Exploratory Analysis Research Articles

Validity of Ultra-Short-Term Heart Rate Variability Derived from Femoral Arterial Pulse Waveform in a British Military Cohort.

Various non-electrocardiogram (ECG) based methods are considered reliable sources of heart rate variability (HRV) measurement. However, the ultra-short recording of a femoral arterial waveform has never been validated against the gold-standard ECG-based 300s HRV and was the aim of this study.A validity study was conducted using a sample from the first follow-up of the longitudinal ADVANCE study UK. The participants were adult servicemen (n = 100); similar in age, rank, and deployment period (Afghanistan 2003-2014). The femoral arterial waveforms (14s) from the pulse wave velocity (PWV) assessment, and ECG (300s) were recorded at rest in the supine position using the Vicorder™ and Bittium Faros™ devices, respectively, in the same session. HRV analysis was performed using Kubios Premium. Resting heart rate (HR) and root mean square of successive differences (RMSSD) were reported. The Bland-Altman %plots were constructed to explore the PWV-ECG agreement in HRV measurement. A further exploratory analysis was conducted across methods and durations.The participants' mean age was 38.0 ± 5.3 years. Both PWV-derived HR (r = 0.85) and RMSSD (rs=0.84) showed strong correlations with their 300s-ECG counterparts (p < 0.001). Mean HR was significantly higher with ECG than PWV (mean bias: -12.71 ± 7.73%, 95%CI: -14.25%, -11.18%). In contrast, the difference in RMSSD between the two methods was non-significant [mean bias: -2.90 ± 37.82% (95%CI: -10.40%, 4.60%)] indicating good agreement. An exploratory analysis of 14s ECG-vs-300s ECG measurement revealed strong agreement in both RMSSD and HR.The 14s PWV-derived RMSSD strongly agrees with the gold-standard (300s-ECG-based) RMSSD at rest. Conversely, HR appears method sensitive.

Rationale and Design of a Multicenter Trial on Exploratory Analysis of the Effects of Advance Care Planning Guided by the Prediction Program of Heart Failure Prognosis on Quality of Life in Patients With Heart Failure - ACQUAINT-Trial.

Background: Preplanning of care is necessary for patients with endstage heart failure (HF), but advance care planning (ACP) before the loss of a patient's comprehensive capacity is not yet routine for the public or the medical community. The challenge in accurately predicting a patient's prognosis is a strong barrier to implementing ACP. To address this problem, several models for risk stratification have been proposed and are available in clinical settings. Methods and Results: We randomized the procedure to provide estimated patient survival information to attending physicians and then assessed whether there was a change in (1) the frequency of ACP initiation occurred (physician-side evaluation), and/or (2) the patients' quality of life, including mental state (patient-side evaluation). Conclusions: This multicenter, open-label, single-blinded randomized clinical trial aims to assess the hypothesis that providing information on the estimated survival of a patient to the attending physicians will improve the frequency of ACP initiation and quality of life in patients with HF.

Optimal patient selection for yttrium-90 glass plus chemotherapy in the treatment of colorectal liver metastases: additional quality of life, efficacy, and safety analyses from the EPOCH study.

