The technical backdrop to their argument is a field advancing on multiple fronts simultaneously. A review by Pan and colleagues, published in the same journal, traces how CRISPR-Cas9 and its increasingly refined descendants, including base editing, prime editing, and AI-guided RNA design, are converging with cell and vector engineering to offer potentially curative options for children with rare monogenic diseases. Base editing chemically converts one DNA letter into another without cutting both strands of the double helix, while prime editing allows more precise insertions and deletions with fewer unwanted byproducts. Machine learning tools are accelerating the design of RNA molecules and delivery vehicles, shortening development timelines that once stretched over decades.

The clinical results are no longer theoretical. Several gene therapy products now carry approval from the Food and Drug Administration or the European Medicines Agency for pediatric indications, and dozens more sit in active clinical trials. Diseases once uniformly fatal or progressively disabling, such as spinal muscular atrophy and metachromatic leukodystrophy, now have potentially curative options. The commentary describes this as an inflection point, but one whose promise is fragile, because access for children today and development of new therapies tomorrow hinge on coverage decisions made in insurance boardrooms as much as in laboratories.

Price is the most visible obstacle. Atidarsagene autotemcel, marketed as Lenmeldy, is a one-time therapy for metachromatic leukodystrophy with a list price of 4.25 million dollars, making it among the most expensive medicines ever approved. Onasemnogene abeparvovec, sold as Zolgensma, is a single infusion for spinal muscular atrophy priced near 2.1 million dollars. Exagamglogene autotemcel, known as Casgevy, the first CRISPR-edited cell therapy approved for sickle cell disease, and lovotibeglogene autotemcel, or Lyfgenia, a lentiviral-edited counterpart, list in a similar range. These figures dwarf the cost of conventional orphan drugs and raise immediate questions about affordability for health plans serving children.

Yet the authors caution against reading these prices as simple profiteering. The costs reflect the genuine expense of manufacturing an individualized cell or gene product, a process that involves harvesting a patient’s own cells, engineering them in specialized facilities, performing quality control, and returning them to the patient, all under regulatory scrutiny. Independent health economic assessments have judged several of these therapies cost-effective when measured against the lifetime value of a one-time cure compared with years or decades of standard care, which for conditions like sickle cell disease includes repeated hospitalizations, transfusions, and pain crises. From that perspective, a multimillion-dollar price tag can represent a bargain over a lifetime, even as it creates an acute budget shock for any single insurer.

This tension between long-term value and short-term affordability lies at the heart of the coverage problem. A child treated at age three may remain enrolled with a health plan for only a few years before the family changes jobs or coverage, meaning the insurer that pays for the cure may never capture the savings from avoided care. Economists describe this as a mismatch between who pays and who benefits, and it gives payers a rational incentive to delay or deny coverage in the hope that someone else will bear the cost. For families, the consequence is that access can depend on the accident of which insurance plan covers a child in a given year.

The commentary also examines the frontier of ultra-rare disease, where the economics become even more difficult. Landmark cases such as patient-specific in vivo gene editing for a rare genetic condition and patient-customized oligonucleotide therapy, each developed for a single individual, have demonstrated that bespoke treatments are technically feasible. But therapies designed for one or a handful of patients will never recoup their development costs through sales, no matter how high the price. The authors point to proposed funding approaches for N-of-1 trials of individualized gene-targeted therapies and to efforts to overcome barriers to commercially pre-viable gene and cell therapies for rare and ultra-rare diseases as signs that researchers and policymakers are searching for models that do not depend on conventional market returns.

Regulatory innovation is moving in parallel. The FDA has launched a framework for accelerating the development of individualized therapies for ultra-rare diseases, an acknowledgment that the agency’s traditional pathways were designed for drugs manufactured at scale rather than treatments built for one patient. On the payment side, the Centers for Medicare and Medicaid Services have expanded access to gene therapies through innovative state agreements, and proposals for a national benefit for cell and gene therapies have been advanced in health policy forums. These arrangements, including outcome-based contracts in which manufacturers receive full payment only if a therapy works as promised, represent early attempts to spread risk between manufacturers, payers, and the public.

For the pediatric community, the stakes are unusually high because timing matters in a way it does not in adult medicine. Many of the conditions targeted by gene editing are progressive, and the therapies work best, or only, when administered before irreversible organ damage occurs. Newborn screening programs increasingly identify affected infants in the first days of life, creating a narrow window in which regulatory approval, insurance authorization, manufacturing capacity, and clinical delivery must all align. A delay of months in coverage negotiation can convert a curative intervention into a palliative one, which is why the authors frame payment policy as an integral component of the therapy itself rather than an administrative afterthought.

The commentary closes with a call to build the policy environment deliberately rather than reactively. The authors argue that without coordinated action on coverage, reimbursement, and financing, the remarkable science described by Pan and colleagues will reach only a fraction of the children who could benefit, and that uncertain payment prospects may deter investment in therapies for the rarest conditions of all. The tools of molecular biology have, in their telling, largely been proven; the rulebook that determines who can use them is still being written, and the next chapter will be drafted not by geneticists but by policymakers, insurers, and the families advocating for their children.

Subject of Research: Insurance coverage and reimbursement policy for pediatric gene and cell therapies

Article Title: Editing the rulebook: building the policy environment for children to access gene therapy

Article References: Pulcini, C. D., Chua, K.-P., Conti, R. M., On behalf of the Pediatric Policy Council, Keller, D., Montez, K., Ragavan, M., Lorch, S., Plax, K., Cheng, T., Geme, J. S., Lakshmanan, A., & Mariani, T. J. (2026). Editing the rulebook: building the policy environment for children to access gene therapy. Pediatric Research. https://doi.org/10.1038/s41390-026-05588-y

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05588-y

Keywords: gene therapy, CRISPR, pediatrics, health policy, insurance coverage, drug pricing, rare disease, sickle cell disease, spinal muscular atrophy, reimbursement, base editing, ultra-rare disease

The biological target of the study is the central event in sickle cell pathology: the polymerization of hemoglobin S. The disease stems from a single point mutation in the beta-globin gene, in which glutamic acid at the sixth position is replaced by valine. When oxygen levels fall, this seemingly small change causes hemoglobin molecules to clump into rigid fibers, deforming red blood cells into their characteristic sickle shape. These rigid cells clog capillaries, a process known as vaso-occlusion, triggering painful crises, hemolysis and progressive organ damage. Repeated cycles of polymerization and depolymerization also generate oxidative stress, depleting nitric oxide in the vasculature and fueling inflammation that involves platelets, neutrophils and the endothelium.

