The study, published in the Journal of Perinatology by a team led by Sharada H. Gowda of Indiana University and Riley Children’s Hospital, gathered written PDA management guidelines from hospitals belonging to the Children’s Hospitals Neonatal Consortium, a network of 44 quaternary-level neonatal intensive care units in the United States and Canada. Between November 2023 and February 2024, the researchers emailed designated representatives at every member center, asking whether their institution maintained a formal written guideline for managing the condition in premature infants and requesting a copy if one existed. Thirty-eight of the 44 centers responded, an 86 percent response rate, and 25 of those, roughly two-thirds, provided written protocols for analysis.

What the researchers found was a field united by a broad philosophy but divided on nearly every practical detail. Most guidelines described a stepwise approach that begins with expectant, or watchful, management, escalates to drug therapy when the ductus becomes hemodynamically significant, and reserves procedural closure for infants who fail medical treatment. Yet beneath that shared skeleton, the specifics varied dramatically. Screening strategies, diagnostic thresholds, drug choices, dosing schedules, feeding policies, and the timing of interventions all differed from center to center, sometimes in striking ways.

The diagnosis itself is the first fault line. Hemodynamically significant PDA, abbreviated hsPDA, refers to a ductal shunt substantial enough to disturb the infant’s circulation, potentially stealing blood from the gut and lungs and contributing to serious complications such as bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and prolonged intensive care stays. Because clinical signs such as a heart murmur, bounding pulses, or worsening respiratory status are notoriously nonspecific, objective echocardiographic assessment has become the cornerstone of diagnosis. In the survey, 88 percent of guidelines specified echocardiographic criteria, most commonly ductal diameter, the left atrium-to-aorta ratio, shortened isovolumic relaxation time, and flow reversal in the descending aorta. Less frequently cited markers included flow reversal in the celiac trunk or middle cerebral artery, parameters that reflect more severe systemic hypoperfusion.

Clinical criteria appeared in 80 percent of the guidelines, and respiratory support requirements dominated that category. Among centers that referenced breathing support, 42 percent cited escalating respiratory needs, 37 percent required at least noninvasive ventilation or nasal continuous positive airway pressure, and a small number demanded intubation or used a quantitative respiratory severity score. Other clinical triggers included pulmonary edema, cardiomegaly, pulmonary hemorrhage, widened pulse pressure, and a hyperdynamic precordium, the pounding chest sensation produced by a large shunt. Only 12 percent of centers, however, employed a formal clinical scoring system, a strikingly low figure given growing evidence that composite scores may predict outcomes better than any single parameter.

Screening practices revealed similar heterogeneity. Ninety-two percent of guidelines described risk-based or symptom-based screening for the condition, but the timing of the first echocardiogram ranged from within 36 hours of birth for the most immature infants at some centers to delayed evaluation in the second week of life at others. Some centers screened purely on gestational age, some purely on symptoms, and about a third used a combination of the two. This scatter mirrors the unsettled evidence base: randomized trials and meta-analyses have repeatedly failed to show a clear benefit of routine early treatment compared with expectant management, leaving each institution to chart its own course through the ambiguity.

When treatment is warranted, ibuprofen has emerged as the workhorse drug, recommended as first-line pharmacotherapy by more centers than any alternative. Indomethacin, the traditional cyclooxygenase inhibitor that dominated PDA therapy for decades, has been displaced, while intravenous acetaminophen, increasingly popular at the bedside, remains underrepresented in formal protocols, a discrepancy the authors interpret as evidence that written guidelines lag behind evolving clinician preferences. A quarter of centers recommended prophylactic therapy for the highest-risk infants, such as those born before 25 to 26 weeks without antenatal steroid exposure, with some using indomethacin and others administering acetaminophen at 15 milligrams per kilogram every six hours for twelve doses. The number of treatment courses allowed also varied widely, from a single course at one center to as many as four at others.

