Time-dependent Treatment Effects Research Articles

Nobiletin Stimulates Adrenal Hormones and Modulates the Circadian Clock in Mice.

Polymethoxyflavonoids, such as nobiletin (abundant in Citrus depressa), have been reported to have antioxidant, anti-inflammatory, anticancer, and anti-dementia effects, and are also a circadian clock modulator through retinoic acid receptor-related orphan receptor (ROR) α/γ. However, the optimal timing of nobiletin intake has not yet been determined. Here, we explored the time-dependent treatment effects of nobiletin and a possible novel mechanistic idea for nobiletin-induced circadian clock regulation in mice. In vivo imaging showed that the PER2::LUC rhythm in the peripheral organs was altered in accordance with the timing of nobiletin administration (100 mg/kg). Administration at ZT4 (middle of the light period) caused an advance in the peripheral clock, whereas administration at ZT16 (middle of the dark period) caused an increase in amplitude. In addition, the intraperitoneal injection of nobiletin significantly and potently stimulated corticosterone and adrenaline secretion and caused an increase in Per1 expression in the peripheral tissues. Nobiletin inhibited phosphodiesterase (PDE) 4A1A, 4B1, and 10A2. Nobiletin or rolipram (PDE4 inhibitor) injection, but not SR1078 (RORα/γ agonist), caused acute Per1 expression in the peripheral tissues. Thus, the present study demonstrated a novel function of nobiletin and the regulation of the peripheral circadian clock.

Time to Anticoagulation Reversal and Outcomes After Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is the deadliest stroke subtype, and mortality rates are especially high in anticoagulation-associated ICH. Recently, specific anticoagulation reversal strategies have been developed, but it is not clear whether there is a time-dependent treatment effect for door-to-treatment (DTT) times in clinical practice. To evaluate whether DTT time is associated with outcome among patients with anticoagulation-associated ICH treated with reversal interventions. This cohort study used data from the American Heart Association Get With The Guidelines-Stroke quality improvement registry. Patients with ICH who presented within 24 hours of symptom onset across 465 US hospitals from 2015 to 2021 were included. Data were analyzed from January to September 2023. Anticoagulation-associated ICH. DTT times and outcomes were analyzed using logistic regression modeling, adjusted for demographic, history, baseline, and hospital characteristics, with hospital-specific random intercepts to account for clustering by site. The primary outcome of interest was the composite inpatient mortality and discharge to hospice. Additional prespecified secondary outcomes, including functional outcome (discharge modified Rankin Scale score, ambulatory status, and discharge venue), were also examined. Of 9492 patients with anticoagulation-associated ICH and documented reversal intervention status, 4232 (44.6%) were female, and the median (IQR) age was 77 (68-84) years. A total of 7469 (78.7%) received reversal therapy, including 4616 of 5429 (85.0%) taking warfarin and 2856 of 4069 (70.2%) taking a non-vitamin K antagonist oral anticoagulant. For the 5224 patients taking a reversal intervention with documented workflow times, the median (IQR) onset-to-treatment time was 232 (142-482) minutes and the median (IQR) DTT time was 82 (58-117) minutes, with a DTT time of 60 minutes or less in 1449 (27.7%). A DTT time of 60 minutes or less was associated with decreased mortality and discharge to hospice (adjusted odds ratio, 0.82; 95% CI, 0.69-0.99) but no difference in functional outcome (ie, a modified Rankin Scale score of 0 to 3; adjusted odds ratio, 0.91; 95% CI, 0.67-1.24). Factors associated with a DTT time of 60 minutes or less included White race, higher systolic blood pressure, and lower stroke severity. In US hospitals participating in Get With The Guidelines-Stroke, earlier anticoagulation reversal was associated with improved survival for patients with ICH. These findings support intensive efforts to accelerate evaluation and treatment for patients with this devastating form of stroke.

