The original multi-institutional analysis included 1,127 patients with metastatic breast cancer. According to the correspondence, findings involving TP53, AKT1, overall survival, disparities in PI3K inhibitor use and a survival disadvantage among Black patients relied on borderline p-values from uncorrected comparisons across 19 supplementary tables. The comment argues that accounting for multiple comparisons would strengthen the evidence for the reported associations. It also describes the genomically annotated dataset as a valuable contribution while identifying issues that require further scrutiny.

One concern is that high-deprivation patients had lower rates of visceral, nodal and soft-tissue metastasis. The comment proposes that this pattern may be consistent with reduced circulating tumor DNA shedding, which could help explain some observed differences in mutation frequencies, particularly for AKT1. The evidence available in the correspondence does not directly measure ctDNA shedding, so this remains a potential confounder rather than a demonstrated explanation. The authors call for direct assessment of ctDNA shedding when evaluating whether mutation-frequency differences reflect tumor biology or differences in detectable circulating DNA.

The correspondence also raises concerns about an AKT1 subgroup hazard ratio of 6.27 that was based on approximately five events. It notes that this falls below commonly recommended events-per-variable thresholds and calls for transparent event-count reporting. The central recommendation is to address multiplicity correction, evaluate ctDNA shedding and provide fuller details about the events underlying subgroup survival estimates. These criticisms call for cautious interpretation; they do not demonstrate that the original associations are false, nor do they resolve the independent contributions of neighborhood deprivation, tumor characteristics, treatment use and survival.

Subject of Research: Methodological scrutiny of neighborhood deprivation, tumor genomics and survival in metastatic breast cancer

Article Title: Comment on “Associations of neighborhood deprivation with breast cancer tumor genomics, targeted treatment use, and survival”

Article References: Fatima, Z., Choudhary, S., & Choudhary, H. Z. (2026). Comment on “Associations of neighborhood deprivation with breast cancer tumor genomics, targeted treatment use, and survival”. Breast Cancer Research and Treatment, 220(1), Article 9. https://doi.org/10.1007/s10549-026-08100-6

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08100-6

Keywords: metastatic breast cancer, neighborhood deprivation, tumor genomics, circulating tumor DNA, PI3K inhibitors, survival analysis, multiple comparisons, health disparities, Comment, Associations, neighborhood, deprivation

The correspondence responds to a retrospective study by Jafarpour and colleagues, published in the same journal in 2025, which analyzed bloodstream infections over a six-year period at a tertiary teaching hospital in Iran, comparing pre-pandemic and pandemic phases. Bloodstream infections, in which bacteria or fungi circulate in the blood and can seed organs throughout the body, are among the most lethal healthcare-associated infections. The Iranian team found that the etiological profile remained dominated by Gram-negative organisms, a pattern consistent with previous studies from tertiary care settings. Gram-negative bacteria, whose outer membranes make them inherently harder to treat, include some of the most formidable pathogens in modern hospitals.

Yet beneath that stable surface, important changes were underway. The researchers documented an increase in Enterobacterales, the order of Gram-negative bacilli that includes Escherichia coli, Klebsiella species, and Enterobacter species. At the same time, Stenotrophomonas maltophilia, a non-fermenting bacillus that had been a notable player in pre-pandemic bloodstream infections, declined markedly. This redistribution matters clinically because Enterobacterales carry well-characterized resistance mechanisms, including extended-spectrum beta-lactamases and carbapenemases, that can spread rapidly between species and hospitals. A shift toward these organisms, even without a change in overall Gram-negative predominance, can translate into harder-to-treat infections and narrower therapeutic options.

The resistance data accompanying these shifts are the most alarming element of the findings. The Iranian study reported a concerning rise in antimicrobial resistance, particularly among Gram-negative pathogens, with increased resistance spanning multiple antibiotic classes, including carbapenems, often the last reliable line of defense against multidrug-resistant Gram-negative infections. The proportion of methicillin-resistant Staphylococcus aureus, or MRSA, increased substantially, while high rates of vancomycin-resistant enterococci persisted. Collectively, the authors suggest that while the overall epidemiological pattern of bloodstream infections remained stable, the COVID-19 pandemic may have contributed to a shift toward more resistant organisms, effectively raising the resistance floor of the hospital microbiome.

