Differential Treatment Effects Research Articles

Evaluating Ki67 and Oncotype DX Breast Recurrence Score during neoadjuvant treatment with letrozole/abemaciclib or chemotherapy in patients with highly proliferative HR+/HER2- breast cancer participating in the GEICAM CARABELA trial.

576 Background: CARABELA (NCT04293393) is a phase 2 randomized trial comparing 12 months of neoadjuvant letrozole/abemaciclib (let/abema) vs. 6 months of neoadjuvant chemotherapy (CT) for stage II-III, Ki67≥20%, HR+/HER2- breast cancer patients. Let/abema failed to show similar residual cancer burden (RCB) 0-I rates compared to CT (13% vs. 18%), highlighting the need to identify response biomarkers to CDK4/6 inhibitors and to determine which patients cannot avoid CT. Methods: We explored the predictive role of baseline (BL) Ki67 and Recurrence Score (RS) in tumor samples, and their changes during treatment. Ki67 was centrally determined using a standardized assay (Ki67 MIB-1 pharmDx, Dako Omnis, Agilent Technologies) at BL, 2 weeks (2w), and surgery. RS result was assessed at BL and at surgery (Exact Sciences), in the case of RCB=0, RS and Ki67 was assigned a value of 0. We examined the association of BL Ki67 and RS with RCB 0-I rates as independent variables, by logistic regression (adjusting by disease stage and cN), checking for treatment interaction. Results: BL Ki67 and RS showed similar distributions between arms; median Ki67: let/abema 38% vs CT 36% ( P=0.528); median RS: let/abema 27 vs CT 30 ( P=0.188). Although we could not detect a differential treatment effect based on BL Ki67 or RS, rates of RCB0-I were higher in the CT arm both for high Ki67 (≥40%) and high RS (>25) (table 1). In addition, BL Ki67 as a continuous variable was associated to RCB 0-I only in the CT arm (OR 0.954; 95%CI 0.922-0.988, P=0.006), with an interaction P=0.05. Ki67 suppression was higher in let/abema arm, with a lower median Ki67 at 2w: let/abema 0% vs. CT 21.7% ( P<0.0001), but not at surgery: let/abema 0% vs. CT 2.25% ( P=0.157). In addition, rates of Ki67 <2.7% were higher with let/abema compared to CT at 2w (68% vs. 6%, P<0.0001), but not at surgery (53% vs. 45%, P=0.157). Moreover, 17% of patients in the let/abema arm shifted from 2w Ki67<2.7% to surgery Ki67≥2.7%, while only 2% did so with CT ( P<0.0001). Median RS at surgery was higher in let/abema arm (22 vs. 19 in CT, P=0.028), and CT induced higher downstaging from BL high (>25) to low (≤25) RS at surgery (36% vs. let/abema 20%, P=0.024). Conclusions: Highly proliferative tumors Ki67 (≥40%) or those with high Recurrence Score (>25) exhibited higher rates of RCB 0-I when treated with chemotherapy, than when treated with letrozole/abemaciclib. This suggests that relying solely on letrozole/abemaciclib as systemic treatment for these tumors may be insufficient. Clinical trial information: NCT04293393 . [Table: see text]

Estimating benefit from dose dense adjuvant chemotherapy for early breast cancer in the PANTHER randomized phase 3 trial.