Abstract 145: Anticoagulation-Related Intracerebral Hemorrhage and Time to Reversal Treatment After Intracerebral Hemorrhage in the United States

Background: Anticoagulation-associated intracerebral hemorrhage (AC-ICH) often results in death. Specific reversal agents are available, but it is not clear whether there is a time-dependent treatment effect. We characterized patients with AC-ICH and investigated the relationship between time to treatment and outcome. Methods: We analyzed data from 9492 AC-ICH patients who presented within 24 hours of onset across 465 hospitals reporting any anticoagulation reversal treatment in GWTG-Stroke from 2015 to 2021. For patients with available door-to-treatment (DTT) times, outcomes were analyzed using logistic regression models adjusted for demographic, history, baseline, and hospital characteristics. A spline plot for mortality was generated for DTT and in-patient mortality from the adjusted predicted outcome probability. Results: Among 9492 patients admitted within 24h of AC-ICH, the median age was 77 years, 45% female, and NIHSS median 11. 79% (7469) received reversal treatment and 21% (2143) did not. Among reversal patients, pretreatment AC was warfarin in 62.2% and a direct oral anticoagulant in 37.8%. For 5224 patients with documented times, median onset to treatment time was 232 (IQR 142-185) minutes and DTT was 82 (58-117) mins, with DTT ≤60m for 27.7%. DTT ≤60 minutes was associated with lower odds of mortality than a DTT of >61-180 minutes (aOR 0.83 [95% CI: 0.69-1.00]). Factors associated with DTT ≤ 60 minutes include white non-Hispanic race, higher blood pressure, lower NIHSS, and a larger hospital size. Spline plotting showed a steep mortality increase with longer DTT in the first 30-minutes post-arrival (Figure). Conclusion: In US hospitals participating in GWTG-Stroke reporting reversal therapy, most patients with AC-ICH received reversal agents. Earlier administration was associated with improved survival. These findings support intensive efforts to accelerate evaluation and treatment for patients with this devastating form of stroke.

Abstract 22: Time to Treatment and the Effect of Intravenous Thrombolysis Before Thrombectomy: An Individual Participant Data Meta-Analysis

Introduction: The benefit of intravenous thrombolysis for acute ischemic stroke declines with longer time from symptom onset. It is not known whether a similar time-dependent treatment effect modification of intravenous thrombolysis (IVT) is present in patients undergoing thrombectomy. Methods: Individual participant data meta-analysis from six randomized controlled trials comparing IVT plus thrombectomy vs thrombectomy alone. Primary analysis was performed testing for heterogeneity of the treatment effect. We estimated the effect of onset-to-expected-IVT times on the association between allocated treatment (intravenous thrombolysis plus thrombectomy vs thrombectomy alone) and disability at 3 months (modified Rankin scale, mRS). Results: In 2313 participants (IVT plus thrombectomy [n = 1160]; thrombectomy alone [n = 1153]; median age, 71 years, IQR 62-78 years; 44.3% female), the median onset-to-expected-IVT time was 2h 28min (IQR, 1h 46min to 3h 17min). We observed a statistically significant interaction between onset-to-expected-IVT times and treatment group effect (pinteraction=0.02), with the treatment effect of IVT plus thrombectomy vs thrombectomy alone declining over time (e.g., common adjusted Odds Ratio for a one-step mRS shift toward improvement 1.49, 95%CI 1.13-1.96 at 1h; 1.25, 95% CI 1.04-1.49 at 2h; 1.04, 95% CI 0.88-1.23 at 3h). If treated before 2h 20min after symptom onset, participants allocated to IVT plus thrombectomy were significantly less disabled at 90 days than participants allocated to thrombectomy alone. Conclusions: This individual participant data meta-analysis of patients with ischemic stroke presenting at thrombectomy-capable stroke centers demonstrated time-dependence of the treatment effect of IVT plus thrombectomy vs thrombectomy alone. Intravenous thrombolysis showed clinical benefit if it was administered within 2h 20min after symptom onset.

