Too good to be true: Are GLP-1 receptor agonists the new metformin?

Recently, a health-care database study showed that persons with type 2 diabetes taking GLP-1 receptor agonists (GLP-1 RA) had a significantly lower risk of 10 out of 13 obesity-related cancers than patients taking insulin (Wang L, et al. JAMA Netw Open. 2024 7: e2421305). For some cancers, hazard ratios <0.5 were reported. This is reminiscent of studies published >10 years ago showing that people with type 2 diabetes taking metformin had a lower risk of many types of cancer than those not taking metformin. In some studies, also risk reductions of >50 % were reported. The strong effects observed in the metformin studies were explained by time-related biases, in particular, immortal time bias. In the current GLP-1 RA study, it was striking that the curves for the cumulative incidence of several cancers in GLP-1 RA and insulin users diverged immediately after therapy onset. This indicates that there is most likely a time-related bias: insulin is given at much later stages of type 2 diabetes than GLP-1 RA. The current study suggests that one should be sceptical about database results when spectacular risk reductions are reported. Time-related bias should always be considered as an alternative explanation.

Revisiting the Effect of the Resistance to Gas Accumulation in Constant Volume Systems on the Membrane Time Lag.

The time-lag method is commonly used to determine membrane permeability, diffusivity and solubility in a single gas permeation experiment in a constant volume system. An unwritten assumption on which this method relies is that there is no resistance to gas accumulation in the downstream receiver of the system. However, this is not the case, even with the specially designed receiver used in this study when, in addition to tubing, the receiver utilizes an additional accumulation tank. The resistance to gas accumulation originates from a finite diffusivity (Knudsen diffusion) of gases in tubing, which are magnified by "resistance-free" accumulation tank(s). As a result of the resistance to gas accumulation, the time lag of the membrane is underestimated, which leads to an overestimation of gas diffusivity in the membrane. The experimentally predicted resistances in different configurations of the receiver, expressed by the difference in the time lag at two different receiver locations, were several times greater than the theoretically predicted values. A high molecular PPO membrane was used to demonstrate this effect. The time lags measured at different locations differed by as much as 30%. The diffusivity of nitrogen in a PPO of 4.04 × 10-12 m2/s determined at the optimum configuration of the receiver is at least 50% lower than the literature-reported values.

Comparing two hazard curves when there is a treatment time-lag effect.

In cancer and other medical studies, time-to-event (eg, death) data are common. One major task to analyze time-to-event (or survival) data is usually to compare two medical interventions (eg, a treatment and a control) regarding their effect on patients' hazard to have the event in concern. In such cases, we need to compare two hazard curves of the two related patient groups. In practice, a medical treatment often has a time-lag effect, that is, the treatment effect can only be observed after a time period since the treatment is applied. In such cases, the two hazard curves would be similar in an initial time period, and the traditional testing procedures, such as the log-rank test, would be ineffective in detecting the treatment effect because the similarity between the two hazard curves in the initial time period would attenuate the difference between the two hazard curves that is reflected in the related testing statistics. In this paper, we suggest a new method for comparing two hazard curves when there is a potential treatment time-lag effect based on a weighted log-rank test with a flexible weighting scheme. The new method is shown to be more effective than some representative existing methods in various cases when a treatment time-lag effect is present.

Economic and life cycle cost analysis of building-integrated photovoltaic system for composite climatic conditions.

An insulated building-integrated photovoltaic (PV) roof prototype is designed, developed, and experimentally monitored for the composite climatic conditions in the current work. The prototype is monitored based on hourly indoor room temperature, relative humidity, discomfort index, decrement factor time lag, and power generation. To validate the results, a heat conduction equation was developed and simulated considering actual lower income group (LIG) building size and materials. Second-order polynomial equations were derived from simulation results to optimize insulation thickness. Additionally, the economic analysis of the insulated building-integrated Photovoltaic (BIPV) roof was analyzed and compared to the reinforced concrete cement (RCC) roof. The results reveal that insulated BIPV roofs outperform the RCC roof, reducing indoor temperatures by 3.34 ℃ to 1.37 ℃ within an optimum thickness range of 0.0838-0.1056 m. A time lag of 1 h and a significant reduction in decrement factor up to 0.29 are achieved. The average discomfort index of the proposed roof during sunshine hours was found to be between 23 and 26.5. The insulated BIPV roofs with levelized cost of electricity (LCOE) of the 3.38 Rs/kWh gave a payback period of 6.32 years and a higher internal rate of return of 29.4 compared to RCC roof. The current study increases the feasibility of PV modules to be used as building material.

