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Radiographic worsening in patients with glioblastoma undergoing treatment may be due to tumor recurrence or treatment effect. The overall prognosis of these patients based on histologic findings at the time of repeat resection is not well established.Patients with glioblastoma at our institution were identified. Patients who only had 1 surgery were excluded. Demographic and clinical data were recorded. The histologic diagnosis at the time of repeat surgery was recorded as either tumor recurrence or pseudoprogression. For this study, pseudoprogression was defined as absence of tumor histologic features and could show coagulative necrosis, reactive gliosis, and/or inflammatory infiltration.A total of 115 patients were identified, 106 with tumor recurrence and 9 with pseudoprogression. The pseudoprogression group had a greater percentage of patients with OIn patients with worsening imaging, the absence of tumor on histologic diagnosis is associated with improved survival from the time of second surgery.

With increased focus on CO2 storage, hydraulic fracturing, and steam injection operations in recent years, understanding of fluid induced seismicity has drawn a lot of attention amongst researchers and practicing engineers. Reactivation of existing dormant faults due to injection operations can lead to flow through or along the fault from the reservoir to undesirable zones. It poses a serious challenge that requires careful study so that measures could be taken to avoid such occurrence. In this paper, a method is presented where geomechanical response is used to compute the slip tendency when the stress changes in a reservoir due to fluid injection. The slip tendency is considered as the main variable to determine whether the fault is reactivated or not. It is computed based on the effective stress normal to the fault surface, and the tangential stress. When the effective stress on a fault surface is reduced due to the increase of pore pressure in grid-blocks adjacent to the fault, it can potentially make the slip tendency exceed the critical limit. In such a case, the transmissibility of grid-blocks on both sides of the fault are increased to allow the fluid to flow into the fault and subsequently along the fault. When the fluid leaks from the reservoir to another zone through the fault, the effective stress on grid-blocks adjacent to the fault increases as the pore pressures in those grid-blocks decrease. This will in turn reduce the slip tendency. Therefore, the transmissibility in this case will also decrease to a value smaller than the one when the fault reactivated. The algorithm allows the fault to be reactivated or deactivated to cope with the pressure change in the reservoir. The slip displacement at the fault is also estimated. The method is implemented in a multidimensional, multiphase flow simulator to demonstrate the advantages of using geomechanics for predicting fault reactivation, which can lead to leakage of fluids from the reservoir to other zones or to the surface. Three examples, two synthetic and one field, are presented to illustrate application of the procedure. The proposed method of fault reactivation modeling is suitable for implementing in any fluid flow simulator with geomechanics capability. It is intended for studying and designing of safe injection strategies that avoid undesirable fault reactivation.

Introduction Insufficient sleep alters emotional processing, leading to impaired recognition and expression of emotions, greater endorsements of punishing behaviors, and withdrawal of compassionate helping. Using data from two national surveys, we investigated whether sleep quality and sleep duration were associated with willingness to donate to local charities, religious institutions, and political parties. Methods We conducted secondary analyses of two independent samples: Wave 5 and Wave 6 of the Baylor Religion Survey (BRS-5 and BRS-6). The BRS-5 included 1,501 participants (2017) and the BRS-6 included 1,248 participants (2021). Both surveys used random address-based sample methodologies to approximate population-representative samples, with stratification weighting targets matching national demographics for age, gender, race/ethnicity, education, and region. Each survey inquired about donations to local charities, religious institutions, and political parties. In addition, the BRS-5 included questions about sleep duration and sleep quality (restedness, sleep onset latency); BRS-6 only included questions about sleep quality. Results In the BRS-5, people were more likely to donate to a local charity and a religious institution if they had better sleep durations (charity: p = .004, OR = 1.39; institution: p = .05, OR: 1.45) and better sleep quality (charity: p = .015, OR=1.18; institution: p = .003, OR: 1.38). Some of these outcomes remained significant after controlling for income, age, gender, and race/ethnicity (e.g., institution donations and sleep quality: p = .026, OR = 1.30; sleep duration: p = .05, OR = 1.48). Similar outcomes emerged in the BRS-6, with better sleep quality being associated with more local charity donations (p < .001, OR=1.33), even after adjusting for income and demographic factors (p = .029, OR=1.19). Sleep measures were not significantly associated with donations to political parties after adjusting for demographic factors. Conclusion Better sleep was associated with a greater likelihood to donate locally. There is likely a bidirectional relationship between sleep outcomes and prosocial behaviors. Support (if any) National Science Foundation (1920730 and 1943323). BRS-5 and BRS-6 were supported by the John Templeton Foundation.