Ambient plasma treated tungsten disulfide for electrochemical energy applications

Tungsten disulfide (WS2) is modified, by using ambient solution plasma, for electrochemical energy applications which are hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and flexible supercapacitor applications. Herein, the effect of time-dependent plasma treatment on WS2 is investigated, resulting that the optimum time (60 min) shows the best performances of low overpotential of −0.19 V at −10 mA cm−2 and 0.21 V at 10 mA cm−2 with the corresponding Tafel slopes of 113 mV dec−1 and 124 mV dec−1 for HER and OER, respectively. In addition, a high specific capacitance of 157.5 F g−1 at 1 A g−1 with an energy density of 14 Wh kg−1 and power density of 400 W kg−1 for the flexible supercapacitor is obtained. Reliable flexibility with high specific capacitance retention (94.0%) and coulombic efficiency (89.5%) after 5000 cycles are also demonstrated. The increased electrochemically active surface area, lower impedance, and the phase transition from 2H to 1T, compared to the precursor WS2, by the ambient plasma are ascribed to the better HER, OER, and supercapacitor performance.

Terrorism, banking, and informal savings: Evidence from Nigeria

Conflict-affected societies have lower levels of economic growth. The financial development literature argues that one mechanism behind this is conflict increasing instability, lowering savings. However, the development studies literature highlights that conflict increases precautionary savings. I address this ambiguity arguing that savings do not necessarily fall, rather people opt for informal over formal savings channels as the latter are perceived as vulnerable to conflict. Informal savings are not recorded, explaining why some studies find that savings fall. The analysis uses data from the Nigerian General Household Survey Panel and the Global Terrorism Database with a dose response difference-in-difference model, exploiting variation in terrorism events within 500 5-km-squared locations over 2010–2018. The results confirm my intuition and are robust to several exercises, including to potential bias from heterogeneous time-dependent and dynamic treatment effects. Mechanism analysis suggest that post-conflict changes in risk aversity plays a role. The study ends with policy insights.

Abstract WP81: Validation Of Artificial Intelligence To Limit Delays In Acute Stroke Treatment And Endovascular Therapy (VALIDATE)

Introduction: Analyses from early- and late-window thrombectomy trials for acute large vessel occlusion (LVO) stroke have consistently demonstrated a strong time-dependent treatment effect for best outcomes. The utilization of an artificial intelligence (AI)-based care coordination platform to support LVO diagnosis and treatment has the potential to assist in reducing door to puncture times and improve outcomes. Hypothesis: Utilization of an AI-based care platform in the management of LVO patients may significantly decrease door to Neurointerventionalist (NIR) notification time. Methods: Acute stroke consultations seen by TeleSpecialists, LLC physicians in the emergency department in 166 facilities (17 states) that utilized VIZ.AI software or did not have an AI software from December 1, 2021 through March 31, 2022 were extracted from the Telecare TM database. Facilities that neurology does not initiate contact with NIR were excluded. The encounters were analyzed by age, ethnicity, last known normal, arrival time, initial telemedicine stroke code activation time (TCA), candidacy for thrombolytics, door to needle time (DTN), advanced imaging, presence of LVO, time NIR accepted, premorbid modified Rankin Score, and NIHSS score. Patients were divided into two groups (utilization and non-utilization of the AI platform) and median door to NIR notification times were compared. There was a 4 minute shorter time to TCA at AI hospitals. Results: A total of 14,116 patients (8,557 AI and 5,559 non-AI) were included. The median door to NIR notification time for AI was 50 minutes (40, 82) and non-AI was 89.5 minutes (59.3, 122), p <0.001. There was a small but significantly shorter time (3 minutes) from door to TCA at AI hospitals. Median DTN times for thrombolytics was also lower with AI, 40 minutes (30, 52) vs 44 minutes (32, 57.5) for non-AI, p=0.018. The AI group had more advanced imaging performed, a higher percentage of LVOs identified, and a higher percentage accepted by NIR. Conclusion: Hospital utilization of an AI-based care coordination platform was associated with a significant decrease of 39.5 minutes in the time to NIR contact, increase in patients taken for intervention, and lower DTN times for thrombolytics.

Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma.

Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however, the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed the survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54-0.90, P = .006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR = 0.76, 0.66-0.88, P = .0003). Antibody seropositivity to EBV was separately associated with improved survival (HR = 0.71, 0.53-0.96, P = .028). Antibody positivity to 2 other common viruses (CMV, HSV) was not associated with altered survival. Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.