Feeding practices during therapy, long a source of anxiety because of theoretical concerns about gut injury, showed a reassuring convergence. Not a single guideline recommended holding feeds entirely during pharmacotherapy, and most centers either allowed full feeding, restricted volume modestly, or permitted trophic feeds. This aligns with accumulating evidence that withholding feeds prolongs the time needed to reach full nutrition without reducing gastrointestinal complications, and that feed interruption may even explain some of the poor outcomes previously attributed to the drugs themselves. On the expectant side, centers that described conservative management uniformly recommended fluid restriction of 120 to 140 milliliters per kilogram per day, with most also endorsing higher breathing pressures, diuretics, and higher hemoglobin targets, while explicitly encouraging rather than restricting nutrition.

Perhaps the most consequential trend captured by the survey is the rise of transcatheter closure. Ninety-two percent of guidelines addressed device-based closure, and 83 percent of those recommended a course of pharmacotherapy before resorting to the catheter procedure. Minimum weight thresholds for device closure ranged from 650 to 1,800 grams, and several centers specified waiting until 14 or 21 days of life. Surgical ligation, once the default definitive treatment, appeared in only 48 percent of guidelines and was frequently reserved for infants too small for the catheter approach. The shift reflects the maturation of minimally invasive occluder devices and a growing recognition that surgical ligation carries risks of its own, including vocal cord paralysis and the controversial post-ligation syndrome, for which, remarkably, only one center in the entire consortium offered written guidance.

The authors are careful to note the study’s limits: written guidelines may not match what actually happens at the bedside, the survey captured no patient outcomes, and the findings come exclusively from large referral centers that may not represent community hospitals. The timing also matters, since the data collection preceded several landmark trials, including BeNeDuctus, BabyOSCAR, and the Neonatal Research Network PDA Randomized Clinical Trial, each of which concluded that conservative management performs as well as or better than drug treatment, though all were constrained by early termination, treatment crossover, and the exclusion of the sickest infants. Still, the picture that emerges is of a specialty in transition, holding onto a common stepwise framework while awaiting the evidence needed to settle its deepest disagreements. For the smallest patients, whose lives often hinge on decisions made within hours of birth, the path from a leaking vessel in the heart to a healed one still depends, to a remarkable degree, on which hospital door they enter first.

Subject of Research: Variation in diagnosis and management of hemodynamically significant patent ductus arteriosus across neonatal intensive care units

Article Title: Variations in diagnosis and management of hemodynamically significant patent ductus arteriosus across neonatal intensive care units in the Children’s Hospitals Neonatal Consortium

Article References: Gowda, S. H., Levy, P. T., Hamrick, S., Keene, S., Sen, S., Rajgarhia, A., Rao, R., Ball, M. K., Weems, M. F., & on behalf of CHNC Cardiac Focus Group (2026). Variations in diagnosis and management of hemodynamically significant patent ductus arteriosus across neonatal intensive care units in the Children’s Hospitals Neonatal Consortium. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02910-8

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02910-8

Keywords: patent ductus arteriosus, preterm infants, neonatal intensive care, echocardiography, ibuprofen, acetaminophen, transcatheter closure, surgical ligation, clinical guidelines, Children's Hospitals Neonatal Consortium, hsPDA, neonatology

The ductus arteriosus is a fetal shortcut that connects the pulmonary artery to the aorta, allowing blood to bypass the fluid-filled, non-functioning lungs before birth. In most babies, the vessel seals itself within the first days of life. In premature infants, however, closure often fails. The problem is remarkably common: an estimated 66 to 79 percent of neonates born weighing less than 1000 grams still have a patent ductus at seven days of age. Whether that open vessel is merely a lingering remnant or a genuine threat to fragile organs depends on its hemodynamic significance, meaning the degree to which it steals blood from the systemic circulation and floods the lungs. And that, precisely, is where consensus collapses, because no universally accepted standard exists for defining when a ductus has crossed the line from benign to dangerous.

The new study, led by Paige E. Condit and John S. Hokanson of the University of Wisconsin-Madison, set out to map this contested terrain. Between February and April 2024, the researchers distributed an anonymous Qualtrics survey to members of the American Academy of Pediatrics Section on Neonatal-Perinatal Medicine, the Section on Cardiology and Cardiac Surgery, and the Pediheart.net online community. Roughly 504 providers began the survey and 422 completed it, yielding an overall response rate of about 8 percent. The analytic sample included 315 neonatologists and 107 pediatric cardiologists. Importantly, the neonatology group was stratified by whether the respondent’s institution offered in-house catheter-based ductal closure, a proxy for the highest-acuity Level IV neonatal intensive care units, allowing the investigators to probe whether access to advanced procedural capability shapes clinical judgment.