Background We previously conducted a study in primary care practices assessing the impact of an educational session paired with peer comparison feedback on antibiotic prescribing, demonstrating a reduction in overall prescribing for respiratory tract diseases (RTDs). However, the lasting effects of this intervention on antibiotic prescribing patterns without ongoing feedback are unknown. Methods To study the long-term effects of this feedback on antibiotic prescribing, we analyzed prescribing trends for 14 months after the initial study. We collected encounter-level data, including patient and provider information, ICD-10 codes, and antibiotics prescribed. RTDs were grouped into tiers based on prescribing appropriateness: tier 1 (almost always indicated), tier 2 (may be indicated), and tier 3 (rarely indicated). A χ2 test was used to compare proportions of antibiotic prescribing between three time periods: pre-intervention, intervention, and post-intervention (following cessation of provider feedback). A mixed-effects multivariable logistic regression analysis was performed to assess the association between the period and antibiotic prescribing. Results We analyzed 260,900 encounters (127,324 pre-intervention, 58,431 during the intervention, and 75,145 post-intervention) from 28 practices, with patient, provider and practice characteristics in Table 1. Rates of antibiotic prescribing for RTD visits were higher in the post-intervention period than the intervention period (28.9% vs 23.0%, p< 0.001), but remained lower than the 35.2% pre-intervention rate (Figure 1, p< 0.001). In multivariable analyses, the odds of receiving a prescription was higher in the post-intervention compared to the intervention period for tier 2 (OR 1.19, 95% CI 1.10–1.30, p< 0.05) and tier 3 (OR 1.20, 95% CI 1.12–1.30) indications, but was still lower when compared to the pre-intervention period for each tier (OR 0.66, 95% CI 0.59–0.73 for tier 2; OR 0.68, 95% CI 0.61–0.75 for tier 3) (Table 2). Table 1 includes patient, provider, and encounter level demographics. Table 2 includes the results of the multivariable analysis. Figure 1 is a graph of proportion of encounters with an antibiotic prescribed over time. The time period associated with the intervention is highlighted and graphs are separated by tier of appropriateness of antibiotic prescribing associated with the encounter. Conclusion The effects of this targeted educational and feedback program last beyond the intervention period, but without ongoing provider feedback there is a trend toward increased prescribing. Future studies are needed to determine optimal strategies to maintain the efficacy of this intervention. Disclosures Kathleen Degnan, MD, Gilead: Grant/Research Support Michael Z. David, MD PhD, Contrafect: Grant/Research Support|GSK: Advisor/Consultant|Johnson and Johnson: Advisor/Consultant.

Abstract Modified Cam-Clay model is often used for simulation of soft geomaterials such as soil or sand. In this model, Young’s modulus continuously changes via the bulk modulus. Poisson’s ratio can change or be kept constant. If the Poisson’s ratio is kept constant, shear modulus will change with time. If the shear modulus is kept constant, Poisson’s ratio is allowed to change with time. In general, the effective stress tensor at time t+1 can be computed when all state variables at time t are known. The material can be either in elastic or plastic mode depending on the stress state. In the case of plasticity, there are many steps involved to obtain a correct stress so that the equilibrium force balance could be satisfied within a tolerance. In the case of plastic deformation when the stress is out of a yield surface at time t+1, the stress must be brought back to the yield surface. The stress computation procedure during loading and unloading has an important effect on the results of deformation and rebounding after a plastic deformation. In this study a new approach for stress computation during loading and plastic unloading path is introduced. In the new proposed method, the relationship between mean effective stress change and volumetric strain change is used as a parameter to determine the amount of plastic deformation during unloading. The new approach will be appropriate for any case with large residual strain and a proposed exponential parameter (n) will determine based on the value of residual strain. A sensitivity analysis was carried out for different values of the exponential parameter which showed the displacement to be gradually less sensitive when the value of the parameter “n” is 1.003 or higher during the unloading stage. This method was then implemented and successfully tested for a study on matured offshore Malaysian field.