To understand why a viral pandemic would drive bacterial resistance, the Brazilian commentators point to the mechanics of selective pressure. Intensified and often empirical antibiotic use during the COVID-19 pandemic exposed bacterial populations to sustained antimicrobial assault, killing susceptible strains and leaving resistant ones to flourish and spread. In intensive care units, where patients undergo multiple invasive procedures and are managed with broad empirical antimicrobial therapy, this pressure operates at maximum intensity. The commentators note that the situation in Brazil was particularly challenging, given the already high burden of healthcare-associated infections and the clinical complexity of ICU patients, who often require mechanical ventilation, central venous catheters, and urinary devices that serve as gateways for bacterial entry.

The Brazilian team’s own data confirm and expand upon the Iranian observations. In a descriptive, single-center study conducted at a tertiary university hospital, the researchers retrospectively analyzed 474 patients with laboratory-confirmed COVID-19 admitted to a dedicated COVID-19 intensive care unit between June 2020 and December 2021. Clinical data were collected from medical records, and infections were classified as healthcare-associated when symptoms appeared at least 48 hours after admission without evidence of infection at the time of entry. Ventilator-associated pneumonia was defined by the presence of at least 10 to the fifth colony-forming units per milliliter in tracheal aspirate cultures from patients on invasive mechanical ventilation for at least 48 hours, while bloodstream infection required a positive blood culture collected at least 48 hours after hospital or ICU admission.

The results are sobering. The Brazilian team observed a 44.5 percent incidence of secondary healthcare-associated infections diagnosed by microbiological criteria, meaning 211 of 474 critically ill COVID-19 patients developed laboratory-confirmed secondary infections. Of these, 45.3 percent were caused by Gram-negative microorganisms, predominantly involving the lungs and bloodstream. In total, 757 microorganisms were recovered from the 474 patients, and 79.4 percent of those isolates, 601 of 757, were antimicrobial-resistant. Bacterial identification and susceptibility testing were performed using the VITEK 2 automated system, with non-susceptibility classified according to the international expert definitions proposed by Magiorakos and colleagues, based on Clinical and Laboratory Standards Institute interpretive criteria.

Antimicrobial use was high in both the Iranian and Brazilian settings, with the main emphasis on beta-lactams, particularly broad-spectrum agents, though the use of polymyxins and antifungals was unexpectedly high. A trend toward increased prescribing was observed among patients with bloodstream infections, possibly related to the more rapid clinical progression and higher mortality in these cases, which may justify the empirical use of last-resort agents. The commentators report that Escherichia coli showed reduced susceptibility to meropenem, Klebsiella species exhibited significant rises in resistance to tetracycline, ciprofloxacin, and gentamicin, and Enterobacter species demonstrated increased resistance to most evaluated antibiotics, reinforcing the trend of expanding resistance among Gram-negative bacilli. These findings align with Brazilian data from Braga and colleagues and Urzedo and colleagues, which showed that antimicrobial resistance rates and antibiotic consumption were lower before the pandemic, suggesting the pandemic contributed to a worsening resistance scenario.

The convergence of evidence from different geographic regions highlights a critical global issue: the consequences of widespread, intense, and empirical antimicrobial use during the COVID-19 pandemic. Studies across Latin America consistently report high prevalence rates of antimicrobial use, particularly broad-spectrum antibiotics, especially during the pandemic, and the indiscriminate use of these agents exerts selective pressure on microorganisms, promoting acquired resistance mechanisms and limiting therapeutic options. Similar to Brazil, Iran has implemented institutional antimicrobial stewardship programs, but chronic challenges remain, including high use of empirical broad-spectrum antibiotics in hospital and ICU settings. In Brazilian tertiary hospitals, reported healthcare-associated infection prevalence ranges from 44.3 to 79.4 percent, with pneumonia and bloodstream infections among the most frequent, and the microorganisms most often isolated in high-morbidity infections are Gram-negative bacilli, notably the non-fermenting Pseudomonas aeruginosa and Acinetobacter baumannii, alongside Klebsiella pneumoniae and Escherichia coli.