Examining evidence of time-dependent treatment effects: an illustration using regression methods

BackgroundFor the design and analysis of clinical trials with time-to-event outcomes, the Cox proportional hazards model and the logrank test have been the cornerstone methods for many decades. Increasingly, the key assumption of proportionality—or time-fixed effects—that underpins these methods has been called into question. The availability of novel therapies with new mechanisms of action and clinical trials of longer duration mean that non-proportional hazards are now more frequently encountered.MethodsWe compared several regression-based methods to model time-dependent treatment effects. For illustration purposes, we used selected endpoints from a large, community-based clinical trial of low dose daily aspirin in older persons. Relative and absolute estimands were defined, and analyses were conducted in all participants. Additional exploratory analyses were undertaken by selected subgroups of interest using interaction terms in the regression models.DiscussionIn the trial with median 4.7 years follow-up, we found evidence for non-proportionality and a time-dependent treatment effect of aspirin on cancer mortality not previously reported in trial findings. We also found some evidence of time-dependence to an aspirin by age interaction for major adverse cardiovascular events. For other endpoints, time-fixed treatment effect estimates were confirmed as appropriate.ConclusionsThe consideration of treatment effects using both absolute and relative estimands enhanced clinical insights into potential dynamic treatment effects. We recommend these analytical approaches as an adjunct to primary analyses to fully explore findings from clinical trials.

Time-Dependent Endovascular Treatment Effect According to Collateral Status in Basilar Artery Occlusion.

Prior studies on anterior circulation stroke have demonstrated that the benefits of endovascular treatment (EVT) may be absent in patients with poor collaterals. Our study focused on patients with basilar artery occlusion (BAO) to investigate time-dependent EVT effects according to the posterior circulation collateral score (PC-CS). The BASILAR study was a nationwide prospective Chinese registry of consecutive BAO patients. Patients were divided into groups receiving standard medical therapy alone (SMT group) or SMT plus EVT (EVT group). Restricted cubic spline analyses (RCSA) were performed to explore the nonlinear and linear relationships between EVT time and outcomes for different PC-CS. We included 828 patients with acute BAO. Compared with the poor collateral (PC-CS 0-3), the adjusted odds ratio of favorable outcome was 1.311 in patients with moderate (PC-CS 4-5) (95% CI, 0.781-2.201) and 1.899 with good (PC-CS 6-10) collateral (1.125-3.207) for EVT. RCSA revealed that in patients with PC-CS 0-3, the favorable outcome probability after EVT significantly decreased to 10% within 6h and stabilized thereafter (Pnonlinearity = 0.035), while in patients with moderate and good collateral, the probability was maintained at approximately 30% and 40% respectively, even beyond 6h (all Pnonlinearity > 0.05). Among patients with BAO, good collateral circulation was independently associated with improved outcomes along with the usage of thrombectomy. Patients with poor collaterals should receive EVT as early as possible, especially within 6h of symptom onset, while the time window may be extended in patients with moderate and good collaterals. Unique identifier: ChiCTR1800014759.

Individual Patient Data Meta-analysis of Drug-eluting Versus Bare-metal Stents for Percutaneous Coronary Intervention in Chronic Versus Acute Coronary Syndromes

New-generation drug-eluting stents (DES) strongly reduce restenosis and repeat revascularization compared with bare-metal stents (BMS) for percutaneous coronary intervention. There is residual uncertainty as to whether other prognostically relevant outcomes are affected by DES versus BMS concerning initial presentation (chronic coronary syndrome [CCS] vs acute coronary syndrome [ACS]). We performed an individual patient data meta-analysis of randomized trials comparing new-generation DES versus BMS (CRD42017060520). The primary outcome was the composite of cardiac death or myocardial infarction (MI). Outcomes were examined at maximum follow-up and with a 1-year landmark. Risk estimates are expressed as hazard ratio (HR) with 95% confidence interval (CI). A total of 22,319 patients were included across 14 trials; 7,691 patients (34.5%) with CCS and 14,628 patients (65.5%) with ACS. We found evidence that new-generation DES versus BMS consistently reduced the risk of cardiac death or MI in both patients with CCS (HR 0.83, 95% CI 0.70 to 0.98, p <0.001) and ACS (HR 0.83, 95% CI 0.75 to 0.92, p <0.001) (p-interaction=0.931). This benefit was mainly driven by a similar reduction in the risk of MI (p-interaction=0.898) for both subsets (HR_CCS 0.80, 95% CI 0.65 to 0.97; HR_ACS 0.79, 95% CI 0.70 to 0.89). In CCS and ACS, we found a time-dependent treatment effect, with the benefit from DES accumulating during 1-year follow-up, without offsetting effects after that. In conclusion, patients with CCS were slightly underrepresented in comparative clinical trials. Still, they benefited similarly to patients with ACS from new-generation DES instead of BMS with a sustained reduction of cardiac death or MI because of lower event rates within 1 year.

