately and maintained a steady four to six hydrogen bonds, occasionally reaching seven, throughout the entire 100 nanoseconds. Its average root-mean-square deviation of 0.215 nanometers was the lowest of the series, and its solvent-accessible surface area of 255.90 square nanometers indicated the most compact, tightly bound complex. ND10 required roughly 50 nanoseconds to settle but then held its final pose with remarkable rigidity, achieving the steadiest plateau in the RMSD analysis.

Free-energy calculations using the MM/GBSA method over 501 trajectory snapshots quantified these differences with impressive precision. Naproxen’s binding free energy averaged minus 13 kilocalories per mole, while ND2 reached minus 16.5 and ND10 minus 25.4 kilocalories per mole. ND4 was in a class of its own at minus 46 kilocalories per mole, powered by an enormous van der Waals contribution of nearly minus 49 kilocalories per mole and an electrostatic term of minus 27 kilocalories per mole, reflecting its extended hydrogen-bond network with TYR324, ARG89, and ARG120. Per-residue energy decomposition confirmed that Arg120 contributed favorably to ND4 binding, demonstrating that the amide linkage had successfully recreated the anchoring interaction that the carboxylic acid once provided. Conformational analysis added a final layer of insight: 75 percent of the ND4 trajectory occupied a single conformational family, compared with only 43 percent for naproxen, whose energy landscape was fragmented across many shallow, poorly defined basins.

The authors are careful to frame these findings as exploratory rather than conclusive. Computational docking, dynamics, and ADMET predictions cannot fully capture the complexity of living systems, and predicted binding affinities do not always translate to in vitro or in vivo efficacy and safety. Experimental verification of the amide modification’s impact on cyclooxygenase selectivity, anti-inflammatory activity, metabolic stability, and gastrointestinal protection remains essential. Still, the study stands as a compelling demonstration of modern computer-aided drug design, showing how density functional theory, electrostatic mapping, validated docking, long-timescale simulation, and ensemble free-energy calculations can converge to identify ND4 and ND10 as lead candidates worthy of synthesis and biological testing. If laboratory work confirms what the simulations suggest, the humble painkiller in millions of medicine cabinets could one day be replaced by a safer, more potent descendant of itself.

Subject of Research: Computational design of naproxen amide derivatives as improved anti-inflammatory COX inhibitors

Article Title: Structure-based computational design of naproxen analogues with improved anti-inflammatory activity by DFT analysis, ADMET assessment, molecular docking, and molecular dynamics simulations

Article References: Abdullah, A., & Akhtar, M. (2026). Structure-based computational design of naproxen analogues with improved anti-inflammatory activity by DFT analysis, ADMET assessment, molecular docking, and molecular dynamics simulations. Results in Chemistry, 31, Article 103933. https://doi.org/10.1016/j.rechem.2026.103933

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103933

Keywords: naproxen, NSAIDs, COX-2 inhibition, computer-aided drug design, molecular docking, molecular dynamics simulation, DFT, ADMET, MM/GBSA, amide derivatives, gastrointestinal toxicity, drug discovery

The research, conducted by a team affiliated with Minia University in Egypt, set out to answer a deceptively simple question: does the color of your quinoa matter when it comes to protecting your gut? The investigators compared ordinary white quinoa against a tri-color blend combining white, red, and black seeds in a rat model of indomethacin-induced gastric injury. Their rationale rested on well-documented chemistry. Red and black quinoa varieties typically carry substantially higher total phenolic content and greater radical-scavenging capacity than the pale traditional grain, thanks to pigments such as anthocyanins and betalains. The team hypothesized that this richer phytochemical arsenal would translate into measurably better gastroprotection.

Three signature compounds anchored the mechanistic case. Procyanidin B2, an oligomeric proanthocyanidin, is known to scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress the NF-κB inflammatory master switch. Cinchonain IB, a complex flavanol derivative, has been associated with cytokine modulation and tissue repair. Kaempferol-3-O-rutinoside, a common flavonol, may downregulate inducible nitric oxide synthase and COX-2 while reinforcing the gastric mucus barrier. Because the density of these molecules varies dramatically between quinoa varieties, the researchers reasoned that a head-to-head dietary trial could reveal whether phytochemical diversity directly determines therapeutic potency.

The experimental design was deliberately food-based rather than extract-based. Thirty-six male Sprague Dawley rats were randomly assigned to six groups of six, following the ethical 3Rs principle to minimize animal use. Baked bread was prepared from either refined wheat flour, flour containing 40 percent white quinoa powder, or flour containing 40 percent tri-color quinoa powder, then ground and blended into a standard rodent diet at a 25:75 ratio. Daily portions were weighed and remnants collected to verify that every rat consumed a statistically uniform 21 to 23 grams of food per day, ensuring that any differences in outcome reflected the grain itself rather than unequal intake. After 21 days of feeding, injury was induced with a single oral dose of 30 milligrams per kilogram of indomethacin.

The results were striking. Indomethacin alone devastated the stomachs of control rats: gastric pH plummeted from 3.93 to 1.66, malondialdehyde, a lipid peroxidation marker of oxidative damage, surged from 0.15 to 0.23 nanomoles per gram, and reduced glutathione, the tissue’s primary endogenous antioxidant, collapsed from 1.80 to 0.71 milligrams per gram. Both quinoa diets pushed these values back toward baseline, but the tri-color blend consistently outperformed the white variety. Most notably, malondialdehyde in the tri-color group fell to 0.14 nanomoles per gram, essentially restoring oxidative balance, while glutathione recovered to 1.30 milligrams per gram, a 72 percent restoration compared with roughly 56 percent for white quinoa.