The commentators caution that their study was conducted at a single Brazilian tertiary university hospital during the pandemic, and that comparisons with other cohorts should be interpreted with care due to differences in population characteristics, clinical settings, and study designs, with the retrospective design and sample size potentially limiting some analyses. Nevertheless, the message is clear and urgent. The findings highlight the substantial burden of healthcare-associated infections caused by resistant organisms among critically ill COVID-19 patients, particularly ventilator-associated pneumonia and bloodstream infections, and emphasize the importance of continuous surveillance to guide empirical antibiotic treatment strategies, strengthen infection prevention measures, and optimize antimicrobial stewardship in intensive care settings. Addressing these challenges, the authors argue, is essential to mitigate the impact of antimicrobial resistance during future public health emergencies, because the next pandemic will arrive in hospitals already populated by bacteria shaped by the selective pressures of this one.

Subject of Research: Changes in microbiological characteristics of bloodstream infections before and after the COVID-19 pandemic in a tertiary teaching hospital in Iran

Article Title: Comment on: Changes in microbiological characteristics of bloodstream infections before and after the COVID-19 pandemic in a tertiary teaching hospital in Iran

Article References: Sabino, S. S., Fernandes, A. M., Queiroz, N. L., de Brito, C. S., Queiroz, L. L., Melgarejo, C. R. V., Gontijo Filho, P. P., & Ribas, R. M. (2026). Comment on: Changes in microbiological characteristics of bloodstream infections before and after the COVID-19 pandemic in a tertiary teaching hospital in Iran. BMC Infectious Diseases, 26(1), Article 1668. https://doi.org/10.1186/s12879-026-14075-y

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14075-y

Keywords: bloodstream infection, antimicrobial resistance, COVID-19, Gram-negative bacteria, healthcare-associated infections, MRSA, carbapenem resistance, intensive care unit, antimicrobial stewardship, Enterobacterales, Comment, Changes

The four families in question are not household names, even among entomologists. The Elateridae, commonly known as click beetles, are perhaps the most familiar, thanks to the distinctive mechanism that allows adults to flip themselves into the air when turned on their backs. But they are also notorious for being difficult to identify to species level, a reputation that has historically discouraged detailed faunal surveys. The Eucnemidae and Throscidae are smaller and even less studied, while the Cerophytidae contain just a single European species, Cerophytum elateroides, itself a saproxylic specialist of old deciduous trees. Despite their obscurity, these families play important ecological roles: many are saproxylic and serve as bioindicators for the conservation of natural woodland habitats, while a handful of phytophagous click beetle species, particularly in the genus Agriotes, are significant agricultural pests whose larvae, known as wireworms, damage cultivated crops.

The study area covers 1,223 square kilometres of the Geneva basin, a geological depression straddling the Franco-Swiss border and framed by the Jura mountains to the northwest, the Vuache to the west, the Salève to the southeast and the Voirons to the east. The basin opens onto Lake Geneva, the largest body of freshwater in Western Europe, which sits at 372 metres above sea level. The highest point in the study perimeter reaches 1,720 metres at Crêt de la Neige in the Jura. This altitudinal range of nearly 1,350 metres, combined with the basin’s position at the crossroads of three major biogeographic zones — the Swiss Plateau, the Alps and the Jura — creates an extraordinary variety of habitats, from riparian woodlands and oak forests to montane conifer stands, all within a relatively small surface area.