To (a) identify rates of hospital readmission and emergency department (ED) re-presentation for asthma within a 12-month period, (b) estimate the effects of modifiable hospital, general practitioner (GP) and home environmental factors on hospital readmission, ED re-presentations and rescue oral corticosteroid use.We recruited 767 children aged 3-18 years who were admitted to 3 hospitals in Victoria, Australia between 2017 and 2018 with a validated diagnosis of asthma on chart review. Primary outcome was hospital readmission with asthma within 12 months of index admission. Secondary outcomes were ED re-presentation for asthma and rescue oral corticosteroid use. All outcomes were identified through linked administrative datasets. Their caregivers and 277 nominated GPs completed study surveys regarding the home environment and their usual asthma management practices respectively.Within 12 months of an index admission for asthma 263 (34.3%) participants were readmitted to a hospital for asthma, with participants between the ages of 3-5 years accounting for 69.2% of those readmitted. The estimated effect of GP reported guideline discordant care on the odds of readmission was OR 1.57, 95% CI 1.00-2.47,Hospital readmissions among Australian children with asthma are increasing, and linked datasets are important for objectively identifying the health services burden of asthma. They also confirm the important role of the GP in the management of pediatric asthma.

Conventionally, magnetism arises from the strong exchange interaction among the magnetic moments of d- or f-shell electrons. It can also emerge in perfect lattices from nonmagnetic elements, such as that exemplified by the Stoner criterion. Here we report tunable magnetism in suspended rhombohedral-stacked few-layer graphene (r-FLG) devices with flat bands. At small doping levels (

PURPOSE: Prosthetic joint infection (PJI) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) can be a devastating diagnosis. Debridement, antibiotics and implant retention (DAIR) is a preferred treatment modality for acute PJI. A retrospective analysis of infected primary arthroplasties to evaluate the success of DAIR and factors influencing its outcomes. METHODS: We retrospectively reviewed all patients who underwent DAIR for PJI at our unit between 2010 and 2018. Patients who underwent revision surgery as an index procedure, arthroscopic washout and those with less than two years of follow-up were excluded. Treatment failure was defined as revision arthroplasty for recurrence of infection within 2 years of the index procedure. Chi-square and Fischer’s exact test were used to compare between patient factors and DAIR outcomes. Kaplan–Meier survival curve and log-rank test were used to analyse implant survivorship following DAIR. RESULTS: Of the sixty patients (40 knees, 20 hips) who underwent DAIR, eighteen (13 knees, 5 hips) required revision arthroplasty within 2 years accounting for a success rate of 70%. Predictive factors for revision were American Society of Anaesthesiologist (ASA) score of greater than 2 (p = 0.021), BMI > 35 (p = 0.046), C Reactive protein (CRP) > 200 mg/L (p = 0.007) and Staphylococcus aureus growth (p = 0.012). The five-year survival rate for DAIR was 70%, which remained constant after two years from DAIR. CONCLUSION: Success rate of DAIR in PJI was 70% which was comparable to similar studies in the literature. ASA > 2, BMI > 35, CRP > 200 and staphylococcus aureus growth were predictors for DAIR failure. Implant survival rate and duration were better following DAIR in early-onset PJI.

International audience; Rationale: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown.Objectives: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2

Background Liver transplant hepatic venous anastomoses are usually created using “bicaval” or “piggyback” techniques, which may result in unfavorable angulation between the inferior vena cava and hepatic veins, and makes hepatic vein catheterization and tissue sampling during transjugular liver biopsy (TLB) technically challenging. Purpose To compare the technical successes and complications of TLBs for recipients of liver transplants with bicaval and piggyback hepatic vein anastomoses. Material and Methods Information on type of hepatic vein surgical anastomosis was available for 190 adult patients in whom 306 consecutive TLBs were performed during 2009–2017: 158 with bicaval and 148 with piggyback anastomoses. The primary outcome of procedural success was defined as obtaining a tissue sample sufficient to make a pathologic diagnosis. Results A technical success rate of 97% with adequate liver tissue for diagnosis was similar between the anastomotic groups ( P = 0.50). TLB was unsuccessful in 3% of patients with piggyback anastomoses due to unfavorable hepatic venous anatomy whereas biopsy was successful in all patients with bicaval anastomoses ( P = 0.02). Fluoroscopy times were not significantly different (12.1 vs. 13.9 min, P = 0.08). Rates of major complication were similar between the two groups (3% vs. 3%, P > 0.99). Conclusion TLB is safe and effective for liver transplant patients regardless of the type of hepatic vein anastomosis. While failure to catheterize or advance the stiffened biopsy cannula into the hepatic vein is more likely to occur in patients with piggyback anastomoses, this is a rare occurrence.

