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Background Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. Methods Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150–200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. Results A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. Conclusions The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM. ClinicalTrials.gov NCT02617589

Aim: To evaluate among multiple myeloma (MM) patients, the proportions with first-line bortezomib/lenalidomide/dexamethasone (VRd) dose modifications and the associated baseline patient characteristics. Patients & methods: Adult MM patients treated with first-line VRd were selected from the Optum claims database. VRd dose modifications were defined based on lenalidomide dose. Results: Among 1497 MM patients, 33% received VRd lite and 22% VRd reduced. Compared with VRd regular, VRd lite usage was more likely to be associated with patients aged ≥75 years and female sex; VRd reduced usage was more likely to be associated with female sex and frailty. Conclusion: A large proportion of MM patients received VRd dose modifications in the real-world, which could potentially result in reduced effectiveness of VRd.

This study was conducted in patients treated for initial venous thromboembolism (VTE) for approximately 6 months to enhance understanding of the risk factors to inform clinical decision-making about long-term anticoagulation therapy. This retrospective cohort study was conducted using a large administrative claims database in the United States. A Cox proportional hazards model was used to examine demographic and clinical characteristics associated with recurrent VTE. A total of 13 831 patients had an index VTE event, and recurrent VTE occurred in 844 (6.1%) of these patients over a median follow-up of 22.8 months. Baseline comorbidities of arrhythmia, congestive heart failure, and chronic kidney disease were significantly associated with recurrent VTE. During the period of anticoagulation treatment after the index VTE, use of antidepressants was associated with an increased risk of recurrent VTE, whereas use of antibiotics and major surgery were associated with a decreased risk. In the 6 months prior to index VTE, anti-inflammatory agents and major surgery were associated with a decreased risk of recurrent VTE. The type of index VTE was also significantly associated with recurrent VTE, with an increased risk observed in patients with pulmonary embolism (PE) alone or PE with deep vein thrombosis (DVT) versus DVT alone. This real-world analysis identified baseline comorbidities, medications, and index VTE type to be factors predictive of recurrent VTE among patients treated for index VTE for approximately 6 months. Consideration of these factors may assist in the identification of patients who may benefit from extended anticoagulant therapy.

In recent years, researchers, pharmaceutical companies, and political makers gradually using more real-world data (RWD) to produce real-world evidence (RWE) for policy-making. A research team of Harvard University launched the RCT DUPLICATE project in 2018, aiming to replicate 30 randomized controlled trials using the medical claims database in order to explore methods for quantifying the efficacy-effectiveness gap and explain its potential sources, to enhance the credibility of the RWE. This paper reviews the background of RCT DUPLICATE Initiative, highlights the research purposes, research design and implementation process of the RCT DUPLICATE Initiative, to help domestic scholars better understand the scope and application value of RWE.近些年，医疗产品监管机构开始重新审视真实世界证据（RWE）对监管决策的潜在价值。RWE能否代替金标准随机对照试验（RCT）产生的证据尚不确定。哈佛大学研究团队于2018年发起了RCT DUPLICATE项目，旨在利用医疗索赔数据库模拟30个RCT，以探索效力-效果差距的量化方法并解释其潜在来源，增强RWE的可信度。本文回顾了RCT DUPLICATE项目的产生背景，重点介绍RCT DUPLICATE项目的研究目的、研究设计和实施流程，以期帮助国内学者更好地理解RWE的适用范围和应用价值。.

With the promotion and application of big medical data, non-interventional real-world evidence (RWE) has been used by regulators to assess the effectiveness of medical products. This paper briefly introduces the latest progress and research results of the RCT DUPLICATE Initiative launched by the research team of Harvard University in 2018 and summarizes relevant research experience based on the characteristics of China's medical service to provide inspiration and reference for domestic scholars to conduct related RWE research in the future.随着医疗大数据的推广与应用，监管机构开始使用非随机化的真实世界证据（RWE）来评估医疗产品的有效性。本文简要介绍了哈佛大学研究团队于2018年发起RCT DUPLICATE项目的最新进展与研究成果，并结合我国医疗服务特点总结了相关研究经验，为国内学者今后开展相关RWE研究提供借鉴。.