Current therapies reflect the limits of treating a downstream process. Hydroxyurea raises fetal hemoglobin levels and reduces sickling, voxelotor binds hemoglobin reversibly to keep it in its oxygenated state, and crizanlizumab blocks platelet-mediated adhesion. L-glutamine offers antioxidant support, while regular transfusions manage severe cases. The only curative option, hematopoietic stem cell transplantation from a matched sibling donor, is limited by donor scarcity, cost and serious risks including graft-versus-host disease. Gene editing therapies are emerging but remain inaccessible to most patients globally. This therapeutic gap motivated the Indian team to search for small molecules that could directly inhibit hemoglobin S polymerization while simultaneously counteracting oxidative stress.

The researchers chose two pharmacophores with complementary biological credentials. The first is caffeic acid, a phenolic compound found in coffee, wine, tea and propolis, which has documented antioxidant, anti-inflammatory and anti-carcinogenic properties. Previous experimental work showed that caffeic acid increases the delay time for hemoglobin polymerization, a direct anti-sickling effect, and significantly lowers the concentration of ferryl hemoglobin formed during peroxide reactions. The second is phthalimide, whose derivatives, including the thalidomide family, have been shown to increase gamma-globin expression and fetal hemoglobin production while lowering tumor necrosis factor alpha, giving them both anti-sickling and anti-inflammatory potential.

Using an AI-assisted online tool called Mol-Opt, the team generated bioisosteric analogues of both scaffolds, systematically swapping functional groups to improve potency, pharmacokinetics and safety while preserving the molecular features responsible for activity. This yielded 373 candidate analogues across the two series. Each was then screened through a battery of computational filters. The ADMET Lab 3.0 platform predicted absorption, distribution, metabolism, excretion and toxicity parameters, while the Osiris Property Explorer provided drug-likeness and drug-score assessments. Encouragingly, every analogue satisfied Lipinski’s rule of five, the Pfizer rules and, with few exceptions, the Golden Triangle criteria, suggesting the designed molecules occupy drug-like chemical space with reasonable prospects for oral absorption.

The pharmacokinetic and toxicity screens narrowed the field considerably. Among the caffeic acid derivatives, compounds such as C-168, C-2, C-29, C-195 and C-27 stood out for combining high drug scores with low predicted toxicity. Analogue C-2 proved especially notable, showing the lowest hemotoxicity and genotoxicity values in its series. In the phthalimide series, P-60 and P-41 displayed excellent ADME balance with minimal tissue accumulation and very low skin sensitization, although several otherwise promising analogues, including P-155, P-171, P-202 and P-248, were rejected because of alarmingly high predicted genotoxicity, illustrating how computational toxicity screening can eliminate liabilities before any laboratory synthesis takes place.

The decisive test came from molecular docking against the crystal structure of deoxyhemoglobin S, available in the Protein Data Bank under the identifier 2HBS at 2.05 angstrom resolution. Using the Pyrex implementation of AutoDock Vina, the team docked the analogues into the hemoglobin active site and visualized the interactions with ICM Browser Pro. The phthalimide analogue P-2 achieved the study’s best binding affinity at minus 10.4 kilocalories per mole, followed by P-56 at minus 10.3. Among the caffeic acid derivatives, C-2 led with minus 9.0 kilocalories per mole, ahead of C-72 and C-68. For comparison, the approved drugs hydroxyurea, L-glutamine and voxelotor were docked under the same conditions, and the top analogues outperformed them, forming networks of hydrogen bonds and hydrophobic contacts with residues including LYS-66, ASN-102, ASP-99, VAL-98, LEU-28 and PHE-41.

Because a good docking score does not guarantee that a ligand remains bound in the dynamic environment of a real protein, the two lead compounds were subjected to 100-nanosecond molecular dynamics simulations using the Desmond package in the Schrödinger suite. The P-2 hemoglobin complex proved remarkably stable: after an initial equilibration period, the ligand’s root mean square deviation, fitted to the protein, settled within 1.2 to 2.2 angstroms and remained steady for the rest of the simulation. The C-2 complex showed somewhat greater fluctuation, with average protein RMSD values between 0.8 and 3.2 angstroms, but still maintained its binding pose within the active pocket. Contact analysis revealed that the ligands were held in place by a combination of hydrogen bonds, hydrophobic interactions and water bridges involving residues such as PHE-41, LYS-95, VAL-98, ASP-99 and GLU-43, providing a plausible structural basis for sustained anti-sickling activity.

To probe the electronic foundations of the two leads, the researchers performed density functional theory calculations using the ORCA 5.0.4 program at the B3LYP level with the def2-TZVP basis set. Compound C-2 displayed a HOMO energy of minus 8.63 electron volts localized over its catechol pi-system, identifying it as the principal electron-donating region, while its LUMO at minus 5.23 electron volts spread across the nicotinate ring and ester carbonyl groups. The resulting HOMO-LUMO gap of 3.40 electron volts indicates moderate electronic delocalization and efficient charge-transfer pathways, properties associated with reversible electron transfer and enhanced biological activity. Compound P-2 showed a smaller gap of 2.62 electron volts, with the HOMO distributed over its aromatic indole and benzoyl amide regions and the LUMO concentrated at the carbonyl nicotinate position, suggesting good conjugation and moderate chemical reactivity across the amide framework.