521 Background: Adjuvant dose dense chemotherapy for early breast cancer improves patient outcomes across all subgroups compared with standard interval treatment. However, the effect of dose dense treatment based on individual patient risk and over time, and the performance of the PREDICT model at this setting are not well-studied. Methods: This is an exploratory analysis from the phase 3 PANTHER trial (NCT00798070) that compared adjuvant sequential epirubicin/cyclophosphamide (EC) and docetaxel (D) administered in either tailored dose dense (tDD EC/D, every 2 weeks) or standard interval schedule (FEC/D, every 3 weeks) to patients with high-risk resected early breast cancer. Dose tailoring in the experimental arm was performed according to a predefined algorithm based on hematologic and non-hematologic toxicity. We evaluated the performance of PREDICT in terms of calibration and discrimination in the entire cohort and subgroups of interest, conducted a subpopulation treatment effect pattern plot (STEPP) analysis and observed the relative treatment effect over time. Results: The intention-to-treat population consists of n=2003 randomized patients. Median follow-up was 10.3 years (interquartile range, 9.1 – 10.5 years). PREDICT consistently underestimated 5-year (absolute difference 1.4%) and 10-year overall survival (absolute difference 6.6%) in the entire population and across all subgroups, but mostly so in the highest risk patients where the difference between observed and predicted 10-year survival reached 20.4% for patients with tumors larger than 5 cm. Discriminatory accuracy was lower for 10-year than for 5-year survival (AUC 0.728 and 0.786, respectively), although the difference in model performance between the two treatment groups was small. In STEPP analysis, absolute benefit from tDD EC/D in the primary endpoint of breast cancer relapse free survival was stable across risk-defined overlapping subpopulations and ranged from 3.8% in the lowest risk patients to 3.6% in the highest risk ones. There was no evidence of differential treatment effect through time (pinteraction >0.1 for all time-to-event endpoints). Conclusions: In this largely node-positive population, PREDICT consistently overestimated risk for death in all patient subgroups. We could not reliably identify any subgroup not benefiting from dose dense treatment, which should be the standard of care for primary resected high-risk breast cancer. Clinical trial information: NCT00798070 .

Timing of Complete Revascularization Stratified by Index Presentation During On- and Off-Hours

Recent trials suggested immediate complete revascularization (ICR) as a safe alternative to staged complete revascularization (SCR), but the impact of the respective percutaneous coronary intervention strategies between on- versus off-hours is unclear.On-hours was defined as an index revascularization performed between 8 AM and 6 PM, Monday to Friday, or else the procedure was defined as performed during off-hours. The primary endpoint consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia driven revascularization and cerebrovascular events at 1 year follow-up. We used Cox regression models to relate randomized treatment with study endpoints. We evaluated multiplicative and additive interactions between on- vs. off-hours and randomized treatment.The BIOVASC trial enrolled 1097 and 428 patients during on- and off-hours respectively. Patients randomized during off-hours were more likely to present with ST-segment elevation myocardial infarction (66.4% vs. 29.5%, p < 0.001). The composite primary outcome occurred in 8.4% and 10.1% of patients randomized to ICR and SCR respectively during on-hours (HR 0.80, 95% CI 0.54 to 1.19). During off-hours the primary composite outcome occurred in 5.4% and 7.7% in ICR and SCR (0.69, 95% CI 0.32 to 1.46) with no evidence of a differential effect (interaction pmultiplicative = 0.70, padditive = 0.56). No differential effect was found between treatment allocation and on- versus off-hours in any of the secondary outcomes.In conclusion, no differential treatment effect was found when comparing immediate complete revascularization versus staged complete revascularization in patients presenting with acute coronary syndrome and multivessel disease during on- or off-hours.

Success rates of intensive aphasia therapy: real-world data from 448 patients between 2003 and 2020.

Aphasia is a devastating consequence after stroke, affecting millions of patients each year. Studies have shown that intensive speech and language therapy (SLT) is effective in the chronic phase of aphasia. Leveraging a large single-center cohort of persons with aphasia (PWA) including patients also in the subacute phase, we assessed treatment effects of intensive aphasia therapy in a real-world setting. Data were collected at the Aachen aphasia ward in Germany between 2003 and 2020. Immediate treatment responses across different language domains were assessed with the Aachen Aphasia Test (AAT) using single-case psychometrics, conducted before and after 6-7 weeks of intensive SLT (10 h per week, median (IQR) dosage = 68 (61-76)). We adjusted for spontaneous recovery in subacute patients. Differential treatment effects between subgroups of chronicity and predictors of therapy response were investigated. A total of 448 PWA were included (29% female, median (IQR) age = 54 (46-62) years, median (IQR) time post-onset = 11 (6-20) months) with 12% in the early subacute, 15% in the late subacute and 74% in the chronic phase of aphasia. The immediate responder rate was 59%. Significant improvements in all AAT subtests und subscales were observed hinting at broad effectiveness across language domains. The degree of therapy-induced improvement did not differ between the chronicity groups. Time post-onset, dosage of therapy and aphasia severity at the beginning of treatment were predictors of immediate treatment response. Intensive therapy protocols for aphasia after stroke are yielding substantial responder rates in a routine clinical setting including a wide range of patients.