Viewing faces that are perceived as emotionally expressive evokes enhanced neural responses in multiple brain regions, a phenomenon thought to depend critically on the amygdala. This emotion-related modulation is evident even in primary visual cortex (V1), providing a potential neural substrate by which emotionally salient stimuli can affect perception. How does emotional valence information, computed in the amygdala, reach V1? Here we use high-resolution functional MRI to investigate the layer profile and retinotopic distribution of neural activity specific to emotional facial expressions. Across three experiments, human participants viewed centrally presented face stimuli varying in emotional expression and performed a gender judgment task. We found that facial valence sensitivity was evident only in superficial cortical layers and was not restricted to the retinotopic location of the stimuli, consistent with diffuse feedback-like projections from the amygdala. Together, our results provide a feedback mechanism by which the amygdala directly modulates activity at the earliest stage of visual processing.

Resting-state functional magnetic resonance imaging (rsfMRI) has shown considerable promise for improving our understanding of brain function and characterizing various mental and cognitive states in the healthy and disordered brain. However, the lack of accurate and precise estimations of comparable functional patterns across datasets, individuals, and ever-changing brain states in a way that captures both individual variation and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses.We posit that using reliable network templates and advanced group-informed network estimation approaches to accurately and precisely obtain individualized (dynamic) networks that retain cross-subject correspondence while maintaining subject-specific information is one potential solution to overcome the aforementioned barrier when considering cross-study comparability, independence of subject-level estimates, the limited data available in single studies, and the low signal-to-noise ratio (SNR) of rsfMRI.Toward this goal, we first obtained a reliable and replicable network template. We combined rsfMRI data of over 100k individuals across private and public datasets and selected around 58k that meet quality control (QC) criteria. We then applied multi-model-order independent component analysis (ICA) and subsampling to obtain reliable canonical intrinsic connectivity networks (ICNs) across multiple spatial scales. The selected ICNs (i.e., network templates) were also successfully replicated by independently analyzing the data that did not pass the QC criteria, highlighting the robustness of our adaptive template to data quality.We next studied the feasibility of estimating the corresponding subject-specific ICNs using a multivariate-spatially constrained ICA as an example of group-informed network estimation approaches. The results highlight that several factors, including ICNs themselves, data length, and spatial resolution, play key roles in successfully estimating the ICNs at the subject level. Large-scale ICNs, in general, require less data to achieve a specific level of spatial similarity with their templates (as well as within- and between-subject spatial similarity). Moreover, increasing data length can reduce an ICN’s subject-level specificity, suggesting longer scans might not always be desirable. We also show spatial smoothing can alter results, and the positive linear relationship we observed between data length and spatial smoothness (we posit that it is at least partially due to averaging over intrinsic dynamics or individual variation) indicates the importance of considering this factor in studies such as those focused on optimizing data length. Finally, the consistency in the spatial similarity between ICNs estimated using the full-length of data and subset of it across different data lengths may suggest that the lower within-subject spatial similarity in shorter data lengths is not necessarily only defined by lower reliability in ICN estimates; rather, it can also be an indication of brain dynamics (i.e., different subsets of data may reflect different ICN dynamics), and as we increase the data length, the result approaches the average (also known as static) ICN pattern, and therefore loses its distinctiveness.

Background There is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings. Methods This retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model. Results A total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients Conclusions The majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.