Inflammation told a parallel story. Cyclooxygenase activity more than doubled in the indomethacin-only controls, reaching 5.20 units per milligram, and nuclear NF-κB p65 climbed from 1.62 to 3.81 micrograms per milliliter. Tri-color quinoa supplementation cut COX activity to 2.96 and NF-κB to 2.11, a 45 percent reduction relative to injured controls, with white quinoa trailing slightly behind. Pepsin activity, a measure of the digestive enzyme that can chew through a compromised mucosa, followed the same pattern. The authors attribute these effects to the tri-color blend’s presumed abundance of anthocyanins, betalains, procyanidins, and cinchonains, compounds that literature links to glutathione regeneration and suppression of inflammatory signaling.

Under the microscope, the differences became visually unmistakable. Blinded pathologists, scoring tissue independently with strong agreement, graded necrosis, edema, and inflammation on a zero-to-three scale. Injured control rats scored 2.4 for necrosis, 2.8 for edema, and 2.6 for inflammation, reflecting extensive mucosal destruction, inflammatory infiltration, and submucosal swelling. White quinoa roughly halved those scores, but tri-color quinoa reduced necrosis to 0.4, edema to 0.6, and inflammation to 0.5, an 83 percent drop in mucosal necrosis and near-complete preservation of the gastric architecture. Body weight told the same tale: indomethacin-treated controls gained only 39 grams over the study, while quinoa-fed injured rats gained 42 to 44 grams, indicating that the grain blunted the drug’s systemic as well as local toll.

To probe mechanism, the team turned to molecular docking against human crystal structures of the gastric proton pump Atp4a, COX-2, and NF-κB. Procyanidin B2 bound the proton pump with an affinity of minus 8.9 kilocalories per mole, outperforming the co-crystallized reference ligand and offering a theoretical basis for quinoa acting as a natural acid-secretion moderator. Cinchonain IB delivered the standout result at NF-κB, binding at minus 8.2 kilocalories per mole through hydrogen bonding with Lys417 and hydrophobic contact with Phe439, a mode resembling synthetic NF-κB inhibitors. The authors also note that baking may not destroy these compounds: internal crumb temperatures during standard baking hover around 95 to 98 degrees Celsius, and heat can even release bound phenolics into more bioaccessible forms, which helps explain why a bread-based intervention worked.

The study also raised gastric pH in treated animals, from 1.66 to 2.10 in the tri-color group, possibly through the buffering action of quinoa’s organic acids such as malate and citrate, and boosted mucin production, thickening the physical mucus barrier that stands between acid and epithelium. Together with the antioxidant and anti-inflammatory data, these findings sketch a coherent, multi-front defense: quinoa compounds simultaneously neutralize radicals, calm inflammatory transcription, buffer luminal acidity, and reinforce the mucus lining. The authors caution, however, that they could not perform chromatographic profiling of their specific extracts because the batch was exhausted, so attribution to individual compounds remains literature-based and suggestive rather than definitive.

The limitations are real. Only male rats were studied, leaving sex-specific responses unexplored; a single high-dose time point cannot capture the dynamics of long-term human consumption; and no human trial data exist yet. Still, the central message is compelling and unusually practical: the pigmented seeds of a climate-resilient Andean pseudocereal, eaten as ordinary bread, outprotected their paler counterpart against one of the most common drug side effects in medicine. If future chromatographic, dose-ranging, and clinical studies confirm the effect, tri-color quinoa could move from trendy salad topping to evidence-backed dietary ally for the millions of people who need daily NSAID relief but cannot afford to sacrifice their stomachs along the way.

Subject of Research: Gastroprotective effects of white and tri-color quinoa against NSAID-induced gastric injury

Article Title: Comparative Evaluation of White Quinoa and Tri‐Color Quinoa on Indomethacin‐Induced Gastrointestinal Damage

Article References: Alqahtani, N. S., Hassan, H. M., Mohamed, H. M., Gazaly, F. M., & Sadeek, R. A. (2026). Comparative Evaluation of White Quinoa and Tri‐Color Quinoa on Indomethacin‐Induced Gastrointestinal Damage. Food Science & Nutrition, 14(10), Article e72418. https://doi.org/10.1002/fsn3.72418

Image Credits: AI Generated

DOI: 10.1002/fsn3.72418

Keywords: quinoa, NSAIDs, indomethacin, gastric ulcer, gastroprotection, polyphenols, procyanidin B2, cinchonain IB, NF-κB, oxidative stress, functional foods, molecular docking

The clinical problem the researchers targeted is widespread. Non-steroidal anti-inflammatory drugs such as indomethacin relieve pain, fever, and inflammation, but they do so partly by inhibiting cyclooxygenase-1, an enzyme that helps produce the prostaglandins that keep the gastric mucosa healthy. Stripping away that protection leaves the stomach wall exposed to acid and pepsin, and indomethacin additionally ignites inflammatory signaling cascades that kill epithelial cells. Current countermeasures, chiefly proton pump inhibitors like omeprazole, suppress acid secretion by blocking the gastric H+/K+-ATPase, but long-term use of these drugs carries its own concerns, motivating the search for gentler, food-based alternatives.

Petasites japonicus offered an intriguing candidate. The plant has traditionally been used in East Asia for tension headaches and gastrointestinal spasms, and in Europe and North America for migraines, bronchial asthma, and seasonal allergic rhinitis. Its leaves and stems are rich in phenolic acids, including chlorogenic acid and fukinolic acid, along with several dicaffeoylquinic acid derivatives. To capture these compounds efficiently, the team reflux-extracted one kilogram of dried, ground plant material with either water or 50 percent aqueous ethanol at 50 degrees Celsius for five hours. High-performance liquid chromatography then quantified the phenolic content of each preparation.

The solvent choice mattered considerably. The 50 percent ethanol extract contained 42.48 milligrams of fukinolic acid per gram, compared with 25.35 milligrams in the water extract, while chlorogenic acid levels were nearly identical at roughly 13.5 milligrams per gram. Adding in the dicaffeoylquinic derivatives, the ethanol extract delivered a total polyphenol content of 80.21 milligrams per gram against 53.31 for water. On that chemical basis, the researchers selected the ethanol extract for all biological testing, reasoning that its richer phenolic payload would better represent the plant’s active potential.