Evaluating transarterial radioembolization (TARE) in patients with metastatic colorectal carcinoma of the liver who have progressed on first-line chemotherapy (EPOCH) demonstrated superior outcomes using yttrium-90 glass microspheres plus chemotherapy (TARE/Chemo) vs chemotherapy (Chemo) to treat colorectal liver metastases. Additional exploratory analyses were undertaken to assess the impact of TARE/Chemo on efficacy, safety, time to subsequent therapy, time to deterioration in quality of life (QoL), and identify criteria for improved patient selection. Time to deterioration in QoL was analyzed for the primary study population. Subsequently, a post hoc analysis was undertaken to identify subgroups for which time to deterioration in QoL was improved with TARE/Chemo vs Chemo. Progression-free survival (PFS), hepatic (h)PFS, time to subsequent therapy, and safety outcomes were compared between treatments. The primary population showed no significant difference in time to deterioration in QoL between treatment arms; however, significance was seen in 2 identified subgroups, namely: Subgroup A (N = 303) which excluded patients with both Eastern Cooperative Oncology Group (ECOG) 1 and baseline CEA ≥ 35ng/mL from both treatment arms; subgroup B (N = 168) additionally excluded patients with KRAS (Kirsten rat sarcoma) mutation. In subgroup A, TARE/Chemo patients (N = 143) demonstrated superior outcomes vs Chemo (N = 160): PFS (9.4 vs. 7.6 months, hazard ratio (HR): 0.64; 1-sided P = .0020), hPFS (10.8 vs. 7.6 months, HR: 0.53; 1-sided P < .0001), time to deterioration in QoL (5.7 vs. 3.9 months, HR: 0.65; 1-sided P = .0063), and time to subsequent therapy (21.2 vs. 10.5 months, HR: 0.52; 1-sided P < .0001). Subgroup B patients showed similar but larger significant differences between treatment arms. Median PFS, hPFS, and time to deterioration in QoL were numerically greater for TARE/Chemo in both subgroups vs the primary population, with the greatest magnitude of difference in subgroup B. Both subgroups exhibited higher percentage of CEA responders and improved ORR with TARE/Chemo vs chemo alone. Safety (reported as event rate/100 patient-years) was higher with Chemo in all populations. Additional efficacy analyses in the primary population are also reported. Careful patient selection, including consideration of the prognostic factors ECOG, baseline CEA, and KRAS status, sets outcome expectations in patients with colorectal liver metastases suitable for TARE/Chemo as second-line treatment (Trial Registry Number: NCT01483027).

The Role of Diet and the Gut Microbiota in Reactive Aggression and Adult ADHD—An Exploratory Analysis

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition, of-ten persistent into adulthood and accompanied by reactive aggression. Associations of diet and the gut-microbiome with ADHD as well as emotional behaviors suggest potential clinical rele-vance of both. However, studies on diet and the gut-microbiome in human reactive aggression are lacking, and should investigate the interaction between diet and the gut-microbiome leading to behavioral changes to assess their potential clinical relevance. In this study, we investigated the interaction of diet and gut-microbiota with adult ADHD and reactive aggression in 77 adults with ADHD and 76 neurotypical individuals. We studied the relationships of ADHD and reactive ag-gression with dietary patterns, bacterial community and taxonomic differences of 16S-sequenced fecal microbiome samples, and potential mediating effects of bacterial genus abundance on signifi-cant diet-behavior associations. The key findings include: (1) An association of high-energy intake with reactive aggeression scores (pFDR = 4.01 × 10−02); (2) Significant associations of several genera with either reactive aggression or ADHD diagnosis with no overlap; and (3) No significant mediation effects of the selected genera on the association of reactive aggression with the high-energy diet. Our results suggest that diet and the microbiome are linked to reactive aggression and/or ADHD individually, and highlight the need to further study the way diet and the gut-microbiome inter-act.

Comparison of internal and external reference populations for occupational cancer surveillance in a cohort drawn from a diverse workforce.

Prior analyses of the Occupational Disease Surveillance System (ODSS) have compared cancer rates using internal referent groups. As an exploratory analysis, we sought to estimate cancer risk using general population reference rates to evaluate the impact that the comparison population has on findings from our surveillance program. A cohort of approximately 2.3 million workers in Ontario, Canada with an accepted lost-time workers' compensation claim were followed for all cancer diagnoses between 1983 and 2018. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated for workers in specific occupational groups using (1) all other workers in the ODSS cohort, and (2) the general population of Ontario. SIRs using the general population reference group were generally equal to or modestly lower compared to SIRs using the internal reference group. Within occupation groups, SIRs had a discordant direction of association (increased rate in the internal comparison and decreased in the external comparison) for some cancer sites including urinary, prostate, and colorectal. Findings emphasize the importance of the choice of reference group when evaluating cancer risks in large occupational surveillance cohorts. Importantly, the magnitude of confounding and the healthy worker hire bias may depend on the occupation group and cancer site of interest.