The authors conclude that the combined computational workflow, spanning bioisosteric design, ADMET prediction, docking, dynamics and quantum chemistry, has delivered two credible lead candidates, P-2 and C-2, that merit progression toward laboratory validation. Experimental studies to confirm their anti-sickling activity are reportedly underway. As with any purely computational study, the predictions remain hypotheses until synthesis, binding assays and animal or clinical testing are completed, and the high genotoxicity flags on several analogues underline the need for careful optimization. Nevertheless, the work demonstrates how a rational, multi-method in silico pipeline can compress the early stages of drug discovery, potentially cutting costs and timelines for a disease that has waited decades for a truly transformative small-molecule therapy.

Subject of Research: Computational screening of phthalimide and caffeic acid analogues as potential anti-sickling agents for sickle cell disease

Article Title: Computational screening of some newer potential anti-sickling compounds using docking, ADMET, DFT, and molecular dynamics approaches

Article References: Verma, D., Ahirwar, B., Vaishnav, Y., & Gahrewal, M. (2026). Computational screening of some newer potential anti-sickling compounds using docking, ADMET, DFT, and molecular dynamics approaches. Discover Chemistry, 3(1), Article 495. https://doi.org/10.1007/s44371-026-00942-9

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00942-9

Keywords: sickle cell disease, hemoglobin S polymerization, molecular docking, ADMET, molecular dynamics simulation, DFT, bioisosteres, phthalimide, caffeic acid, drug discovery, computer-aided drug design, vaso-occlusion

Sickle cell disease begins with a single amino acid substitution in hemoglobin, producing hemoglobin S, which polymerizes when oxygen tension falls. The result is the characteristic sickle shape: red blood cells become rigid, lose their deformability, and lodge in capillary beds, causing the ischemic pain known as vaso-occlusive crisis. In pregnancy, this biology collides with profound physiologic change. Plasma volume expands, the coagulation system shifts toward hypercoagulability, and inflammatory mediators rise, all of which can heighten the risk of crises, acute chest syndrome, and venous thrombosis. According to the source report, anemia and episodic pain affect more than half of pregnant individuals with sickle cell disease, preterm delivery occurs in 9 to 45 percent of such pregnancies, and fetal growth restriction appears in roughly 8 to 21 percent of cases.

The statistical backdrop is sobering. In a large United States cross-sectional study cited in the report, preeclampsia occurred in 10.9 percent of deliveries among patients with sickle cell disease, compared with 4.5 percent in controls. Preeclampsia itself is defined by the American College of Obstetricians and Gynecologists as new-onset hypertension after 20 weeks of gestation with proteinuria, or severe features even without proteinuria. Those severe features include systolic blood pressures of at least 160 mmHg or diastolic pressures of at least 110 mmHg, thrombocytopenia, impaired liver function, renal insufficiency, pulmonary edema, or new cerebral or visual symptoms. For a patient whose red cells already struggle to perfuse her tissues, the added vascular insult of preeclampsia creates a dangerous physiological double bind.

The patient in this case arrived at 33 weeks and 2 days of gestation in severe pain from a vaso-occlusive crisis. Her history included type 2 diabetes, obesity, and avascular necrosis of the right knee, a classic sickle cell complication in which bone tissue dies from interrupted blood supply. Her outpatient regimen already included buprenorphine, a partial opioid agonist, along with acetaminophen. Two days later she returned with left thigh pain rated 8 out of 10 despite her medications, and her blood pressure measured 143/90 mmHg. Intravenous hydromorphone provided minimal relief, prompting admission for inpatient pain control. Laboratory evaluation revealed a hemoglobin of 9.6 g/dL and a hematocrit of 26.2 percent, while a venous duplex ultrasound ruled out deep vein thrombosis as the cause of her leg pain.

One of the most technically interesting aspects of the case involved blood banking. The patient’s antibody screen was positive with a complex antibody profile, meaning her immune system carried antibodies that could react against common red cell antigens. Finding compatible packed red blood cells became genuinely difficult, a problem compounded by the fact that transfusion in sickle cell disease carries risks of alloimmunization, in which further antibodies develop, along with transfusion-related infection and iron overload. Rather than waiting for an emergency, the team transfused 4 units of crossmatched blood while the patient was clinically stable, raising her hemoglobin ahead of anticipated delivery-related blood loss. Intraoperative cell salvage, a technique that recovers blood lost during surgery for reinfusion, was planned as a backup but ultimately was not needed.

Then came the preeclampsia. During the admission, the patient developed repeated severe-range systolic blood pressures, documented between 165/86 and 167/90 mmHg. Notably, no proteinuria assessment was documented, but severe-range pressures alone satisfied diagnostic criteria. Her kidney function remained intact, with a creatinine of 0.59 mg/dL, indicating that end-organ damage had not yet taken hold. The team initiated oral nifedipine at 60 mg every 12 hours, a calcium channel blocker that relaxes vascular smooth muscle, and planned intrapartum magnesium sulfate for seizure prophylaxis, the standard safeguard against eclamptic convulsions. Serial fetal growth surveillance continued because both sickle cell disease and diabetes elevate the risk of fetal growth abnormalities, with an estimated fetal weight tracking at the 60th percentile.

The delivery decision arrived at 35 weeks when a biophysical profile score of 4 out of 8 signaled fetal compromise. Induction of labor was attempted, but after 7 hours of oxytocin augmentation, the cervix remained dilated at only 4 centimeters. The patient requested a primary cesarean section. Labor analgesia had been established through an epidural catheter, which the team redosed for surgical anesthesia, the preferred approach because neuraxial techniques avoid the airway manipulation and hemodynamic swings of general anesthesia. However, immediately after delivery the patient reported intense intraoperative pressure, and after discussion, the anesthesiologists converted to general anesthesia using fentanyl, propofol, succinylcholine, and ketamine, with midazolam, morphine, and ketorolac added for maintenance and analgesia. Hemodynamics remained stable through induction and emergence, a critical detail given the fragility of a preeclamptic, recently transfused patient.

