Ovine forestomach matrix, or OFM, belongs to a family of biomaterials known as extracellular matrix bioscaffolds. The material is processed from the layered tissue of the sheep’s forestomach, preserving much of its natural structural architecture, including collagen fibers and associated proteins that mammalian tissues recognize as familiar building instructions. When surgeons suture or lay an OFM device into a wound, it does not simply patch the defect. Instead, it acts as a temporary biological scaffold that invites the patient’s own cells to migrate in, form new blood vessels, and progressively rebuild missing or damaged tissue. Over weeks to months, the body remodels and ultimately replaces the scaffold with functional vascularized tissue. This regenerative mechanism is what distinguishes bioscaffolds from purely inert synthetic implants, and it is also why their safety profile, particularly regarding infection and immune reactions, matters so much to reconstructive surgeons.

The MASTRR Registry was deliberately designed to capture the messiness of real clinical practice. It is a prospective, multicenter, single-arm, open-label observational study operating under the IDEAL framework, a structured pathway for evaluating surgical and device innovations that explicitly recommends observational registries at both the exploratory and long-term surveillance stages. Rather than enrolling only the healthiest patients with the cleanest wounds, the registry applied broad inclusion criteria with minimal exclusions, enrolling patients across trauma, colorectal, burn, and limb salvage specialties. The study received centralized institutional review board oversight, is registered with ClinicalTrials.gov under identifier NCT05243966, and is ultimately approved to enroll up to 800 subjects, making it, according to the investigators, the largest registry-based study of its kind for bioscaffolds in soft tissue reconstruction.

The patient population captured in this interim analysis was, by any measure, medically formidable. Most subjects were middle-aged men, with a median age of 54 years, and more than half carried an American Society of Anesthesiologists physical status classification of III, indicating severe systemic disease that limits daily function. Nearly 36 percent had type 2 diabetes, about 30 percent had vascular disease, and almost a quarter used nicotine products, all factors known to impair wound healing. The defects themselves were equally challenging: nearly 60 percent were chronic, having persisted for more than a month, and roughly 90 percent were classified as clean-contaminated or contaminated under the Centers for Disease Control and Prevention wound classification system. Exposed bone, tendon, or viscera appeared in 11.4 percent of defects, and confirmed osteomyelitis, a serious infection of bone, was present in 15 percent. The median defect area for dermal reconstructions was 24 square centimeters, with some reaching far larger.

The range of conditions treated underscores the versatility the registry was built to probe. Diabetic foot ulcers accounted for 22.6 percent of defects, many of them deep Wagner grade 2 or 3 wounds, followed by traumatic injuries at 16.5 percent, ostomy takedown reconstructions at 11.2 percent, pilonidal sinus disease at 10.8 percent, and pressure injuries at 9.7 percent, most of the latter being stage 4 wounds involving muscle and exposed structures. Surgeons deployed the OFM devices in three main ways: topically for dermal reconstruction in 65.2 percent of cases, as an implant to reinforce soft tissue flaps or fill dead space in about a quarter of cases, and to augment closure of fistulae, including perianal, enterocutaneous, and rectovaginal types, in roughly 10 percent. Notably, a median of just one product application was needed per defect, and negative pressure wound therapy was used adjunctively in fewer than a quarter of procedures.

The safety results are the heart of the analysis. Fifty-nine adverse events were reported across the 411 subjects during a median follow-up of 27.1 weeks, meaning 12.2 percent of patients experienced one or more events, a figure that falls to 8 percent when only events involving the treated defect are considered. Each event was graded for severity using the Common Terminology Criteria for Adverse Events framework and assessed for causality under ISO 14155 guidance, the international standard for clinical investigation of medical devices. The verdict was striking: 79.9 percent of events were deemed unrelated to the device and 18.6 percent unlikely related, with no events classified as definitely or possibly related and a single probable case. That lone event involved redness, pain, and swelling on a lower extremity defect suggestive of an allergic reaction, prompting partial removal of the graft; the patient was treated with antihistamines, went on to receive a split-thickness skin graft, and completed wound closure while remaining in the study.

Events occurring at the index defect itself were infrequent and mostly minor. Superficial infections occurred at 2.9 percent of subjects, wound dehiscence at 3.2 percent, and deep tissue infection at just 0.7 percent, with only three deep infections reported across the entire cohort and none requiring device extraction. Pilonidal sinus reconstruction generated the highest share of defect-related events, largely dehiscence of the primary closure, while seven of the 33 index defect events required reoperation, most commonly simple incision and drainage. Eight deaths were reported during the study, but clinical review attributed all of them to progression of severe pre-existing cardiopulmonary, renal, or malignant disease, and none were considered related to the index procedure or the OFM treatment. The remaining events were systemic or incidental, including pneumonia, sepsis, and thrombophlebitis, reflecting the frailty of the population rather than the device.

Perhaps the most provocative comparison in the paper concerns infection. A long-running argument in biomaterials holds that synthetic scaffolds should resist infection better than tissue-derived biologics, yet the registry data suggest otherwise. A recent meta-analysis of a polyurethane-based bioscaffold in complex reconstruction, pooling 34 studies and 208 subjects, reported an overall complication rate of 27.9 percent and an infection rate of 25.8 percent. Another comparative meta-analysis found postoperative infection rates of 26.24 percent for polyurethane matrices and 18.79 percent for a crosslinked collagen and chondroitin sulfate scaffold in burns, while a third reported a generalized infection incidence of 16.9 percent for the latter material. Against those figures, the 0.7 percent deep infection rate and 2.9 percent superficial infection rate observed with OFM in a heavily contaminated, comorbid population challenge the assumption that synthetics hold an infection advantage, and the authors of those earlier meta-analyses had themselves urged clinicians to weigh risks carefully before adopting those products.

The registry framework has also proven productive beyond safety surveillance, generating a series of indication-specific subgroup analyses from a common prospective data collection platform. These include complex lower extremity reconstruction, where a median of 30 days was needed to achieve complete granulation tissue coverage; traumatic defects across four level 1 trauma centers, where vascularized tissue coverage was achieved in a median of 22.5 days; deep partial-thickness burns, where a single OFM application produced a median 14-day healing time with minimal pain and favorable scar scores; and late-stage pressure injuries, where approximately 60 percent wound area reduction was achieved without postoperative complications. A comparative study of pilonidal sinus reconstruction found that adding an OFM graft under a fasciocutaneous advancement flap significantly reduced surgical dehiscence, lowered treatment costs, and improved patient quality of life relative to a matched cohort reconstructed without the graft.

The investigators are careful to acknowledge the limits of their evidence. The registry lacks a contemporaneous control group, so direct comparative claims about relative safety cannot be drawn; the deliberately heterogeneous population, while ideal for an IDEAL stage 2b evaluation, may obscure indication-specific differences; the interim analysis carries a median follow-up of only about 27 weeks, leaving late complications and long-term durability to be characterized; and adverse event categorization relied on investigator judgment. Even so, as one of the largest prospective evaluations of a bioscaffold in soft tissue reconstruction reported to date, the interim MASTRR data make a compelling case that a scaffold spun from an abundant food-industry byproduct can be deployed safely in some of the most hostile wounds surgery has to offer, and that registry-based real-world evidence deserves a permanent seat alongside randomized trials in judging emerging medical devices.

Subject of Research: Real-world safety of ovine forestomach matrix bioscaffolds in complex soft tissue reconstruction

Article Title: Safety of Ovine Forestomach Matrix Across 474 Soft Tissue Defects: Interim Results from the Prospective Multicenter MASTRR Registry

Article References: Short, T., Lawlor, J., Martyka, P., Wolf, J. H., Felton, J. M., Smith, A. A., Nasseri, Y. Y., Barnajian, M., Vassy, W. M., Cormican, M., Kumar, P., Choi, J. J., Lau, L., Loftus, J. H., Bernal, N. P., Butts, C. A., Dillingham, C. S., Leneweaver, K. J., Simon, J., … May, B. C. H. (2026). Safety of Ovine Forestomach Matrix Across 474 Soft Tissue Defects: Interim Results from the Prospective Multicenter MASTRR Registry. Advances in Therapy. https://doi.org/10.1007/s12325-026-03768-0

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03768-0

Keywords: ovine forestomach matrix, bioscaffold, soft tissue reconstruction, MASTRR Registry, adverse events, real-world evidence, wound healing, diabetic foot ulcers, trauma surgery, burns, pilonidal sinus, IDEAL framework

Doxorubicin is an anthracycline antitumor antibiotic and one of the most widely used injectable chemotherapeutics in veterinary medicine. It acts on cancer cells through a battery of mechanisms, including DNA intercalation, inhibition of DNA and RNA polymerases, inhibition of topoisomerase II, DNA alkylation, and the generation of reactive oxygen species. That versatility makes it a staple against many canine malignancies, both as a single agent and within multi-drug protocols. But its toxicity profile is equally well known. Gastrointestinal adverse events and myelosuppression, the suppression of bone marrow activity, are the dose-limiting toxicities, and dogs receiving doxorubicin as a single agent experience gastrointestinal side effects more frequently than with most other intravenous chemotherapeutics.