The methodology behind the census was rigorous and multi-layered. The authors drew on targeted field surveys conducted between 2018 and 2023, a critical analysis of the published literature dating back to the 1970s, and systematic examination of museum and private collections. Digital databases from both Switzerland and France — including info fauna, Faune Genève, the Inventaire national du patrimoine naturel (INPN) and the Pôle invertébrés Auvergne-Rhône-Alpes — were mined for records from 2013 to 2023. Crucially, the authors only accepted species whose presence could be validated by at least one correctly labelled specimen in a reliable collection, or by a digital record accompanied by a photograph showing the diagnostic characters of the species. This conservative approach meant that 13 insufficiently documented Elateridae species were classified as doubtful and listed separately, while 9 further species (8 Elateridae and 1 Throscidae) that are potentially present but not yet recorded were discussed in dedicated commentaries.

The final tally comprises 1 species of Cerophytidae, 102 species of Elateridae, 14 species of Eucnemidae and 9 species of Throscidae. When compared with national totals, the results are striking: the Geneva basin hosts nearly 70 percent of the Swiss fauna for these four families and 45 percent of the continental French fauna, despite the fact that a significant proportion of French species are restricted to the Mediterranean south. Even more remarkably, more than 86 percent of the species known from Haute-Savoie, 92 percent of those from the Ain and 88 percent of those from the canton of Vaud are present within the study perimeter, even though the basin covers only a small fraction of each of these territories.

The explanation for this exceptional richness lies in a combination of biogeographic context and habitat availability. The Geneva basin acts as a gateway from the Jura and the Alps towards the Rhône valley, and its position at the junction of the Plateau, Alpine and Jura biogeographic zones means that species from all three regions can coexist. The diversity of open habitats — rivers, ponds, meadows, annual and perennial crops — and forest habitats, including oak-hornbeam woodlands, riparian forests, beech forests, fir-beech forests, spruce plantations and pine woods, adds further layers of complexity. The abundance of isolated trees is also significant: nearly 250,000 are catalogued for the canton of Geneva alone. Many rare saproxylic species are tied to old, senescent or dead trees, whether standing alone, lining avenues or at forest edges, and the basin is particularly well supplied with centuries-old oaks whose dendro-microhabitats — hollow trunks, sap runs, dead branches — support specialised beetle communities.

Among the 44 species of high patrimonial value, several stand out for their rarity and ecological specialisation. Lacon querceus, once considered very rare in both France and Switzerland, develops in the red pulvulent rot of old oaks and beeches colonised by the sulphur polypore (Laetiporus sulphureus), and recent observations suggest it is expanding in the region. Crepidophorus mutilatus, classified as critically endangered in the Auvergne-Rhône-Alpes region, is a discreet species whose larvae colonise various deciduous trees but show a marked preference for old, decaying poplars still standing in wetlands and alluvial corridors. Porthmidius austriacus, also critically endangered regionally, and Podeonius acuticornis, listed as endangered on both the European and regional red lists, are among the most threatened click beetles in the basin. Microrhagus pyrenaeus, considered one of the rarest Eucnemidae in Europe, develops in the white rot of old deciduous wood at an advanced stage of decay, preferentially oak.

Several species were recorded for the first time from specific administrative territories during the survey. Microrhagus pyrenaeus, Ampedus brunnicornis, Ampedus cardinalis, Ischnodes sanguinicollis and Cardiophorus gramineus are new for Haute-Savoie. Ampedus sinuatus is new for the Geneva basin, while Hylis simonae is new for the canton of Geneva. Most notably, Brachygonus campadellii, a species only described in 2000, is new for the canton of Geneva and for Switzerland as a whole, having been captured in interception traps placed in an alignment of old senescent oaks and in a decaying dead willow.