Pulmonary health effects of wintertime particulate matter from California and China following repeated exposure and cessation.

Epidemiological studies show strong associations between fine particulate matter (PM2.5) air pollution and adverse pulmonary effects. In the present study, wintertime PM2.5 samples were collected from three geographically similar regions-Sacramento, California, USA; Jinan, Shandong, China; and Taiyuan, Shanxi, China-and extracted to form PMCA, PMSD, and PMSX, respectively, for comparison in a BALB/c mouse model. Each of four groups was oropharyngeally administered Milli-Q water vehicle control (50 µL) or one type of PM extract (20 µg/50 µL) five times over two weeks. Mice were necropsied on post-exposure days 1, 2, and 4 and examined using bronchoalveolar lavage (BAL), histopathology, and assessments of cytokine/chemokine mRNA and protein expression. Chemical analysis demonstrated all three extracts contained black carbon, but PMSX contained more sulfates and polycyclic aromatic hydrocarbons (PAHs) associated with significantly greater neutrophil numbers and greater alveolar/bronchiolar inflammation on post-exposure days 1 and 4. On day 4, PMSX-exposed mice also exhibited significant increases in interleukin-1 beta, tumor necrosis factor-alpha, and chemokine C-X-C motif ligands-3 and -5 mRNA, and monocyte chemoattractant protein-1 protein. These combined findings suggest greater sulfate and PAH content contributed to a more intense and progressive inflammatory response with repeated PMSX compared to PMCA or PMSD exposure.

In vivo and in vitro inflammatory responses to fine particulate matter (PM2.5) from China and California.

Ambient PM2.5 was collected during the winter season from Taiyuan, Shanxi, China; Jinan, Shandong, China; and Sacramento, California, USA, and used to create PMSX, PMSD, and PMCA extracts, respectively. Time-lag experiments were performed to explore the in vivo and in vitro toxicity of the PM extracts. In vivo inflammatory lung responses were assessed in BALB/c mice using a single oropharyngeal aspiration (OPA) of PM extract or vehicle (CTRL) on Day 0. Necropsies were performed on Days 1, 2, and 4 post-OPA, and pulmonary effects were determined using bronchoalveolar lavage (BAL) and histopathology. On Day 1, BAL neutrophils were significantly elevated in all PM- versus CTRL-exposed mice, with PMCA producing the strongest response. However, histopathological scoring showed greater alveolar and perivascular effects in PMSX-exposed mice compared to all three other groups. By Day 4, BAL neutrophilia and tissue inflammation were resolved, similar across all groups. In vitro effects were examined in human HepG2 hepatocytes, and U937 cells following 6, 24, or 48 h of exposure to PM extract or DMSO (control). Luciferase reporter and quantitative polymerase chain reaction assays were used to determine in vitro effects on aryl hydrocarbon receptor (AhR) activation and gene transcription, respectively. Though all three PM extracts activated AhR, PMSX produced the greatest increases in AhR activation, and mRNA levels of cyclooxygenase-2, cytochrome P450, interleukin (IL)-8, and interleukin (IL)-1ß. These effects were assumed to result from a greater abundance of polycyclic aromatic hydrocarbons (PAHs) in PMSX compared to PMSD and PMCA.

Sorption/Diffusion Contributions to the Gas Permeation Properties of Bi-Soft Segment Polyurethane/Polycaprolactone Membranes for Membrane Blood Oxygenators.

Due to their high hemocompatibility and gas permeation capacity, bi-soft segment polyurethane/polycaprolactone (PU/PCL) polymers are promising materials for use in membrane blood oxygenators. In this work, both nonporous symmetric and integral asymmetric PU/PCL membranes were synthesized, and the permeation properties of the atmospheric gases N2, O2, and CO2 through these membranes were experimentally determined using a new custom-built gas permeation apparatus. Permeate pressure vs. time curves were obtained at 37.0 °C and gas feed pressures up to 5 bar. Fluxes, permeances, and permeability coefficients were determined from the steady-state part of the curves, and the diffusion and sorption coefficients were estimated from the analysis of the transient state using the time-lag method. Independent measurements of the sorption coefficients of the three gases were performed, under equilibrium conditions, in order to validate the new setup and procedure. This work shows that the gas sorption in the PU/PCL polymers is the dominant factor for the permeation properties of the atmospheric gases in these membranes.

A Novel Time Lag Method for the Analysis of Mixed Gas Diffusion in Polymeric Membranes by On-Line Mass Spectrometry: Pressure Dependence of Transport Parameters.