Background Long-acting injectable (LAI) antipsychotics use is associated with improved adherence which can reduce the rate of relapse, hospitalization, and associated costs in patients with schizophrenia. Young adults could be at higher risk of poor adherence, hence use of LAI in this population may offer a benefit but the evidence is limited. This study aimed to compare clinical and economic outcomes before and after the initiation of LAI antipsychotics in commercially insured young adults (18-35 years of age) with schizophrenia. Methods A retrospective claims data study was conducted using the data from the IBM MarketScan® Commercial Claims and Encounters (CCAE) Database. Patients with a continuous enrollment of at least 1-year before and 1-year after the first observed schizophrenia diagnosis (index date) and with the use of ≥1 typical or atypical LAI antipsychotic during the post-index follow-up period were included. A pre-post analysis was conducted to compare relapse rates, healthcare resource utilization, and costs before (from index date to LAI initiation) and after LAI initiation (to end of follow up). Results A total of 2222 patients who initiated LAIs after an index schizophrenia diagnosis were identified. The per patient per month (PPPM) composite relapse event rate (0.109 pre-LAI to 0.073 post-LAI) and hospitalization rate (0.091 to 0.058), all-cause inpatient visits (0.231 to 0.119), and length of stay (2.694 to 1.092 days) significantly decreased from before LAI initiation to after LAI initiation with similar trends seen for mental health and schizophrenia-related measures (all significant; P P Conclusions Treatment with LAI antipsychotics was associated with a decrease in relapse event rate, healthcare resource utilization, and costs after LAI initiation compared to before LAI initiation in commercially insured young adults with schizophrenia. Treatment with LAIs in young adults with schizophrenia is potentially associated with significant cost savings to commercial payers.

We present the results of a time-coincident event search for low-energy electron antineutrinos in the KamLAND detector with gamma-ray bursts from the Gamma-ray Coordinates Network and Fermi Gamma-ray Burst Monitor. Using a variable coincidence time window of $\pm$500s plus the duration of each gamma-ray burst, no statistically significant excess above background is observed. We place the world's most stringent 90% confidence level upper limit on the electron antineutrino fluence below 17.5 MeV. Assuming a Fermi-Dirac neutrino energy spectrum from the gamma-ray burst source, we use the available redshift data to constrain the electron antineutrino luminosity and effective temperature., 9 pages, 3 figures

Background Social determinants of health (SDH), including food insecurity, are associated with depression in the general population. This study estimated the prevalence of depression and food insecurity and evaluated the impact of food insecurity and other SDH on depression in adults with rheumatoid arthritis (RA). Methods Adults (≥ 18 years) with RA were identified from the 2013–2014 and 2015–2016 National Health and Nutrition Examination Survey (NHANES). Depression was defined as a score of ≥ 5 (mild depression: 5–9; moderate-to-severe depression: 10–27) using the Patient Health Questionnaire-9 (PHQ-9). Food insecurity was assessed with the 18-item US Household Food Security Survey Module. Adults with household-level marginal-to-very-low food security were classified as experiencing food insecurity. The prevalence of depression and food insecurity among participants with RA were estimated. Weighted logistic regression was used to evaluate the association between depression and participants’ characteristics including SDH. Penalized regression was performed to select variables included in the final multivariable logistic regression. Results A total of 251 and 276 participants from the 2013–2014 and the 2015–2016 NHANES, respectively, had self-reported RA. The prevalence of depression among these participants was 37.1% in 2013–2014 and 44.1% in 2015–2016. The prevalence of food insecurity was 33.1% in 2013–2014 and 43.0% in 2015–2016. Food insecurity was associated with higher odds of having depression (OR 2.17, 95% CI 1.27, 3.72), and the association varied by depression severity. Compared with participants with full food security, the odds of having depression was particularly pronounced for those with very low food security (OR 2.96, 95% CI 1.48, 5.90) but was not significantly different for those with marginal or low food security. In the multivariable regression, being female, having fair/poor health condition, any physical disability, and ≥ 4 physical limitations were significantly associated with depression. Conclusions In adults with self-reported RA, the prevalence of depression and food insecurity remained high from 2013 to 2016. We found that depression was associated with SDH such as food insecurity, although the association was not statistically significant once adjusted for behavioral/lifestyle characteristics. These results warrant further investigation into the relationship between depression and SDH among patients with RA.

The COVID-19 pandemic disrupted conventional medical education for surgical trainees with respect to clinical training, didactics, and research. While the effects of the COVID-19 pandemic on surgical trainees were variable, some common themes are identifiable. As hordes of COVID-19 patients entered hospitals, many surgical trainees stepped away from their curricula and were redeployed to other hospital units to care for COVID-19 patients. Moreover, the need for social distancing limited traditional educational activities. Regarding clinical training, some trainees demonstrated reduced case logs and decreased surgical confidence. For residents, fellows, and medical students alike, most didactic education transitioned to virtual platforms, leading to an increase in remote educational resources and an increased emphasis on surgical simulation. Resident research productivity initially declined, although the onset of virtual conferences provided new opportunities for trainees to present their work. Finally, the pandemic was associated with increased anxiety, depression, and substance use for some trainees. Ultimately, we are still growing our understanding of how the COVID-19 pandemic has redefined surgical training and how to best implement the lessons we have learned.