The patrimonial analysis drew on multiple European and national reference lists, including the list of primary forest relic species in Central Europe, the European red list of saproxylic beetles, the regional red list for Auvergne-Rhône-Alpes, the French list of saproxylic bioindicator beetles and the Swiss list of emblematic saproxylic beetles. Species linked to primary forest structures — those dependent on habitats that have existed continuously since primeval times — include Cerophytum elateroides, Ampedus brunnicornis, Ampedus elegantulus, Brachygonus dubius, Brachygonus ruficeps, Cardiophorus gramineus, Crepidophorus mutilatus, Elater ferrugineus, Ischnodes sanguinicollis, Lacon querceus, Megapenthes lugens, Podeonius acuticornis, Microrhagus pyrenaeus and Nematodes filum. The presence of so many primary forest indicators in a landscape that has been shaped by human activity for centuries underscores the importance of the basin’s remnant old-growth features, particularly its veteran oaks.

The findings carry a clear conservation message. The saproxylic beetles of high patrimonial value indicate the preponderant interest of conserving old trees — notably oaks — as well as dead wood of all diameters, in forests, agricultural landscapes and urban green spaces alike. Many of these species already benefit from conservation measures thanks to action plans for the protection of the European protected stag beetle Cerambyx cerdo in the cantons of Geneva and Vaud, and numerous other saproxylic species gain from the umbrella protection this species affords under Annex II of the Bern Convention. However, the authors warn that past forestry practices, including clear-cutting and the replacement of native species with exogenous plantations such as Douglas fir, have degraded some forest massifs, while the abandonment of traditional silvopastoralism has affected wild plant communities and the phytophagous beetles that depend on them. With climate change driving higher temperatures and intensified summer droughts, forest ecosystems will continue to evolve, and the fauna of these four beetle families will need to adapt. The authors call for a major sampling effort across all habitats — including dry grasslands, marshes, peat bogs and riverbanks — to document the relationships between species and environments of interest, and to work with authorities to limit biodiversity erosion. The results will feed into a future regional atlas and red list, providing a foundation for the conservation of this unexpectedly rich corner of Europe.

Subject of Research: Liste commentée des Cerophytidae, Elateridae, Eucnemidae et Throscidae du bassin genevois (Coleoptera)

Article Title: Liste commentée des Cerophytidae , Elateridae , Eucnemidae et Throscidae du bassin genevois ( Coleoptera )

Article References: Blanc, M., Breitenmoser, S., & Rochet, C. (2024). Liste commentée des Cerophytidae, Elateridae, Eucnemidae et Throscidae du bassin genevois (Coleoptera). Alpine Entomology, 8, 51-64. https://doi.org/10.3897/alpento.8.116799

Image Credits: AI Generated

DOI: 10.3897/alpento.8.116799

Keywords: Liste, comment, Cerophytidae, Elateridae, Eucnemidae, Throscidae, bassin, genevois, Coleoptera, scientific research

The correspondence responds to a scoping review by Munir and colleagues, published in the same journal in May 2026, which examined the clinical relevance of sleep disturbance, or insomnia, in patients with advanced cancer receiving palliative care. Scoping reviews are designed to map the breadth of existing evidence rather than pool it statistically, and the original review highlighted how frequently sleep problems are reported by this patient population while also exposing the fragmented ways in which researchers have defined and measured them. Yan and Zhang use their comment to push the conversation further, contending that the clinical relevance of insomnia is not merely a matter of prevalence but of consequence, and that the field needs sharper tools to capture both.

The technical heart of the debate lies in measurement. Sleep disturbance in palliative care has traditionally been assessed through patient-reported instruments, and one of the most widely used is the sleep item of the Edmonton Symptom Assessment System, a brief screening tool that asks patients to rate the severity of their symptoms on simple numeric scales. Research published in BMJ Supportive & Palliative Care by Yennurajalingam and colleagues in 2015 showed that patient-reported sleep disturbance in advanced cancer is common, that it can be predicted from other symptom profiles, and that the ESAS sleep item performs reasonably well as a screening instrument. But a single numeric rating compresses an enormously complex phenomenon, one that spans difficulty falling asleep, frequent awakenings, early morning waking, and non-restorative sleep, into a single point on a scale. Critics argue that this compression obscures the very features of insomnia that carry clinical meaning.