The pharmacology threaded through this case reflects the delicate calculus of analgesia in pregnancy. Acetaminophen remains first-line for vaso-occlusive pain, though recent studies have raised questions about possible associations with childhood asthma or neurodevelopmental outcomes. Nonsteroidal anti-inflammatory drugs are avoided late in gestation because they can prematurely close the fetal ductus arteriosus and reduce amniotic fluid. Patients maintained on buprenorphine should continue their therapy through labor to prevent withdrawal, with full opioid agonists such as hydromorphone added for breakthrough pain and neonates observed for withdrawal if exposure is prolonged. A systematic review cited in the report found no definitive regimen for treating sickle cell pain crises in pregnancy, which means care rests on early recognition of triggers, timely analgesia, judicious fluids, and close maternal-fetal monitoring rather than any standardized protocol.

The postpartum course underscored that delivery resolves neither disease. Magnesium sulfate continued for 24 hours, nifedipine continued for blood pressure control, and the patient received 6 weeks of enoxaparin for venous thromboembolism prophylaxis, an important measure because preeclampsia and sickle cell disease both amplify clotting risk. Hematology recommended maintaining hemoglobin above 10 g/dL with transfusion support and continuing high-dose folic acid to support red cell production. Endocrinology discontinued insulin in favor of metformin for the diabetes. The neonate, weighing 2.565 kg, thrived. The authors emphasize that the lesson of this case is coordination: hematology, obstetrics, anesthesiology, palliative care, and endocrinology each held one thread of a clinical picture in which a single misstep, an incompatible transfusion, an uncontrolled pressure, an abrupt withdrawal, could have unraveled everything. As more individuals with sickle cell disease reach childbearing age, cases like this one map the terrain that multidisciplinary teams must navigate.

Subject of Research: Peripartum anesthetic management of pregnancy complicated by sickle cell disease and preeclampsia

Article Title: Peripartum Anesthetic Management of a Patient With Sickle Cell Disease and Preeclampsia

Article References: Dow, M., Srinivasan, A., & Ayad, S. (2026). Peripartum Anesthetic Management of a Patient With Sickle Cell Disease and Preeclampsia. Clinical Case Reports, 14(10), Article e73662. https://doi.org/10.1002/ccr3.73662

Image Credits: AI Generated

DOI: 10.1002/ccr3.73662

Keywords: sickle cell disease, preeclampsia, vaso-occlusive crisis, obstetric anesthesia, cesarean delivery, blood transfusion, magnesium sulfate, buprenorphine, pregnancy complications, epidural analgesia, fetal surveillance, multidisciplinary care

Suzanne Gaston Eskin, known to everyone as Suzie, was born in Houston, Texas, in 1939 and earned her bachelor’s and master’s degrees in biology at Rice University before completing a doctorate in zoology at the University of Texas at Austin in 1969. Her early career at Baylor College of Medicine placed her alongside the legendary cardiac surgeon Dr. Michael DeBakey, where she contributed to the development of early generations of left ventricular bypass pumps. That work posed a deceptively simple question: why do artificial surfaces and vascular grafts fail inside the body? Her answer was to bring the living cells of the vessel wall into the laboratory, isolating and culturing endothelial and smooth muscle cells on synthetic substrates and measuring how they responded to the physical forces associated with blood flow. These in vitro vascular cell culture models became one of her most enduring gifts to the scientific community, allowing researchers everywhere to dissect tissue-level responses to injury and disease under controlled conditions.

Larry Vern McIntire arrived at Rice University in 1970 as a freshly minted chemical engineer, holding degrees from Cornell and Princeton and a deep expertise in fluid mechanics. Where biologists saw cells, Larry saw systems governed by shear stress, viscosity, and transport phenomena. He applied that training to cardiovascular physiology with a rigor that transformed the field, rising to chair the Department of Chemical Engineering in 1981, direct the Institute of Biosciences and Bioengineering in 1991, and found the Department of Bioengineering in 1997. In 2003 he took the helm of the joint Georgia Institute of Technology and Emory University Biomedical Engineering department, expanding it into a program of national and international prominence before his retirement in 2013. His election as a fellow of the National Academy of Engineering, along with four other professional societies, reflected a career spent building bridges between engineering and medicine.

The technical heart of their partnership lay in the flow chamber. Larry innovated parallel plate flow chambers into continuous-flow systems that could sustain living cell cultures for long periods under precisely controlled shear stresses, while complementary devices stretched cells to mimic the cyclic wall stresses of a beating artery. With these tools, the couple and their collaborators made a discovery that now sits in every mechanobiology textbook: endothelial cells respond differently to distinct mechanical forces, altering the secretion of molecules such as prostacyclin and tissue plasminogen activator depending on the flow regime they experience. This gave rise to the concept of mechanochemical signal transduction, the idea that mechanical stimuli are converted into biochemical instructions inside the cell. Later, using high-throughput gene expression methods, they identified mechanosensitive genes that no one had previously suspected of playing a role in vascular biology, opening research directions that continue today.

Their flow systems also illuminated some of medicine’s most stubborn clinical problems. In sickle cell disease, the couple showed that adhesion between sickled erythrocytes and endothelial cells is dramatically enhanced under shear conditions, marking a key initiating event in the microvascular occlusion that causes excruciating pain crises. Crucially, they established that vaso-occlusion is not simply a consequence of stiffened red blood cells clogging narrow vessels, but a dynamic, flow-dependent process driven by endothelial activation, including the release of ultra-large von Willebrand factor multimers and the expression and shedding of adhesion molecules. Vaso-occlusion, in other words, is a coupled biomechanical and biochemical process, a reframing that unified previously separate lines of research and suggested new therapeutic targets.

