Nevin Manimala

JAMA. 2026 Jun 17. doi: 10.1001/jama.2026.7745. Online ahead of print.

ABSTRACT

IMPORTANCE: Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies.

OBJECTIVE: To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population.

DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025.

INTERVENTIONS: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy.

MAIN OUTCOMES AND MEASURES: This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee).

RESULTS: The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively.

CONCLUSIONS AND RELEVANCE: Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05184712.

PMID:42307937 | DOI:10.1001/jama.2026.7745

Health Promot Chronic Dis Prev Can. 2026 Jun;46(6):237-244. doi: 10.24095/hpcdp.46.6.03.

ABSTRACT

INTRODUCTION: Chronic conditions are highly prevalent in Canada and are commonly examined as a single, aggregated exposure in population research on social isolation. Such approaches emphasize overall disease burden but make it difficult to distinguish the independent contributions of diagnostic category, chronic pain and disability. In this study, we examine these dimensions separately to assess how each is associated with social isolation among Canadian adults.

METHODS: Using the 2022 Mental Health and Access to Care Survey (n = 9861), the association between chronic conditions, chronic pain, and disability in relation to social support was assessed, using the Social Provisions Scale (SPS-10), applying multivariable linear regression.

RESULTS: More severe disability was negatively associated with social support (B = -0.09, 95% CI = -0.11, -0.08). Those with more functional impairments experienced lower social support which typically indicates greater social isolation.

CONCLUSION: When examined jointly, functional disability, but not chronic disease category or chronic pain, was independently associated with lower social support. These findings indicate that social isolation among Canadian adults is more closely related to functional limitation than to diagnostic labels, underscoring the importance of function-focused approaches in research and intervention.

PMID:42307906 | DOI:10.24095/hpcdp.46.6.03

Health Promot Chronic Dis Prev Can. 2026 Jun;46(6):215-225. doi: 10.24095/hpcdp.46.6.01.

ABSTRACT

INTRODUCTION: The objective of this study is to evaluate adherence to seven Canadian Lower-Risk Cannabis Use Guideline (LRCUG) recommendations among Canadian university students and identify subgroups of high-risk users.

METHODS: We analyzed survey data collected across four Canadian universities under the World Mental Health-International College Student (WMH-ICS) initiative. Seven of the ten 2017 LRCUG recommendations were evaluated. Zero-inflated Poisson models were employed to examine the sociodemographic correlates of (1) any lifetime cannabis use; and (2) the number of unmet LRCUG recommendations, conditional on lifetime use. Additionally, multivariable binary logistic regression models examined the sociodemographic correlates of adherence to individual recommendations.

RESULTS: Among the 27 236 respondents, the prevalence of lifetime cannabis use was 33.8%. Of the seven recommendations evaluated, “choosing lower-strength cannabis products” had the lowest adherence rate (29.0%), followed by “not smoking cannabis” (36.7%). “Not using synthetic cannabis” had the highest adherence rate (96.1%), followed by “delaying cannabis use until age 16” (91.2%). Men, non-heterosexual students, students living in shared housing, and domestic students were more likely to use cannabis and, among users, reported risky use. While White students were more likely to use cannabis, among users, many non-White student groups reported riskier use.

CONCLUSION: Although most students did not use cannabis and many of the LRCUG recommendations had high rates of adherence, there were low rates of choosing lower-strength cannabis products and avoiding smoking cannabis among users. Study findings highlight specific recommendations and subpopulations to inform tailoring of future interventions targeting university students.

PMID:42307904 | DOI:10.24095/hpcdp.46.6.01

Spine Deform. 2026 Jun 17. doi: 10.1007/s43390-026-01481-0. Online ahead of print.

ABSTRACT

BACKGROUND: Delayed presentation of Adolescent Idiopathic Scoliosis (AIS) is common in the UK and is characterised by larger Cobb angles at diagnosis. The size of the Cobb angle influences the mode and effectiveness of treatment strategies and worsens the overall outcome and prognosis. Severe scoliosis typically necessitates surgical correction. We hypothesised that social deprivation may be one factor that contributes to delayed presentation.

AIMS: To assess whether social deprivation is associated with greater spinal curvature at first consultation.