In the laboratory, the extract proved strikingly protective. When human gastric adenocarcinoma AGS cells and Hs746T gastric carcinoma cells were exposed to 800 micromolar indomethacin for three hours, viability collapsed to 55.4 percent and 69.2 percent of control levels respectively. Pretreatment with the extract for one hour beforehand significantly blunted that damage, lifting viability to 71.9 percent in AGS cells at 50 micrograms per milliliter and 82.4 percent in Hs746T cells at 100 micrograms per milliliter. Crucially, the extract showed no cytotoxicity on its own across the entire 1 to 100 micrograms per milliliter range tested, and the researchers noted that dietary polyphenols naturally reach comparable concentrations in the gastric lumen before absorption.

Molecular analysis revealed three converging mechanisms. First, indomethacin sharply reduced MUC5AC, the predominant mucin glycoprotein that forms the stomach’s protective mucus barrier, dropping it to 0.65-fold in AGS cells and 0.48-fold in Hs746T cells; extract pretreatment restored those levels substantially. Second, the extract suppressed indomethacin-driven upregulation of acid secretion machinery, including the histamine H2 receptor gene HRH2 and subunits of the proton pump, ATP4A and ATP4B, which assemble into the H+/K+-ATPase that pumps acid into the stomach. Third, it dampened inflammation: indomethacin had boosted expression of inducible nitric oxide synthase and cyclooxygenase-2 and triggered phosphorylation of the transcription factor NF-κB and its inhibitor IκB-α, but the extract pulled all of these markers back down in a dose-dependent manner. Upstream, the extract also quieted the MAPK kinases ERK, JNK, and p38, whose indomethacin-induced phosphorylation reached as high as 8.24-fold in AGS cells before treatment brought it down.

The animal experiments translated these cellular findings into whole-body protection. Fifty male Sprague-Dawley rats were divided into control, indomethacin, omeprazole, and two extract-dose groups, with the test substances given orally once daily for seven days before a single 75 milligrams per kilogram dose of indomethacin. After quality-control exclusions, seven rats per group were analyzed. Macroscopic examination showed extensive hemorrhagic lesions in the indomethacin group, but the ulcer index fell to 0.58-fold at 50 milligrams per kilogram of extract and 0.40-fold at 100 milligrams per kilogram. Histological scoring told the same story: severe mucosal erosion, epithelial disruption, submucosal edema, and leukocyte infiltration in the indomethacin group scored 4.0, while extract treatment reduced the score to 1.3 and 0.7 at the two doses, with the lower dose matching omeprazole’s 1.3.

Tissue analyses confirmed the same molecular signature seen in culture. Indomethacin cut gastric MUC5AC protein to 0.58-fold of control, but extract restored it to 0.85-fold and 0.99-fold at the two doses. The drug raised Hrh2 mRNA to 3.28-fold and Atp4b to 1.16-fold; the higher extract dose brought these down to 1.88-fold and 0.85-fold respectively, the latter essentially matching control levels. Inflammatory chemistry followed suit: gastric nitric oxide rose from 3.52 to 5.86 micromolar under indomethacin and TNF-α from 1.39 to 1.98 picograms per milliliter, while extract treatment reduced both, and phosphorylated NF-κB, IκB-α, ERK, JNK, and p38 all declined dose-dependently in tissue lysates.

To probe how the plant’s signature compounds might act directly on drug targets, the team docked chlorogenic acid and fukinolic acid against the H+/K+-ATPase, the histamine H2 receptor, cyclooxygenase-2, and the TNF-α trimer, using omeprazole, cimetidine, and aspirin as reference ligands. The phenolic acids bound the proton pump through the residue Cys813 and the H2 receptor through Asp98, and their strongest predicted affinities came at cyclooxygenase-2, where chlorogenic acid scored −9.3 and fukinolic acid −9.0 kilocalories per mole, comfortably outperforming aspirin’s −6.7. Both compounds also showed moderate binding at the TNF-α trimer interface. The authors caution that docking is predictive and that the whole extract, not isolated compounds, produced the observed effects, with future work needed to isolate individual contributions.

The dose translation is perhaps the most striking practical detail. Applying US Food and Drug Administration body-surface-area conversion, the highest rat dose of 100 milligrams per kilogram corresponds to a human equivalent dose of 16.22 milligrams per kilogram, roughly 973 milligrams daily for a 60-kilogram adult. Based on the extraction yield, that amount equates to eating approximately 6.5 grams of fresh Petasites japonicus leaves and stems, an entirely ordinary dietary quantity. The authors acknowledge limitations, including the cancer-derived nature of the cell lines and the absence of direct measurements of gastric juice volume, pH, and acidity, and they call for follow-up studies using primary cells, gastric organoids, or pylorus-ligated models. Even so, the convergence of preserved mucus barriers, dampened acid-pump genes, and suppressed NF-κB and MAPK signaling across cells, rats, and simulations makes a compelling case that this everyday vegetable deserves attention as a functional food ingredient for protecting the stomach against painkiller injury.