Using marginal structural joint models to estimate the effect of a time-varying treatment on recurrent events and survival: An application on arrhythmogenic cardiomyopathy.

In many clinical applications to evaluate the effect of a treatment, randomized control trials are difficult to carry out. On the other hand, clinical observational registries are often available and they contain longitudinal data regarding clinical parameters, drug therapies, and outcomes. In the past, much research has addressed causal methods to estimate treatment effects from observational studies. In the context of time-varying treatments, marginal structural models are often used. However, most analyses have focused on binary outcomes or time-to-the-first event analyses. The novelty of our approach is to combine the marginal structural methodology with the case where correlated recurrent events and survival are the outcomes of interest. Our work focuses on solving the nontrivial problem of defining the measures of effect, specifying the model for the time-dependent weights and the model to estimate the outcome, implementing them, and finally estimating the final treatment effects in this life-history setting. Our approach provides a strategy that allows obtaining treatment effect estimates both on the recurrent events and the survival with a clear causal and clinical interpretation. At the same time, the strategy we propose is based on flexible modeling choices such as the use of joint models to capture the correlation within events from the same subject and the specification of time-dependent treatment effects. The clinical problem which motivated our work is the evaluation of the treatment effect of beta-blockers in arrhythmogenic right ventricular cardiomyopathy (ARVC/D), and the dataset comes from the Trieste Heart Muscle DiseaseRegistry.

Effect of metformin on arginine and dimethylarginines in patients with advanced type 2 diabetes: A post hoc analysis of a randomized trial.

To study the effect of metformin on plasma levels of arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), indicators of the nitric oxide pathway. In this post hoc analysis of the HOME trial, we analysed plasma levels of arginine, ADMA and SDMA during the 4.3-year follow-up (comparing the effects of metformin versus placebo on top of insulin therapy). Statistical analysis was performed with a mixed model approach, in which simultaneously constant treatment effects were estimated, as well as time-dependent treatment effects. We found that metformin compared with placebo did not affect ADMA or SDMA plasma levels but rapidly decreased arginine plasma levels and hence the arginine to ADMA ratio. The constant treatment effect on ADMA was 0.99 (95% CI 0.97, 1.00) relative to placebo and the time-dependent treatment effect was 1.00 (95% CI 1.00, 1.01). By contrast, the constant treatment effect on arginine was 0.86 (95% CI 0.84, 0.88), with only a minimal time-dependent change of 1.01 (95% CI 1.00, 1.01). The potential benefits of metformin on endothelial function cannot be explained by a decrease in ADMA or by improved global arginine availability. The clinical significance of the decreased arginine plasma levels is not clear and can be harmful or beneficial, depending on the mechanism involved. However, a potential effect of metformin on the nitric oxide pathway is not restricted to the studied metabolites.

MSR13 Comparison of Three Network Meta-Analysis Methods Based Non-Ph in a Cost-Effectiveness Considering Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

Network meta-analysis (NMA) of time-to-event outcomes often relies on pooling of hazard ratios (HR). However, in immuno-oncology, there is increasing evidence of time-dependent treatment effects and violation of proportional hazard (PH) assumption within trials. This study assessed the impact of three network meta-analysis methods on the economic evaluation result of two immunotherapies for second-line treatment of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC).

The effects of caffeine on the motility and viability of stallion spermatozoa at different temperature conditions.