The problem with the current standard lies in its assumptions. Doses of doxorubicin, like many chemotherapies, are calculated using body surface area, a practice originally adopted to normalize doses across species on the grounds that surface area better reflects basal metabolic rate than body weight alone. Yet body surface area cannot account for the factors that actually determine how much drug circulates in a patient: distribution, metabolism, and excretion. The evidence that something is amiss has been accumulating for years. Smaller dogs suffer more severe adverse events when dosed by body surface area, which is why dogs under 15 kilograms are typically treated with a weight-based dose of 1 milligram per kilogram instead. The formula, in short, is imperfect.

Pharmacokinetics offers a way out. Rather than asking how much drug was administered, pharmacokinetic-guided dosing asks how much drug the patient actually absorbed and retained over time, quantified as the area under the drug concentration-time curve, or AUC. Previous work in canine patients demonstrated that predicted doxorubicin AUC correlates with neutropenia, the dangerous drop in neutrophils that marks bone marrow suppression, as well as with total white blood cell counts and the surviving fraction of neutrophils at the nadir, the lowest point of the count. Human medicine has already capitalized on this logic. Pharmacokinetic-guided dosing of docetaxel reduced variability in bone marrow suppression by up to 50 percent, and individualized fluorouracil dosing in metastatic colorectal cancer significantly improved objective response rates compared with conventional dosing.

The Davis team, led by Sridhar Madan Veluvolu together with Robert B. Rebhun, Jaeyoung Kim, and Luke Anthony Wittenburg, built on a tool developed earlier in their laboratory: a limited sampling model that predicts total doxorubicin exposure from just three blood samples. Under the protocol, dogs received a standard 30 milligrams per square meter dose by 20-minute intravenous infusion, and blood was drawn at five, 45, and 60 minutes after the infusion ended. Serum doxorubicin concentrations were measured with a validated liquid chromatography tandem-mass spectrometry assay, linear from 10 to 750 nanograms per milliliter, and plugged into a weighted equation that estimates the AUC over the first six hours. The elegance of the approach is its practicality: three time points instead of an exhaustive sampling series makes prospective clinical use feasible.

The prospective study ran from June 2021 to August 2022 at the UC Davis Veterinary Medical Teaching Hospital, enrolling tumor-bearing dogs at least 15 kilograms in weight with favorable performance scores and no cardiac dysfunction or multidrug-resistance gene mutations. Ten dogs met the criteria, but three were withdrawn after a single dose because of owner-perceived adverse events, leaving seven patients who completed three full cycles of doxorubicin with complete blood counts at baseline and at the seven-day nadir after each dose. Owners filled out standardized questionnaires about gastrointestinal signs after every treatment and were asked to keep their pets on a consistent diet to make those observations as comparable as possible.

The headline result is stark. Measured and dose-normalized doxorubicin concentrations varied nearly tenfold between patients at the sampled time points, and there was no significant correlation between the total milligram dose a dog received and its predicted AUC. When the coefficient of variation was calculated after normalizing for dose, the average within-patient variability across three cycles was just 4.7 percent, while the average between-patient variability was 25.4 percent, a difference that was highly statistically significant. Before dose normalization the within-patient figure was 10.7 percent against 22.5 percent between patients. Notably, the within-patient variability observed in these dogs, ranging from 2.8 to 9 percent, is lower than the 6 to 59 percent reported in humans, while the between-patient variability in dogs was tighter than the 37 to 93 percent seen in human studies.

The model also proved its worth as a predictive instrument. Although no significant relationship emerged between predicted AUC and absolute neutrophil counts across all data points, the picture sharpened when the analysis focused on dogs whose seven-day neutrophil counts were genuinely lower than baseline, suggesting the true nadir had been captured. For those patients, higher exposure correlated significantly with a lower surviving fraction of neutrophils. The limited sampling model, using baseline neutrophil count and predicted AUC together, successfully predicted the absolute nadir neutrophil count with a mean prediction error of just 3.3 percent. Three neutropenic events were captured during the study, two of which occurred at the highest predicted exposures, and one patient who received a 25 percent dose reduction after severe neutropenia subsequently showed a 25 to 32 percent drop in exposure, an encouraging hint that the model tracks dose changes faithfully.

The gastrointestinal findings add a patient-centered dimension. Using owner-reported scores, the researchers found that higher predicted AUC correlated significantly with decreased appetite and increased nausea, though not with vomiting or diarrhea, and no significant relationship emerged for composite gastrointestinal scores. The authors caution that owner scoring of subjective signs carries inherent bias, but the correlations suggest that the patients with the highest drug exposure are also the ones feeling the worst, a pattern that personalized dosing could potentially flatten. The study had clear limitations, including its small size of seven completers, strict eligibility criteria that may not represent the broader population of treated dogs, and unexplored genetic factors, since doxorubicin disposition involves influx and efflux transporters and metabolizing enzymes whose variants in dogs remain poorly characterized.

What comes next is the crucial question of targets. The researchers emphasize that no one yet knows what AUC a dog should hit to maximize tumor response while minimizing toxicity, and that target may differ from patient to patient. In human docetaxel therapy, AUC-guided dose adjustment dramatically increased the proportion of patients within the therapeutic window and improved disease control rates. Neutropenia itself may serve as a double-edged biomarker, since in canine lymphoma it has been associated with longer remission and survival times, hinting that the right amount of bone marrow suppression may signal effective dosing. For now, the Davis team’s message is simple and provocative: the same dose produces wildly different exposures in different dogs, but each dog is remarkably consistent with itself. That consistency is precisely what makes individualized dosing achievable, and the first treatment cycle may be all the information a clinician needs to get there.

Subject of Research: Pharmacokinetic variability of doxorubicin exposure in dogs with cancer using a limited sampling model

Article Title: Comparison of interpatient and intrapatient variability in doxorubicin exposure using a validated limited sampling model in dogs with cancer

Article References: Veluvolu, S. M., Rebhun, R. B., Kim, J., & Wittenburg, L. A. (2025). Comparison of interpatient and intrapatient variability in doxorubicin exposure using a validated limited sampling model in dogs with cancer. Veterinary Oncology, 2(1), Article 24. https://doi.org/10.1186/s44356-025-00038-z

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00038-z

Keywords: doxorubicin, veterinary oncology, pharmacokinetics, limited sampling model, chemotherapy dosing, body surface area, neutropenia, AUC, dogs, adverse events, personalized medicine, canine cancer

The scale of the investigation is striking. The researchers extracted 12,763 adverse event reports involving riociguat from the United States Food and Drug Administration’s Adverse Event Reporting System, known as FAERS, and a further 17,316 reports from VigiAccess, the World Health Organization’s public gateway to global pharmacovigilance data. Together these databases capture hundreds of thousands of reports submitted by healthcare professionals, patients, and manufacturers across dozens of countries, offering a view of drug safety that no single trial can match. Women accounted for the majority of reports in both databases, a pattern consistent with the epidemiology of pulmonary hypertension, which disproportionately affects women, but also a finding that would prove consequential when the team examined sex-specific reactions.

At the heart of the analysis lies a statistical technique called disproportionality analysis, the workhorse of modern pharmacovigilance. Rather than simply counting how often a reaction appears, disproportionality methods ask whether a particular drug-event pair occurs together more often than would be expected by chance, given the overall composition of the database. The team applied multiple established algorithms, including the reporting odds ratio, the proportional reporting ratio, and Bayesian confidence propagation methods, each with defined thresholds for what constitutes a meaningful signal. Requiring agreement across several independent algorithms reduces the risk that a single statistical quirk will be mistaken for a genuine safety concern, a persistent problem in spontaneous reporting data where reporting biases and confounding abound.

The results largely vindicated the drug’s known safety profile. The most frequently reported adverse events were dyspnoea, the medical term for breathlessness, and hypotension, or abnormally low blood pressure. Both are biologically plausible for riociguat: the drug works by enhancing the nitric oxide signalling pathway, relaxing blood vessels and lowering pulmonary vascular resistance, so systemic vasodilation and its consequences are expected effects pushed to an uncomfortable extreme in some patients. The strongest statistical signals included diastolic hypotension and bendopnoea, a subtle symptom in which breathlessness occurs while bending over, such as when putting on shoes. Bendopnoea is increasingly recognized as an early marker of worsening cardiac function, and its emergence as a signal suggests clinicians are documenting it more systematically in this patient population.