Objectively measured sleep tells a different story again. Actigraphy, a technique in which a small wrist-worn sensor records movement over days or weeks, allows researchers to derive rest-activity rhythms and sleep parameters without relying on subjective report. In an exploratory machine learning study published in Cancers in 2023, Patel, Davies, and colleagues, working with Dijk, combined actigraphy-derived rest-activity and sleep parameters with routine clinical data to explore prognostication in advanced cancer. The study suggested that objective sleep and circadian features, when fused with clinical variables through machine learning models, could contribute to predicting outcomes in this population. For Yan and Zhang, this line of evidence points toward a future in which sleep is not just a symptom to be rated but a physiological signal to be integrated into routine clinical assessment and even prognostic modeling.

The prognostic angle is what gives the correspondence its urgency. In advanced cancer, clinicians and families alike want to know how much time remains, and the search for reliable prognostic markers is one of palliative care’s most active research frontiers. Sleep disturbance may seem an unlikely candidate, but disrupted rest-activity rhythms are known to reflect underlying physiological deterioration, and studies have linked poor sleep quality in advanced lung cancer to anxiety and depression in both patients and caregivers, as He and colleagues reported in BMJ Supportive & Palliative Care in 2020. Mercadante and colleagues, writing in the International Journal of Clinical Practice in 2021, documented high rates of insomnia among patients with advanced lung cancer admitted to palliative care services, underscoring that the problem is not marginal but affects a substantial share of the population at the very end of life.

What makes the Yan and Zhang comment technically significant is its insistence on distinguishing between insomnia as a subjective complaint and sleep disturbance as an objective physiological phenomenon. The two do not always align. A patient may report severe insomnia while actigraphy shows relatively preserved sleep duration, or conversely may underreport disturbance that objective monitoring reveals to be profound. This dissociation matters clinically because the mechanisms driving the two may differ, ranging from pain and medication effects to circadian rhythm disruption and neuroendocrine changes associated with advanced disease. Treating them as a single entity, the correspondence implies, risks misdirecting both research and therapy, and the scoping review’s finding of heterogeneous definitions across studies only reinforces the point.

The therapeutic implications are equally consequential. Insomnia in palliative care is frequently managed with hypnotic medications, yet evidence for their effectiveness in this population is limited, and concerns about sedation, falls, and drug interactions weigh heavily in patients whose systems are already burdened by disease and polypharmacy. Non-pharmacological approaches, including cognitive behavioral therapy adapted for cancer populations, light exposure interventions, and structured sleep hygiene programs, offer alternatives, but their availability in palliative care settings remains uneven. Yan and Zhang’s argument that sleep deserves systematic clinical attention implies that screening should be routine, that assessment should distinguish subjective from objective disturbance, and that treatment pathways should be tailored to the mechanisms identified in each patient rather than applied generically.

There is also a broader scientific payoff to taking sleep seriously in this population. Sleep and circadian biology are increasingly recognized as windows into systemic physiology, and disrupted rest-activity rhythms have been associated with inflammation, metabolic dysregulation, and neuroendocrine stress across a range of diseases. In advanced cancer, where multiple organ systems are failing simultaneously, the pattern of sleep disruption may carry diagnostic information that conventional symptom scales cannot capture. The machine learning approach of Patel and colleagues represents an early attempt to exploit this information, and if future studies validate the prognostic value of actigraphy-derived sleep parameters, sleep monitoring could become as standard in palliative care as pain assessment is today.

For patients and families, the message from this correspondence is ultimately a human one. Sleepless nights in advanced cancer are not a trivial side effect to be endured in silence, but a symptom with measurable physiological correlates, prognostic significance, and treatable mechanisms. The comment by Yan and Zhang, published as a correspondence in Supportive Care in Cancer in October 2026, adds its voice to a growing chorus calling for sleep disturbance to be recognized as clinically relevant in its own right, not merely as a companion symptom to pain or depression. As the field moves from scoping reviews that map the evidence toward studies that test interventions and validate objective monitoring, the hope is that the nights of patients in palliative care will become a little less fragmented, and that clinicians will finally give sleep the attention its clinical relevance demands.