The headline result is a portrait of deep disagreement over echocardiography, the ultrasound technique on which virtually all modern ductal assessment rests. Respondents were asked to rank the clinical utility of 14 echocardiographic parameters on a three-point importance scale; the analysis focused on the nine parameters most commonly included in published scores and guidelines. Of those nine, the specialists agreed on the importance of only two: retrograde flow in the post-ductal aorta and the diameter of the ductus itself. For the remaining seven, including measures of left ventricular output, left atrial to aortic root ratio, and end-diastolic flow velocity in the branch pulmonary arteries, neonatologists and cardiologists assigned statistically different levels of both familiarity and importance. The largest familiarity gaps appeared for pulmonary artery end-diastolic flow velocity and left ventricular outflow, with effect sizes reaching the large range, a signal that the two specialties are not merely quibbling over fine points but diverging on fundamental diagnostic building blocks.

One intriguing pattern emerged from the stratification: neonatologists working at centers with in-house catheter closure capability tended to answer more like cardiologists than did their colleagues at centers without such programs. The authors attribute this to daily collaboration, noting that proximity to interventional cardiology likely exposes neonatologists to the same imaging vocabulary and interpretive habits. The implication is sobering for the field, because it suggests that even within a single specialty, the perceived meaning of an echocardiographic image may depend less on the image itself than on the institutional culture surrounding it. When two subspecialties disagree on which markers define hemodynamic significance, confusion can ripple through clinical handoffs, treatment decisions, and even the design of research studies, since cardiology-led and neonatology-led investigations may prioritize different aspects of ductal evaluation.

Formal scoring systems, which were developed precisely to resolve this ambiguity, remain strikingly underused. Only a minority of respondents reported employing any echocardiographic or clinical scoring system, with routine use ranging from 7.8 percent among neonatologists without catheter programs to 19.4 percent among those with them. The survey was conducted before the American Academy of Pediatrics released its recent clinical practice guideline, which recommends a combined echocardiographic and clinical approach with specific criteria required from each domain, so adoption may shift. But the authors point to a deeper problem: several validated scores exist, including the El-Khuffash score, which incorporates gestational age, ductal diameter, flow velocity, and left ventricular measures and has shown strong prediction of chronic lung disease or death with an area under the curve of 0.92, yet none has been proven in a randomized trial to improve outcomes when used to guide treatment compared with clinical judgment alone. A small feasibility trial of score-guided therapy did not demonstrate a statistically significant benefit, and the Iowa score’s reported reductions in severe bronchopulmonary dysplasia cannot be cleanly attributed to the score because the protocol bundled early screening echocardiography and other care changes together.

The survey also documented a quiet revolution in treatment delivery. Medical therapy was available to 99 percent of respondents, but prophylactic treatment was rare, reported by just 12.3 percent. Among first-line agents, acetaminophen narrowly led at 32.8 percent, followed by ibuprofen at 30.5 percent and the older indomethacin at 23.9 percent, with significant differences between specialties, partly because nearly half of cardiologists reported not making these pharmacologic recommendations at all. Most providers, 59 percent, said they would attempt medication-based closure twice before recommending a procedure, while about a quarter would try three times. When it came to procedural closure, the landscape has flipped: 72.1 percent of respondents said they rarely recommend surgical ligation, while catheter-based occlusion, recommended often by 65.1 percent of cardiologists and 48.1 percent of catheter-equipped neonatologists, has been rapidly adopted. An overwhelming 89 percent of respondents named the Amplatzer Piccolo device as their preferred occlusion device, a preference that did not differ by specialty. This shift follows studies suggesting better respiratory outcomes and lower mortality with transcatheter closure compared with surgery, even though no definitive trial has yet shown transcatheter closure to be superior to expectant management.

Screening practices added another layer of variation. Only 13.5 percent of respondents reported that their facility used routine screening echocardiograms for ductal evaluation. Among those who did, the average timing was 28.3 weeks’ gestation, but the spread was wide: neonatologists with in-house catheter programs screened earliest at a mean of 27.5 weeks, those without screened at 27.8 weeks, and cardiologists reported a mean of 31.0 weeks, a statistically significant difference with a medium effect size. The authors caution, however, that the question about screening echocardiography may have been interpreted differently across specialties, a reminder that survey-based comparisons of practice carry their own measurement hazards.