Subject of Research: Gastroprotective effects of Petasites japonicus ethanol extract against NSAID-induced gastric ulcer

Article Title: Gastroprotective effects of a dietary Petasites japonicus ethanol extract against indomethacin-induced gastric injury via regulation of mucosal defense, acid secretion-related targets, and inflammation

Article References: Hwang, B., Hwang, S.-K., Kim, J.-Y., Song, J.-H., Son, Y.-J., Kim, H., Jung, W., Lee, J. J., Cho, S.-C., Chung, H., & Moon, S.-K. (2026). Gastroprotective effects of a dietary Petasites japonicus ethanol extract against indomethacin-induced gastric injury via regulation of mucosal defense, acid secretion-related targets, and inflammation. Journal of Agriculture and Food Research, 31, Article 103325. https://doi.org/10.1016/j.jafr.2026.103325

Image Credits: AI Generated

DOI: 10.1016/j.jafr.2026.103325

Keywords: Petasites japonicus, gastric ulcer, indomethacin, NSAIDs, MUC5AC, NF-κB, MAPK, proton pump, chlorogenic acid, fukinolic acid, functional food, gastroprotection

The clinical stakes are considerable. Bronchopulmonary dysplasia, defined by the need for supplemental oxygen or respiratory support at a corrected gestational age of thirty-six weeks, affects a substantial proportion of infants born before twenty-eight weeks of gestation and is associated with long-term respiratory morbidity, neurodevelopmental impairment, and rehospitalization throughout childhood. Its pathogenesis is multifactorial, involving inflammation, infection, hyperoxia exposure, impaired alveolar and vascular development, and genetic and environmental interactions. Because no single therapy has proven reliably protective, clinicians scrutinize every drug that reaches the developing lung for possible harm, and the analgesics and anti-inflammatory agents used in the first weeks of life are no exception.

The story of these drugs in the neonatal intensive care unit begins with the ductus arteriosus itself. Increased blood flow across a patent ductus arteriosus can be associated with increased pulmonary blood circulation and morbidity, a hemodynamic burden that physicians have tried to relieve since the latter part of the twentieth century by closing a hemodynamically significant ductus in the hope of improving outcomes. The pharmacological workhorses of that effort have been cyclooxygenase inhibitors, chiefly indomethacin and ibuprofen, which reduce prostaglandin signaling and allow the vessel to constrict and close. Both drugs have been used extensively for ductal closure, but both carry side effects and safety concerns in preterm infants, including effects on renal perfusion, gastrointestinal integrity, and platelet function, concerns that have driven a decades-long search for alternatives.

That search produced one of the more memorable accidental discoveries in modern neonatology. As recounted by Sharma and Bhandari, Hammerman and colleagues observed that the use of acetaminophen in preterm infants led to closure of the patent ductus arteriosus, a finding reported in case series that surprised many observers. The mechanism is plausible: acetaminophen acts on prostaglandin synthesis through pathways distinct from classical cyclooxygenase inhibition, and the ductus in the preterm infant remains sensitive to even modest reductions in prostaglandin activity. Following those initial case reports, multiple trials demonstrated that acetaminophen was as effective in closing the ductus as the two established non-steroidal anti-inflammatory drugs, ibuprofen and indomethacin. Crucially, those studies did not look only at closure rates; they also examined associated morbidities, and bronchopulmonary dysplasia emerged as the outcome of greatest interest.

The evidence on that outcome, however, has been reassuringly consistent so far. A large multicenter trial conducted by Gupta and colleagues, published in the New England Journal of Medicine, showed no significant difference in the incidence of bronchopulmonary dysplasia between groups of infants treated with ibuprofen and those given placebo. A retrospective study by Jensen and colleagues compared one group of infants receiving acetaminophen with another receiving ibuprofen or indomethacin and found that the incidence of death or grade 2 to 3 bronchopulmonary dysplasia was similar in both groups. These findings suggested that neither class of drug, when used for ductal closure, clearly worsens the risk of chronic lung disease, at least within the populations and dosing regimens studied.

The BeNeDuctus trial added an important dimension to this debate. This large multicenter randomized non-inferiority trial compared expectant management of a significant patent ductus arteriosus, meaning careful observation without immediate drug treatment, against early treatment with ibuprofen. The trial showed no difference in the incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, or death between the two management strategies. That result was consequential in its own right, because it suggested that routine early pharmacological closure of the ductus may not be necessary for all affected infants. But it also created an unexpected opportunity: some patients in both subgroups received acetaminophen, not for ductal closure but for analgesia, meaning the trial inadvertently enrolled a cohort of extremely preterm infants exposed to the drug for reasons unrelated to their ductus.

Hoornenborg and colleagues exploited that opportunity in their secondary analysis, asking whether paracetamol given as an analgesic was associated with an increased risk of bronchopulmonary dysplasia in extremely preterm infants. The question matters because acetaminophen is among the most widely administered medications in neonatal intensive care, used for procedural and postoperative pain and increasingly considered for ductal closure. If the drug carried even a modest risk to the developing lung, the population-level consequences could be substantial given how many preterm infants receive it. Sharma and Bhandari frame their commentary around exactly this tension between therapeutic utility and pulmonary safety.

Concern about acetaminophen’s effects on the lung is not merely theoretical. Laboratory studies referenced in the commentary have shown that toxic acetaminophen exposure can induce distal lung endoplasmic reticulum stress, proinflammatory signaling, and emphysematous changes in the adult murine lung, and that the developing murine lung appears susceptible to acetaminophen toxicity in ways independent of the hepatic damage for which the drug is best known. Investigators have also raised the possibility that acetaminophen exposure in early life could have lifelong consequences for respiratory health. On the other side of the ledger, ibuprofen has its own pulmonary profile: animal work has documented vascular and pulmonary effects of ibuprofen on neonatal lung development, and recent studies indicate that inhibition of the mitochondrial integrated stress response can ameliorate ibuprofen-induced endothelial dysfunction in models of neonatal hyperoxia-induced lung injury. Both drug classes, in other words, have biological plausibility for lung effects that clinical trials have so far not translated into clear harm.

Interpreting this literature requires attention to the difficulty of the outcome itself. Bronchopulmonary dysplasia is now understood as a syndrome with multiple pulmonary phenotypes in the preterm infant, and its diagnosis has been refined through evidence-based approaches that grade severity by the level of respiratory support required. Newer tools, including magnetic resonance imaging phenotyping and life-course approaches to lung function monitoring after preterm birth, are reshaping how researchers detect subtle drug effects that survival-based or oxygen-based definitions may miss. The commentary’s authors, who have previously argued that bronchopulmonary dysplasia research must move from the bedside to the bench and back again, emphasize that postnatal inflammation, corticosteroid effects on lung development, and gene-environment interactions all complicate any attempt to isolate the contribution of a single analgesic or anti-inflammatory drug.