The sex-stratified analysis produced some of the study’s most clinically actionable findings. After adjusting for age and body weight, two variables that could otherwise explain differences in drug exposure and metabolism, female patients reported significantly more dyspnoea, headache, nausea, vomiting, and chest pain than male patients. Such gender differences in adverse drug reactions are an area of growing scientific interest, driven by known variations in body composition, hormonal influences, renal and hepatic clearance, and even the historical underrepresentation of women in pivotal trials. For riociguat, the pattern implies that women may need closer monitoring during dose titration, particularly for gastrointestinal intolerance and blood pressure-related symptoms, and that prescribers should not assume trial-derived tolerability data apply uniformly across sexes.

Drug-drug interaction analysis added a second layer of concern. The team identified 30 interaction signals, and the companies of riociguat proved telling: endothelin receptor antagonists accounted for 36.67 percent of the signals and oral anticoagulants for 33.33 percent. Both drug classes are staples of pulmonary hypertension care, meaning the interactions are not exotic edge cases but routine combinations encountered in everyday practice. Endothelin receptor antagonists and riociguat both affect vascular tone, raising questions about additive haemodynamic effects, while anticoagulants are standard in chronic thromboembolic disease and interact with any drug that influences bleeding risk or hepatic metabolism. The authors used multiple signal-detection algorithms for the interaction analysis as well, and their supplementary tables transparently flag which signals were supported by only a single method, an unusually honest approach to the uncertainty inherent in this kind of data mining.

Timing proved to be another revealing dimension. The median time to onset of adverse events was 225 days, with an interquartile range spanning from 47 days to just over 710 days. This long and widely distributed onset window carries a sobering implication: riociguat toxicity is not confined to the initiation period that trials and early monitoring tend to emphasize. A substantial fraction of reactions emerge months or even years into therapy, precisely when patients and clinicians have settled into a sense of security. Sustained vigilance, rather than a brief introductory monitoring burst, appears to be what the data demand, and the late-onset pattern also complicates causal attribution, since comorbid disease progression can mimic drug effects in this progressive illness.

Crucially, the team did not stop at database mining. They cross-validated their pharmacovigilance signals against the safety data from six riociguat clinical trials, finding general concordance between the real-world reports and the trial evidence for established concerns such as hypotension, gastrointestinal disorders, and peripheral edema. But the databases also yielded signals that trials had not flagged, most notably traumatic fractures and pain in the jaw. Traumatic fractures could plausibly reflect falls precipitated by dizziness or syncope from hypotension, an indirect but clinically important chain of harm, while jaw pain raises questions that will require targeted follow-up. These discrepancies illustrate the complementary nature of the two evidence systems: trials establish causation with rigor but limited statistical power for rare events, while spontaneous reports detect rare and unexpected events but cannot by themselves prove causation.

The practical culmination of the study is a pharmacist-led management framework built on the narrative evidence review and the pharmacovigilance findings. The workflow is organized into three phases: pre-treatment evaluation, treatment initiation, and maintenance, with six core responsibilities assigned to pharmacists. These are drug interaction management, safety signal recognition, patient education, efficacy and safety assessment, professional documentation, and quality indicators. The framework reflects a broader shift in hospital practice, in which pharmacists move from dispensing roles into direct therapeutic management, particularly for high-risk medications like riociguat that demand blood pressure monitoring, careful titration, and constant attention to a patient’s full medication list. Given that the interaction signals cluster around drugs pulmonary hypertension patients take routinely, the pharmacist’s cross-checking role becomes not a luxury but a structural safeguard.

The study carries the usual caveats of spontaneous reporting research. FAERS and VigiAccess suffer from underreporting, inconsistent reporting quality, missing denominators that make incidence rates impossible to calculate, and the reporting biases that come with media attention and litigation. The authors were careful to frame their findings as signals warranting attention rather than proven causal effects, and the ethics declarations note that the use of publicly available, anonymized data required no institutional review board approval. Still, the convergence of evidence from two independent global databases, agreement across multiple statistical algorithms, and validation against six clinical trials gives these findings a weight that single-database studies often lack. For the growing population of patients living with pulmonary hypertension, the message is one of informed vigilance: riociguat remains a valuable therapy, but its safety profile is broader, later-emerging, and more sex-dependent than the label alone suggests, and the pharmacist may be the most important person watching for what the label does not say.

Subject of Research: Post-marketing safety evaluation of the pulmonary hypertension drug riociguat using FAERS and VigiAccess pharmacovigilance databases

Article Title: Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework

Article References: Hong, X., Guo, C., Wang, H., Cai, H., & Zhao, S. (2026). Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01245-6

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01245-6

Keywords: riociguat, pharmacovigilance, FAERS, VigiAccess, adverse events, pulmonary hypertension, drug-drug interactions, hypotension, pharmacist-led management, drug safety, gender differences, disproportionality analysis

Zanubrutinib belongs to a class of targeted drugs known as Bruton’s tyrosine kinase inhibitors, or BTK inhibitors, which block a signaling protein that B cells, the immune cells that turn malignant in chronic lymphocytic leukemia, rely on for survival and proliferation. First-generation inhibitors such as ibrutinib transformed outcomes for this patient population but carried a burden of off-target effects, because they also inhibited related kinases including those involved in cardiac rhythm, platelet aggregation, and other signaling pathways. Zanubrutinib was engineered for greater selectivity, binding BTK more completely while sparing neighboring targets, and the new cohort study set out to test whether that improved pharmacological profile translates into better tolerability and sustained disease control outside the carefully curated environment of a clinical trial.

The researchers interrogated treatment patterns across the full cohort with unusual granularity. Therapy was discontinued in 76 patients, or 18.5 percent of the total, but the reasons tell an encouraging story. Disease progression accounted for only 32 discontinuations, or 7.8 percent of all patients, meaning the vast majority of patients who stopped the drug did so for reasons unrelated to treatment failure. Patient preference led 25 patients, or 6.1 percent, to discontinue, adverse events prompted 15 patients, or 3.7 percent, to stop, and four patients, or 1.0 percent, died of unknown causes. In an era when treatment duration on continuous oral therapy is a key measure of a drug’s real-world value, these numbers suggest that zanubrutinib keeps patients on treatment and keeps their disease in check for extended periods.

Perhaps the most clinically consequential finding concerns dose reductions, a topic that has generated anxiety among both oncologists and patients. Forty-six patients, or 11.2 percent of the cohort, required at least one dose reduction, most commonly because of adverse events, which affected 17 patients, or 4.1 percent, or because of patient preference, cited by 26 patients, or 6.3 percent. The critical question has always been whether lowering the dose compromises efficacy. The answer from this cohort appears to be no. Among the 46 patients who reduced their dose, the researchers observed no cases of disease progression or death after the reduction occurred, over a median follow-up of 10.9 months from the first dose modification. While the follow-up window is relatively short and the subgroup modest in size, the signal is reassuring for the many patients who need to taper their dose to manage side effects.

The study also shed light on a growing phenomenon in leukemia care: switching between BTK inhibitors. Fifty-four patients in the cohort moved to zanubrutinib from another BTK inhibitor without any evidence of disease progression, meaning they switched for tolerability or convenience rather than treatment failure. Thirty-two of these patients made the move because of adverse events on their previous drug, 19 because of patient preference, and four for unknown reasons, with some reasons overlapping. The median duration of zanubrutinib treatment after the switch was 10.1 months among patients who switched due to side effects and 16.5 months among those who switched by preference. Most notably, progression-free survival had not been reached in either group at the time of analysis, indicating that patients who transition from an older BTK inhibitor to zanubrutinib for non-progressive reasons can continue to achieve durable disease control on the newer agent.

From a technical standpoint, the study’s design merits attention. The investigators conducted a retrospective, multicenter cohort analysis drawing on data from hospitals across China, including Peking University People’s Hospital, the First Affiliated Hospital of Nanjing Medical University, Nanfang Hospital, West China Hospital, and several others, with Peking University People’s Hospital serving as the central ethics committee. The primary endpoint was progression-free survival, the standard measure of how long patients live without their disease worsening, analyzed with confidence intervals to quantify uncertainty. The three-year PFS estimate of 91.6 percent for treatment-naive patients carried a 95 percent confidence interval of 83.8 to 95.8 percent, while the 83.2 percent estimate for later-line patients spanned 74.6 to 89.1 percent. These intervals, while wide in places due to the evolving follow-up time, place real-world outcomes squarely in the territory previously reported in registration trials, a consistency that strengthens confidence in the drug’s effectiveness.

The distinction between initial and later-line therapy matters enormously in chronic lymphocytic leukemia, an indolent malignancy that predominantly affects older adults and often follows a relapsing course over many years. Patients receiving zanubrutinib as initial therapy had not been exposed to prior BTK inhibition and typically had fewer accumulated resistance mechanisms. Those receiving it later had often been through chemoimmunotherapy or earlier targeted agents. The roughly eight-percentage-point gap in three-year progression-free survival between the two groups is consistent with the expected biology, yet the fact that later-line patients still achieved better than 83 percent freedom from progression at three years underscores how much the BTK inhibitor class has reshaped the prognosis of relapsed and refractory disease, which was historically one of the most difficult scenarios to manage.