Indeed, the study’s limitations deserve as much attention as its findings. With an 8 percent response rate, non-response bias is a real concern; respondents may be more interested or experienced in ductal management than their silent colleagues, so the results reflect an engaged subset rather than a nationally representative sample. The survey did not capture practice setting, patient volume, or how often respondents actually manage hsPDA, all of which could confound the specialty comparisons. Membership overlap between the cardiology organizations means some cardiologists may have received duplicate invitations and potentially responded more than once, and multiple responses from the same institution could have skewed resource-availability estimates. The survey instrument lacked formal psychometric validation, multiple statistical comparisons were performed without correction for multiplicity, and respondents averaged 18 years in practice, which may not capture the habits of newer generations of clinicians.

Still, the big picture is hard to escape. A vessel present in most extremely premature infants is being diagnosed, scored, medicated, and closed in wildly different ways across the country, by specialists who cannot agree on which ultrasound measurements matter most. The authors call for studies that correlate echocardiographic findings with clinical outcomes and with hemodynamic data from cardiac catheterization, the gold standard of direct measurement, to finally anchor the definition of hemodynamic significance in physiology rather than tradition. Until that evidence arrives, the treatment of the premature ductus will remain what this survey reveals it to be: a high-stakes judgment call, made at the bedside of the smallest patients, under rules that two specialties are still writing separately.

Subject of Research: Diagnosis and management of hemodynamically significant patent ductus arteriosus in premature infants

Article Title: Current practices in the management of hemodynamically significant patent ductus arteriosus

Article References: Condit, P. E., Erdmann, A. A., Zhang, X., Ndukwe, E., Fernandez, J., & Hokanson, J. S. (2026). Current practices in the management of hemodynamically significant patent ductus arteriosus. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02914-4

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02914-4

Keywords: patent ductus arteriosus, premature infants, echocardiography, neonatology, pediatric cardiology, catheter closure, scoring systems, survey, neonatal intensive care, acetaminophen, ibuprofen, surgical ligation

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

The researchers focused on the pentagonal window cavity of the fluorinated form of MIL-101(Cr), known as MIL-101(Cr)-F, and simulated the adsorption of the S-enantiomer of ibuprofen in liquid water using molecular dynamics. Their simulations yielded a loading of 483 milligrams of ibuprofen per gram of framework within this single cavity type, corresponding to 77 ibuprofen molecules adsorbed simultaneously. That figure is consistent with estimates previously reported in the literature, a point of validation that matters enormously in a field where simulated capacities sometimes diverge wildly from experimental measurements. The agreement suggests that the computational model captures the essential physics of a crowded, water-filled nanoscale cage.

One of the study’s most striking findings is what the authors did not find. Despite the framework’s rich chemistry, including open metal sites and polar functional groups that might be expected to anchor incoming drug molecules, no specific adsorption sites emerged on the metal-organic framework itself. Instead, the ibuprofen molecules distributed themselves across three distinct adsorption zones within the cavity model, occupying regions defined more by geometry and collective interactions than by any single privileged binding pocket. This picture of diffuse, zonal adsorption challenges the intuitive notion that a molecule entering a crystalline cage should snap onto a well-defined site, and it reframes how chemists should think about capacity in mesoporous frameworks.

The dominant forces holding ibuprofen in place turned out to be familiar workhorses of supramolecular chemistry. Pi-pi interactions between the framework’s organic linkers and the aromatic ring of ibuprofen provide the primary glue, stacking the drug’s benzene ring against the terephthalate-based walls of the cage. Complementing this stacking, electrostatic interactions arise between the oxygen atoms of the inorganic clusters and the hydrogen atoms of the ibuprofen molecule. Together, these weak but numerous contacts allow dozens of drug molecules to coexist inside a single cavity, each jostling in liquid water yet collectively achieving a high loading. The result illustrates a general principle of adsorption in crowded environments: many weak interactions can outperform a few strong ones.