Differential effects of acute and chronic hydrocortisone treatment on pyroptosis

Pyroptosis is a programmed and inflammation-inducing cell death that occurs predominantly in macrophages. It is characterized by the inflammasome-mediated activation of caspase-1, leading to cell lysis. During pyroptosis, pro-inflammatory mediators such as IL-1β are released extracellularly to further recruit and activate other immune cells. Thus, pyroptosis plays a crucial role in the prevention of the spread of pathogens. The clinically applied synthetic glucocorticoid, hydrocortisone (HC), has strong immunoregulatory properties. It may act as an immunosuppressive agent by negatively regulating pro-inflammatory gene transcription but has also shown immune-sensitizing properties. The conditions that determine the immunosuppressive or immune-sensitizing actions of HC during an infection are not fully clear. We hypothesized that the outcome may differ depending on the onset and duration of its administration. Therefore, we investigated the impact of acute (treatment upon infection) and chronic (24 h pre-treatment before infection) HC treatment on pyroptosis induction and execution in THP-1 macrophage-like cells. The focus was on pyroptosis-associated signaling pathways, inflammasome assembly and activation, IL-1β, and cell death. Physiological HC concentration and HC deprivation were used as controls. Compared to the physiological concentration, cells displayed augmented inflammasome activation and IL-1β release following acute HC treatment. Conversely, the whole pyroptosis machinery was suppressed by chronic HC administration.These in vitro investigations demonstrate pro-inflammatory actions of acute HC exposure and the immunosuppressive effects of chronic treatment. These differential effects on pyroptosis emphasize the importance of individualized HC medication in patients upon infection, and suggest the inclusion of IL-1β as a marker for current immune capacities.

Invasive freshwater snails are less sensitive to population density than native conspecifics.

Understanding how and why some species or lineages become invasive is critically important for effectively predicting and mitigating biological invasions. Here, we address an important unanswered question in invasion biology: do key life-history traits of invasive versus native lineages within a species differ in response to key environmental stressors? We focus on the environmental factor of population density, which is a fundamental characteristic of all populations, and investigate how changes in density affect native versus invasive Potamopyrgus antipodarum (New Zealand mudsnail). P. antipodarum has invaded 39 countries and detrimentally affects invaded environments. Previous studies of native and invasive populations and from laboratory experiments have demonstrated that growth and reproduction of P. antipodarum is sensitive to population density, though whether and how this sensitivity varies across native versus invasive lineages remains uncharacterized. We quantified individual growth rate and reproduction in P. antipodarum from multiple distinct native and invasive lineages across three different population density treatments. The growth of native but not invasive lineages decreased as density increased. There was no differential effect of density treatment on embryo production of invasive versus native snails, but a significantly higher proportion of snails were reproductive in high density compared to intermediate density for invasive lineages. In native lineages, there were no significant differences in the relative frequency of reproductive snails across density treatments. While the extent to which these results from our laboratory study can be extrapolated to the more complex natural world remain unclear, our findings are consistent with a scenario where differential sensitivity to population density could help explain why some lineages become successful invaders. Our findings also align with previous studies that show that invasive P. antipodarum lineages exhibit a relatively wide range of tolerance to environmental stressors.

Differential Psychological Treatment Effects in Patients With Late-Life Depression and a History of Childhood Maltreatment

ObjectiveThis is the first interventional study to assess the impact of childhood maltreatment (CM) on psychological treatment outcomes in patients with late-life depression (LLD). MethodsThis is a secondary analysis of a multicenter, randomized controlled trial with 251 participants aged ≥60 years with moderate to severe depression. Participants were randomly assigned to cognitive behavioral therapy for late life depression (LLD-CBT) or to a supportive intervention (SUI). Treatment outcomes were measured by changes in the Geriatric Depression Scale (GDS). ResultsIn the intention-to-treat sample (n = 229), both LLD-CBT (n = 115) and SUI (n = 114) significantly reduced depressive symptoms in patients with CM, with large effects at post-treatment (d = 0.95 [95% CI: 0.65 to 1.25] in LLD-CBT; d = 0.82 [95% CI: 0.52 to 1.12] in SUI). A significant treatment group*CM interaction (F(1,201.31) = 4.71; p = .031) indicated greater depressive symptom reduction in LLD-CBT compared to SUI at week 5 and post-treatment for patients without CM, but not at 6-month follow-up. Across both treatments, higher severity of the CM subtype ‘physical neglect’ was associated with a smaller depressive symptom reduction (F(1,207.16) = 5.37; p = .021). ConclusionsSpecific and non-specific psychotherapy effectively reduced depressive symptoms in older individuals with depression and early trauma. For patients without early trauma, LLD-CBT may be preferable over SUI. Considering early trauma subtypes may contribute to develop personalized treatment approaches.