Why does real-world evidence of this kind matter so much? Registration trials enroll selected patients, often excluding those with significant comorbidities, competing medications, or atypical disease features, and they monitor adherence intensively. Routine practice is different. Patients forget doses, stop drugs because they feel well, reduce doses on their own initiative, and switch therapies based on quality-of-life considerations that never appear in a case report form. By documenting that only 3.7 percent of patients discontinued zanubrutinib because of adverse events, and that dose reductions did not precipitate disease progression, this nationwide cohort provides the kind of pragmatic evidence that health systems, guideline committees, and prescribing physicians need when weighing treatment options for a disease that may require years of continuous oral therapy.

The findings also carry implications for how clinicians counsel patients about side effect management. Patient preference was the single most common reason for both dose reduction and discontinuation in this cohort, a reminder that shared decision-making is not a formality but a genuine determinant of treatment trajectories. Some patients in the study chose to reduce or stop their medication despite adequate tolerability, and the data suggest that, at least within the observed follow-up, such choices did not immediately translate into disease progression. That said, the authors and the broader hematology community would caution that longer observation is needed before dose attenuation can be considered fully equivalent to continuous full-dose therapy, particularly given the indolent nature of the disease and the possibility of late relapse.

Taken together, the study offers a comprehensive portrait of zanubrutinib as it is actually used: a drug with high selectivity for its target, low rates of discontinuation for toxicity, reassuring outcomes after dose modification, and strong progression-free survival in both first-line and later-line settings. As BTK inhibitors continue to evolve and as fixed-duration combinations challenge the paradigm of continuous therapy, cohorts like this one, registered as NCT06489184 on ClinicalTrials.gov, will remain essential for understanding how these powerful targeted agents perform in the hands of real patients and real physicians, far from the protocolized confines of the clinical trial.

Subject of Research: Real-world effectiveness, dose modification and discontinuation patterns of the BTK inhibitor zanubrutinib in chronic lymphocytic leukemia/small lymphocytic lymphoma

Article Title: Dose modifications, discontinuation patterns and PFS of zanubrutinib in 410 CLL/SLL patients – a nationwide real-world cohort

Article References: Yang, S., Zhu, H., Hu, L., Feng, R., Guo, X., Niu, T., Shen, K., Li, Z., Dong, Y., Wang, B., Su, L., Wang, L., Wang, L., Sun, W., Fang, F., Zhao, Y., Huang, X., & Li, J. (2026). Dose modifications, discontinuation patterns and PFS of zanubrutinib in 410 CLL/SLL patients – a nationwide real-world cohort. BMC Cancer. https://doi.org/10.1186/s12885-026-17043-6

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17043-6

Keywords: zanubrutinib, chronic lymphocytic leukemia, small lymphocytic lymphoma, BTK inhibitor, progression-free survival, dose reduction, real-world evidence, drug discontinuation, adverse events, hematology, targeted therapy, BMC Cancer

The research team, led by Youran Li and Ting Zhang of the Department of Gastroenterology, Hepatology and Nutrition at Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, set out to answer three questions that clinicians and families frequently ask: how often do adverse events occur after fecal microbiota transplantation in children with autism, how severe are those events, and do any patient or procedure characteristics predict who will experience them. The study was registered with the Chinese Clinical Trial Registry under identifier ChiCTR2200055943 and received ethical approval from the hospital’s review committee, with informed consent obtained from the guardians of all participants in accordance with the Declaration of Helsinki.

The children enrolled ranged in age from two to seventeen years, an age span that captures the early childhood period in which autism diagnoses are typically made as well as the school-age and adolescent years. Each child received transplants through one of three delivery routes: oral capsules containing lyophilized, freeze-dried donor microbiota; a nasojejunal tube, which passes through the nose into the jejunum, the middle section of the small intestine; or a transendoscopic enteral tube, which is positioned during an endoscopic procedure to deliver the transplant deeper into the digestive tract. These routes differ substantially in invasiveness, cost, and the degree of clinical support required, and the researchers were particularly interested in whether the method of delivery influenced tolerability.

To evaluate safety rigorously, the team graded every adverse event using the Common Terminology Criteria for Adverse Events, a standardized grading system widely used in clinical research in which Grade 1 denotes mild symptoms and Grade 5 denotes death. They then applied a multivariate generalized estimating equations model, a statistical approach well suited to repeated-measures data in which the same child contributes multiple procedures over time. This method allowed the investigators to adjust for correlated observations within individual patients and to isolate the independent effect of candidate risk factors, including delivery route, on the likelihood of an adverse event.

The headline finding is striking in its simplicity: across all 604 procedures, adverse events occurred in only 15, an overall incidence of 2.5 percent. Every single event was acute, meaning it began within 48 hours of the procedure, and every event was Grade 1, the mildest category on the severity scale. None of the events was severe, and none persisted. The median duration of symptoms was 28 hours, after which all events resolved spontaneously without long-term consequences. The most frequent symptoms reported were vomiting and irritability, both of which are recognizable, transient reactions in young children undergoing gastrointestinal interventions.

Long-term surveillance added a further layer of reassurance. The researchers followed the children longitudinally after their procedures and observed no delayed adverse outcomes, addressing one of the persistent concerns about microbiota-based therapies: that transferring living microbial communities might carry risks, such as the transmission of pathogens or the seeding of dysbiosis, that only become apparent months or years later. The field has grappled with this question seriously in recent years, particularly after documented transmissions of drug-resistant organisms in adult patients prompted regulatory tightening around donor screening and stool banking. The Shanghai team’s longitudinal data, while observational, suggest that in this pediatric population and under their screening and preparation protocols, delayed harms did not materialize.

Perhaps the most consequential finding concerns delivery route. The transendoscopic enteral tube approach carried an adverse event rate of 26.3 percent, dramatically higher than the other methods. Oral capsules produced adverse events in just 1.7 percent of procedures and the nasojejunal tube in 1.8 percent, both figures indicating favorable tolerability. When the multivariate model was run, transendoscopic delivery emerged as the sole independent risk factor, with an adjusted odds ratio of 21.90 and a P value below 0.001, meaning that after accounting for other variables, children receiving transplants via this route had roughly twenty-two times the odds of experiencing an adverse event compared with those receiving other routes.

The authors of the study conclude that fecal microbiota transplantation demonstrates favorable acute tolerability in children with autism spectrum disorder and that oral capsules, with their low adverse event rate and non-invasive nature, represent a preferred delivery route. This conclusion carries practical weight for clinics considering microbiota-based interventions in pediatric populations. Capsules avoid the discomfort and anxiety associated with tubes, do not require endoscopic facilities, and can be administered in outpatient settings, all of which matter when the recipients are young children, many of whom may have sensory sensitivities or difficulty tolerating medical procedures. The finding that the most invasive route was also the least well tolerated aligns with broader clinical intuition and with pediatric literature on procedure-related nausea and vomiting.

The study sits within a rapidly evolving research landscape. Previous work by some of the same investigators, published in BMC Microbiology in March 2025, examined the long-term safety of fecal microbiota transplantation in Chinese children from 2013 to 2023 across various pediatric indications, and the new report narrows the focus specifically to autism. Internationally, an open-label study published in Microbiome in 2017 reported that microbiota transfer therapy altered gut ecosystems and improved gastrointestinal and autism-related symptoms, and a follow-up in Scientific Reports in 2019 described benefits persisting two years after treatment. More recently, a randomized, double-blind, placebo-controlled trial published in Clinical Translation Medicine in 2024 tested oral fecal microbiota transplantation in children with autism, adding methodological rigor to a field long dominated by small and uncontrolled studies. Meanwhile, basic research published in Nature Microbiology in 2024 has identified multikingdom microbial markers associated with autism, and work in Cell Host and Microbe has shown that donor-recipient microbial interactions influence which microbial strains actually take hold after transplantation, a finding with implications for how donor-recipient matching might one day be optimized.

Caution remains warranted in interpreting the new findings. The study is observational rather than randomized, it reports safety rather than efficacy, and its single-center design means the results reflect one institution’s donor screening protocols, preparation methods, and clinical monitoring practices. The very low adverse event rate may partly reflect careful patient selection and experienced procedural teams, and other centers may not replicate identical figures. Nonetheless, the scale of the dataset, with 604 procedures across 224 children, the standardized adverse event grading, the statistical adjustment for repeated measures, and the longitudinal follow-up together make this one of the most informative real-world safety profiles available for pediatric fecal microbiota transplantation in autism. For families and clinicians weighing whether microbiota-based therapy has a place in the care of children with autism spectrum disorder, the message from Shanghai is measured but meaningful: in experienced hands, with appropriate donor screening and a preference for oral capsules, the acute and long-term safety picture appears reassuring, even as questions about therapeutic benefit continue to be tested in controlled trials.