The same experimental logic extended to inflammation and cancer. Their studies demonstrated that selectin ligands coordinate the initial rolling and adhesion of neutrophils to inflamed endothelial cells under venous shear conditions, while β2 integrins mediate the subsequent transmigration into tissue, and that these same interactions govern the formation of neutrophil-platelet aggregates in flowing blood. These were among the first studies to identify specific molecular pathways for force-selective cell adhesion, and they spearheaded mechanobiologically unified models of sickle cell pathophysiology, inflammation, and tumor cell adhesion during metastasis. The message was consistent: to understand how cells behave in the bloodstream, one must understand the physics of the bloodstream.

Blood clots themselves proved equally obedient to mechanical principles. Drawing on his training in non-Newtonian fluid mechanics, Larry investigated the viscoelastic properties of clots long before modern high-resolution microscopy existed, arguing that clot strength depends not only on platelet density but also on platelet aggregability and clot contractility. By adapting real-time visualization techniques from their flow chambers, Larry, Suzie, and collaborators showed that different hemostatic mechanisms regulate distinct phases of mural thrombus formation, and that dynamic adhesion models are essential for evaluating antiplatelet therapies. Perhaps most elegantly, their work on platelet interactions with von Willebrand factor revealed catch-slip bonds, molecular attachments that strengthen under increasing force before eventually releasing. This counterintuitive behavior explains why platelets and von Willebrand factor dominate arterial thrombi but not venous ones, a distinction of direct relevance to heart attack and stroke. The couple’s curiosity even reached into the cytoskeleton, where atomic force microscopy and molecular dynamics simulation revealed catch-slip bonds in actin regulated by signaling molecules.

Beyond the laboratory, the couple built institutions and, just as deliberately, built people. Larry mentored nearly one hundred graduate students and postdoctoral fellows, co-advising thirty-one doctoral students with Suzie. Their laboratory attracted trainees from across the globe from the 1970s onward, and the tribute emphasizes that their commitment to international and women scientists was practical rather than symbolic: they placed trainees in positions to succeed and expected them to do so. Many of those trainees now hold leadership positions across academia and industry. Larry also championed tissue engineering in its infancy, co-editing the early reference volume Frontiers in Tissue Engineering in 1998, launching an annual summer short course now in its thirty-third year, and chairing a federal panel whose report guided international investment in the field. With colleagues he co-authored the textbook Bioengineering Fundamentals, and as Editor-in-Chief of the Annals of Biomedical Engineering from 2002 to 2009 he doubled the journal’s impact factor and helped spawn two sister journals, defining biomedical engineering as an independent and impactful discipline.

Suzie Eskin passed away on March 27, 2024, after bravely battling Lewy body disease, and Larry McIntire passed away on January 23, 2026, in Stone Mountain, Georgia. What they leave behind is more than a bibliography of more than 250 publications, from the effects of mechanical trauma on leukocytes to endothelial cell migration modeled with Markov chains. They leave a way of thinking, in which the pulsing, shearing, stretching forces of the circulatory system are treated as first-class biological signals, and in which engineering rigor and biological curiosity are inseparable. Their former students, now writing their memorial, pledge to carry forward the same curiosity, integrity, and kindness that defined two scientists who proved that the best collaborations, like the best bonds, can grow stronger under load.

Subject of Research: Memorial tribute to vascular mechanobiology pioneers Dr. Suzanne G. Eskin and Dr. Larry V. McIntire

Article Title: In memory of Dr. Suzanne G. Eskin (1939–2024) and Dr. Larry V. McIntire (1943–2026)

Article References: Brey, E. M., Conway, D. E., Diamond, S. L., Frangos, J. A., Gonzalez, A. L., Hubbell, J. A., Konstantopoulos, K., Lawrence, M. B., Lee, C.-Y., Nguyen, K. T., Ramasubramanian, A. K., Shiu, Y.-T., Williams, M. R., & Yee, A. (2026). In memory of Dr. Suzanne G. Eskin (1939–2024) and Dr. Larry V. McIntire (1943–2026). Annals of Biomedical Engineering. https://doi.org/10.1007/s10439-026-04387-0

Image Credits: AI Generated

DOI: 10.1007/s10439-026-04387-0

Keywords: mechanobiology, vascular biology, endothelial cells, shear stress, sickle cell disease, thrombosis, von Willebrand factor, tissue engineering, biomedical engineering, mentorship, catch-slip bonds, Rice University

Sickle cell disease is caused by mutations in the hemoglobin gene and comes in several distinct genotypes. The most common and often most severe form is hemoglobin SS, but patients may also carry hemoglobin SC disease or one of two sickle beta-thalassemia variants, Sβ+ and Sβ0, each with different clinical trajectories and treatment needs. Complicating matters further, many people carry only the sickle cell trait, a benign carrier state that must be reliably distinguished from actual disease in any epidemiological analysis. Hospital databases, which increasingly fuel retrospective research on these rare conditions, typically identify patients through ICD-10 diagnostic codes, but those codes frequently record only that a patient has sickle cell disease, not which subtype, and sometimes they flag patients who do not have the disease at all.

To address this, Loris Azoyan of Sorbonne Université, INSERM and the Assistance Publique – Hôpitaux de Paris, along with Olivier Steichen and colleagues across five French expert centers, developed an algorithm built from regular expressions: pattern-matching rules that scan unstructured clinical text for the specific phrases clinicians use when documenting a patient’s hemoglobin genotype. The approach deliberately avoided heavyweight machine learning. Instead, it relied on the fact that French clinical reports, from consultation notes to laboratory results, tend to mention sickle cell genotypes in formulaic ways, using standard genetic shorthand that can be captured with carefully crafted textual patterns. The researchers made the regular expressions, the R analysis script containing the classification algorithm, and fictional illustrative patient texts openly available in an Open Science Framework repository, so that other teams can adapt the method to their own data warehouses.

The scale of the evaluation was considerable. The team included every adult patient with at least one ICD-10 code for sickle cell disease who had consulted or been hospitalized at least once between August 1, 2017 and January 29, 2025 at the five participating expert centers of the Greater Paris University Hospitals. In total, 10,868 patients met the entry criteria, and their records contained 561,924 clinical documents issued between 2013 and 2025. The algorithm processed all of those reports in five minutes, a throughput that would be unthinkable with manual chart review and that demonstrates why text-mining tools are becoming essential for research on conditions whose clinical details live in narrative documents rather than structured fields.