Laser interstitial thermal therapy (LITT) remains a promising advance in the treatment of primary central nervous system malignancies. As indications for its use continue to expand, there has been growing interest in its ability to induce prolonged blood brain barrier (BBB) permeability through hyperthermia, potentially increasing the effectiveness of current therapeutics including BBB-impermeant agents and immunotherapy platforms. In this review, we highlight the mechanism of hyperthermic BBB disruption and LITT-induced immunogenic cell death in preclinical models and humans. Additionally, we summarize ongoing clinical trials evaluating a combination approach of LITT and immunotherapy, which will likely serve as the basis for future neuro-oncologic treatment paradigms. There is evidence to suggest a highly immunogenic response to laser interstitial thermal therapy through activation of both the innate and adaptive immune response. These mechanisms have been shown to potentiate standard methods of oncologic care. There are only a limited number of clinical trials are ongoing to evaluate the utility of LITT in combination with immunotherapy. LITT continues to be studied as a possible technique to bridge the gap between exciting preclinical results and the limited successes seen in the field of neuro-oncology. Preliminary data suggests a substantial benefit for use of LITT as a combination therapy in several clinical trials. Further investigation is required to determine whether or not this treatment paradigm can translate into long-term durable results for primary intracranial malignancies.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001). Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. See related commentary by Wick and Wagener, p. 1535

BACKGROUND The blood brain barrier (BBB) remains a potential barrier to central nervous system (CNS) penetration of novel immunotherapies in recurrent glioblastoma (rGBM). Laser interstitial thermal therapy (LITT) was recently demonstrated to induce BBB disruption. When combined with anti-PD1 blockade, LITT may therefore potentiate host T-cell mediated cytotoxicity. This phase I/II study aims to evaluate the safety and efficacy of combining LITT and the PD-1 inhibitor pembrolizumab for rGBM. METHODS Phase I treated eligible bevacizumab-naïve high grade glioma patients with LITT and the anti-PD1 inhibitor pembrolizumab at 3 dose levels (100, 150, and 200 mg IV Q3W; 3 patients at each level), while phase II was restricted to rGBM patients only with the recommended phase II dose (RP2D) of pembrolizumab. Phase II was initially designed to randomize rGBM to either pembrolizumab or pembrolizumab+LITT but was later amended to receive only pembrolizumab+LITT after 16 patients were randomized (10 pembrolizumab+LITT arm, 6 pembrolizumab-alone arm). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan Meier method, and adverse events (AE) documented. RESULTS Phase I enrolled 9 patients (7 rGBM and 2 anaplastic astrocytomas, 33% IDH-mut, 44% MGMTp-methylated) with no dose limiting toxicities (DLT), prompting selection of 200mg Q3W as the RP2D. Phase II interim analysis included 34 rGBM patients (9% IDH-mut, 50% MGMTp-methylated; 6 receiving pembrolizumab alone and 28 pembrolizumab+LITT) plus two Phase I rGBM patients who received RP2D. On per-protocol analysis, pembrolizumab+LITT cohort had improved PFS (median PFS 10.5 months vs 2.1 months) and OS (median OS 11.4 months vs 5.2 months) than pembrolizumab alone. A single treatment-related grade 3 AE was noted (respiratory infection). CONCLUSION: LITT may be safely combined with pembrolizumab for rGBM with promising clinical outcomes on interim analysis. Enrollment for Phase II, correlative studies, and continued AE documentation are ongoing. Clinical Trial ID NCT02311582.