Subject of Research: Safety and tolerability of fecal microbiota transplantation in children with autism spectrum disorder

Article Title: Acute Tolerability and Long-Term Surveillance of Fecal Microbiota Transplantation in Children with Autism: A Real-World Study of 604 Procedures

Article References: Li, Y., Yu, W., Liu, R., Xiao, P., Li, X., & Zhang, T. (2026). Acute Tolerability and Long-Term Surveillance of Fecal Microbiota Transplantation in Children with Autism: A Real-World Study of 604 Procedures. Advances in Therapy. https://doi.org/10.1007/s12325-026-03797-9

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03797-9

Keywords: fecal microbiota transplantation, autism spectrum disorder, pediatrics, gut microbiome, adverse events, oral capsules, donor screening, long-term safety, Shanghai Children's Hospital, clinical trial, gastroenterology, neurodevelopmental disorders

The FOCUS-PDCA cycle is a structured framework for continuous quality improvement that has migrated from manufacturing into healthcare over recent decades. The acronym describes a disciplined sequence: Find a process to improve, Organize a team that knows the process, Clarify current knowledge of how it works, Understand the root causes of problems and variation, and Select the improvement most likely to work. That selection is then fed into the PDCA loop—Plan, Do, Check, Act—in which a change is planned, implemented, measured against expectations, and either standardized or revised. The genius of the method lies in its refusal to accept a single fix as final; the cycle turns again and again, forcing institutions to verify that improvements actually hold rather than merely declaring victory and moving on.

The 6S method, by contrast, operates at the level of the physical workplace. Derived from the Japanese lean manufacturing tradition, it comprises Seiri (sort, removing unnecessary items), Seiton (set in order, arranging what remains for efficient access), Seiso (shine, systematic cleaning), Seiketsu (standardize, codifying best practices), Shitsuke (sustain, building the discipline to maintain standards), and Safety, the addition that distinguishes 6S from the original 5S of factory floors. In a hospital equipment context, this means properly sorted storage rooms, labeled and logically arranged devices, routine cleaning regimens, standardized procedures for checking and returning equipment, and an organizational culture in which staff internalize these habits rather than treating them as occasional campaigns. Each S addresses a failure mode familiar to any clinician who has hunted for a working blood pressure cuff at three in the morning.

The question Chen and Zhuo set out to answer was whether combining these frameworks would produce measurable gains in hospital medical equipment management compared with routine procedures. Their study design was a comparative evaluation involving 200 medical devices in a single hospital. One hundred devices managed under routine procedures from January to June 2024 served as the control group. Another 100 devices, managed from July to December 2024 under the integrated FOCUS-PDCA plus 6S approach, formed the observation group. The researchers then compared the two phases across five domains: management quality, safety-related attribution of incidents, adverse event incidence, maintenance indicators, and user satisfaction among staff who operated the equipment.

The results, reported with statistical significance at P < 0.05 across all comparisons, were striking. Devices in the observation group achieved higher total and dimensional quality scores than those in the control group, indicating that the integrated framework improved not just overall performance but the specific subcomponents of management practice. Just as importantly, the incidence of safety-related problems and adverse events dropped significantly under the combined approach. In a domain where equipment failure can translate directly into patient harm—a mislabeled pump setting, an unavailable defibrillator, a monitor with a degraded alarm—reducing safety incidents is not an abstract quality metric but a matter of clinical risk.

The maintenance data may prove the most persuasive element for hospital administrators watching their budgets. The observation group showed reduced maintenance frequency, shorter repair times, and lower maintenance costs relative to the control group. This triad matters because equipment downtime carries a cascade of consequences: canceled procedures, borrowed or rented substitutes, staff frustration, and in some cases compromised care. Devices that break down less often and return to service faster effectively expand the usable fleet without any new capital expenditure. Lower maintenance costs, meanwhile, release resources that can be redirected toward training, replacement planning, or direct patient services.

User satisfaction told a parallel story. Clinical staff rated the equipment under the integrated approach significantly higher across every dimension surveyed: performance and reliability, cleanliness, maintenance responsiveness, supply support efficiency, and technical training. These dimensions are not incidental. Cleanliness reflects the Seiso and Seiketsu disciplines; maintenance responsiveness reflects the structured problem-solving of FOCUS-PDCA; supply support and training reflect the organizational clarity that both frameworks cultivate. When frontline users notice the difference, the improvement has penetrated the daily texture of hospital work rather than residing only in an administrative report.

The study builds on a growing body of evidence for both methods individually. FOCUS-PDCA has been credited with reducing the distribution defect rate of sterile packages, optimizing critical laboratory test values, improving emergency collaboration among thoracic surgery nurses, and reducing complications after transradial cardiac intervention. The 6S approach has been shown to improve workplace productivity in primary health centers in India and to enhance operating room nursing practice. What the new research adds is the demonstration that the two methods, which address complementary dimensions of hospital operations—the procedural and the physical—yield additive benefits when applied together to equipment management, a domain that is often treated as an afterthought compared with clinical quality initiatives.

Why should this particular combination work so well? The answer likely lies in how each framework compensates for the other’s blind spots. FOCUS-PDCA excels at diagnosing systemic problems and driving iterative improvement, but it can become abstract if the daily environment remains disorganized. 6S excels at creating an orderly, standardized, self-sustaining physical workspace, but on its own it risks becoming a superficial cleanup exercise that decays once attention shifts. Integrated, the two methods create a feedback system: 6S establishes the stable, visible, disciplined baseline, while FOCUS-PDCA continuously probes that baseline for weaknesses, tests corrections, and locks in gains as new standards. The Safety element of 6S, in turn, gives the PDCA cycle a concrete target that maps directly onto clinical risk reduction.

The findings arrive at a moment when hospitals worldwide face mounting pressure from aging equipment fleets, tightening budgets, and rising expectations for patient safety. The appeal of the FOCUS-PDCA plus 6S approach is its accessibility: it requires no new technology infrastructure, no expensive software, and no specialized consultants, only organizational commitment, defined responsibilities, and the persistence to keep the improvement cycle turning. For hospital administrators searching for high-yield, low-cost interventions, the study offers a compelling data point that old management disciplines, applied rigorously and in combination, can still deliver distinctly modern results in the machinery of care.

Subject of Research: An evaluation of the FOCUS-PDCA cycle combined with 6S management for improving hospital medical equipment management quality, safety, and user satisfaction

Article Title: Application of the FOCUS-PDCA Cycle Management Combined with the 6S Management Method in Hospital Medical Equipment Management

Article References: Application of the FOCUS-PDCA Cycle Management Combined with the 6S Management Method in Hospital Medical Equipment Management. (n.d.). https://doi.org/10.1007/s40846-026-01056-4

Image Credits: AI Generated

DOI: 10.1007/s40846-026-01056-4

Keywords: FOCUS-PDCA, 6S management method, medical equipment management, hospital administration, quality improvement, patient safety, adverse events, maintenance costs, user satisfaction, lean management, healthcare management, medical devices

Unlike earlier generations of medical exoskeletons, which typically require crutches or a walker and rely on pre-programmed, rigid gait patterns, self-balancing designs aim to keep the user upright dynamically, allowing more natural overground movement. That added freedom, however, introduces new engineering challenges: the control system must continuously stabilize the body without the external support of walking aids, and the user must trust that the machine will not tip. Before any device of this kind can move toward clinical deployment, its developers must rigorously assess usability, operational reliability, and safety — which is precisely what this study set out to do.

The evaluation was deliberately structured to capture the experience of both sides of the human-machine partnership: the device users and the trained operators who supervise them. Three adult participants with chronic motor-complete spinal cord injury, with neurological injury levels between T3 and T10 and ASIA Impairment Scale grades A to B, took part in twelve sessions over a four-week period. Six operators, all members of the research team, completed parallel assessments. The protocol unfolded across three distinct phases designed to mirror how a real clinical introduction of the technology might proceed.

In the first phase, participants underwent screening and intake, including anthropometric evaluations and familiarization with the device through a simulator. The second phase focused on physical preparation: fitting the exoskeleton, practicing the donning and doffing procedures, and collecting baseline performance measurements. Only in the third phase did participants begin true intervention exposure, progressing through sit-to-stand movements, overground walking, and tasks drawn from the Functional Gait Assessment, a standardized clinical measure of walking ability. This phased design allowed the researchers to observe how users and operators adapted to the technology incrementally, while documenting every friction point along the way.