The results painted a nuanced picture of the cohort. For 1,259 patients, no sickle-related term could be found anywhere in their clinical reports, immediately raising questions about why their coded diagnoses existed in the first place. Among the remaining 9,609 patients, 1,802, or 18.8 percent, had only non-specific sickle mentions that did not permit any classification. Another 1,502 patients, 15.6 percent, were classified as having sickle cell trait rather than disease. The algorithm assigned 6,234 patients, or 64.9 percent, to a definite sickle cell disease subtype: 4,443 of them, or 71.3 percent, had hemoglobin SS disease; 1,431, or 23.0 percent, had SC disease; 263, or 4.2 percent, had the Sβ+ form; and 97, or 1.6 percent, carried the more severe Sβ0 genotype. Just 71 patients, 0.7 percent, remained unresolved even after the full analysis.

To determine whether the algorithm’s assignments could be trusted, the researchers conducted a manual review of a stratified random sample of 1,510 patients, using that expert adjudication as the reference standard against which the automated classification was measured. The algorithm achieved an overall positive predictive value of 94.0 percent, with a 95 percent confidence interval of 92.6 to 95.4, and subtype-level performance ranged from 91.4 percent to a perfect 100 percent. In practical terms, when the algorithm says a patient has hemoglobin SC disease or Sβ0 thalassemia, that statement is very likely to be confirmed by a human expert reading the same records. For retrospective cohort studies, where the alternative is either laborious manual review or crude diagnostic codes, that level of precision represents a meaningful advance.

Perhaps the most consequential finding of the study concerns the ICD-10 codes that medico-administrative research typically relies on. The team evaluated several commonly used selection strategies based on those codes, varying how many codes were required to confirm a patient’s status and how unclassified patients were treated. The positive predictive value of code-only strategies ranged from as low as 58.1 percent to 88.3 percent depending on those assumptions. In other words, depending on the strategy chosen, a substantial fraction of patients identified through coding alone may not actually have sickle cell disease, or may carry only the trait. The authors warn that this creates a real risk of misclassification when researchers rely solely on administrative coding, a concern that echoes previous validation work on hospital discharge diagnoses in France and on sickle cell case definitions in the United States.

The implications reach beyond sickle cell disease itself. As hospital data warehouses and national health databases become standard infrastructure for epidemiology, the gap between what is coded and what is clinically true has become a central methodological challenge. Previous efforts have used natural language processing to extract information from clinical text for populating registries, identifying patients with specific conditions, and detecting complications such as contrast-associated kidney injury. The Paris team’s contribution is to demonstrate that even a deliberately simple, transparent set of pattern-matching rules, rather than a complex deep-learning model, can achieve high accuracy for a genetically defined condition, provided clinicians document the relevant details consistently. The authors emphasize, however, that their performance figures may reflect the specific subtype demographics, the expertise of the five expert centers, and local documentation practices, so other institutions should expect to validate and adapt the approach on their own data.

The study also touches on the emerging role of generative artificial intelligence in medical informatics research, though in an unusual way. The authors disclose that they used OpenAI’s ChatGPT solely to generate fictional illustrative clinical texts demonstrating the algorithm’s functionality, allowing them to publish realistic French-language medical report examples without exposing any real patient data. No generative AI tool was used for the analysis itself, the design of the algorithm, or the writing of the manuscript, and the authors take full responsibility for the generated content. The underlying clinical reports and patient-level data, meanwhile, cannot be shared publicly because of their sensitive nature and French data protection regulations, with access restricted under the governance of the AP-HP Clinical Data Warehouse, whose scientific and ethics committee approved the retrospective study under the French MR-004 reference methodology for reusing healthcare data in research.

For clinicians and researchers, the message is twofold. First, high-quality clinical documentation matters: the algorithm’s success depended entirely on clinicians writing genotype information into reports, and the authors highlight the importance of such documentation for retrospective research. Second, any study that builds a sickle cell cohort purely from ICD-10 codes should treat its findings with caution, because a meaningful proportion of code-positive patients may be misclassified. By pairing an open, reusable text-classification algorithm with a rigorous manual validation and an honest assessment of coding accuracy, the Paris team has provided both a practical tool and a methodological warning, ones that could shape how sickle cell disease research is conducted across France and beyond as hospitals continue to digitize their clinical narratives.

Subject of Research: Validation of a regular-expression algorithm for classifying sickle cell disease subtypes from unstructured clinical reports and assessing ICD-10 coding accuracy

Article Title: Classifying Sickle Cell Disease Subtypes from Clinical Reports: Algorithm Validation and ICD-10 Accuracy Assessment in Five French Hospitals

Article References: Azoyan, L., Leblanc, J., Santin, A., Chantalat-Auger, C., Le Jeune, S., Affo, L., Arlet, J.-B., Bartolucci, P., & Steichen, O. (2026). Classifying Sickle Cell Disease Subtypes from Clinical Reports: Algorithm Validation and ICD-10 Accuracy Assessment in Five French Hospitals. Journal of Medical Systems, 50(1), Article 134. https://doi.org/10.1007/s10916-026-02461-7

Image Credits: AI Generated

DOI: 10.1007/s10916-026-02461-7

Keywords: sickle cell disease, sickle cell trait, natural language processing, electronic health records, ICD-10, clinical text mining, hemoglobin SS, hemoglobin SC, regular expressions, rare disease research, hospital databases, diagnostic coding accuracy

Sickle cell disease is a single-gene disorder that affects hemoglobin, the oxygen-carrying molecule in red blood cells. A single mutation causes hemoglobin molecules to polymerize under certain conditions, deforming red cells into rigid, crescent shapes that lodge in small blood vessels. The consequences are cascading: vaso-occlusion triggers episodes of excruciating pain, chronic hemolytic anemia, inflammation, and progressive damage to organs including the kidneys, lungs, brain, and spleen. The disease is among the costliest chronic conditions in medicine, measured in both direct health care expenditure and lost human potential, and it disproportionately affects people of African, Mediterranean, Middle Eastern, and South Asian ancestry. Yet for all its molecular simplicity—one gene, one known mutation—the disease behaves with bewildering variability. Some patients endure frequent crises and early organ failure while others, carrying the same genotype, live comparatively well for decades. The reason for this divergence has remained one of the field’s most stubborn mysteries.

