Statistical Bias in “On-Treatment” Analyses in Randomized Controlled Trials When Dosing Frequency Differs Between Treatments

While intention-to-treat analyses in randomized controlled trials provide unbiased comparisons of randomized treatment policies, many investigators also execute “On-Treatment” analyses that count events occurring while participants are still receiving randomized treatment. “On-Treatment” analyses, which are not supported by randomization, lead to non-comparable treatment groups and hence potential inferential errors. This article concerns another problem related to “On-Treatment” analysis when the study interventions have different dosing frequencies, for example, when one treatment is dosed daily and the other monthly. Failing to account properly for such differential dosing in the analysis can introduce serious additional bias. We discuss potential pitfalls associated with such analyses and provide a simple remedy to attenuate the problem introduced when comparing treatments with differential dosing frequency: to wit, extend the “On-Treatment” period by an amount equal to the dosing frequency. We illustrate the approach with the ASCEND trial program. The ASCEND Trials, which compared daprodustat to standard of care in patients with anemia of chronic kidney disease, administered the treatments under different dosing frequencies.

The disinherited: the politics of Christian conversion in colonial India by Mou Banerjee, Cambridge, Massachusetts & London, England, Harvard University Press, 2025, 368 pp., $49.95 (hardback), ISBN-10: 9780674268036; ISBN-13: 978-0674268036

Helicobacter pylori induces the production of interleukin-37 to promote broad immunosuppression and enhance colonization

Helicobacter pylori infects approximately half of the world’s population, resulting in lifelong gastric infections. To promote lifelong colonization, H.   pylori modulates host immunity via unknown mechanisms. Here we show that H.   pylori can harness the pan-immunosuppressive cytokine interleukin-37 (IL-37) to facilitate pathogenesis, enhance colonization and prevent the development of innate, cellular and humoral immunity. We show that H.   pylori increased the production of IL-37 in human gastric biopsies, and IL-37 secretion by gastric epithelial cells and human gastric mucosoids. We found that H.   pylori induced IL-37 secretion by epithelial cells via activation of host pathogen recognition receptors TLR2, TLR4 and NOD1, in addition to the H.   pylori -encoded cag pathogenicity island, revealing that H.   pylori utilises multiple mechanisms to induce IL-37 production during infection. Once produced, IL-37 attenuated TLR2, TLR4 and NOD1-mediated activation and TLR-mediated IL-8 responses to H.   pylori infection. Using transgenic mice expressing human IL-37, we found that IL-37 promoted immunosuppression by significantly increasing H.   pylori colonization, limiting gastric inflammation, and reducing H.   pylori -specific antibody responses. Furthermore, we identified the multiple mechanisms whereby IL-37 functions to impair the development of adaptive immunity. IL-37 abolished human T and B cell responses by impairing their activation, migration, and preventing immune synapse formation. Moreover, IL-37 inhibited proliferation of gastric-derived H.   pylori -specific T cells isolated from H.   pylori -infected patients, revealing a mechanism whereby IL-37 functions to prevent pathogen-specific cellular immune responses. Collectively, our findings reveal that H.   pylori induces production of the pan-immunosuppressive cytokine IL-37 to enhance colonization, modulate gastritis and suppress innate, cellular and humoral immunity to ultimately promote pathogenesis in the host. These findings advance our understanding of H.   pylori -mediated disease and identify gastric IL-37 as a therapeutic target to combat H.   pylori infection and associated diseases.