The deepest surprise came when the team probed the carboxylic acid group of ibuprofen, the chemical handle that quantum chemistry calculations suggested should coordinate directly to a chromium atom in the framework’s inorganic cluster. In isolation, that coordination looks energetically favorable, and the quantum chemical calculations indeed showed it forming. But molecular dynamics in liquid water told a different story. A layer of three water molecules assembled around the carboxylic group, each forming hydrogen bonds with the oxygen sites of the acid. This molecular water shell acted as a physical barrier, preventing the carboxylic group from ever approaching the chromium atoms closely enough to coordinate.

This water-mediated shielding effect carries significant implications for how researchers design and interpret adsorption experiments with metal-organic frameworks in aqueous settings. If the strongest potential binding interaction between a pollutant and an adsorbent can be silently neutralized by a thin film of water, then predictions based on dry-state quantum chemistry may dramatically misjudge which interactions govern real-world performance. The study demonstrates that hydration must be treated as an active participant in adsorption, not a passive background. For ibuprofen capture by MIL-101(Cr), the practical adsorption mechanism is dictated by pi-stacking and electrostatics, while the chromium sites remain effectively off-limits under liquid-water conditions.

The methodological toolkit behind these conclusions reflects the current state of the art in multiscale molecular simulation. The authors employed the OPLS all-atom force field, augmented with parameters generated through the SwissParam web service and the MATCH atom-typing toolset, to describe the organic molecules. Initial configurations were constructed with PACKMOL, biased sampling of collective variables was handled through the Colvars framework, and the production dynamics ran on the NAMD engine, with analysis performed using MDAnalysis and visualization in VMD. Quantum chemistry calculations were carried out with the ORCA program system, using CM5 charges suitable for condensed-phase modeling. This combination allowed the team to bridge the gap between electronic-structure accuracy and the long time scales needed to observe hydration shells forming and holding.

The broader context makes the work timely. Ibuprofen belongs to a large family of emerging contaminants, including pharmaceuticals and personal care products, that conventional treatment infrastructure was never designed to remove. Reviews of the field document their occurrence, ecological risk, and health effects across the globe, and metal-organic frameworks have emerged as versatile adsorbents and degradation platforms for these pollutants. MIL-101(Cr) in particular has been tested extensively, both as a pristine material and in composite forms with natural polymers, graphene oxide, and doped variants, for capturing ibuprofen and related drugs such as naproxen. The same framework has also been explored for drug delivery, carbon dioxide capture, water vapor adsorption, and chromatographic separation, making a detailed mechanistic understanding of its aqueous adsorption behavior valuable far beyond a single pollutant.

What sets the new study apart is its insistence on simulating the realistic competitive environment of liquid water rather than the cleaner but less relevant case of a dry framework exposed to a guest molecule. Previous simulation work had examined ibuprofen energetics in mesoporous frameworks and the behavior of confined water in MIL-101, but the Chilean team brought the two threads together to reveal their interplay. The three-water-molecule barrier around the carboxylic group is precisely the kind of emergent phenomenon that only appears when solvent, adsorbate, and framework are all treated explicitly and simultaneously. It is a vivid reminder that nanoscale water is not a spectator.

For engineers designing next-generation water treatment media, the message is actionable. Enhancing pi-stacking surfaces, tuning electrostatic complementarity, or modifying the framework to disrupt the protective water shell around acidic functional groups could all raise adsorption performance in ways that dry-state intuition would miss. Conversely, the confirmed high loading of 483 milligrams per gram in a single cavity type underscores why MIL-101(Cr) remains a benchmark material. As pharmaceutical contamination of waterways accelerates worldwide, studies like this one, funded by Chile’s Agencia Nacional de Investigación y Desarrollo under grant ANID Fondecyt No. 11230774, provide the molecular-level blueprint needed to turn porous crystals into practical guardians of clean water.