Where does this leave clinicians and families? The accumulating trial evidence, from the Gupta ibuprofen trial, the Jensen retrospective comparison, the BeNeDuctus trial, and now the Hoornenborg secondary analysis, points toward a consistent conclusion: neither acetaminophen nor the classical non-steroidal anti-inflammatory drugs, as used in contemporary neonatal practice, has been shown to increase the incidence of bronchopulmonary dysplasia or death in extremely preterm infants. At the same time, Sharma and Bhandari’s commentary underscores that the question of pulmonary safety has not been closed as definitively as the ductus itself. Preclinical signals of lung toxicity, the heterogeneity of bronchopulmonary dysplasia phenotypes, and the possibility of long-term respiratory consequences all argue for continued vigilance. As randomized trials of prophylactic acetaminophen for ductal closure and expectant management strategies continue to mature, the developing lung remains the outcome against which every neonatal drug must ultimately be judged.

Subject of Research: Pulmonary safety of acetaminophen and NSAID treatment for patent ductus arteriosus in preterm infants

Article Title: Does use of acetaminophen and/or NSAIDs increase the risk of developing bronchopulmonary dysplasia?

Article References: Sharma, R., & Bhandari, V. (2026). Does use of acetaminophen and/or NSAIDs increase the risk of developing bronchopulmonary dysplasia?. Pediatric Research. https://doi.org/10.1038/s41390-026-05526-y

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05526-y

Keywords: bronchopulmonary dysplasia, acetaminophen, NSAIDs, patent ductus arteriosus, preterm infants, BeNeDuctus trial, neonatology, ibuprofen, indomethacin, Pediatric Research, lung development, neonatal intensive care

Peptic ulcer bleeding, often abbreviated PUB, is one of the most feared complications in gastroenterology. It occurs when an open sore in the lining of the stomach or the first part of the small intestine erodes into a blood vessel, producing external digestive hemorrhage or a drop in hemoglobin greater than two grams per deciliter. Despite major advances in endoscopic therapy and acid suppression over the past two decades, patients who experience one such bleed remain at elevated risk of another. For those also taking antithrombotic medications—drugs such as antiplatelet agents and anticoagulants that are essential for preventing heart attacks and strokes—the calculus becomes even more delicate, because both the ulcer and the cardiovascular system compete for clinical attention.

The conventional wisdom, embedded in multiple international guidelines, holds that eradicating H. pylori, a spiral-shaped bacterium that colonizes the gastric mucosa and is a principal cause of peptic ulcer disease, is a cornerstone of preventing recurrent bleeding. Yet much of the evidence underpinning that recommendation predates the era of widespread, long-term proton pump inhibitor use, the powerful acid-suppressing drugs that have become near-universal prescriptions after a bleeding event. The Spanish team set out to test whether the bacterium still drives recurrence in a contemporary, real-world population in which acid suppression is the norm rather than the exception.

To answer the question, the investigators conducted a retrospective, multicenter cohort study of consecutive patients who suffered a first episode of peptic ulcer bleeding between 2008 and 2023 in real clinical settings across Spain. To be included, patients required endoscopically confirmed gastric or duodenal ulcers or erosions together with evidence of bleeding. Those with non-peptic causes of upper gastrointestinal hemorrhage, peptic ulcers without bleeding, bleeding from the small bowel or colon, missing clinical data, or death during the index hospitalization were excluded. Follow-up continued until the first recurrence of ulcer bleeding, death, loss to follow-up, or the end of the review period, yielding a mean observation time of 6.4 years with a standard deviation of 4.7 years—a remarkably long window for a study of this kind.

The cohort ultimately comprised 1,675 patients. At discharge after their first bleeding episode, 525 of them, or 31 percent, were prescribed antithrombotic therapy, while 1,021 patients, or 61 percent of the entire cohort, received long-term proton pump inhibitor prescriptions. Notably, among the antithrombotic users themselves, 429 patients, representing 82 percent, were given indefinite PPI therapy, underscoring just how thoroughly acid suppression has penetrated routine care for this group. After the initial bleed and any eradication treatment, 94 patients, or 5.6 percent, remained H. pylori-positive, 936 patients, or 56 percent, tested negative, and 645 patients, or 38 percent, were never tested for the bacterium—a sizable untested fraction that itself reflects themessiness of real-world medicine.

The headline finding for the whole cohort was striking. Overall, 7.2 percent of patients experienced a first recurrence of peptic ulcer bleeding during follow-up. But when the researchers stratified by H. pylori status, recurrence climbed to 22 percent among those who remained positive, fell to 7.7 percent among those who were negative, and dropped to just 4.2 percent among the untested. Using Cox regression analysis adjusted for age, sex, use of non-steroidal anti-inflammatory drugs, and long-term PPI prescription, the team calculated that patients who stayed H. pylori-positive had a 3.7-fold higher risk of recurrence compared with H. pylori-negative patients, with a 95 percent confidence interval of 2.3 to 6.1. When the comparison was restricted to patients who remained positive versus those who had been successfully eradicated, the risk was 4.7 times higher, with a confidence interval of 2.6 to 8.7. In other words, in the general population of bleeders, the bacterium remains a potent and measurable driver of recurrent hemorrhage.

The picture changed dramatically, however, when the researchers turned to the 525 patients on antithrombotic drugs. In this subgroup, the overall incidence of first recurrence was only 5.1 percent. Among H. pylori-positive antithrombotic users, recurrence reached 7.1 percent; among H. pylori-negative users, 8 percent; and among the untested, just 2 percent. Counterintuitively, the positive patients did not fare worse than the negative ones, and after statistical adjustment the team found no significant risk differences across H. pylori status groups. The wide confidence intervals that accompany such subgroup analyses temper any strong claims, but the signal is clear: within this heavily PPI-protected population, H. pylori status no longer predicted who would bleed again.