The purpose of this study was to evaluate the dose- and time-dependent effect of caffeine treatment on the motility and viability of stallion spermatozoa at different temperatures. Six dose groups (A to F) were established with changing caffeine concentrations (from 0.625 to 10 mg/mL). The control samples were prepared by diluting the ejaculate only with physiological salt solution. The samples were examined after 0, 1, 2 and 3 h of incubation at 5 °C and 37 °C. The motility parameters were evaluated by Computer Assisted Semen Analyzer (CASA) system, and the viability was assessed by the mitochondrial toxicity test at the end of the incubation. A positive effect of the lowest tested caffeine concentration on the motility parameters was observed throughout the incubation period at 5 °C. At the end of the 3h incubation, the viability in every sample in these groups, treated with any caffeine concentration, showed lower values compared to the control. At the higher incubation temperature (37 °C), caffeine positively affected the motility in samples B (P < 0.05) and D, E, F (P < 0.001) after 3 h of incubation; however, the viability showed a slightly decreasing tendency. Our results suggest that caffeine, in an optimal concentration, may be used as a component of stallion semen extenders.

Association of dynamic changes in serum levels of HBV DNA and risk of hepatocellular carcinoma

Background and aimsWe aimed to examine the risk of HCC associated with the long-term change patterns in HBV DNA levels.MethodsWe conducted a longitudinal study of 6,301 participants with chronic HBV infection (CHB) from October 2012 to June 2019 and measured serum levels of HBV DNA at enrollment and during follow-up. The dynamic change patterns of HBV DNA were identified by group-based trajectory models. The associations between change patterns of HBV DNA and HCC were estimated using Cox regression models.ResultsDuring 35,112 person-years of follow-up, 182 participants developed HCC (518.34 per 105 person-years). Five trajectory groups of repeated measurement of HBV DNA were identified. The risk of HCC was significantly higher for the “high, fast-declined” group whose HBV DNA spontaneously decreased from > 2000 IU/mL at baseline compared with those with persistent undetected HBV DNA (reference group; 963.96 per 105 person-years, HR = 2.62, 95% CI, 1.82 to 3.77, P < 0.001). In addition, the “rebound” group whose HBV DNA level increased from undetectable level to > 20,000 IU/mL from baseline to the end of follow-up also showed an obviously higher cumulative HCC incidence rate (1193.29 per 105 person-years, HR = 4.17, 95% CI, 1.87 to 9.31, P < 0.001). The positive association remained stable after taking the potential effect of time-dependent antiviral treatment into account.ConclusionsSignificant variability in serum levels of HBV DNA presented during long-term follow-up. Regular monitoring of serum levels of HBV DNA and antiviral treatment are required for the clinical management of CHB patients, as well as those with undetected HBV DNA.

Assessing Opioid Use Disorder Treatments in Trials Subject to Non-Adherence via a Functional Generalized Linear Mixed-Effects Model

The opioid crisis in the United States poses a major threat to public health due to psychiatric and infectious disease comorbidities and death due to opioid use disorder (OUD). OUD is characterized by patterns of opioid misuse leading to persistent heavy use and overdose. The standard of care for treatment of OUD is medication-assisted treatment, in combination with behavioral therapy. Medications for opioid use disorder have been shown to improve OUD outcomes, including reduction and prevention of overdose. However, understanding the effectiveness of such medications has been limited due to non-adherence to assigned dose levels by study patients. To overcome this challenge, herein we develop a model that views dose history as a time-varying covariate. Proceeding in this fashion allows the model to estimate dose effect while accounting for lapses in adherence. The proposed model is used to conduct a secondary analysis of data collected from six efficacy and safety trials of buprenorphine maintenance treatment. This analysis provides further insight into the time-dependent treatment effects of buprenorphine and how different dose adherence patterns relate to risk of opioid use.

Ambient plasma treated molybdenum disulfide as bifunctional electrocatalysts

Molybdenum disulfide (MoS2) is modified by using ambient solution plasma for hydrogen and oxygen evolution reactions (HER and OER). The modified MoS2 exhibits low overpotential of −0.18 V at −10 mAcm−2 for HER and 1.40 V at 10 mAcm−2 for OER with Tafel slope of 95 and 65 mVdec−1, respectively. The improved HER and OER performance is attributed to increased electrochemical active surface area and reduced impedance compared to precursor MoS2. The effect of time dependent plasma treatment on MoS2 is also investigated, indicating that the optimal time (90 min) shows better HER and OER performance.