Effect of Subgroups on Study Outcomes in Unresectable Hepatocellular Carcinoma Undergoing Upfront Systemic Treatment: A Meta-analysis.

Immunotherapy improved the outcome of patients with unresectable hepatocellular carcinoma, but not all studies are in agreement, nor is it clear whether certain subgroups have really benefited. This study aims to perform an updated meta-analysis of trials comparing upfront immunotherapy-based regimens versus tyrosin-kinase inhibitors, and some exploratory analyses. After a systematic review, randomized trials of immunotherapy-based regimens versus tyrosin-kinase inhibitors were selected. A meta-analysis assessed the relationship between treatment arm and overall survival. Based on the resulting heterogeneity, a further investigation of 11 variables by meta-regression and an exploration of subgroups were planned. Eight studies were selected. From the meta-analysis, the overall survival improvement for the immunotherapy-based arms was consistent (HR: 0.77, CI: 0.68-0.88), although heterogeneity between studies was significant (Q=16.37; P=0.0373; I2=51.1%). After meta-regression, the effect of the experimental arm was more pronounced in the elderly and lost among patients with HCV-related liver disease. Subgroups suggested a favorable effect of immunotherapy in patients with HBV-related hepatocellular carcinoma, extrahepatic dissemination, and elevated alpha-fetoprotein. The study results confirm the significant overall survival improvement after immunotherapy-based regimens but suggest different effects on the outcome depending on age, etiology of liver disease, and tumor burden.

Adolescents With a High Burden of New-Onset Mood Symptoms After Sport-Related Concussion Benefit From Prescribed Aerobic Exercise, a Secondary Analysis of 2 Randomized Controlled Trials.

Approximately 20% of students with sport-related concussion (SRC) report new symptoms of anxiety and depression which may be associated with delayed recovery and increased risk for developing a mood disorder. Early prescribed aerobic exercise facilitates recovery in athletes with concussion-related exercise intolerance. We studied the effect of aerobic exercise treatment on new mood symptoms early after SRC. Exploratory secondary analysis of 2 randomized controlled trials (RCT). Sports medicine clinics associated with UB (Buffalo, NY), CHOP (Philadelphia, PA), and Boston Children's Hospital (Boston, MA). Male and female adolescents (aged 13-18 years) diagnosed with SRC (2-10 days since injury). Participants were randomized to individualized targeted heart rate aerobic exercise (n = 102) or to a placebo intervention designed to mimic relative rest (n = 96). Incidence of Persisting Post-Concussive Symptoms (PPCS, symptoms ≥28 days). First RCT recruited from 2016 to 2018 and the second from 2018 to 2020. Of 198 adolescents, 156 (79%) reported a low burden (mean 1.2 ± 1.65/24) while 42 (21%) reported a high burden (mean 9.74 ± 3.70/24) of emotional symptoms before randomization. Intervention hazard ratio for developing PPCS for low burden was 0.767 (95% CI, 0.546-1.079; P = 0.128; β = 0.085) and for high burden was 0.290 (95% CI, 0.123-0.683; P = 0.005; β = 0.732). High burden of mood symptoms early after injury increases risk for PPCS, but the sports medicine model of providing early targeted aerobic exercise treatment reduces it. Nonsports medicine clinicians who treat patients with a high burden of new mood symptoms after concussion should consider prescribing aerobic exercise treatment to reduce the risk of PPCS and a mood disorder.

Conceptualizing Explorative Data Analysis in Applied Statistics

The paper examines the conceptual comprehension of explorative data analysis and its application. The content analysis technique has been deployed and hypothetical examples have been used for explaining its application for the completion of this study. Generally, it is sensible to begin any statistical analysis with an informal, exploratory examination of the data, and this is often called exploratory data analysis (short form EDA). The ingredients of EDA are discussed in this paper and it is suggested that it is important to observe EDA as an integral part of statistical inference, and several examples are presented to show the usages of EDA. Many graphical techniques are used in EDA that discerns what data set can reveal further beyond formal modeling of data or hypothesis testing task. This really enables researcher to gain depth knowledge of the variables in data sets and their relationship. Similarly, the study explores about the stem and leaf display, five number summaries, box and whisker plot and outliers. Stem and leaf display helps in listing data in array and also aids in finding data as minimum and maximum values. Similarly, five number summaries are useful to determine the shape of the distribution. Furthermore, box and whiskers plot visually display data through quartiles or using five number summaries whereas outliers incorporate to uncover the values that lie beyond the whiskers.