Feedback was collected through structured, self-administered questionnaires. Participants rated ease of use, user confidence, and system design, while operators provided their own ratings covering setup workflow, device control, and perceived stability. The results painted a cautiously encouraging picture. Participants reported high usability overall, particularly praising the ease of system setup and expressing strong confidence in the device. Operators rated usability as moderate, reflecting genuine enthusiasm for the device’s rehabilitation potential tempered by real-world difficulties during early familiarization.

Those difficulties are exactly the kind of granular data that beta-stage testing exists to capture. Participants identified several areas needing improvement: the process of transferring onto the device before donning it, the clarity of the device’s messaging on its displays, and the smoothness of movement transitions between different activities. Operators, meanwhile, flagged challenges in device setup, the responsiveness of the joystick controller, and their perception of system stability during early sessions. None of these findings invalidates the technology; rather, they map out the engineering and training priorities that must be resolved before the device can safely leave the laboratory.

The safety findings deserve particular attention, because they illustrate the complexity of deploying powered mobility devices in a population with sensory and motor impairment. Adverse events recorded during the study included skin irritation and bruising — known risks for exoskeleton users, whose insensate skin endures direct mechanical loading from rigid braces and straps. More seriously, one participant sustained a tibial fracture during a sit-to-stand-to-sit transfer. The post-event review concluded that contributing factors were multifactorial and did not identify a confirmed device malfunction. Bone health is a critical concern in chronic spinal cord injury, as prolonged immobilization leads to significant loss of bone mineral density, making even routine transfers a potential fracture risk. This single event underscores why the study’s authors argue that future work must embrace multifactorial risk-mitigation strategies that account for participant-specific factors, training and setup conditions, and device operation as an integrated whole.

The study’s conclusions are measured but optimistic. The Beta 2 investigational prototype demonstrated positive usability from users and showed potential to support rehabilitation-related activities according to operators. The authors recommend that future development focus on improving system responsiveness and operator workflow, alongside the broader risk-mitigation framework. Notably, the manuscript also includes a brief manufacturer commentary contextualizing how the device has evolved, a transparency gesture that reflects the collaborative nature of the project, which was supported by Team I WILL and the UHN Foundation, with equipment and technical support from Human in Motion Robotics under an Innovation Solutions Canada grant.

What makes this pilot study significant beyond its small sample is its methodological honesty. Usability research in rehabilitation robotics often emphasizes performance metrics — walking speed, distance, physiological outcomes — while giving less attention to the lived experience of the humans strapped into the machine. By systematically collecting feedback from both users and operators across a phased protocol, the research team has produced a template for how investigational devices should be evaluated before clinical deployment. The study also acknowledges the people who made it possible: the device users who, as the authors write, bravely participated in this phase I trial and materially contributed to the usability assessment.

The road from investigational prototype to clinically available device remains long, and this study’s findings — from joystick responsiveness to fracture risk during transfers — will feed directly into the next iteration of the technology. But the core message is one of momentum. A self-balancing exoskeleton that users found easy to set up and confidence-inspiring, that operators judged capable of supporting rehabilitation goals, and whose safety profile could be characterized and understood in detail, represents a meaningful step toward a future in which standing and walking are realistic options for people living with paralysis. As self-balancing robotic gait technology continues to mature, studies like this one will define the standards by which the field earns the trust of its users.

Subject of Research: Usability and safety evaluation of a self-balancing overground exoskeleton for adults with chronic motor-complete spinal cord injury

Article Title: Pilot usability and participant experience evaluation with an investigational self-balancing overground exoskeleton in adult users with chronic motor-complete paraplegia

Article References: Tsang, P., Souza, W. H., Walden, T. P., Park, E. J., Arzanpour, S., Dehghani, H., Peykari, B., & Craven, B. C. (2026). Pilot usability and participant experience evaluation with an investigational self-balancing overground exoskeleton in adult users with chronic motor-complete paraplegia. BioMedical Engineering OnLine. https://doi.org/10.1186/s12938-026-01623-5

Image Credits: AI Generated

DOI: 10.1186/s12938-026-01623-5

Keywords: spinal cord injury, exoskeleton, self-balancing robotics, usability, rehabilitation robotics, overground walking, paraplegia, adverse events, functional gait assessment, wearable technology, pilot study, assistive technology

Diabetes affects roughly one in 200 cats, making it one of the most common endocrine diseases in the species. Traditional management relies on insulin, but success depends heavily on an owner’s ability to give injections reliably, recognize signs of poor glycemic control, and perform home blood glucose monitoring. For many owners, the financial cost, the stress of handling an unwilling cat, and the disruption of daily routines prove overwhelming; previous research has found that up to 10 percent of owners elect euthanasia rather than pursue treatment. Against that backdrop, once-daily oral SGLT2 inhibitors represented a genuine breakthrough. In clinical trials, bexagliflozin achieved a treatment success rate of 84.0 percent by day 56, while velagliflozin reached 88.4 percent by day 30, and a randomized non-inferiority trial showed that once-daily velagliflozin matched twice-daily insulin in glycemic control without episodes of clinical hypoglycemia.

Yet both drugs carry an FDA-mandated Boxed Warning for diabetic ketoacidosis (DKA) and euglycemic DKA, a life-threatening metabolic complication that has appeared in a small but clinically meaningful proportion of treated cats. Pre-market trials also documented gastrointestinal effects such as vomiting, diarrhea, and anorexia, along with other drug-specific events listed in the prescribing information. Because spontaneous reporting systems can capture safety signals that emerge only after a drug reaches a much broader population, the research team, led by Xiaoheng Lai and Maohua Chen of China, turned to the ADAE database maintained by the FDA Center for Veterinary Medicine. The database serves as an early warning system, collecting reports from veterinarians and owners about suspected adverse drug events in animals across the United States.

The researchers extracted every adverse event report submitted for cats receiving bexagliflozin between the fourth quarter of 2022 and the second quarter of 2025, and for velagliflozin between the third quarter of 2023 and the second quarter of 2025. After deduplication and merging of follow-up reports, the dataset contained 34,187 adverse event reports for cats in total, of which 2,876 involved bexagliflozin and 2,776 involved velagliflozin. Each report was coded using the Veterinary Dictionary for Drug Regulatory Activities terminology, a four-tiered hierarchy that organizes events from broad system organ classes down to specific low-level terms. The study followed the READUS-PV reporting guidelines to ensure transparent and standardized conduct of the disproportionality analysis.

At the heart of the study lies a statistical technique called disproportionality analysis, which asks a deceptively simple question: does a particular adverse event appear more often in reports for a given drug than would be expected if that drug were no more likely than any other to cause it? The team employed a case/non-case design in which the reporting proportion of each adverse event for the target drug was compared with the reporting proportion for all other drugs in the database. Four separate algorithms were applied in parallel: the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS). Crucially, a signal was only accepted when all four algorithms met their threshold criteria simultaneously, a conservative standard designed to suppress false positives arising from sparse data or multiple testing.

The results revealed striking differences between the two drugs. Bexagliflozin-related adverse events spanned 22 system organ classes, with statistically significant signals at the organ-class level for investigations, endocrine system disorders, and renal and urinary disorders. Among the 25 positive preferred terms, the strongest signals included weight fluctuation, glucosuria, and abnormal serum protein. Velagliflozin-related events covered 19 system organ classes, with significant signals for endocrine system disorders and investigations, and its 19 positive preferred terms were led by ketonuria, hypochloremia, and acid-base disorders. In a head-to-head comparison restricted to the overlapping reporting period, bexagliflozin showed stronger signals for diabetic ketoacidosis (ROR 7.40 versus 5.53) and ketosis (9.54 versus 7.16), while velagliflozin displayed markedly stronger signals for ketonuria (30.89 versus 7.27) and hypochloremia (8.18 versus 4.75). Ketosis was the most frequently reported event for both drugs, appearing in 1,290 bexagliflozin reports and 927 velagliflozin reports.

Timing proved to be another point of divergence. The median time-to-onset of adverse events was 9 days for bexagliflozin compared with 5 days for velagliflozin, and the median duration was 14 days versus 8 days. More than half of the events for both drugs emerged within the first 10 days of treatment, but velagliflozin showed a higher proportion of very early events, with 63.16 percent occurring within the first week compared with 16.00 percent for bexagliflozin. Stratified analysis showed that for both drugs, diabetic ketoacidosis, diarrhea, and ketosis were rapid-onset events, while bexagliflozin was additionally associated with several prolonged-duration events, including polydipsia with a median duration of 420 days and polyuria lasting a median of 90 days. The authors caution, however, that increased thirst and urination are also classic signs of diabetes itself, so those extended durations may reflect underlying disease progression rather than direct drug effects.