Sample size and power calculation for testing treatment effect heterogeneity in cluster randomized crossover designs.

The cluster randomized crossover design has been proposed to improve efficiency over the traditional parallel-arm cluster randomized design. While statistical methods have been developed for designing cluster randomized crossover trials, they have exclusively focused on testing the overall average treatment effect, with little attention to differential treatment effects across subpopulations. Recently, interest has grown in understanding whether treatment effects may vary across pre-specified patient subpopulations, such as those defined by demographic or clinical characteristics. In this article, we consider the two-treatment two-period cluster randomized crossover design under either a cross-sectional or closed-cohort sampling scheme, where it is of interest to detect the heterogeneity of treatment effect via an interaction test. Assuming a patterned correlation structure for both the covariate and the outcome, we derive new sample size formulas for testing the heterogeneity of treatment effect with continuous outcomes based on linear mixed models. Our formulas also address unequal cluster sizes and therefore allow us to analytically assess the impact of unequal cluster sizes on the power of the interaction test in cluster randomized crossover designs. We conduct simulations to confirm the accuracy of the proposed methods, and illustrate their application in two real cluster randomized crossover trials.

Finding the best subgroup with differential treatment effect with multiple outcomes.

Precision medicine aims to identify specific patient subgroups that may benefit the most from a particular treatment than the whole population. Existing definitions for the best subgroup in subgroup analysis are based on a single outcome and do not consider multiple outcomes; specifically, outcomes of different types. In this article, we introduce a definition for the best subgroup under a multiple-outcome setting with continuous, binary, and censored time-to-event outcomes. Our definition provides a trade-off between the subgroup size and the conditional average treatment effects (CATE) in the subgroup with respect to each of the outcomes while taking the relative contribution of the outcomes into account. We conduct simulations to illustrate the proposed definition. By examining the outcomes of urinary tract infection and renal scarring in the RIVUR clinical trial, we identify a subgroup of children that would benefit the most from long-term antimicrobial prophylaxis.

Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype–phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10–3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10–131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype–phenotype screens in diverse populations.

Collaborative inference for treatment effect with distributed data-sharing management in multicenter studies.

Data sharing barriers present paramount challenges arising from multicenter clinical studies where multiple data sources are stored and managed in a distributed fashion at different local study sites. Merging such data sources into a common data storage for a centralized statistical analysis requires a data use agreement, which is often time-consuming. Data merging may become more burdensome when propensity score modeling is involved in the analysis because combining many confounding variables, and systematic incorporation of this additional modeling in a meta-analysis has not been thoroughly investigated in the literature. Motivated from a multicenter clinical trial of basal insulin treatment for reducing the risk of post-transplantation diabetes mellitus, we propose a new inference framework that avoids the merging of subject-level raw data from multiple sites at a centralized facility but needs only the sharing of summary statistics. Unlike the architecture of federated learning, the proposed collaborative inference does not need a center site to combine local results and thus enjoys maximal protection of data privacy and minimal sensitivity to unbalanced data distributions across data sources. We show theoretically and numerically that the new distributed inference approach has little loss of statistical power compared to the centralized method that requires merging the entire data. We present large-sample properties and algorithms for the proposed method. We illustrate its performance by simulation experiments and the motivating example on the differential average treatment effect of basal insulin to lower risk of diabetes among kidney-transplant patients compared to the standard-of-care.

Differential Treatment Effects of Subgroup Analyses in Phase 3 Oncology Trials From 2004 to 2020

Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited. To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials. This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov. Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes. Among 785 trials, 379 studies (48%) enrolling 331 653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P = .006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P = .01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101). In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.