METHODS: A retrospective study of children presenting with AIS to a major UK children’s hospital between 2013 and 2022. Cobb angle and the English Index of Multiple Deprivation (IMD) 2019 rank were initially analysed as continuous variables using scatter plot visualisation and linear regression. Subsequently, a case-control analysis was performed with revised groupings: cases were defined as patients with large, neglected curves (Cobb angle > 70°) and controls as patients with nonoperative scoliosis (Cobb angle < 50°). Patients with Cobb angles between 50° and 70° (n = 31) were excluded from the case-control analysis to reduce misclassification. Statistical analysis included descriptive statistics, linear regression, and logistic regression.

RESULTS: A total of 364 patients were identified. Linear regression of IMD rank against Cobb angle across the full cohort demonstrated a non-significant regression coefficient (β = 19.90, p = 0.335), with a Pearson correlation of r = 0.051. After excluding 31 patients with Cobb angles 50-70°, the case-control analysis included 113 cases and 220 controls. Logistic regression yielded an odds ratio for IMD decile of 0.992 (95% CI 0.923-1.066, p = 0.828), confirming no significant association between social deprivation and curve severity.

CONCLUSION: This study did not find a significant association between social deprivation and severity of scoliosis at presentation. Findings were consistent across both continuous and categorical analyses. However, the lack of variability in the studied population and potential overmatching may have limited the ability to detect meaningful differences. Large-scale, multicentre studies are needed.

PMID:42307890 | DOI:10.1007/s43390-026-01481-0

Behav Res Methods. 2026 Jun 17;58(7):201. doi: 10.3758/s13428-026-03070-5.

ABSTRACT

In this study we examine how a mixed-effects model with crossed random effects for individuals and variables estimates within- and between-variability in longitudinal multivariate trajectories from cohort-sequential designs. These designs are characterized by large proportions of planned missing data, and they usually require continuous-time metrics. Via simulations, we evaluated different model outcomes under various conditions regarding the size of clusters (individuals and variables) and the complexity of the trajectories. Results show that (a) this model can estimate the general trajectories (common to all individuals and variables) and their variability, plus the variable-specific trajectories through the predictions of the levels of the random factors; (b) the standard errors of the random effects are wide, yet they are important for making substantive decisions for specific variables; and (c) the model predictions can adequately forecast individual and variable-specific complete trajectories from just a few observations per individual. These results are supported in an empirical illustration using cognitive developmental data. These findings show that researchers can obtain complete individual trajectories for multiple variables throughout a target age range. The relative simplicity of this model in comparison with other alternatives makes it a promising and accessible tool for multivariate longitudinal data analysis.

PMID:42307878 | DOI:10.3758/s13428-026-03070-5

Health Econ Rev. 2026 Jun 17. doi: 10.1186/s13561-026-00808-x. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic constituted a public health emergency in Thailand from March 2020 to October 2022, testing the resilience of the health financing system. This study establishes an analytical framework to examine Thailand’s public health financing arrangements and their subsequent impacts on public hospital financial reserves during this crisis.

METHODS: This mixed-methods study developed an analytical framework to examine Thailand’s public health financing response. The study analyzed COVID-19 public health expenditure data (Fiscal Years (FY) 2020-2022) and financial data from 866 Ministry of Public Health hospitals (FY 2015-2022) using descriptive statistics and trend analysis. These quantitative findings were integrated with a thematic analysis of 21 key informant interviews.

RESULTS: Thailand enhanced health financing resilience through adaptive revenue mobilization and flexible resource allocation. Between FY 2020 and 2022, the government expanded fiscal space by mobilizing approximately US$13.78 billion via the Emergency Loan Decrees, Central Budget, and Social Security Fund. Universal Health Coverage (UHC) mechanisms expanded service coverage and expedited provider reimbursement. During delayed loan disbursements, public hospitals used internal financial reserves to bridge funding gaps and maintain service continuity. Consequently, net hospital reserves increased substantially by the pandemic’s end compared to pre-pandemic baselines.

CONCLUSIONS: Thailand strategically leveraged its UHC system and mobilized emergency and pre-existing public funds to secure fiscal space and maintain system resilience. However, temporary funding influxes may mask localized resource strains on hospital financial reserves. To enhance future resilience, Thailand should establish a dedicated health emergency reserve fund, streamline extra-budgetary mechanisms, and adopt flexible procurement regulations.