What might explain this apparent paradox? One plausible mechanism centers on gastric acidity itself. H. pylori promotes ulcer formation and recurrence partly through inflammation and disruption of the mucosal barrier, but acid secretion remains a critical cofactor in the cascade that turns a colonized stomach into a bleeding ulcer. Proton pump inhibitors suppress acid output profoundly and durably, and with 82 percent of antithrombotic users in this cohort taking them indefinitely, the pharmacological floor beneath the mucosa may be high enough that eradicating the bacterium adds little additional protection. In patients without such acid suppression, or in whom PPI therapy is intermittent, the bacterium retains its full pathogenic force—precisely the pattern the whole-cohort analysis revealed. The finding also echoes a broader shift in ulcer epidemiology: as H. pylori prevalence falls and non-steroidal anti-inflammatory drug and antithrombotic use rises, drug-induced mucosal injury has overtaken infection as the dominant cause of bleeding ulcers in many settings.

The authors are careful to frame their work as preliminary, and several limitations deserve attention. The retrospective design means the researchers depended on records and testing practices that varied across centers and years, and the 38 percent of patients never tested for H. pylori introduce the possibility of selection effects—clinicians may have been less likely to test patients they judged to be at low risk. The antithrombotic subgroup, though sizable at 525 patients, yielded relatively few recurrence events, which limits statistical power and widens uncertainty around the null finding. Confounding by indication is also possible, since patients receiving antithrombotics differ systematically from those who do not. The study’s ethics approval came from the ethics committee of Aragón under code EPA22/065, with the informed consent requirement waived owing to the observational design, and the statistical analysis was supported by the Group of Translational Research in Digestive Diseases of the Aragón Health Research Institute, the CIBERehd network, and the FORTALECE program of the Spanish Ministry of Science and Innovation.

Even with those caveats, the implications are hard to ignore. Millions of people worldwide take antithrombotic drugs for cardiovascular protection, and a meaningful share of them carry H. pylori or have uncertain infection status. If prolonged acid suppression largely neutralizes the bacterium’s contribution to recurrent bleeding in these patients, clinicians may be able to prioritize adherence to PPI therapy, careful antithrombotic dosing, and avoidance of non-steroidal anti-inflammatory drugs over exhaustive pursuit of eradication in every case. At the same time, the stark 3.7-fold elevation in recurrence risk among H. pylori-positive patients in the broader cohort is a vivid reminder that eradication remains essential for most survivors of ulcer bleeding. The study does not overturn the eradication paradigm; it carves out a well-defined exception and, in doing so, maps the boundary conditions of one of gastroenterology’s most durable beliefs. Larger prospective studies, ideally with systematic testing of all patients, will be needed to confirm where that boundary truly lies—but for now, the message from Spain is that in the modern, acid-suppressed, real-world clinic, the bacterium’s grip on bleeding risk may be loosening, at least for those whose hearts and vessels demand blood thinners.

Subject of Research: Helicobacter pylori status and recurrence of peptic ulcer bleeding in antithrombotic users

Article Title: No significant association between H. pylori status and peptic ulcer bleeding recurrence among antithrombotic users: a preliminary study in a real-world population with high PPI use

Article References: Martínez-Domínguez, S. J., Ceamanos-Ibarra, E., Gallego-Llera, B., Jiménez-Benedí, M., Bujanda, L., Jardón-Piérola, O., Izaguirre-Arostegi, A., Cuarán, C., Pascual, A., Almenara, L., & Lanas, Á. (2026). No significant association between H. pylori status and peptic ulcer bleeding recurrence among antithrombotic users: a preliminary study in a real-world population with high PPI use. BMC Medicine. https://doi.org/10.1186/s12916-026-05275-z

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05275-z

Keywords: Helicobacter pylori, peptic ulcer bleeding, antithrombotics, proton pump inhibitors, gastrointestinal bleeding, ulcer recurrence, Cox regression, retrospective cohort study, NSAIDs, eradication, BMC Medicine, gastroenterology

The research team, led by investigators at Samsung Medical Center in Seoul, drew on the Korean Nationwide Cancer Public Library Database, a national registry that links cancer diagnoses with prescription records, hospital visits, and death certificates. From this resource they identified 14,736 women newly diagnosed with ovarian or fallopian tube cancer between 2012 and 2019. Because South Korea’s National Health Insurance Service covers virtually the entire population, the database captures an unusually complete picture of real-world medication use, avoiding the recall bias that plagues studies asking patients to remember what they took years earlier.

The investigators classified NSAID exposure in two complementary ways. First, they looked at timing relative to diagnosis: women who filled NSAID prescriptions only within the six months after diagnosis were labeled POST users, while those who used the drugs both before and after diagnosis were labeled PRE and POST users. Second, they measured frequency of use after diagnosis, dividing patients into low users who took NSAIDs less than one day per week, intermediate users taking one to three days per week, and high users taking four or more days per week. This dual classification allowed the team to distinguish whether sustained use around the diagnostic window mattered more than intensity of use afterward.

The biological rationale for the study rests on decades of evidence that inflammation is not merely a symptom of cancer but an active participant in its progression. NSAIDs block cyclooxygenase enzymes, known as COX-1 and COX-2, which convert arachidonic acid into prostaglandins such as prostaglandin E2. In the ovarian tumor microenvironment, prostaglandin E2 has been linked to immune suppression, angiogenesis through vascular endothelial growth factor signaling, and the recruitment of myeloid-derived suppressor cells, all of which can blunt the body’s antitumor defenses and undermine chemotherapy. By dampening these pathways, NSAIDs have shown anticancer effects in other malignancies, including head and neck squamous cell carcinoma, prompting researchers to ask whether the same logic applies to ovarian cancer, a disease notoriously resistant to treatment in its advanced stages.