The mechanistic explanation for the shared ketosis signal lies in the physiology of SGLT2 inhibition. These drugs work by blocking glucose reabsorption in the kidney, causing excess glucose to be excreted in urine, but monotherapy relies on sufficient residual endogenous insulin production. When insulin is inadequate, metabolism can shift toward ketone production and ultimately ketoacidosis. SGLT2 inhibitors also stimulate glucagon secretion, further promoting ketogenesis. Notably, euglycemic DKA can occur without marked hyperglycemia, which risks diagnostic delay if owners and clinicians are not alert to the possibility. The study reinforces existing recommendations that blood beta-hydroxybutyrate concentrations be assessed at baseline and monitored closely during the first 14 days of therapy, with values above 2.4 mmol/L typically necessitating insulin and values between 1.0 and 2.4 mmol/L warranting reassessment within two to three days.

Beyond the metabolic risks, the analysis identified significant signals for urinary tract infection with both drugs, consistent with clinical trials in which positive urine cultures were among the most frequently reported events for velagliflozin, and for pancreatitis or elevated pancreatic enzymes, a finding complicated by the fact that diabetes itself is a common risk factor for feline pancreatitis. Electrolyte disturbances, particularly hypochloremia, hypokalemia, hyponatremia, and hypophosphatemia with velagliflozin, also emerged prominently, possibly arising secondarily from gastrointestinal fluid losses. An unexpected signal for hypoglycemia appeared with bexagliflozin despite its absence from the product label, prompting the authors to suggest that prescribing information and post-marketing studies be updated. The descriptive data showed predominantly male, older, heavier cats among reported cases, with euthanasia reported in roughly 7 percent of reports for both drugs and death in 1.77 percent of each.

The authors are careful to acknowledge the limitations inherent in spontaneous reporting systems. Under-reporting, reporting bias, variable data quality, and the lack of detailed clinical narratives mean that disproportionality signals represent statistical associations and hypotheses, not established causation or true incidence rates. The absence of a disease-matched comparator, such as insulin reports, may have inflated signals tied to diabetes severity itself. Nevertheless, a sensitivity analysis confirmed that the core signals were robust, and the study provides veterinarians with actionable, drug-specific guidance: vigilant ketone monitoring in the first two weeks regardless of the drug chosen, electrolyte surveillance especially with velagliflozin, and particular attention to weight changes and persistent urinary signs with bexagliflozin. As oral SGLT2 inhibitor use expands in feline practice, this real-world evidence offers a data-driven foundation for individualized treatment decisions and tailored safety monitoring in the management of feline diabetes.

Subject of Research: Post-marketing pharmacovigilance of SGLT2 inhibitors for feline diabetes using the FDA Animal Drug Adverse Events database

Article Title: Post-marketing safety monitoring of sodium-glucose cotransporter 2 inhibitors for diabetes in cats: a pharmacovigilance study based on the FDA ADAE database

Article References: Post-marketing safety monitoring of sodium-glucose cotransporter 2 inhibitors for diabetes in cats: a pharmacovigilance study based on the FDA ADAE database. (n.d.). https://doi.org/10.1093/jvimsj/aalag193

Image Credits: AI Generated

DOI: 10.1093/jvimsj/aalag193

Keywords: bexagliflozin, velagliflozin, SGLT2 inhibitors, feline diabetes, pharmacovigilance, FDA ADAE database, disproportionality analysis, diabetic ketoacidosis, ketosis, adverse events, veterinary internal medicine, drug safety

The research, led by Belarmino Gonçalves of the Portuguese Oncology Institute of Porto and Thiago Franchi Nunes of Interventix in Campo Grande, Brazil, brought together ten tertiary referral centers across South America and Europe. Between January 2018 and July 2025, the investigators analyzed 68 diagnostic percutaneous transhepatic cholangioscopy, or PTCS, procedures performed in patients whose cross-sectional imaging and prior endoscopic evaluation had been nondiagnostic, or whose anatomy made standard endoscopic access impossible. Crucially, cases performed primarily to treat gallstones were excluded, isolating a cohort in which the sole purpose of the camera voyage into the ducts was to determine whether cancer was present.

The technique itself is a remarkable feat of interventional radiology. Using ultrasound and fluoroscopic guidance, physicians thread a needle through the liver into the bile ducts and establish a percutaneous tract, typically secured with a 10 to 12 French introducer sheath. Through that sheath, flexible cholangioscopes, single-operator platforms, or single-use ultra-slim endoscopes measuring roughly 2.8 to 3.5 millimeters in outer diameter are advanced directly into the biliary tree. Saline irrigation clears the field, allowing the operator to inspect the duct lining in real time — something computed tomography and magnetic resonance cholangiopancreatography fundamentally cannot do, since they offer only indirect views of the biliary mucosa. Some centers perform the cholangioscopic inspection in the same session when tract and sheath conditions permit; others prefer a staged approach roughly 48 to 72 hours later to allow decompression and reduce infection risk in patients with cholangitis or complex anatomy.

During each procedure, operators recorded two kinds of optical judgments before any tissue results were known. The first was a global impression — a binary real-time call of benign versus malignant that integrated everything seen during the examination. The second was a checklist of five predefined visual criteria: tumor vessels appearing as tortuous neovessels, hypervascular mucosa, nodular or polypoid masses, papillary projections, and infiltrative lesions marked by irregular mucosa and loss of normal duct architecture. When recorded images or videos were available, blinded investigators independently reviewed the material against the checklist, with disagreements resolved by consensus, adding a layer of methodological rigor to what has historically been a subjective art.

The results against the gold standard of histopathology were striking. Malignancy was ultimately confirmed in 57 of the 68 procedures, reflecting the referral-enriched, high-risk nature of the population. Against that benchmark, the operator’s global impression achieved 84.2 percent sensitivity, 90.9 percent specificity, and 85.3 percent accuracy. Most notable was the positive predictive value of 98.0 percent: when an experienced operator called a lesion malignant on direct visualization, that call was almost always right. The negative predictive value of 52.6 percent, by contrast, shows that a benign-appearing duct cannot safely rule out cancer — tissue sampling remains essential. The authors caution that these predictive values must be interpreted in light of the unusually high cancer prevalence in this cohort.

Among the individual visual criteria, two emerged as the most trustworthy warning signs. An infiltrative appearance showed 90.9 percent specificity and was strongly associated with malignant histopathology, carrying an odds ratio of 13.75 and a positive predictive value of 97.1 percent. Tumor vessels were also significantly linked to cancer, with an odds ratio of 4.57. Hypervascular mucosa, by comparison, offered little discriminatory power. The researchers then explored combined decision rules: using the permissive rule of tumor vessels or infiltrative appearance raised sensitivity to 84.2 percent at moderate specificity, while the restrictive rule requiring both features achieved 100 percent specificity — a powerful rule-in finding when tissue is scarce — albeit with sensitivity dropping to 36.8 percent. These PTCS-specific heuristics remain hypothesis-generating and await prospective validation.

Safety data were equally informative. Adverse events occurred in 10 of 68 procedures, or 14.7 percent, graded using the modified CIRSE classification system. Two events were grade I, five were grade II, and three were grade IV — the latter all infectious complications requiring intensive care-level support such as vasopressors or ventilation, rather than mechanical injury from the instruments themselves. The predominance of low-grade complications underscores the importance of standardized antibiotic prophylaxis, careful biliary decompression, controlled irrigation strategies, and structured post-procedure monitoring for anyone undergoing antegrade cholangioscopy.

The study’s context matters. In patients with surgically altered anatomy — bilioenteric anastomoses or Roux-en-Y reconstructions accounted for nearly a third of the cohort — conventional endoscopic retrograde cholangiopancreatography is often impossible or has already failed. Traditional blind or fluoroscopy-guided biopsies perform poorly for infiltrative, flat, or submucosal tumors, frequently returning nondiagnostic or discordant samples. Prior meta-analyses have shown that cholangioscopy-guided targeted biopsy outperforms fluoroscopy-guided sampling for indeterminate strictures, and consensus guidelines now frame cholangioscopy as a problem-solving tool. What has been missing, the authors argue, is multicenter real-world evidence about how the percutaneous, antegrade version of the technique performs across diverse devices, operators, and health systems — a gap this Brazil-and-Europe network directly addresses.

The investigators are candid about the limitations. The retrospective design limits control of confounding and standardization, and partial verification bias is possible. The high prevalence of malignancy limits generalizability to lower-risk populations, and procedural heterogeneity — different scopes, sheath sizes, sedation protocols, and timing — reflects the reality of a varied referral network but complicates interpretation. Confidence intervals around some analyses were wide, and inter-observer reproducibility was not formally assessed. Still, the single-session design, which avoided within-patient clustering, and the combination of operator impression with structured criteria strengthen the findings considerably.