Despite decades of research and the growing emergence of new treatment modalities, Glioblastoma (GBM) frustratingly remains an incurable brain cancer with largely stagnant 5-year survival outcomes of around 5%. Historically, a significant challenge has been the effective delivery of anti-cancer treatment. This review aims to summarize key innovations in the field of medical devices, developed either to improve the delivery of existing treatments, for example that of chemo-radiotherapy, or provide novel treatments using devices, such as sonodynamic therapy, thermotherapy and electric field therapy. It will highlight current as well as emerging device technologies, non-invasive versus invasive approaches, and by doing so provide a detailed summary of evidence from clinical studies and trials undertaken to date. Potential limitations and current challenges are discussed whilst also highlighting the exciting potential of this developing field. It is hoped that this review will serve as a useful primer for clinicians, scientists, and engineers in the field, united by a shared goal to translate medical device innovations to help improve treatment outcomes for patients with this devastating disease.

We present the results of a search for core-collapse supernova neutrinos, using long-term KamLAND data from 2002 March 9 to 2020 April 25. We focus on the electron antineutrinos emitted from supernovae in the energy range of 1.8--111 MeV. Supernovae will make a neutrino event cluster with the duration of $\sim$10 s in the KamLAND data. We find no neutrino clusters and give the upper limit on the supernova rate as to be 0.15 yr$^{-1}$ with a 90% confidence level. The detectable range, which corresponds to a >95% detection probability, is 40--59 kpc and 65--81 kpc for core-collapse supernovae and failed core-collapse supernovae, respectively. This paper proposes to convert the supernova rate obtained by the neutrino observation to the Galactic star formation rate. Assuming a modified Salpeter-type initial mass function, the upper limit on the Galactic star formation rate is, 10 pages, 4 figures, accepted for publication in Astrophysical Journal

8039 Background: VRd (bortezomib/lenalidomide/dexamethasone) has become one of the established treatment regimens in the US for multiple myeloma (MM). Due to toxicities, dose adjustments are often required for VRd. This real-world study described the patient characteristics and factors associated with dose adjustment among MM patients treated with VRd as first line (1L) therapy. Methods: Adult MM patients treated with 1L VRd were selected from the Optum Clinformatics database (Nov 1, 2015-Sep 30, 2020). Patient characteristics were evaluated during a 6-month baseline period. Dose adjustments were defined based on lenalidomide (len) dose received during 1L. Receipt of > 15mg len was categorized as VRd regular, ≤15mg len as VRd lite, and initial len dose > 15mg reduced to ≤15 mg over treatment period as VRd reduced. Baseline factors associated with different VRd dose categories were studied using multinomial logistic regression. Results: Among the 1497 patients identified, the mean (SD) age was 69 (9.5) years (52% ≥70), 51% were male, 59% were White, 37% were frail, and 67% with Medicare. Baseline Charlson Comorbidity Index was 4.2, with hypertension (70%), hyperlipidemia (56%), renal impairment (26%), and CVD (25%) being the most prevalent comorbidities. Over half of the patients received an adjusted dose, VRd lite (33%) and VRd reduced (22%). Overall, for patients treated with 1L VRd, median follow-up was 16.2 months; median duration of 1L was 4.9 months (among those with confirmed end of therapy); and median TTNT was 14.5 months. Compared to VRd regular, use of VRd lite was over 6 times more likely to be associated with patients ≥75 years of age, about 2 times more likely to be associated with females, and about 40% less likely to be associated with commercial insurance vs. Medicare; VRd reduced was 1.3 times more likely to be associated with females, and 1.5 times more likely to be associated with frail patients (table). No differences were observed among different races. Conclusions: Over half of the MM patients treated with 1L VRd in the real-world were > 70 years of age and over one-third were frail. A large proportion of patients received a modified dose of VRd. Receipt of VRd lite dose was highly associated with older age (≥75 years), and receipt of VRd reduced dose was associated with frailty. These dose adjustments may potentially result in reduced efficacy of the VRd regimen in the real-world relative to controlled clinical trials, which needs to be assessed in future studies. [Table: see text]