Comparative assessment of growth curves in Brazilian white Morada Nova hair sheep breed.

The Morada Nova sheep breed is essential for the economy of the semi-arid region of Northeast Brazil, standing out for its adaptability, resistance to parasites and reproductive ability. However, the white variant is endangered, highlighting the importance of studies on its productivity to support conservation efforts. This study focuses on the growth curve of the Morada Nova sheep breed, using nonlinear models and analyzing flock profiles. Total of 764 observations of 165 animals from four farms in Ceará and Rio Grande do Norte, Brazil, were analyzed. Canonical discriminant analysis (CDA) was used for the exploratory analysis and four nonlinear models were used to study the growth curve. Weight from birth to 270days of age, absolute growth rate (AGR), and the impact of sex on growth curves were assessed. Sex and farm are significant discriminating variables (P < 0.05) for the studied effects (weight and age). Weight was the primary phenotypic biomarker that discriminated between the two indicators, while age was a discriminating indicator only for the core effect. The Gompertz model was the most efficient, presenting the lowest residuals and greatest convergence. The study reveals new information about the growth of Morada Nova sheep, the white variety, including weight differences between the sexes at all analyzed ages and an inflection point before 90days of age. These discoveries contribute to the understanding of the breed's growth and help in the formulation of conservation strategies.

Biochemical and Anthropometric Outcomes in Paediatric Patients with Heterozygous Familial Hypercholesterolemia after COVID-19 Pandemic Lockdowns: An Exploratory Analysis

The COVID-19 pandemic lockdowns affected the lifestyles of children and adolescents, leading to an increase in childhood obesity. Paediatric patients with familial hypercholesterolemia (FH) may be more susceptible to lockdown effects due to their increased cardiovascular risk. However, data are lacking. We investigated the effect of lockdowns on the metabolic profile of paediatric patients with FH. Blood lipids and anthropometry measured in September 2021–April 2022 were retrospectively compared with pre-pandemic values. Thirty participants were included (1–16 years; 57% female). From baseline to post-pandemic, median [P25, P75] blood LDL-C concentration was 125 [112, 150] mg/dL vs. 125 [100, 147] mg/dL (p = 0.894); HDL-C was 58 [52, 65] mg/dL vs. 56 [51, 61] mg/dL (p = 0.107); triglycerides were 64 [44, 86] mg/dL vs. 59 [42, 86] mg/dL (p = 0.178). The BMI z-score did not change significantly (0.19 [−0.58, 0.89] vs. 0.30 [−0.48, 1.10], p = 0.524). The lack of deterioration in metabolic profiles during lockdowns is positive, as some deterioration was expected. We speculate that patients and caregivers were successfully educated about healthy lifestyle and dietary habits. Our results should be interpreted with caution since the study sample was small and heterogeneous. Multicentre research is needed to better understand the impact of lockdowns on this population.

Production factors, regional economic development and agriculture in brazil: A spatial econometrics approach

Agriculture has a great effect on the development process of a region and production land, labor, and technology are determinant factors in its dynamism. This work carries out a spatial analysis for each production factor of Brazilian municipalities in 2006 and 2017 and intends to verify if there are patterns of association and agglomerations. This work is applied research of quantitative and exploratory nature. The Exploratory Analysis of Spatial Data (ESDA) was used to perform spatial analysis for each production factor in Brazilian municipalities in 2006 and 2017 and to check the patterns of association and agglomerations. The main agricultural activities and practice are related to exports as proposed by North. The formation of clusters verified both in the use of the factors of land, labor and technology, and in the value of agricultural production has a polarized role in the Brazilian space, as described by Perroux. This polarization and the formation of clusters expanded at certain points over time, indicating the formation of new links with neighboring municipalities (a la Hirschman). The spatial association pattern was significant in all analyzed variables, with emphasis on the non-physical technology factor, presenting the highest spatial autocorrelation coefficient in both periods analyzed.