PMID:42307858 | DOI:10.1186/s13561-026-00808-x

Bull Math Biol. 2026 Jun 17;88(7):119. doi: 10.1007/s11538-026-01684-6.

ABSTRACT

Extrusomes are extrusive organelles found in a variety of organisms, including cnidarians, dinoflagellates, and protists. These organelles typically contain a fluid-filled capsule that houses a structure, such as a coiled tubule or barb, which is rapidly ejected toward a target. Although the ejection mechanisms and morphology vary widely, a common feature is the rapid acceleration of the ejected structure through a fluid. In this paper, we develop an idealized model to simulate the collapse of an extrusome capsule, which enables the ejection of a barb or other internal structure. Specifically, we used the immersed boundary method to numerically simulate the collapse of a simplified capsule, modeled as the two sides of an elliptical shell with a flat plate along the bottom. As the capsule collapses, the elliptical sides straighten, ejecting both the internal fluid and the enclosed structure towards either free fluid or a flexible target. We investigate the effects of key model parameters, such as the size of the capsule opening. We also explore the role of the Reynolds number (Re), to consider the fluid dynamics across a range of regimes, from inertial-dominated flows relevant to some extrusome firings to viscous-dominated flows characteristic of cellular-scale processes. Our results demonstrate that decreasing the capsule opening gap size leads to increased firing velocity and shorter ejection times. Similarly, increasing the capsule’s minor axis reduces the time it takes the barb to reach the target as a larger volume of fluid is moved. The relationship between Re and the time to contact is nonmonotonic, but higher Re values generally result in faster target contact, even at longer initial distances. Furthermore, we observe that higher Re values enhance the robustness of the target contact in different configurations. Finally, we quantify how the stiffness of the barb affects its ability to reach the target. We find that the large deformations of the flexible barbs slow their trajectories and that the stiffer barbs hit their targets sooner. These findings provide a foundational understanding of the biomechanics and fluid dynamics of extrusome ejection through the collapse of a capsule. The insights gained may contribute to the development of microinjectors in drug delivery, where precise and rapid mechanical movements are critical.

PMID:42307851 | DOI:10.1007/s11538-026-01684-6

Environ Monit Assess. 2026 Jun 17;198(7):735. doi: 10.1007/s10661-026-15593-7.

ABSTRACT

This study presents a comprehensive spatiotemporal assessment of key ambient air pollutants (PM_2.5, PM₁₀, SO₂, NO₂, NH_3, O₃, and CO) across seven urban and semi-urban districts of the Uttar Pradesh National Capital Region (UP-NCR), India, during 2019-2023. Despite an overall decline of approximately 23% in particulate matter concentrations over the study period, annual mean PM_2.5 (88 ± 15 µg/m³) and PM₁₀ (185 ± 28 µg/m³) levels consistently exceeded the National Ambient Air Quality Standards. Land use and land cover (LULC) analysis revealed a 7.06% expansion in built-up areas, reflecting rapid urbanization and its influence on local emission patterns. This urban growth was associated with persistent NO₂ enrichment, particularly in Noida, where concentrations increased by 22%. Pronounced seasonal variability was observed, with PM_2.5 concentrations peaking during the post-monsoon season particularly in Noida (200 ± 102 µg/m³) and Ghaziabad (178 ± 99 µg/m³), identified as the regional pollution hotspot. Meteorological analysis revealed strong seasonal influences on pollutant concentrations. Relative humidity exhibited positive correlations with particulate matter during winter (r ≈ 0.44-0.59), reflecting hygroscopic growth and stagnant atmospheric conditions, but strong negative correlations during the monsoon (r ≈ -0.72 to -0.95) due to efficient wet scavenging. Bivariate polar plot analysis identified stagnation-driven pollutant accumulation in densely urbanized districts and wind-induced resuspension of agricultural and crustal dust in peripheral regions. HYSPLIT backward-trajectory clustering further demonstrated substantial contributions from long-range transport originating from western and northwestern source regions during pollution episodes. These findings highlight pronounced spatial heterogeneity and seasonal dynamics in air quality, emphasizing the need for region-specific, airshed-based mitigation strategies across rapidly urbanizing peri-urban corridors.