Over a median follow-up of 2.91 years, 4,108 of the women in the study died, a mortality rate of 27.9 percent. The team used Cox proportional hazards models, the standard statistical framework for survival analysis, adjusting for demographic characteristics, comorbidities measured by the Charlson Comorbidity Index, cancer stage, and treatment-related factors. The results were sobering for those hoping for a simple answer. In the fully adjusted model of the overall cohort, neither the timing of NSAID use nor the frequency of use after diagnosis was significantly associated with all-cause mortality. Women who used NSAIDs both before and after diagnosis had a hazard ratio of 0.94, with a 95 percent confidence interval of 0.88 to 1.01, a range that just crosses the threshold of statistical significance. High-frequency users fared similarly, with a hazard ratio of 0.92 and a confidence interval of 0.82 to 1.04.

But the story changed dramatically when the researchers stratified the cohort by initial treatment sequence, splitting patients into those who received surgery first and those who began with chemotherapy. Among women in the surgery-first group, the associations turned significant. Those who used NSAIDs both before and after diagnosis had a hazard ratio of 0.89, with a confidence interval of 0.82 to 0.97, indicating an eleven percent lower risk of death compared with women who did not. High-frequency users in this subgroup showed an even stronger signal, with a hazard ratio of 0.84 and a confidence interval of 0.73 to 0.98. In the chemotherapy-first subgroup, by contrast, no associations were found at all, regardless of timing or frequency.

Why might surgery-first patients benefit while chemotherapy-first patients show no effect? The authors and observers point to several plausible mechanisms. Surgery itself triggers a profound inflammatory response, releasing cytokines such as tumor necrosis factor-alpha and interleukin-8, and perioperative inflammation is known to suppress tumor-infiltrating lymphocytes, the immune cells that correlate with better outcomes in ovarian cancer. NSAIDs taken around the time of surgery could theoretically blunt this inflammatory surge and preserve antitumor immunity. Patients undergoing chemotherapy first, often those with more advanced or inoperable disease, may represent a biologically different population in which the dominant drivers of mortality are tumor aggressiveness rather than treatment-related inflammation, leaving less room for NSAIDs to matter.

The researchers themselves urge caution, and their language is deliberately restrained. They note that the significant findings in the surgery-first subgroup require cautious interpretation given multiple potential sources of residual confounding. Observational studies of this kind cannot prove causation, and the very fact that NSAID use was associated with benefit in one subgroup but not another raises the possibility of confounding by indication or by underlying health status. Women well enough to undergo primary surgery tend to have earlier-stage disease, better performance status, and different comorbidity profiles than those routed directly to chemotherapy, and even sophisticated statistical adjustment cannot fully erase these differences. Reverse causation is another concern: women with advanced disease may avoid NSAIDs or be prescribed them differently, distorting the apparent relationship between the drugs and survival.

There are also technical limitations inherent to prescription-database research. Over-the-counter NSAID purchases may not be fully captured, meaning some exposure could be misclassified. The study measured all-cause mortality rather than cancer-specific mortality, so deaths from cardiovascular events or other causes dilute any drug-specific signal. The dose and duration of NSAID use were approximated from prescription frequency rather than actual consumption, and the analysis could not distinguish reliably among individual agents, from non-selective NSAIDs such as ibuprofen and naproxen to selective COX-2 inhibitors, each with distinct pharmacology and safety profiles. Supplementary analyses by SEER stage, extent of surgical procedure, and intensive care unit admission were performed to probe the robustness of the findings, but no observational design can eliminate uncertainty entirely.

Still, the scale of the study gives its null and subgroup findings real weight. With nearly fifteen thousand patients drawn from a single-payer national system, this is among the largest investigations of peri-diagnostic NSAID use in ovarian cancer to date, and one of the first in an Asian population, where prior evidence has been sparse. The authors, who declare no competing interests and received no specific funding for the work, emphasize that their results do not support recommending NSAIDs to ovarian cancer patients as a survival intervention. Instead, the surgery-first signal should be viewed as a hypothesis generator, pointing toward randomized or mechanistic studies that could test whether perioperative anti-inflammatory treatment genuinely alters the tumor microenvironment and improves outcomes. Until such evidence arrives, the humble painkillers in nearly every medicine cabinet remain exactly what they have always been for ovarian cancer patients: useful for pain, unproven for survival, and now the subject of a tantalizing question that only further research can answer.

Subject of Research: Peri-diagnostic NSAID use and all-cause mortality in ovarian cancer

Article Title: Peri-diagnostic NSAID use and all-cause mortality in ovarian cancer: nationwide cohort study

Article References: Lim, S., Hong, J.-Y., Seo, J.-H., Chung, Y. E., Kim, S. Y., Han, K., & Lee, Y.-Y. (2026). Peri-diagnostic NSAID use and all-cause mortality in ovarian cancer: nationwide cohort study. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02278-5

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02278-5

Keywords: ovarian cancer, NSAIDs, all-cause mortality, nationwide cohort, inflammation, COX-2, tumor microenvironment, surgery-first, chemotherapy-first, Korea, survival analysis, epidemiology

The mechanics of a prescribing cascade are deceptively simple, which is precisely what makes them so difficult to catch in busy clinical practice. Consider one of the clearest examples highlighted in the study: non-steroidal anti-inflammatory drugs, or NSAIDs, which are among the most widely used medications for pain relief in older populations. NSAIDs are known to raise blood pressure in many patients. When that rise occurs, it can easily be read as the emergence of hypertension, a genuine and serious condition in its own right, leading to a new prescription for antihypertensive medication. What gets lost in that transaction is the causal thread connecting the two drugs. The patient now takes two medications instead of one, carries the side-effect burden of both, and the underlying trigger, the NSAID itself, remains untouched. The cascade, once established, can continue to grow.