Study of Covariates’ Effects in the Presence of Neighbor Effects : An Informative Review

With reference to a Gauss-Markov Model, Analysis of Covariance (ANCOVA) is a standard exercise in the study of differential treatment effects in the presence of covariates. Again in the presence of ‘Neighbor Effects’, we carry out necessary data analysis in a routine manner. In this paper we present a review of this area of research, encompassing both covariates’ effects and neighbor effects. International Journal of Statistical Sciences, Vol.24(1), March, 2024, pp 65-73

Effects of Tirzepatide Versus Basal Insulins in People With Type 2 Diabetes and Different Baseline Glycemic Patterns: Post Hoc Analyses of the SURPASS-3 and SURPASS-4 Trials.

This post hoc analysis assessed change from baseline to week 52 in glycemic parameters for tirzepatide (5, 10, 15 mg) versus insulin degludec (SURPASS-3 trial) and glargine (SURPASS-4 trial) in people with type 2 diabetes and different baseline glycemic patterns, based on fasting serum glucose (FSG) and postprandial glucose (PPG) values. Participant subgroups with low FSG/low PPG, low FSG/high PPG, high FSG/low PPG, and high FSG/high PPG were defined according to the median values of these measures. All tirzepatide doses and basal insulins were associated with decreased HbA1c, FSG, and PPG values from baseline to week 52 in all subgroups (P < 0.05). Within each subgroup, HbA1c and PPG decreases were greater with tirzepatide than insulin (P < 0.05). FSG decreases were generally similar. There were no differential treatment effects by FSG/PPG subgroup. In this post hoc analysis, tirzepatide was associated with superior glycemic control compared with insulin, irrespective of baseline glycemic pattern.

Effects of acute and chronic methylphenidate on prepulse inhibition: A sex difference study in Wistar rats

BackgroundThe utilization of methylphenidate (MPH) is experiencing a notable surge within the adult population. This growth can be attributed to two key factors: its recreational and cognitive enhancement purposes, as well as the rising prevalence of ADHD diagnoses within this population. This study examined acute and chronic oral MPH effects on attention in male and female Wistar rats. To this end, we used a prepulse inhibition (PPI) task, which is widely used to assess psychoactive drug effects in both humans and rodents. This task allowed us to evaluate changes in attention by analyzing sensorimotor gating associated with stimulus selection process. MethodsAnimals were administered a clinically relevant dose of MPH (5 mg/kg) daily for seven days. The estrous cycle phases of the female rats were measured during behavioral sessions. The PPI task was conducted 20 min after drug administration on day 1 (acute), day 7 (chronic), and 48 h post-treatment. ResultsResults indicated that both acute and chronic MPH treatment impaired PPI expression in male rats, but not in female rats, regardless of their estrous cycle phase. Furthermore, a differential effect of chronic MPH treatment on the PPI task was found in male rats. Specifically, on the seventh treatment day, the PPI effect was observed when animals undertook the PPI task for the first time but was impaired in those animals in which the initial PPI session occurred under the acute influence of the drug (day 1). ConclusionsThese findings suggest that the impact of MPH on sensorimotor gating responses may vary based on sex and task experience, possibly leading to state-dependent effects in healthy individuals.

Abstract P131: Individualized Risk Prediction for Type 2 Diabetes: A Secondary Analysis of the Diabetes Prevention Program

Introduction: Type 2 diabetes (T2D) risk prediction models that predict risk with individualized preventive intervention effects can help targeted prevention. Hypothesis: An individualized T2D risk prediction model developed in the Diabetes Prevention Program (DPP) randomized trial that incorporates differential treatment effects based on an individual’s fasting glucose (FG) level and body mass index (BMI) will provide more accurate predictions than a model without individualized treatment effects. Methods: We included 2640 DPP participants randomized to the placebo, metformin, or lifestyle arms. Using 50% of the DPP sample, we developed a non-individualized Cox model predicting T2D risk over 3 years with adjustment for sex, hemoglobin A1c, triglycerides, FG, BMI, and treatment, and an individualized model with adjustment for these variables plus interactions between treatment and age, FG, and BMI. In the remaining 50%, we evaluated the prediction accuracy of both models using the concordance (C)-statistic. We repeated this process 100 times with different random splits. We externally validated models among Multi-Ethnic Study of Atherosclerosis (MESA) adults with prediabetes (n=1067) where model predictions were computed for each intervention scenario and averaged for all participants. Results: Mean (standard deviation) age of participants was 51 (11) years in the DPP and 64 (10) in MESA, with 67% and 54% women, respectively. Mean C-statistics for our individualized and non-individualized prediction models (100 splits) in DPP were 0.71 and 0.70, respectively (table). The individualized model predicted higher benefit of lifestyle intervention at lower BMI levels and higher benefit of both metformin and lifestyle at higher FG. The C-statistic of the individualized model was 0.78 in the MESA validation. Conclusion: Creating individualized estimates of intervention effects can improve accuracy of T2D risk prediction models, allowing patients to make more informed decisions about prevention strategies.