Subject of Research: Palliative Care

Article Title: Comment on: “The clinical relevance of sleep disturbance (‘insomnia’) in patients with advanced cancer receiving palliative care: a scoping review”

Article References: Yan, H., & Zhang, Y. (2026). Comment on: “The clinical relevance of sleep disturbance (‘insomnia’) in patients with advanced cancer receiving palliative care: a scoping review”. Supportive Care in Cancer, 34(11), Article 1115. https://doi.org/10.1007/s00520-026-11359-6

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11359-6

Keywords: insomnia, palliative care, advanced cancer, sleep disturbance, Supportive Care in Cancer, scoping review, symptom assessment, actigraphy, prognostication, patient-reported outcomes, Comment, clinical

The first concern centers on who was actually included in the meta-analysis. According to the commentary, the review stated that eligible participants were individuals with type 1 or type 2 diabetes mellitus, yet studies involving people with gestational diabetes and prediabetes were subsequently included in the analysis. The corresponding PROSPERO registration record, which documents the review protocol in advance, defined the eligible population simply as subjects with diabetes mellitus, without explicitly specifying these additional groups. Fuentes-Barría argues that this drift between the registered protocol and the executed review matters because gestational diabetes and prediabetes differ substantially from established type 1 and type 2 diabetes in pathophysiology, baseline cardiovascular and metabolic risk, and clinical management. Pooling these distinct populations, he contends, inflates clinical heterogeneity and weakens the applicability of the combined estimates to any single patient group.

A second and equally consequential issue involves the nature of the interventions themselves. Not all of the trials included in the meta-analysis tested zinc alone. Some interventions combined zinc with other micronutrients or bioactive compounds, a fact the original authors themselves acknowledged when they conceded that such co-interventions make it difficult to attribute observed effects specifically to zinc. The commentary argues that mixing zinc-only trials with multicomponent interventions introduces another layer of clinical heterogeneity and complicates the interpretation of pooled effects. To resolve this ambiguity, the commentator recommends sensitivity analyses that exclude multicomponent interventions, which would reveal whether the reported benefits survive when the analysis is restricted to trials in which zinc is the sole active agent. Without such analyses, he suggests, readers cannot judge the robustness of the pooled estimates or the extent to which zinc itself deserves credit.

Statistical heterogeneity represents the third pillar of the critique. The commentary highlights that several pooled outcomes showed substantial or even considerable heterogeneity across the included trials. The most striking example is plasma zinc concentration, where the I-squared statistic reached 99 percent, meaning virtually all of the variability between studies reflects real differences rather than chance. Other metabolic and inflammatory outcomes also demonstrated high heterogeneity. Although the original authors applied random-effects models and conducted meta-regression in an attempt to account for this variability, the commentary notes that substantial residual heterogeneity remained unexplained. Under these circumstances, Fuentes-Barría argues, a single pooled estimate carries limited clinical meaning, and its generalizability to diverse patient populations, dosing regimens and treatment durations should be interpreted with pronounced caution.

The fourth concern targets the meta-regression analyses themselves. The original review performed multiple meta-regressions examining age, sex, zinc dose and intervention duration as potential effect modifiers, despite several outcomes being based on a limited number of studies. This is problematic, the commentary explains, because meta-regression generally requires an adequate number of studies per moderator variable to produce reliable results. The Cochrane Handbook, the field’s leading methodological reference, advises caution when fewer than ten studies are available for such analyses. Beyond official guidance, methodological research has shown that meta-regression analyses are frequently undermined by overfitting and other pitfalls that can generate misleading findings. A meta-epidemiological study cited in the commentary found that most published meta-regressions based on aggregate data suffer from such methodological problems. Given the limited number of trials and the multiple moderators examined, the commentator concludes that these dose-response and subgroup associations should be treated as exploratory and hypothesis-generating rather than confirmatory evidence.