Longitudinal gut microbiome dynamics are associated with clinical outcome and toxicity during ibrutinib therapy

Accumulating evidence indicates that the gut microbiome influences therapeutic efficacy and toxicity across cancer treatments; however, its longitudinal dynamics during targeted therapies remain poorly characterized. Here, we performed whole-genome shotgun metagenomic sequencing of 291 longitudinal stool samples collected over one year from 30 patients with hematologic malignancies treated with ibrutinib. Overall gut microbial diversity remained stable at the population level but exhibited markedly divergent temporal trajectories according to clinical outcome, with progressive recovery in responders and blunted or delayed restoration in non-responders. Longitudinal modeling revealed distinct species- and pathway-level microbial dynamics between patients with treatment response or nonresponse, including enrichment of saccharolytic, short-chain fatty acid–associated taxa and metabolic pathways in responders, and expansion of bile acid–modifying, proteolytic, and inflammation-associated microbial features in non-responders. Functional profiling further demonstrated opposing temporal trends in pathways related to carbohydrate fermentation, amino-acid metabolism, and secondary bile acid synthesis. In addition, both baseline microbiome composition and longitudinal remodeling were associated with the development of ibrutinib-associated diarrhea. Together, these findings reveal coordinated, outcome-specific remodeling of the gut microbiome during ibrutinib therapy and highlight longitudinal microbiome trajectories, rather than static baseline features, as potential biomarkers of treatment response and toxicity, as well as targets for microbiome-directed interventions. In conclusion, our findings highlight a potential role of gut microbiome dynamics in modulating response to BTK inhibition and support the need for larger, prospective studies to validate these observations.

Patient specific characteristics and risk of iatrogenic pneumothorax after CT-guided biopsy of the lung parenchyma

CT-guided transthoracic needle aspiration biopsy (CT-TTNAB) is a cornerstone in diagnosing peripheral lung lesions, but iatrogenic pneumothorax (iPTX) is a common, adverse event. The presence of emphysema is a well-known risk factor but emphysema may vary from light to severe, and discrepancy is important for precise prognostic application. To validate that decreasing the diffusion capacity of carbon monoxide (DLCO) is a significant risk factor for the development of iPTX and need for insertion of a pleural device. We conducted a retrospective study of patients undergoing CT-TTNAB for suspected lung cancer between 1 January to 31 December 2023. We recorded age, sex, packyears, performance score (PS), FEV1 (%, categorized), FVC (% of predicted) and DLCO categorized into four groups: >80%, 60–79%, 40–59% and <40% of predicted. Association with iPTX and need for insertion of a pleural device were investigated with multiple logistic regression. Of 328 patients undergoing CT-TTNAB, 160 patients developed iPTX. Multiple logistic regression demonstrated that DLCO < 60% was an independent risk factor for both iPTX (DLCO 40–59%: odds ratio (OR) 2.8; <40%: OR 4.8), and chest tube insertion (OR 5.1, respectively, 15.3). Concerning other variables, only FEV1 30–49% was an independent risk factor (OR 6.5 for chest tube insertion). This study adds novel information to the risk assessment before a CT-TTNAB procedure. We suggest that decreasing DLCO expressed <60%predicted is a clinically meaningful risk factor for both the development of iPTX and need for insertion of a pleural device.

Investigating healthcare pathway management and inequalities using a novel data source: An observational study using linked, routinely collected data from a digital health system

Acute coronary syndromes (ACS) are a common cause of morbidity in the UK. The mainstay of treatment is percutaneous coronary angiography (PCA) + / − percutaneous coronary intervention (PCI). In the Northwest sector of Greater Manchester and Salford, PCI labs are shared between hospitals and trusts, co-ordinated by a bespoke online administration system which routinely collects clinical and demographic data for patients requiring angiography. We are not aware of data from such systems previously being analysed and used to guide health service management. We isolated and linked this dataset for the year 2018 with other admission data to explore variations in the time spent on this treatment pathway (from admission to angiography). Unadjusted analysis shows pathway time is affected by weekday, date of admission, age and gender. Regression analysis using demographic and clinical variables shows a persisting disparity according to admission site and gender, with ethnic disparities that are challenging to explain. Although an observational study, the dataset is collected prospectively and has excellent granularity. As well as demonstrating feasibility of use in investigating equality of access and treatment, we demonstrate its utility for service development, management, and improvement. These methods are easily replicable across other clinical systems and specialties.