Subject of Research: Molecular simulation of S-ibuprofen adsorption from liquid water inside the pentagonal cavity of the metal-organic framework MIL-101(Cr)-F

Article Title: Molecular simulation of the adsorption of S-ibuprofen in liquid water in the pentagonal cavity of MIL-101(Cr)-F

Article References: Molecular simulation of the adsorption of S-ibuprofen in liquid water in the pentagonal cavity of MIL-101(Cr)-F. (n.d.). https://doi.org/10.1007/s10853-026-13822-5

Image Credits: AI Generated

DOI: 10.1007/s10853-026-13822-5

Keywords: metal-organic frameworks, MIL-101(Cr), ibuprofen, molecular dynamics, water purification, adsorption, emerging contaminants, pi-pi interactions, hydration shell, quantum chemistry, pharmaceutical pollution, computational chemistry

What happened next transformed this routine infection into a diagnostic puzzle that physicians rarely encounter. By hospital day 11, imaging showed that the right upper lobe infiltrate had resolved, but new bilateral pleural effusions had appeared in its place. Thoracentesis was performed on both sides of the chest, and both effusions were grossly bloody and exudative. Yet beneath that identical bloody appearance lay a startling discordance: the right-sided fluid was dominated by neutrophils, at 85 percent, while the left-sided fluid was dominated by lymphocytes, at 90 percent. Cytology was negative for malignancy in both samples, and cultures grew no organisms. A single systemic process, such as heart failure or carcinomatosis, could not plausibly produce two fluids with such different cellular signatures. Instead, the findings pointed toward two entirely independent diseases developing simultaneously in the same chest.

The right effusion was straightforward to explain. Parapneumonic effusions are a well-recognised complication of bacterial pneumonia, particularly pneumococcal infection, in which parenchymal inflammation extends to the pleural space and generates a protein-rich, neutrophil-dominant exudate driven by acute inflammation. The antibiotic therapy was working against the pneumonia itself, but the severe initial inflammatory burden likely led to a delayed manifestation of pleurisy, with effusions emerging even as the lung infiltrate retreated. That mechanism accounted for the right hemithorax. The left effusion, with its lymphocyte predominance and later behaviour, was a far more elusive entity that would take months to reveal its full character.

The bloody appearance of both effusions added another layer of complexity. The patient’s antithrombotic regimen included edoxaban, a direct oral anticoagulant, along with aspirin, prescribed after coronary artery bypass grafting approximately 12 months earlier for acute coronary syndrome. Direct oral anticoagulants have been reported to induce spontaneous pleural bleeding, and the clinicians hypothesised that the combination of anticoagulant and antiplatelet therapy exacerbated microvascular oozing within inflamed pleura. Notably, however, the red blood cell counts in the effusions were relatively modest, yielding calculated pleural fluid haematocrits of only 0.18 percent on the right and 0.44 percent on the left, far below the diagnostic threshold for haemothorax. In other words, the bleeding tendency likely painted the exudates red without fundamentally changing their underlying inflammatory nature.

Management reflected the uncertainty. Given the bloody effusions, the team discontinued only the edoxaban and administered haemostatic agents, while continuing aspirin after consultation with the cardiovascular surgery team. Follow-up chest CT on May 21 showed partial resolution of the effusions, and with fever and hypoxaemia resolved, the patient was discharged on May 23. He remained stable as an outpatient for three months. Then, in late August, the left effusion worsened, and a concurrent chest CT revealed a small pericardial effusion that was too small for pericardiocentesis. A repeat left thoracentesis again yielded bloody, lymphocyte-dominant fluid, and C-reactive protein, which had normalised after discharge, had crept back above the institutional upper limit of normal. Echocardiography demonstrated preserved left ventricular function, arguing against heart failure as the cause.

This late recurrence allowed the clinicians to apply formal diagnostic criteria. The 2015 European Society of Cardiology guidelines for pericardial diseases require at least two of five criteria for a diagnosis of post-cardiac injury syndrome, the category that encompasses Dressler syndrome. The patient fulfilled two: pericardial effusion on CT and pleural effusion with elevated inflammatory markers. Fever, pericarditic or pleuritic chest pain, and audible rubs were all absent, making the presentation distinctly indolent. Late-onset Dressler syndrome was suspected, and the team initiated diagnostic therapy with ibuprofen at 600 mg per day, the maximum dose covered by Japanese medical insurance. Follow-up imaging confirmed significant improvement of both the left pleural and pericardial effusions, and no recurrence occurred during 10 months of follow-up after the anti-inflammatory treatment began.