Comparison of statistical methods for the analysis of recurrent adverse events in the presence of non-proportional hazards and unobserved heterogeneity: a simulation study

BackgroundIn preventive drug trials such as intermittent preventive treatment for malaria prevention during pregnancy (IPTp), where there is repeated treatment administration, recurrence of adverse events (AEs) is expected. Challenges in modelling the risk of the AEs include accounting for time-to-AE and within-patient-correlation, beyond the conventional methods. The correlation comes from two sources; (a) individual patient unobserved heterogeneity (i.e. frailty) and (b) the dependence between AEs characterised by time-dependent treatment effects. Potential AE-dependence can be modelled via time-dependent treatment effects, event-specific baseline and event-specific random effect, while heterogeneity can be modelled via subject-specific random effect. Methods that can improve the estimation of both the unobserved heterogeneity and treatment effects can be useful in understanding the evolution of risk of AEs, especially in preventive trials where time-dependent treatment effect is expected.MethodsUsing both a simulation study and the Chloroquine for Malaria in Pregnancy (NCT01443130) trial data to demonstrate the application of the models, we investigated whether the lognormal shared frailty models with restricted cubic splines and non-proportional hazards (LSF-NPH) assumption can improve estimates for both frailty variance and treatment effect compared to the conventional inverse Gaussian shared frailty model with proportional hazard (ISF-PH), in the presence of time-dependent treatment effects and unobserved patient heterogeneity. We assessed the bias, precision gain and coverage probability of 95% confidence interval of the frailty variance estimates for the models under varying known unobserved heterogeneity, sample sizes and time-dependent effects.ResultsThe ISF-PH model provided a better coverage probability of 95% confidence interval, less bias and less precise frailty variance estimates compared to the LSF-NPH models. The LSF-NPH models yielded unbiased hazard ratio estimates at the expense of imprecision and high mean square error compared to the ISF-PH model.ConclusionThe choice of the shared frailty model for the recurrent AEs analysis should be driven by the study objective. Using the LSF-NPH models is appropriate if unbiased hazard ratio estimation is of primary interest in the presence of time-dependent treatment effects. However, ISF-PH model is appropriate if unbiased frailty variance estimation is of primary interest.Trial registrationClinicalTrials.gov; NCT01443130

Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model

ABSTRACT Invasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection occurring mainly in immunocompromised patients. We recently identified IPA as an emerging co-infection with high mortality in critically ill, but otherwise immunocompetent influenza patients. The neuraminidase inhibitor oseltamivir is the current standard-of-care treatment in hospitalized influenza patients; however, its efficacy in influenza-associated pulmonary aspergillosis (IAPA) is not known. Therefore, we have established an imaging-supported double-hit mouse model to investigate the therapeutic effect of oseltamivir on the development of IAPA. Immunocompetent mice received intranasal instillation influenza A or PBS followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Oseltamivir treatment or placebo was started at day 0, day 2, or day 4. Daily monitoring included micro-computed tomography and bioluminescence imaging of pneumonia and fungal burden. Non-invasive biomarkers were complemented with imaging, molecular, immunological, and pathological analysis. Influenza virus-infected immunocompetent mice developed proven airway IPA upon co-infection with Aspergillus fumigatus, whereas non-influenza-infected mice fully cleared Aspergillus, confirming influenza as a risk factor for developing IPA. Longitudinal micro-CT showed pulmonary lesions after influenza infection worsening after Aspergillus co-infection, congruent with bioluminescence imaging and histology confirming Aspergillus pneumonia. Early oseltamivir treatment prevented severe influenza pneumonia and mitigated the development of IPA and associated mortality. A time-dependent treatment effect was consistently observed with imaging, molecular, and pathological analyses. Hence, our findings underscore the importance of initiating oseltamivir as soon as possible, to suppress influenza infection and mitigate the risk of potentially lethal IAPA disease.