PMID:42307838 | DOI:10.1007/s10661-026-15593-7

J Pharmacokinet Pharmacodyn. 2026 Jun 17;53(4):31. doi: 10.1007/s10928-026-10047-6.

ABSTRACT

BACKGROUND: Reliable population pharmacokinetic (PopPK) estimation is often compromised by outliers under Gaussian error models. While post hoc filtering using conditional weighted residuals (CWRES) is common, this approach is often insensitive due to model “masking” from variance inflation.

METHODS: We implemented a one-compartment model in Monolix using a custom likelihood workaround to benchmark four distributions: Normal, Laplace, Generalized Error Distribution (GED), and Student’s t. We assessed CWRES sensitivity under extreme contamination and compared estimation performance using theoretical tail-behavior analysis, controlled simulation studies spanning multiple contamination severities, and a real-world caffeine PK case study with influential terminal-phase deviations.

RESULTS: Simulations revealed that CWRES-based diagnostics are unreliable; extreme outliers frequently produced |CWRES| < 6 because the Normal model inflated residual variance, masking the contamination. Exponential-tail models (Laplace, GED) improved robustness for moderate outliers but failed under extreme deviations due to insufficiently heavy tails. Conversely, the Student’s t model, utilizing power-law tail behavior, maintained stable and minimally biased structural parameter estimates across the contamination settings examined. These patterns were confirmed in the caffeine case study.

CONCLUSIONS: Reliance on CWRES-driven residual screening alone is methodologically fragile. Among the models evaluated, exponential-tail distributions are insufficient for extreme outliers, whereas the Student’s t distribution provided the most consistent stability across the contamination settings examined here and showed the most robust overall performance among the residual-error models evaluated when influential outliers were present.

PMID:42307836 | DOI:10.1007/s10928-026-10047-6

Acta Neurochir (Wien). 2026 Jun 17. doi: 10.1007/s00701-026-06859-7. Online ahead of print.

ABSTRACT

BACKGROUND: The Coalition (Globus Medical) hybrid PEEK-titanium cage has been widely utilized in our practice for Anterior Cervical Discectomy and Fusion (ACDF) over a 5-year period. A preliminary review of all the cases that we performed in these five years show to us an unexpectedly high rate of postoperative cage subsidence with the Coalition (Globus Medical) stand-alone cage. This prompted a formal investigation, the purpose of this study was, therefore, to systematically determine the true rate of subsidence for the Coalition cage in our cohort and to identify the independent risk factors that could explain this finding.

METHODS: We conducted a retrospective analysis of 70 consecutive patients who underwent ACDF with the Coalition cage between 2018 and 2023. Data on demographic, clinical, and surgical variables were collected. The primary outcome was cage subsidence (≥ 3 mm) assessed on lateral radiographs at a mean follow-up of 28.8 months (range 12-48). Independent predictors were identified through a multivariable logistic regression model constructed using the purposeful selection of covariates strategy, a multi-step iterative process that accounts for both statistical significance and confounding effects.

RESULTS: The overall patient-based subsidence rate was 38.6% (27 of 70 patients) at a mean radiographic follow-up of 28.8 months. Interrater reliability for subsidence assessment was substantial (Kappa = 0.759). In the multivariable analysis, preoperative diagnosis of radiculopathy was identified as the only independent predictor of subsidence, with an Adjusted Odds Ratio of 3.51 (95% CI: 1.13-10.91, p = 0.029). Contrary to initial assumptions, multi-level surgery (p = 0.441), smoking status (p = 0.615), and implant dimensions were not significant predictors in this cohort.

CONCLUSION: The Coalition cage demonstrated a high rate of subsidence in this series. A preoperative diagnosis of radiculopathy was the primary independent risk factor for this outcome, rather than multi-level fusion or specific implant characteristics. These findings suggest that the biomechanical requirements of disc height restoration in patients with radiculopathy may predispose them to higher subsidence rates when utilizing this specific standalone integrated fixation device.

PMID:42307831 | DOI:10.1007/s00701-026-06859-7