Dressler syndrome is an immune-mediated pleuropericarditis that classically appears within weeks to a few months of cardiac injury, most often after cardiac surgery such as coronary artery bypass grafting. The prevailing pathophysiological model holds that cardiac injury releases sequestered cardiac antigens, triggering the formation of anti-heart autoantibodies. The time required for this immunological sensitisation inherently creates a latent period between injury and clinical onset. The reported profile of post-cardiac injury syndrome effusions fits this patient’s left-sided fluid almost exactly: such effusions are unilateral in about two thirds of cases and left-sided in the large majority, with no Dressler syndrome patients in one published series showing right-sided unilateral effusions; nearly all are exudates, and roughly three quarters are lymphocyte-predominant.

The timing, however, was extraordinary. Onset occurred approximately 12 months after bypass surgery, exceeding not only the usual latent window but also the nine-month interval described in one of the longest previously reported cases. The authors propose a two-hit hypothesis: the patient developed long-standing latent immune sensitisation following his cardiac surgery, and the intense systemic inflammatory response generated by severe pneumococcal pneumonia acted as a necessary catalyst, reactivating the dormant autoreactive process and culminating in the delayed manifestation of Dressler syndrome. In this framing, the pneumonia did not merely coexist with the immune syndrome; it may have ignited it. The two mechanisms are not mutually exclusive, and an immune-mediated predisposition related to prior cardiac injury may have been unmasked by systemic inflammation from the contralateral infection.

The authors are careful to acknowledge residual diagnostic uncertainty, since a response to non-steroidal anti-inflammatory drugs is common in pleuropericarditis of virtually any cause. A reactive post-infectious serositis following the pneumonia remains a plausible alternative, as autoimmune pleuropericarditis has been reported after community-acquired pneumonia, including Chlamydia pneumoniae-associated cases. Furthermore, no pericardial effusion was present at the time of the initial thoracenteses, and the left effusion was attributed to a post-cardiac injury process only retrospectively, once the August recurrence fulfilled the formal criteria. The lymphocyte-predominant profile and prompt ibuprofen response support an immune-mediated process, but they do not definitively tie it to the prior surgery rather than the preceding infection. Late-onset Dressler syndrome is therefore presented as the most likely clinical diagnosis rather than a certain one.

The broader lesson reaches well beyond this single patient. Clinicians frequently assume that bilateral pleural effusions stem from a single systemic aetiology such as heart failure, renal failure or malignancy, and this assumption can obscure independent localised pathologies that demand separate therapeutic strategies. In this case, the two sides of the chest required targeted antibiotic therapy on the right and anti-inflammatory treatment on the left, and neither intervention alone would have addressed both conditions. The definitive clue was not the grossly bloody appearance, which was identical on both sides and heavily influenced by antithrombotic medications, but the rare and striking discordance of pleural fluid cellular profiles between hemithoraces. For patients with bilateral effusions whose clinical or radiological presentation is atypical, the case argues strongly for bilateral thoracentesis with detailed cellular analysis, a practice this team believes should be adopted far more widely. To their knowledge, a PubMed search identified no previous report of parapneumonic effusion and Dressler syndrome presenting concurrently, and the combination is classically described under the label of Contarini syndrome, in which each side of the chest harbours a different cause.

Subject of Research: A rare case of bilateral bloody pleural effusions arising from two independent causes, concurrent parapneumonic effusion and suspected late-onset Dressler syndrome, distinguished by discordant pleural fluid cellular profiles.

Article Title: Bilateral Bloody Pleural Effusions With Discordant Cellular Patterns: A Case of Concurrent Parapneumonic Effusion and Dressler Syndrome

Article References: Narumi, Y., Hoshino, S., Yamakawa, M., & Amano, Y. (2026). Bilateral Bloody Pleural Effusions With Discordant Cellular Patterns: A Case of Concurrent Parapneumonic Effusion and Dressler Syndrome. Respirology Case Reports, 14(9), Article e70764. https://doi.org/10.1002/rcr2.70764

Image Credits: AI Generated

DOI: 10.1002/rcr2.70764

Keywords: pleural effusion, Dressler syndrome, post-cardiac injury syndrome, parapneumonic effusion, Streptococcus pneumoniae, thoracentesis, coronary artery bypass grafting, edoxaban, lymphocyte-dominant exudate, Contarini syndrome, pericardial effusion, ibuprofen