This paper presents a novel method for transient and steady state mixed gas permeation measurements, using a quadrupole residual gas analyser for the on-line determination of the permeate composition. The on-line analysis provides sufficiently quick response times to follow even fast transient phenomena, enabling the unique determination of the diffusion coefficient of the individual gases in a gas mixture. Following earlier work, the method is further optimised for higher gas pressures, using a thin film composite and a thick dense styrene-butadiene-styrene (SBS) block copolymer membrane. Finally, the method is used to calculate the CO2/CH4 mixed gas diffusion coefficients of the spirobisfluorene-based polymer of intrinsic microporosity, PIM-SBF-1. It is shown that the modest pressure dependence of the PIM-SBF-1 permeability can be ascribed to a much stronger pressure dependence of the diffusion coefficient, which partially compensates the decreasing solubility of CO2 with increasing pressure, typical for the strong sorption behaviour in PIMs. The characteristics of the instrument are discussed and suggestions are given for even more versatile measurements under stepwise increasing pressure conditions. This is the first report on mixed gas diffusion coefficients at different pressures in a polymer of intrinsic microporosity.

Designing cancer immunotherapy trials with random treatment time-lag effect.

In some clinical settings such as the cancer immunotherapy trials, a treatment time-lag effect may be present and the lag duration possibly vary from subject to subject. An efficient study design and analysis procedure should not only take into account the time-lag effect but also consider the individual heterogeneity in the lag duration. In this paper, we present a Generalized Piecewise Weighted Logrank (GPW-Logrank) test, designed to account for the random time-lag effect while maximizing the study power with respect to the weights. Based on the proposed test, both analytic and numeric approaches are developed for the sample size and power calculation. Asymptotic properties are derived and finite sample efficiency is evaluated in simulations. Compared with the standard practice ignoring the delayed effect, the proposed design and analysis procedures are substantially more efficient when a random lag is expected; further, compared with the existing methods by Xu et al considering the fixed time-lag effect, the proposed approaches are significantly more robust when the lag model is misspecified. An R package (DelayedEffect.Design) is developed for implementation.

Development and Characterization of Defect-Free Matrimid® Mixed-Matrix Membranes Containing Activated Carbon Particles for Gas Separation.

In this work, mixed-matrix membranes (MMMs) for gas separation in the form of thick films were prepared via the combination of the polymer Matrimid® 5218 and activated carbons (AC). The AC particles had a mean particle size of 1.5 µm and a mean pore diameter of 1.9 nm. The films were prepared by slow solvent evaporation from casting solutions in chloroform, which had a varying polymer⁻AC ratio. It was possible to produce stable films with up to a content of 50 vol % of AC. Thorough characterization experiments were accomplished via differential scanning calorimetry and thermogravimetric analysis, while the morphology of the MMMs was also investigated via scanning electron microscopy. The gas transport properties were revealed by employing time-lag measurements for different pure gases as well as sorption balance experiments for the filler particles. It was found that defect free Matrimid® MMMs with AC were prepared and the increase of the filler content led to a higher effective permeability for different gases. The single gas selectivity αij of different gas pairs maintained stable values with the increase of AC content, regardless of the steep increase in the effective permeability of the pure gases. Estimation of the solubilities and the diffusivities of the Matrimid®, AC, and MMMs allowed for the explanation of the increasing permeabilities of the MMMs, with the increase of AC content by modelling.

A Guide to Time Lag and Time Lag Shortening Strategies in Oncology-Based Drug Development.

One of the ongoing challenges for academic, biotech and pharma organizations involved in oncology-related research and development is how to help scientists be more effective in transforming new scientific ideas into products that improve patients' lives. Decreasing the time required between bench work and translational study would allow potential benefits of innovation to reach patients more quickly. In this study, the time required to translate cancer-related biomedical research into clinical practice is examined for the most common cancer cases including breast, lung and prostate cancer. The calculated "time lag" typically of 10 years for new oncology treatments in these areas can create fatal delays in a patient's life. Reasons for the long "time lag" in cancer drug development were examined in detail, and key opinion leaders were interviewed, to formulate suggestions for helping new drugs reach from bench to bed side more quickly.

Intrafractional Tracking Accuracy of a Transperineal Ultrasound Image Guidance System for Prostate Radiotherapy.