The Mount Sinai team, led by principal investigator Sarah McCuskee, MD, Assistant Professor of Emergency Medicine and of Global Health and Health Systems Design, believes the answer may lie substantially outside the genome—in the “exposome,” the cumulative measure of every environmental exposure an individual encounters from moment to moment across a lifetime. “We have heard time and time again from our patients: their lives impact their disease, and vice versa,” Dr. McCuskee said in announcing the award. “But until now, how daily life impacts sickle cell disease hasn’t been studied very much. We are excited to partner with people living with sickle cell disease to understand this better, while applying rigorous scientific methods to make sure our conclusions are impactful.” Her framing captures the project’s central ambition: to treat patient experience not as anecdote but as a valid signal that can be rigorously quantified, measured, and validated.

The biological logic behind the hypothesis is grounded in what preliminary work has already hinted at. Neighborhood and personal exposures are known to activate inflammatory pathways, alter vascular tone, and shift metabolic states—all processes directly implicated in sickle cell pathogenesis. Chronic psychosocial stress elevates cortisol and sympathetic nervous system activity, which can promote vasoconstriction and heighten the likelihood of vaso-occlusive events. Elevated ambient temperature is suspected of influencing blood viscosity and dehydration status, both critical variables in a disease where red cells sickle more readily when blood flow slows or plasma volume falls. Airborne particulate matter, particularly fine particles smaller than 2.5 micrometers, known as PM2.5, penetrates deep into the lungs and drives systemic inflammation through oxidative stress, an especially concerning mechanism for patients whose vasculature is already prone to inflammatory damage. Poor access to nutritious food may compromise the antioxidant defenses and hydration status that help keep sickling episodes at bay. Substandard housing—with inadequate heating, cooling, ventilation, or pest exposure—compounds all of these risks simultaneously.

The new study is among the first prospective investigations of exposures in sickle cell disease ever undertaken, and its methodology reflects the sophistication that such a claim demands. The researchers will pursue two complementary strategies. The first links blood samples previously donated by people with sickle cell disease for research to geospatial data on the exposures those individuals experience, drawing on advanced satellite-based models. These models can estimate ambient concentrations of fine particulate matter, neighborhood-level temperatures, and other environmental variables at fine resolution, allowing investigators to connect each participant’s residential history with molecular readouts of their disease state. The second strategy moves into real time: participants will carry portable air-quality sensors that directly measure the particles they breathe, and they will report on diet and stress levels as they occur. These moment-to-moment exposure data will then be linked to measurements of the body’s energy metabolism and inflammatory markers, giving researchers a dynamic picture of how a specific exposure on a specific day translates into molecular changes in the blood.

This pairing of satellite modeling and personal sensing is methodologically significant. Satellite data offers population-scale coverage and historical depth, but it estimates exposure at the ambient level and can miss what individuals actually encounter indoors, in transit, or in microenvironments like subway platforms and workplaces. Portable sensors capture the true inhaled dose but are limited in duration and cohort size. By triangulating the two approaches and anchoring both to biochemical endpoints—energy metabolism and inflammation—the study can distinguish between exposures that merely correlate with disease activity and those that plausibly drive it. If, for example, a spike in personally measured PM2.5 is followed within days by a rise in inflammatory cytokines and markers of hemolysis, the causal chain becomes far harder to dismiss. That kind of evidence, replicated across participants and seasons, is what regulatory policy and clinical guidance ultimately require.

The collaborative architecture of the project is equally deliberate. The research will be conducted in partnership with the Human Immune Monitoring Center at Mount Sinai, which provides deep immunophenotyping capability; the Institute for Exposomic Research at the Icahn School of Medicine, one of the first institutions in the world organized specifically around exposomic science; and the Center for Sickle Cell Disease, which anchors the clinical and community dimensions of the work. Exposomics—the systematic study of non-genetic drivers of health—has gained momentum in cancer, cardiovascular disease, and neurology, but its application to a monogenic disease like sickle cell is comparatively novel and potentially transformative, because it addresses the variability that the gene itself cannot explain.

Community partnership is not an afterthought in this design but a stated structural principle. When the study concludes, the researchers intend to share results widely, including through publicly available maps of neighborhood exposures co-developed with the New York City sickle cell community. That commitment matters for a disease whose patients have historically faced well-documented barriers in health care—under-treatment of pain, delayed emergency care, and skepticism about the severity of their symptoms. By giving the community access to the same exposure data that researchers use, the project aims to convert an academic finding into an advocacy tool, one that residents, clinicians, and policymakers can use to argue for cooler housing, cleaner air, and better food environments in the neighborhoods where sickle cell patients live.

The translational endpoint is clinical. Dr. McCuskee and her colleagues plan to develop tools based on their findings that will help clinicians counsel patients concretely—not in vague exhortations to “stay healthy,” but with specific, evidence-based guidance about which environmental conditions appear to elevate risk for a given individual, and what mitigations may help. Beyond sickle cell disease, the investigators hope the methods themselves—linking personal sensing, geospatial modeling, and molecular biomarkers—could form a template for investigating other chronic and genetic illnesses in which outcomes vary inexplicably from patient to patient, including cystic fibrosis, certain autoimmune conditions, and cardiovascular disease.