Graft Patency and Clinical Outcomes in Patients With Radial Artery Grafts Previously Instrumented for Cardiac Catheterization.

While transradial access is favored for cardiac catheterization, the radial artery (RA) is increasingly preferred for coronary artery bypass grafting. Whether the RA is suitable for use as a graft following instrumentation for transradial access remains uncertain. Consecutive patients from 2015 to 2019 who underwent coronary artery bypass grafting using both the left and right RAs as grafts were included. Instrumented RAs underwent careful preoperative assessment for suitability. The clinical analysis was stratified by whether patients received an instrumented RA graft (instrumented versus noninstrumented groups). Eligible patients with both instrumented and noninstrumented RAs underwent computed tomography coronary angiography to evaluate graft patency. The primary outcome was a within-patient paired analysis of graft patency comparing instrumented to noninstrumented RA grafts. Of the 1123 patients who underwent coronary artery bypass grafting, 294 had both the left and right RAs used as grafts and were included. There were 126 and 168 patients in the instrumented and noninstrumented groups, respectively. Baseline characteristics and perioperative outcomes were comparable. The rate of major adverse cardiac events at 2 years following coronary artery bypass grafting was 2.4% in the instrumented group and 5.4% in the noninstrumented group (hazard ratio, 0.44 [95% CI, 0.12-1.61]; P=0.19). There were 50 patients included in the graft patency analysis. At a median follow-up of 4.3 (interquartile range, 3.7-4.5) years, 40/50 (80%) instrumented and 41/50 (82%) noninstrumented grafts were patent (odds ratio, 0.86 [95% CI, 0.29-2.52]; P>0.99). No significant differences were observed in the luminal diameter or cross-sectional area of the instrumented and noninstrumented RA grafts. There was no evidence found in this study that RA graft patency was affected by prior transradial access, and the use of an instrumented RA was not associated with worse outcomes in the exploratory clinical analysis. Although conduits must be carefully selected, prior transradial access should not be considered an absolute contraindication to the use of the RA as a bypass graft. URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12621000257864.

An exploratory analysis of Early Adopters in education innovations

Purpose The purpose of this study is to gain a better understanding of the conditions and motivations that influence teachers to adopt innovations. Design/methodology/approach Using Diffusion of Innovation theory (Rogers, 2003) and Self-Determination theory (Ryan and Deci, 2017), data from two surveys (n = 568; n = 108) and qualitative follow-up interviews of Early Adopter teachers (n = 16) were triangulated to discern relationships among their identification as Early Adopters, satisfaction of their basic psychological needs (BPN) and their implementation of an educational innovation. Findings Early Adopters had a positive and statistically significant relationship with the implementation of the innovation. Satisfaction of teachers’ BPN had the largest impact on innovation. Research limitations/implications The findings are preliminary and based on a small sample size of teachers. Reliability of the measure of BPN was not as high as the standard, but it did have the largest impact on implementation. Additional studies should explore the connections among Early Adopter teacher motivation, leadership and the satisfaction of their BPN. Practical implications School leaders should leverage the influence of Early Adopters to support innovation, and they should provide additional time, training and resources to supports teachers’ BPN. Originality/value This study examines how to identify and support Early Adopter teachers as enablers of change within schools. We know of no other studies that have used both Diffusion of Innovation theory and Self-Determination theory to understand the motivations of Early Adopter teachers.