PURPOSE: The aim of this study is to evaluate the tracking accuracy of a commercial ultrasound system under relevant treatment conditions and demonstrate its clinical utility for detecting significant treatment deviations arising from inadvertent intrafractional target motion. METHODS: A multimodality male pelvic phantom was used to simulate prostate image-guided radiotherapy with the system under evaluation. Target motion was simulated by placing the phantom on a motion platform. The tracking accuracy of the ultrasound system was evaluated using an independent optical tracking system under the conditions of beam-on, beam-off, poor image quality with an acoustic shadow introduced, and different phantom motion cycles. The time delay between the ultrasound-detected and actual phantom motion was investigated. A clinical case example of prostate treatment is presented as a demonstration of the utility of the system in practice. RESULTS: Time delay between the motion phantom and ultrasound tracking system is 223 ± 45.2 milliseconds including video and optical tracking system frame rates. The tracking accuracy and precision were better with a longer period. The precision of ultrasound tracking performance in the axial (superior-inferior) direction was better than that in the lateral (left-right) direction (root mean square errors are 0.18 and 0.25 mm, respectively). The accuracy of ultrasound tracking performance in the lateral direction was better than that in the axial direction (the mean position errors are 0.23 and 0.45 mm, respectively). Interference by radiation and image quality do not affect tracking ability significantly. Further, utilizing the tracking system as part of a clinical study for prostate treatment further verified the accuracy and clinical appropriateness. CONCLUSIONS: It is feasible to use transperineal ultrasound daily to monitor prostate motion during treatment. Our results verify the accuracy and precision of an ultrasound system under typical external beam treatment conditions and further demonstrate that the tracking system was able to identify important prostate shifts in a clinical case.

Reported estimates of diagnostic accuracy in ophthalmology conference abstracts were not associated with full-text publication.

OBJECTIVE: To assess whether conference abstracts that report higher estimates of diagnostic accuracy are more likely to reach full-text publication in a peer-reviewed journal. STUDY DESIGN AND SETTING: We identified abstracts describing diagnostic accuracy studies, presented between 2007 and 2010 at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting. We extracted reported estimates of sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and diagnostic odds ratio (DOR). Between May and July 2015, we searched MEDLINE and EMBASE to identify corresponding full-text publications; if needed, we contacted abstract authors. Cox regression was performed to estimate associations with full-text publication, where sensitivity, specificity, and AUC were logit transformed, and DOR was log transformed. RESULTS: A full-text publication was found for 226/399 (57%) included abstracts. There was no association between reported estimates of sensitivity and full-text publication (hazard ratio [HR] 1.09 [95% confidence interval {CI} 0.98, 1.22]). The same applied to specificity (HR 1.00 [95% CI 0.88, 1.14]), AUC (HR 0.91 [95% CI 0.75, 1.09]), and DOR (HR 1.01 [95% CI 0.94, 1.09]). CONCLUSION: Almost half of the ARVO conference abstracts describing diagnostic accuracy studies did not reach full-text publication. Studies in abstracts that mentioned higher accuracy estimates were not more likely to be reported in a full-text publication.

Time-lag between symptom onset and laboratory findings in patients with subacute thyroiditis.

OBJECTIVE: The objective of this study was to delineate the frequency of delayed diagnosis in cases of subacute thyroiditis (SAT) and intervals between onset of clinical symptoms and appearance of abnormal laboratory findings. METHODS: We reviewed the medical records of 27 patients (7 men and 20 women) with SAT who visited our hospital between 2007 and 2013. RESULTS: On presentation to the hospital, 5 of 27 SAT cases (18.5%) showed normal laboratory findings. Among these 5 cases, the mean interval between symptom onset and thyrotropin (TSH) suppression was 6.3 weeks, and the mean interval to elevation of fT4 was 6.7 weeks. The longest interval from symptom onset to appearance of an abnormal laboratory finding was 11 weeks. CONCLUSION: Sometimes time-lag exists between onset of clinical symptoms and the appearance of abnormal laboratory findings in patients with SAT. The possibility of this disease should not be excluded from the differential diagnoses for patients with clinical symptoms consistent with SAT but showing normal laboratory findings.

Projecting the yearly mortality reductions due to a cancer screening programme.

The decision on whether to implement a 20-year screening programme for a cancer requires weighing the harms and costs against the health benefits (such as the number of cancer deaths averted every year). The evidence of the benefits is often based on a single-number summary, such as the mortality reduction over the entire follow-up time in a single trial, or an average of such one-number measures from a meta-analysis of several trials. There are several problems associated with using the traditional one-number summaries from trials to deduce the yearly mortality reductions expected from a sustained screening programme. We here propose using a rate ratio curve, and its complement (a mortality reduction curve), to address the mortality impact (timing, magnitude, and duration) of a screening programme. This curve is easy to interpret, as it shows when mortality reductions begin, how big they are, and how long they last. We illustrate when and how such rate ratio curves from screening trials could be computed, and how they could be used to compare reduction patterns expected with different screening regimens. We encourage trialists to report the necessary data to arrive at such projections.