Absent leptomeningeal collateralization is associated with greatest benefit from mechanical thrombectomy in the 6-24 hour time window.

The impact of leptomeningeal collateralization on the efficacy of mechanical thrombectomy (MT) in patients with anterior circulation large vessel occlusion (aLVO) presenting in the 6-24 h time window remains poorly elucidated. Retrospective multicenter study of aLVO patients presenting between 6 and 24 h after stroke onset who received MT plus Best Medical Treatment (BMT) or BMT alone. Leptomeningeal collateralization was assessed using single-phase computed tomography angiography (grade 0: no filling; grade 1: filling ⩽50%; grade 2: filling >50% but <100%; grade 3: filling 100% of the occluded territory). Inverse probability of treatment weighted ordinal regression was performed to assess the association between treatment and shift of the modified Rankin Scale (mRS) score toward lower categories at 3 months. We used interaction analysis to explore differential treatment effects on functional outcomes (probabilities for each mRS subcategory at 3 months) at different collateral grades. Among 363 included patients, 62% received MT + BMT. Better collateralization was associated with better functional outcomes at 3 months in the BMT alone group (collateral grade 1 vs 0: acOR 5.06, 95% CI 2.33-10.99). MT + BMT was associated with higher odds of favorable functional outcome at 3 months (acOR 1.70, 95% CI 1.11-2.62) which was consistent after adjustment for collateral status (acOR 1.54, 95% CI 1.01-2.35). Regarding treatment effect modification, patients with absent collateralization had higher probabilities for a mRS of 0-4 and a lower mortality at 3 months for the MT + BMT group. In the 6-to-24-h time window, aLVO patients with absent leptomeningeal collateralization benefit most from MT + BMT, indicating potential advantages for this group despite their poorer baseline prognosis.

The effect of cross‐border shopping on commodity tax revenue: results from Norway's COVID‐19 border closings

AbstractWe use grocery data from Norway and COVID‐19 border closings to gauge the effect of cross‐border shopping on commodity tax revenue. Detailed store–category‐level data identify differential treatment effects that depend on distance to Swedish stores. Economically significant effects extend to up to two hours' drive from the border, and even further for prominent cross‐border shopping products, such as beer, cigarettes, and carbonated soft drinks. Across all products, cross‐border shopping decreases tax revenue from VAT by 3.6 percent at the national level. National commodity tax revenue from carbonated soft drinks (subject to a sugar tax) is reduced by 8.1 percent and from cigarettes by 11.9 percent.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60

BackgroundOngoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher...

A Pilot Randomized Controlled Trial of Motivation-Based Social Skills Group Treatment with Parent Training.

Despite the popularity of social skills groups, there remains a need for empirical investigation of treatment effects, especially when targeting pivotal aspects of social functioning such as initiations to peers. The goal of the present study was to conduct a randomized controlled trial of a 12-week social intervention (SUCCESS), which combined an inclusive social group with a parent education program. Twenty-five 4- to 6-year-olds with Autism Spectrum Disorder (ASD) were randomized to SUCCESS (N = 11) or to treatment as usual (N = 14). Combining a peer group model with a parent training program, the SUCCESS intervention used naturalistic behavioral techniques (e.g., environmental arrangement, natural reinforcement) to increase social initiations to peers. After 12 weeks, children participating in the SUCCESS program made more frequent initiations to peers than children in the treatment-as-usual group, including more prompted and unprompted initiations to request. Additional gains in clinician-rated social functioning were observed in children randomized to SUCCESS, while differential treatment effects were not detected in parent-rated measures. However, lower baseline social motivation was associated with greater parent-reported initiation improvement. This study provides preliminary support for the efficacy of a naturalistic, behavioral social skills intervention to improve peer initiations for children with ASD. The findings suggest that using a motivation-based social skills group was effective in increasing both prompted and spontaneous initiations to peers, and highlights the need for further research into the role of baseline social motivation in predicting social skills treatment response.