Weight, habitual fibre intake, and microbiome composition predict tolerance to fructan supplementation

Fructans are commonly used as dietary fibre supplements for their ability to promote the growth of beneficial gut microbes. However, fructan consumption has been associated with various dosage-dependent side effects. We characterised side effects in an exploratory analysis of a randomised trial in healthy adults (n = 40) who consumed 18 g/day inulin or placebo. We found that individuals weighing more or habitually consuming higher fibre exhibited the best tolerance. Furthermore, we identified associations between gut microbiome composition and host tolerance. Specifically, higher levels of Christensenellaceae R-7 group were associated with gastrointestinal discomfort, and a machine-learning-based approach successfully predicted high levels of flatulence, with [Ruminococcus] torques group and (Oscillospiraceae) UCG-002 sp. identified as key predictive taxa. These data reveal trends that can help guide personalised recommendations for initial inulin dosage. Our results support prior ecological findings indicating that fibre supplementation has the greatest impact on individuals whose baseline fibre intake is lowest.

Somatosensory temporal sensitivity in adults on the autism spectrum: A high-density electrophysiological mapping study using the mismatch negativity (MMN) sensory memory paradigm.

Atypical reactivity to somatosensory inputs is common in autism spectrum disorder and carries considerable impact on downstream social communication and quality of life. While behavioral and survey work have established differences in the perception of somatosensory information, little has been done to elucidate the underlying neurophysiological processes that drive these characteristics. Here, we implemented a duration-based somatosensory mismatch negativity (MMN) paradigm to examine the role of temporal sensitivity and sensory memory in the processing of vibrotactile information in autistic (n = 30) and neurotypical (n = 30) adults. To capture the variability in responses between groups across a range of duration discrepancies, we compared the electrophysiological responses to frequent standard vibrations (100 ms) and four infrequent deviant vibrations (115, 130, 145, and 160 ms). The same stimuli were used in a follow-up behavioral task to determine active detection of the infrequent vibrations. We found no differences between the two groups with regard to discrimination between standard and deviant vibrations, demonstrating comparable neurologic and behavioral temporal somatosensory perception. However, exploratory analyses yielded subtle differences in amplitude at the N1 and P220 time points. Together, these results indicate that the temporal mechanisms of somatosensory discrimination are conserved in adults on the autism spectrum, though more general somatosensory processing may be affected. We discuss these findings in the broader context of the MMN literature in autism, as well as the potential role of cortical maturity in somatosensory mechanisms.

The effect of Porter’s competitive forces on competitive advantage and organisational performance and the moderating role of management accounting practices

AbstractThis study examines the effect of the intensity of competitive forces on organisational performance and competitive advantage and the moderating role of the use of traditional and contemporary management accounting practices on this relationship. Using survey data collected from 505 US-based financial managers, the findings indicate that the use of traditional management accounting practices was found to positively moderate the effect of the intensity of competitive forces on competitive advantage. Additional exploratory analysis revealed that the extent of use of contemporary management accounting practices positively moderates the effect of the intensity of competitive forces on organisational performance in a product differentiation/high-force environment. The extent of use of contemporary management accounting practices was also found to positively moderate the effect of the intensity of competitive forces on competitive advantage in a low-cost/high-force. However, the extent of use of contemporary management accounting practices was found to negatively moderate the effect of the intensity of competitive forces on competitive advantage in a product differentiation/low-force environment. Finally, the extent of use of traditional management accounting practices was found to negatively moderate the effect of the intensity of competitive forces on organisational performance in the product differentiation/high-force model. These findings provide a preliminary insight into the important role of management accounting practices in the management of competitive forces.

Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer

BackgroundCervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients.ObjectiveWe investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A).MethodsThis single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes.ResultsAmong the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed.ConclusionHPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies.

Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial.

It remains unclear whether metronomic chemotherapy is superior to conventional chemotherapy when combined with immune checkpoint blockade. Here we performed a phase 2 clinical trial of metronomic chemotherapy combined with PD-1 blockade to compare the efficacy of combined conventional chemotherapy and PD-1 blockade using Bayesian adaptive randomization and efficacy monitoring. Eligible patients had metastatic HER2-negative breast cancer and had not received more than one prior line of standard chemotherapy. Patients (total n = 97) were randomized to receive (1) metronomic vinorelbine (NVB) monotherapy (n = 11), (2) NVB plus anti-PD-1 toripalimab (n = 7), (3) anti-angiogenic bevacizumab, NVB and toripalimab (n = 27), (4) conventional cisplatin, NVB and toripalimab (n = 26), or (5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (the VEX cohort) (n = 26). The primary endpoint was disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety. The study met the primary endpoint. The VEX (69.7%) and cisplatin (73.7%) cohorts had the highest DCR. The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. In general, the five regimens were well tolerated, with nausea and neutropenia being the most common adverse events. An exploratory mass cytometry analysis indicated that metronomic VEX chemotherapy reprograms the systemic immune response. Together, the clinical and translational data of this study indicate that metronomic VEX chemotherapy combined with PD-1 blockade can be a treatment option in patients with breast cancer. ClinicalTrials.gov Identifier: NCT04389073 .