BackgroundOrelabrutinib is an oral, highly-selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). Orelabrutinib has been approved for the treatment of B cell malignancies in China. Two distinct lupus animal models showed significant efficacy of orelabrutinib in reducing disease activity, which supported the clinical development of orelabrutinib in Systemic Lupus Erythematosus (SLE).ObjectivesThis phase Ib/IIa, randomized, double-blind, placebo-controlled, dose-finding study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy and biomarkers of orelabrutinib in patients with mild to moderate SLE who received standard of care (SoC) therapy.MethodsPatients diagnosed with SLE by the ACR classification criteria for ≥ 6 months, who had a SLEDAI-2K score ≥5 at screening, and were autoantibody-positive, were randomized 1:1:1:1 to receive oral orelabrutinib at 50mg, 80mg, 100mg or placebo once daily for 12 weeks, respectively.ResultsThis study randomized 60 patients with 55 patients who completed 12-week treatment. Age at baseline was 33.7±9.8 years and 96.7% were female. Baseline disease characteristics were generally balanced across treatment groups. Adverse events (AEs) were reported in 80%, 93.3% and 100% of orelabrutinib treated patients at doses of 50mg, 80mg and 100mg QD respectively versus 85.5% in placebo group. AEs were mostly mild or moderate. Treatment-related SAEs were reported in 3 patients treated with orelabrutinib, only 1 of which was grade 3. No deaths were reported. The plasma exposure of orelabrutinib (AUC and Cmax) was proportionally increased with doses. Nearly complete BTK occupancy was achieved at all dose levels, and the occupancy lasted for 24 hours without any decrease compared to that at 4 hour post-dosing. In all evaluable patients, the SLE Response Index (SRI)-4 response rates at week 12 were 50.0%, 61.5% and 64.3% in patients treated with orelabrutinib at 50mg (n=14), 80mg (n=13) and 100mg (n=14) respectively, compared with 35.7% in patients treated with placebo (n=14), which indicated the trend of dose-dependent improvement. Among the subgroup of patients with SLEDAI-2K≥8 at screening, SRI-4 response occurred in 70%, 70% and 66.7% of patients treated with orelabrutinib at 50mg (n=10), 80mg (n=10) and 100mg (n=9), respectively, compared with 30% who received placebo (n=10). Trends of reduced proteinuria, anti-dsDNA and IgG, total B cells and increased complements C4 were also observed following orelabrutinib treatment.ConclusionOrelabrutinib was generally safe and well tolerated in patients with SLE. Preliminary results also suggested encouraging efficacy which supports further development of orelabrutinib in larger and longer trials for SLE.Table 1.Efficacy results at week 12.All Evaluable PatientsPlaceboOrelabrutinibOrelabrutinibOrelabrutinib50 mg80 mg100 mgN=5514141314SRI-4 response, n (%)5 (35.7%)7 (50.0%)8 (61.5%)9 (64.3%)Treatment difference vs. PBO (%)14.3%25.8%28.6%SLEDAI-2K≥8, N=391010109SRI-4 response, n (%)3 (30.0%)7 (70.0%)7 (70.0%)6 (66.7%)Treatment difference vs. PBO (%)40.0%40.0%36.7%Note: All evaluable patients at week 12 efficacy data were included in the efficacy analysis.Figure 1.SRI-4 response rates at week 12.Disclosure of InterestsRu Li: None declared, Xiaoxia Zhu: None declared, Shengyun Liu: None declared, Xiao Zhang: None declared, Changhao Xie: None declared, Zili Fu: None declared, Anbin Huang: None declared, Lingyun Sun: None declared, Dongzhou Liu: None declared, Jinxia Zhao: None declared, Lin Wu: None declared, Zhoushuai Qin Employee of: InnoCare Pharma Limited., Sichen Li Employee of: InnoCare pharma Limited., Yaorong Liu Employee of: InnoCare pharma Limited., Zhanguo Li: None declared