Looking ahead, the authors call for prospective validation of PTCS-specific optical reporting frameworks, standardized documentation of procedural variables such as tract maturation and irrigation strategy, and quantification of how cholangioscopic findings actually change patient management. Emerging technologies, including standardized image annotation and artificial intelligence-assisted pattern recognition, could sharpen interobserver agreement and refine the visual criteria tailored to percutaneous referral populations. For now, the message for patients with mysterious bile duct blockages is encouraging: a camera threaded through the liver, guided by a trained eye and a disciplined checklist, can bring clarity where scans and standard endoscopy leave only doubt — with a safety profile that is, in most cases, reassuringly benign.

Subject of Research: Diagnostic performance and safety of percutaneous transhepatic cholangioscopy for complex, indeterminate biliary lesions

Article Title: Percutaneous transhepatic cholangioscopy for complex biliary lesions: multicenter real-world diagnostic performance and safety study

Article References: Percutaneous transhepatic cholangioscopy for complex biliary lesions: multicenter real-world diagnostic performance and safety study. (n.d.). https://doi.org/10.1007/s44343-026-00045-3

Image Credits: AI Generated

DOI: 10.1007/s44343-026-00045-3

Keywords: percutaneous transhepatic cholangioscopy, biliary strictures, cholangiocarcinoma, indeterminate biliary lesions, targeted biopsy, interventional radiology, diagnostic accuracy, adverse events, multicenter study, bile duct cancer, Percutaneous, transhepatic

The study, published in Sports Medicine – Open, represents the first systematic effort to quantify how adverse events are monitored and reported in randomized controlled trials of physical activity interventions for people with neurodevelopmental disorders. A research team led by Jinrong He and Xueping Wu of Shanghai University of Sport searched PubMed, Web of Science, Scopus, the Cochrane Library and multiple EBSCO databases, including SPORTDiscus and APA PsycInfo, completing their formal search on November 11, 2025, followed by three rounds of supplementary snowball searching. After screening 41,852 deduplicated records with the help of an active-learning screening tool, they included 309 randomized controlled trials encompassing 322 study arms and 13,228 participants with neurodevelopmental disorders.

The headline finding is stark: not a single one of the 309 trials fully complied with the CONSORT-Harms recommendations, the international standard for systematically monitoring and reporting potential harms in randomized trials. Only 58 studies, roughly one in five, described any adverse event monitoring at all, and most of those relied on passive, non-prespecified procedures such as spontaneous participant self-reports. Just 14 trials implemented prespecified monitoring plans, and only one study assessed adverse events during post-intervention follow-up to detect delayed harm. In other words, the vast majority of trials that established the benefits of exercise for this population did so without any structured mechanism for detecting what might have gone wrong.

Among the studies that did report monitoring results, approximately one quarter documented at least one adverse event or adverse effect. The events were overwhelmingly mild. The most common were delayed-onset muscle soreness following resistance and strength training, minor injuries such as falls, a foot sprain, bruising around the knee, and hypoglycemic episodes during combined neuromuscular training, rashes, blisters or hip pain associated with increasing aerobic exercise volume, and psychological discomfort linked to sensory stimulation or environmental adaptation, including distress from wearing sports headphones, overly rapid session progression, and difficulty adjusting to a swimming pool environment. A smaller number of studies reported health problems such as fever, seizures or respiratory infections, but explicitly judged these unrelated to the intervention.

The withdrawal data told a similarly troubling story. Of the 201 studies that reported participant dropout, 133 gave reasons that did not involve adverse events, but 38 used descriptions so vague that the reviewers could not determine whether the withdrawals were harm-related, with phrases like withdrew for personal reasons offering no diagnostic value. Sixteen studies reported withdrawal reasons involving adverse events such as fractures, general health problems, COVID-19 disruptions, or in one case a child’s fear of horses. Critically, none of the included studies described a systematic procedure for adjudicating withdrawal reasons, and the reports generally lacked the temporal information, severity grading and clinical detail needed to link an event causally to the intervention. Most strikingly, four studies reported withdrawals due to health problems while simultaneously stating that no adverse events had occurred, an internal contradiction that illustrates how easily harm data can slip through the cracks.

To estimate risk quantitatively, the team pooled 45 trials that provided usable adverse event data, using a random-effects Mantel-Haenszel model with a treatment-arm continuity correction to handle the many studies in which neither group reported any events. The pooled relative risk was 1.14, with a 95 percent confidence interval of 0.67 to 1.94, indicating that physical activity interventions did not significantly increase the risk of reported adverse events compared with non-exercise controls. Heterogeneity was minimal, at an I-squared of just 2 percent, and sensitivity analyses using alternative pooling methods, including the Battaglia continuity correction and inverse-variance models with restricted maximum likelihood and DerSimonian-Laird estimators, produced nearly identical results. Meta-regression found no significant moderation by participant age, and dose-response analyses across weekly frequency, session duration, total sessions and total training time revealed no statistically significant association between intervention dose and adverse event risk.

But one subgroup analysis produced a result that reframes the entire field. Trials that used prespecified adverse event monitoring procedures showed a significantly higher risk estimate, with a relative risk of 4.32 and a confidence interval of 1.36 to 13.68, and this moderator alone explained 90 percent of the between-study variance in effect sizes. The authors are careful to interpret this correctly: the elevated estimate does not mean that monitored trials carry genuinely greater risk. Rather, it demonstrates that when researchers actively look for harm, through structured training diaries, proactive querying at prespecified time points, physiological monitoring of heart rate and blood pressure, and explicit stopping rules, they find it. Passive monitoring, by contrast, systematically misses mild events, particularly in a population where individuals may have difficulty recognizing, interpreting or communicating internal states such as pain, fatigue or emotional distress.

This detection gap has particular significance for neurodevelopmental populations. Research on pain perception in autism, for example, suggests atypical pain profiles and underestimation of others’ pain, while people with intellectual disabilities may struggle to report subjective symptoms. Relying exclusively on spontaneous self-reports in such groups, the authors argue, likely leads to missed or misclassified events and systematic underestimation of true harm rates. The descriptive patterns also hint at subtype-specific safety profiles that deserve targeted monitoring: adverse events in intellectual developmental disorder predominantly involved physical and medical problems, autism-related reports centered on sensory and environmental adaptation difficulties such as aquatic and equine settings, and the limited ADHD evidence pointed to psychological burden from intervention arrangements. These patterns remain exploratory, but they suggest that a one-size-fits-all monitoring framework may be insufficient.

The authors also identify deeper structural forces behind the underreporting. Some trials never established monitoring frameworks at the protocol stage, leaving data collection without consistent standards. Others collected harm information but failed to document it completely. The literature on conflicts of interest suggests that when favorable conclusions confer academic or professional benefits, researchers may selectively disclose or downplay unfavorable findings, and social desirability bias in exercise research may dull investigators’ sensitivity to risk signals. The absence of mandatory journal standards for harm reporting allows these problems to compound across the publication cycle. The team proposes concrete remedies: prespecified active monitoring embedded in trial protocols, including pre-session health screening, objective physiological indicators during training, and proactive post-session follow-up; intervention-specific surveillance such as tracking sensory responses in equine therapy; and transparent reporting of planned versus delivered intervention dose, since roughly 70 percent of the included studies failed to report exercise intensity at all, making dose-response analysis impossible.

The bottom line for clinicians and families is cautiously reassuring but conditional. The available evidence does not show that exercise increases overall harm risk for people with neurodevelopmental disorders, and the events that are detected are typically mild and manageable. But the authors emphasize that this conclusion reflects a lack of evidence for excess risk rather than evidence of the absence of risk, given pervasive underreporting and methodological heterogeneity. They recommend that guideline developers give greater weight to trials that used prespecified, active harm surveillance, and that future studies adopt standardized monitoring, structured withdrawal adjudication, and complete descriptive reporting of adverse events. Until the field routinely looks for harm with the same rigor it applies to measuring benefit, the true safety profile of exercise for millions of people with neurodevelopmental disorders will remain partly invisible.

Subject of Research: Adverse event monitoring and reporting in physical activity interventions for people with neurodevelopmental disorders

Article Title: Invisible Harms, Visible Benefits? Adverse Event Reporting in Physical Activity Interventions for Neurodevelopmental Disorders: A Meta-analysis and Critical Appraisal

Article References: He, J., Peng, C., Zhang, L., Wang, D., Tan, X., Wen, X., Shen, X., & Wu, X. (2026). Invisible Harms, Visible Benefits? Adverse Event Reporting in Physical Activity Interventions for Neurodevelopmental Disorders: A Meta-analysis and Critical Appraisal. Sports Medicine – Open, 12(1), Article 129. https://doi.org/10.1186/s40798-026-01095-w

Image Credits: AI Generated

DOI: 10.1186/s40798-026-01095-w

Keywords: adverse events, neurodevelopmental disorders, physical activity interventions, meta-analysis, autism spectrum disorder, ADHD, intellectual disability, CONSORT-Harms, randomized controlled trials, exercise safety, harm monitoring, participant withdrawal