Prevention of Post COVID-19 Condition by Early Treatment with Ensitrelvir in the Phase 3 SCORPIO-SR Trial

This exploratory analysis of the double-blind, phase 3, SCORPIO-SR trial assessed the effect of ensitrelvir in preventing post coronavirus disease 2019 (COVID-19) condition (PCC). Patients with mild-to-moderate COVID-19 were randomized (1:1:1) within 120 hours of symptom onset; received 5-day oral ensitrelvir 125 mg (375 mg on day 1), 250 mg (750 mg on day 1), or a matching placebo once daily; and were assessed for the severity of typical PCC symptoms using a self-administered questionnaire. In total, 341, 317, and 333 patients were assessed in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively (mean age, 35.6–36.5 years; men, 53.3%–58.3%). On days 85, 169, and 337, ensitrelvir 125-mg treatment showed 32.7% (95% confidence interval [CI]: -30.6, 66.1), 21.5% (95% CI: -37.3, 55.6), and 24.6% (95% CI: -43.7, 60.9) reductions versus placebo, respectively, in the risk of any of the 14 acute-phase COVID-19 symptoms (at least one mild, moderate, or severe symptom with general health not returning to the usual level). Ensitrelvir 250-mg treatment showed 10.9% (95% CI: -67.0, 52.8), 9.5% (95% CI: -56.6, 48.0), and 30.6% (95% CI: -36.2, 65.5) risk reductions versus placebo on days 85, 169, and 337, respectively. Risk reductions were observed in any of the 4 neurological symptoms and were more pronounced among patients with high acute-phase symptom scores at baseline and among those with a baseline body mass index ≥25 kg/m2. Ensitrelvir treatment in the acute phase of COVID-19 may reduce the risk of various symptoms associated with PCC. Trial registration numberjRCT2031210350

Revisiting which language declines more in Spanish-English bilinguals with Alzheimer’s disease: Longitudinal decline patterns on the Multilingual Naming Test

Theories of bilingual language production predict that bilinguals with Alzheimer’s disease (AD) should exhibit one of two decline patterns. Either parallel decline of both languages (if decline reflects damage to semantic representations that are accessed by both languages), or asymmetrical decline, with greater decline of the nondominant language (if decline reflects reduced ability to resolve competition from the dominant language with disease progression). Only two previous studies examined decline longitudinally with one showing parallel, and the other asymmetrical, decline. We examined decline over 2-7 years (3.9 on average) in Spanish-English bilinguals (N=23). Logistic regression revealed a parallel decline pattern at one year from baseline, but an asymmetrical decline pattern over the longer decline period, with greater decline of the nondominant language (when calculating predicted probabilities of a correct response). The asymmetrical decline pattern was significantly greater for the nondominant language only when including item-difficulty in the model. Exploratory analyses across dominance groups looking at proportional decline relative to initial naming accuracy further suggested that decline of the nondominant language may be more precipitous if that language was acquired later in life, but the critical interaction needed to support this possibility was not statistically significant in a logistic regression analysis. These results suggest that accessibility of the nondominant language may initially be more resilient in early versus more advanced AD, and that AD affects shared semantic representations before executive control declines to a point where the ability to name pictures in single-language testing block is disrupted. Additional work is needed to determine if asymmetrical decline patterns are magnified by late age of acquisition of the nondominant language, and if more subtle impairments to executive control underlie impairments to language switching that occur in the earliest stages of AD (even preclinically).