The enduring resonance of Steven Feld beyond an anthropology of sound in sound Review of La recherche comme composition , by Steven Feld, curated by Jonathan Larcher and Damien Mottier, Paris, Les Presses du Réel, 2023, 144 pp., $14 (paperback), ISBN: 978-2-37896-325-5

A dual diacylglycerol kinase (DGK) alpha/zeta inhibitor augments the activity of human tumor infiltrating lymphocytes in in vivo and ex vivo models

Endogenous or adoptively transferred tumor-infiltrating lymphocytes (TILs) often lose their functional capacity due to the activation of intrinsic inhibitory pathways, which then limits their ability to control tumor growth. In this study, we examined the effects of blocking a key intracellular inhibitory enzyme, diacylglycerol kinase (DGK) in human T cells, using a novel inhibitor (DGKi) called INCB165451 that blocks both DGKα and DGKζ, the two primary DGK isoenzymes that negatively regulate T cells through the diacylglycerol (DAG) signaling pathway. We first evaluated the effects of the DGKi in enhancing the efficacy of adoptive human T cell transfer in a non-small cell lung cancer (NSCLC) mouse model and found that the DGKi significantly potentiated anti-tumor efficacy through multiple mechanisms, including increased intratumoral T cell infiltration, upregulation of genes associated with inflammatory responses, and reduction of TIL hypofunction, as evidenced by enhanced cytokine production following ex vivo anti-CD3 antibody stimulation. We next studied the effects of the DGKi on human TILs derived from tumor digests or studied in situ in precision-cut tumor slices of both head and neck cancer and NSCLC patient samples. After stimulation of the TILs with anti-CD3 antibodies, we found that the DGKi enhanced gene and protein expression of proinflammatory cytokines and chemokines. Finally, we demonstrated that the DGKi could augment T cell activation in human tumor slices that were stimulated by an anti-EGFR/anti-CD3 bispecific T cell engager (BiTE). These data demonstrate strong activity of the DGKi in human TILs and highlight promising potential avenues for clinical translation.

Management and environmental drivers of soilborne pathogens in smallholder systems of western Kenya

Soilborne pathogens limit productivity, exert chronic stress and may cause severe diseases in many crops, especially in smallholder systems. Despite the damage they cause, there is limited knowledge of the agroecological drivers that determine their abundance in sub-Saharan Africa. In this study, we assessed how farming practices (e.g. cropping systems, and organic input strategies) along with soil and environmental properties, influence the presence and relative abundance of Fusarium and lesion nematodes ( Pratylenchus spp.) across multiple locations in western Kenya. Common farming practices in the region include maize monocultures, maize-legume intercrops, maize in rotation with legumes and vegetables, and perennial-based horticultural systems. Fertilization strategies typically involve organic, inorganic or combined nutrient inputs. We used baiting protocols to assess the abundance of Fusarium and LN in soils collected from 35 smallholder farms. Our findings indicate that agroecological practices such as diversified cropping systems and organic amendments influence soilborne pathogens and important soil health parameters. For example, organic inputs reduced lesion nematode pressure by 56% compared to inorganic systems, while diversified systems supported higher soil carbon and available phosphorus. These results highlight the importance of agroecological management in maintaining soil health and regulating soilborne pathogens to improve smallholder productivity.

Religious Discrimination and Inclusion in U.S. Higher Education: A Critical Examination of Christian Privilege and Religious Pluralism

This study examines religious discrimination and inclusion in U.S. higher education through the lenses of Christian privilege and Critical Religious Pluralism Theory. Using data from the 2025 National Survey of Student Engagement, we analyze how students from diverse religious backgrounds perceive campus inclusivity and how religious discrimination relates to satisfaction. Findings reveal persistent inequities across religious groups and underscore the need for structural reforms to foster genuine religious pluralism on college campuses.