Older adults are especially vulnerable to this pattern for reasons that are both biological and structural. Advanced age typically brings multiple chronic conditions, and multiple conditions mean multiple prescribing physicians, multiple pharmacies and, frequently, a long list of concurrent medications. When a new symptom appears in a patient taking ten or twelve drugs, tracing it back to a specific medication started months earlier is a formidable task for even the most diligent clinician. The symptom is more likely to be attributed to aging, to one of the existing diagnoses, or to a genuinely new disease. Dr. Rochon, who holds the Barry J. Goldlist Chair in Aging and Health at Sinai Health and is a professor of medicine at the University of Toronto, emphasized that these sequences of events are common but often missed in clinical practice. Knowing what medications a patient is taking, when each one was started, and for what indication, she noted, is essential for identifying problematic cascades before they compound.

To move the problem from anecdote to evidence, the research team assembled an interdisciplinary, international group of collaborators and leaders in drug prescribing and geriatric medicine research spanning the United States, Belgium, Italy, Israel and Ireland. The Canadian side of the effort included Sinai Health researchers Drs. Vasily Giannakeas, Nathan Stall and Christina Reppas-Rindlisbacher, along with research staff Wei Wu and Joyce Li. Working with Lavina Matai and Zhiyin Li at ICES, Ontario’s health data institute, the team gained access to population-level prescription data covering the province, an unusually powerful foundation for studying how prescribing patterns unfold across millions of patients over time rather than within the confines of a single clinic or hospital.

The analytical framework rested on work the team had completed previously: with the expertise of twelve international panelists specializing in internal medicine, geriatric medicine and clinical pharmacology, the researchers had compiled a list of sixty-five potentially inappropriate prescribing cascades drawn from the medical literature and expert consensus. Each cascade on that list describes a first drug, a second drug prescribed in response to the first drug’s adverse effect, and a plausible biological mechanism linking the two. The Ontario study then subjected all sixty-five candidates to a rigorous population-level test built on three criteria. First, how common was the initial drug in the population? Second, how often was it actually followed by the second drug in real-world prescribing data? Third, how strong was the observed link between the two prescriptions?

That three-part analysis allowed the researchers to distill the field down to the twenty-four potentially inappropriate prescribing cascades that are both most commonly seen in the Ontario population and most likely to cause harm. The list spans a striking range of everyday therapeutics. Beyond the NSAID-to-blood-pressure-medication pathway, the study points to cascades involving statins, iron supplements and other widely dispensed drugs, illustrating that the risk is not confined to exotic or high-alert medications. It is embedded in the routine, well-intentioned prescribing that happens thousands of times a day across the province. Because the analysis was conducted at the level of an entire population rather than a selected cohort, the findings offer some of the strongest evidence yet that prescribing cascades are a systemic issue rather than a collection of individual clinical errors.

For Dr. Rochon, the findings illuminate a gap that opens quietly, one prescription at a time. Her concern, she explained, is that the conversations between prescribers and patients that would reveal these connections are so often missed, leaving both parties unaware that a sequence of events is unfolding and that the events are connected to one another. Closing that gap, the team argues, requires physicians to treat medication history as a living document that deserves attention at every visit, not merely a static list of current drugs. Clinicians need to ask why each medication was started in the first place, when it was initiated, and whether the newest prescription on the list is genuinely treating a new disease or simply patching over the side effect of an older one. That reflective pause, applied consistently, could interrupt a cascade before a second or third drug is ever added.

The findings carry particular weight for mature women, a population that sits at the center of Dr. Rochon’s research program. Women tend to live with more chronic conditions than men over their lifetimes, are prescribed more drug therapies, and experience more adverse drug events. Each additional medication increases the surface area for harm, and each additional condition complicates the diagnostic picture when a new symptom emerges. A woman managing osteoporosis, arthritis, cardiovascular risk factors and other conditions simultaneously faces a heightened probability that a drug’s side effect will be mistaken for a new diagnosis rather than traced back to its source. The study’s population-level lens makes clear that this is not a marginal concern but a structural feature of how care is delivered to older women, and one that deserves targeted attention in prescribing guidelines and clinical education alike.

The research team’s conclusions point toward concrete, technologically feasible next steps. The first involves automated clinical decision support tools embedded directly in electronic prescribing systems. Such tools could flag a potential prescribing cascade in real time, alerting the prescriber at the exact moment a new prescription is about to be added that the patient is already taking a drug known to produce the symptom now being treated. Delivered at the point of care, this kind of automated awareness could transform prescribing cascades from an invisible population-level phenomenon into a visible, actionable warning. The technology required is not speculative; the underlying data linkages and rule-based logic mirror systems already used to flag drug allergies and dangerous interactions.

The second proposed step is organizational rather than technical: optimizing the role of pharmacists as full members of the care team and integrating them more directly into the prescribing process alongside physicians. Pharmacists possess precisely the expertise needed to spot the signature of a prescribing cascade, a new drug whose start date closely follows an older drug with a known adverse-effect profile, and to initiate a medication review before the cascade deepens. Together, the two strategies address the problem from complementary angles, embedding vigilance in both the software that supports prescribing decisions and the professional relationships that surround them. As populations age and polypharmacy becomes the norm rather than the exception, the Ontario study suggests that the question is no longer whether prescribing cascades cause widespread harm, but how quickly health systems can build the safeguards needed to stop them.

Subject of Research: Potentially inappropriate prescribing cascades in older adults identified through population-level analysis of Ontario prescription data

Article Title: Ontario study identifies potentially harmful drug combinations prescribed to older adults

Article References: Ontario study identifies potentially harmful drug combinations prescribed to older adults. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: prescribing cascades, older adults, polypharmacy, medication safety, geriatric medicine, NSAIDs, blood pressure, statins, clinical decision support, pharmacists, mature women's health, The BMJ