The grant will be distributed over five years, a duration long enough to capture seasonal variation in temperature, air quality, and stress exposures, and to observe whether exposure-driven molecular changes translate into clinical events such as pain crises, emergency department visits, or hospitalizations. If the study delivers on its promise, it could mark a turning point in how medicine understands a disease long defined by its genetics. The mutation in the hemoglobin gene has been known since the middle of the twentieth century; the environmental and social conditions that determine how severely that mutation expresses itself have, by comparison, barely been examined. Mount Sinai’s new program sets out to close that gap, grounded in the conviction that where people live is not background noise to their biology but part of it—and that understanding the two together may finally explain why one gene can produce so many different lives.

The study provides an in-depth examination of various clinical complications faced by patients suffering recurrent vaso-occlusive crises. These complications can include acute chest syndrome, infections, and organ damage, all of which carry serious implications for patient health. Patients often find themselves navigating the healthcare system frequently, which raises questions regarding the adequacy of existing support structures and medical facilities to provide timely, effective care. The burden of managing these complications can be overwhelming, with patients experiencing not just physical pain, but emotional and psychological stresses too.

Mortality rates among SCD patients, particularly those with recurrent vaso-occlusive crises, form a core focus of this investigation. Despite advancements in medical care and access, individuals suffering from SCD continue to face increased mortality. The study delineates the specific demographics and clinical profiles of patients who are most at risk. Acknowledging the demographic trends assists healthcare providers in identifying at-risk populations early, potentially leading to tailored interventions that could save lives and improve outcomes in a population beset by chronic health challenges.

Healthcare resource utilization is another crucial aspect of this study. It highlights the extensive use of emergency departments and hospital admissions among patients experiencing recurrent crises. The findings prompt a critical evaluation of patient care pathways and the overall healthcare system’s responsiveness to the needs of SCD patients. The repeated cycles of crisis and emergency care indicate a pressing need for targeted management strategies designed to minimize hospital visits and streamline care. As healthcare systems face increasing pressures, understanding these utilization patterns becomes essential for efficient resource allocation.

The implications of the study extend beyond individual patient experiences to broader healthcare policy discussions. As SCD continues to affect a significant population in Canada and worldwide, health policymakers must grapple with how best to address this public health issue. Comprehensive strategies that incorporate preventative education, early intervention, and adequate resource availability could lead to reduced crisis episodes and improved quality of life for patients. This research acts as a vital call to action, spotlighting the need for healthcare reform that emphasizes the unique challenges faced by those with sickle cell disease.

Further, the research highlights the economic burden on healthcare systems stemming from recurrent vaso-occlusive crises. Frequent hospitalizations and extensive medical treatments contribute to soaring costs that underscore the necessity for a reevaluation of healthcare funding and resource management. The implementation of preventative measures could significantly reduce financial strain on healthcare systems, showcasing the potential for improved patient care outcomes alongside economic benefits.

Through a thorough analysis of patient data, the study also brings to light the variations in treatment access across different regions. These disparities can exacerbate challenges faced by patients in remote or underserved areas, where access to specialty care may be limited. Addressing these inequities is crucial to ensuring all patients receive the timely treatment they need, which could significantly lower the incidence of vaso-occlusive crises and associated complications.

Equally important is the psychological impact of living with sickle cell disease. The continual burden of pain, hospital visits, and the fear of future health crises can lead to significant emotional distress. Mental health resources tailored to the needs of SCD patients must be included in comprehensive care models. This holistic approach would consider both the physical and mental health challenges faced by patients, ultimately leading to improved overall well-being and quality of life.

The context of this research cannot be overlooked. As non-communicable diseases continue to present numerous challenges in modern healthcare, SCD exemplifies the ongoing struggle to manage chronic conditions effectively. The knowledge gained from this study will influence future research direction, clinical practice, and patient advocacy efforts aimed at addressing the complex needs of individuals affected by sickle cell disease.

Moving forward, the authors note that more extensive longitudinal studies could provide further insight into the long-term outcomes of patients with recurrent vaso-occlusive crises. Such research would help refine treatment protocols and set the groundwork for innovative solutions that could alleviate the patient experience. By continuously examining the multifaceted challenges faced by SCD patients, researchers and healthcare providers can foster a collaborative environment aimed at breaking the cycle of crisis exacerbation and healthcare utilization.

In conclusion, the findings of this study on sickle cell disease in Ontario serve as a critical reminder of the importance of ongoing research and comprehensive care strategies. Only through continued focus on clinical complications, mortality, and healthcare resource utilization can we hope to make strides toward bettering the lives of those affected by this debilitating condition. As the world of medical research evolves, the need for collaborative efforts that bring together patients, healthcare providers, and policymakers remains vital.

In this context, the conversation surrounding sickle cell disease should not only be limited to treatment but also encompass prevention and advocacy for more significant healthcare reforms that address patient needs at all levels. As we strive towards a more knowledgeable and supportive healthcare landscape, it is imperative that we harness the power of research to fuel these endeavors, ensuring a brighter future for patients enduring the hardships of sickle cell disease.

Subject of Research: Recurrent Vaso-Occlusive Crises in Sickle Cell Disease Patients

Article Title: Clinical Complications, Mortality, and Healthcare Resource Utilization of Patients with Sickle Cell Disease with Recurrent Vaso-Occlusive Crises in Ontario, Canada: A Retrospective Cohort Study

Article References:

Lilly, L., Udeze, C., Nightingale, N. et al. Clinical Complications, Mortality, and Healthcare Resource Utilization of Patients with Sickle Cell Disease with Recurrent Vaso-Occlusive Crises in Ontario, Canada: A Retrospective Cohort Study.
Adv Ther (2025). https://doi.org/10.1007/s12325-025-03411-4

Image Credits: AI Generated

DOI: https://doi.org/10.1007/s12325-025-03411-4

Keywords: Sickle Cell Disease, Vaso-Occlusive Crises, Clinical Complications, Mortality, Healthcare Utilization, Chronic Disease Management, Public Health Policy, Patient Care, Mental Health, Economic Burden.