Perhaps the most clinically pointed criticism concerns the gap between the review’s title and its actual findings. The meta-analysis did not demonstrate significant improvements in fasting plasma glucose or HbA1c, the two canonical measures of glycemic control, despite the title emphasizing glycemic control as a primary outcome. Instead, statistically significant effects were observed primarily for surrogate markers, including circulating insulin levels, HOMA-IR as a measure of insulin resistance, C-reactive protein as an inflammatory marker, and various oxidative stress biomarkers. The commentary argues that these statistically significant shifts in surrogate endpoints should not automatically be equated with clinically meaningful improvements in diabetes control or with outcomes that matter to patients, such as reduced complications, improved quality of life or decreased mortality. Research on surrogate endpoints in diabetes trials has repeatedly shown that changes in biomarkers do not always translate into tangible clinical benefit, making this distinction far more than a semantic quibble.

The commentary’s overall message is one of measured skepticism rather than outright rejection. Fuentes-Barría explicitly frames his remarks as a constructive contribution to a clinically relevant topic, acknowledging the importance of the question the original review addressed. Zinc is an essential trace element involved in insulin synthesis, storage and secretion, as well as in antioxidant defense mechanisms, which provides a plausible biological rationale for studying its supplementation in diabetes. However, plausibility of mechanism cannot substitute for methodological rigor in the evidence synthesis that is supposed to translate biology into clinical recommendations. The commentary suggests that the enthusiasm generated by statistically significant pooled effects on biomarkers risks outpacing what the underlying trial data can actually support.

To strengthen the evidence base, the commentator proposes a concrete path forward. Stratified and sensitivity analyses by diabetes phenotype would clarify whether zinc exerts different effects in type 1 diabetes, type 2 diabetes, gestational diabetes and prediabetes, populations whose distinct metabolic contexts could plausibly modify any treatment effect. Restricting analyses to zinc-only interventions would isolate the specific contribution of the mineral from that of co-administered compounds. And prioritizing clinically relevant glycemic outcomes, particularly HbA1c and fasting glucose, over surrogate biomarkers would anchor the conclusions in endpoints that directly inform patient care. These refinements, the commentary argues, could substantially improve both the validity and the clinical interpretability of future updates to this body of evidence.

The exchange is a timely reminder of how meta-analyses, often perceived as the pinnacle of the evidence hierarchy, remain only as reliable as the methodological choices embedded within them. Decisions about which populations to pool, which interventions to combine, how to handle heterogeneity and how many moderator analyses to run can each shift the final estimates and the confidence readers place in them. For the growing number of people with diabetes worldwide who may be considering zinc supplements, and for the clinicians who advise them, the commentary underscores that the current evidence supports caution: meaningful effects on the measures that define diabetes control have not yet been demonstrated, and the significant biomarker changes reported so far should be viewed as signals worth further investigation rather than proof of clinical benefit. As the field awaits more rigorously designed and analyzed syntheses, the debate illustrates the self-correcting nature of scientific publishing, where critical commentary serves as an essential quality-control mechanism for evidence that ultimately shapes real-world health decisions.

Subject of Research: Methodological critique of a meta-analysis on zinc supplementation in diabetes

Article Title: Comment on ‘Effects of Zinc Supplementation on Glycemic Control, Insulin Resistance, Inflammation and Oxidative Stress in Diabetes’

Article References: Fuentes‐Barría, H. (2026). Comment on ‘Effects of Zinc Supplementation on Glycemic Control, Insulin Resistance, Inflammation and Oxidative Stress in Diabetes’. Endocrinology, Diabetes & Metabolism, 9(5), Article e70328. https://doi.org/10.1002/edm2.70328

Image Credits: AI Generated

DOI: 10.1002/edm2.70328

Keywords: zinc supplementation, diabetes, meta-analysis, glycemic control, insulin resistance, HbA1c, inflammation, oxidative stress, clinical heterogeneity, meta-regression, Comment, Effects