BACKGROUND Current liquid-based cancer screening relies on massive deep NGS to detect rare cancer-derived genetic materials - a costly method fraught with high false-negative and false-positive rates. We aim to develop a non-NGS-centered, AI-directed liquid-based detection of GBM stem-like cells (GSCs). METHODS Utilizing a robust AI suite, NETZEN, we defined a common master regulatory gene network (MRGN) of the GBM state in GSCs. Since master regulators (MRs) in MRGN are developmentally restricted, their chromosomal loci are accessible in GSCs but not in normal cells. Downstream factors in MRGN are massively overexpressed in GSCs compared to normal cells. Thus, we measured the following in PBMCs from healthy controls spiked with known quantities of GSCs and patients with GBM: 1) accessibility of MR genes using transposase/transposons carrying unique barcodes to be inserted into the MR’s predetermined accessible locations, and 2) expression of downstream factors using nested qRT-PCR. RESULTS We characterized 10 MRs in GSCs with ≥1 promoter region that is hypomethylated and accessible (by ATACseq) in GBM/GSCs per GSE70175-92460 (19 samples) and GSE67633-96088 (14 samples), or hypermethylated and inaccessible in lymphocytes/PBMCs per GSE98837 (6) and GSE74912 (13). Using barcoded transposons, we specifically disrupted 4 MR’s accessible foci only in GSCs, not in PBMCs. We also identified 50 downstream factors with the top 20 having 3 to 5-orders-of-magnitude higher mean expression in GSCs compared to PBMCs (GSE79362-86884, 451 samples). Currently our method has a detection limit of 0.2-1 GSC per 106 PBMCs. Using the first iteration, we detected MRGN of the GBM state in blood samples of 14 of 14 GBM patients before resection, compared to none of 15 healthy donors. CONCLUSIONS Chromosomal accessibility and signal amplification in MRGN of GSCs provide powerful substrates for a non-NGS, low-cost, liquid-based GBM detection system with high sensitivity and specificity. Further testing and optimization are ongoing.

INTRODUCTION The novel approved GBM treatment TTFields employs alternating, intermediate-frequency (200kHz) electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. Emerging evidence indicates that TTFields may also induce inflammation; however, the mechanism and whether this can be harnessed as cancer immunotherapy remain unclear. METHODS Multiple GBM cell lines were treated with TTFields using Inovitro, an in vitro TTFields system and integrity of the nuclear envelope and content and activation of key DNA sensor inflammatory pathways analyzed by immunostaining, expression profiling, and protein assays. In a syngeneic orthotopic murine model, TTFields-treated GBM cells were used to provide an in-situ vaccination platform. For validation, we performed bulk and single-cell RNAseq of PBMCs from 12 newly diagnosed GBM patients treated with TTFields. RESULTS TTFields induce focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that recruit and intensely activate the 2 major DNA sensors – cGAS and AIM2, and their cognate inflammasomes, thereby releasing pro-inflammatory cytokines and type-1 interferons (T1IFNs) that promote development and maturation of DCs and cytotoxic T cells. In murine model, TTFields-treated GBM cells induce anti-tumor memory immunity both intratumorally and systemically, producing a cure rate of 40% and partial immunity in an additional 25% in a STING- and AIM2-dependent manner. In patients with newly diagnosed GBM patients, we sequenced a total of 193,760 PBMCs and detected robust post-TTFields activation of adaptive immunity via the T1IFN trajectory anchored by plasmacytoid DCs, which was strongly correlated with the TCRαβ clonal expansion index observed in 11 of 12 patients (Spearman coefficient r=-0.8, P=0.014). Importantly, we also defined a T cell-based gene signature predictive of TTFields effects on T cell activation and TCRαβ clonal expansion. CONCLUSION Collectively, these studies define a novel strategy using TTFields to improve immunotherapy in GBM and potentially other solid tumors.

Background The blood-brain barrier (BBB) is a major limiting factor for drug delivery in brain tumors. Laser interstitial thermal therapy (LITT) disrupts the peritumoral BBB. In this study, we examine survival in patients with recurrent glioblastoma (GBM) treated with LITT followed by low-dose doxorubicin, a potent anti-neoplastic drug with poor BBB permeability. Methods Forty-one patients with recurrent GBM were enrolled; thirty patients were evaluable. Participants underwent LITT followed by 6 weekly doxorubicin treatments starting within one week (Early Arm) or at 6–8 weeks (Late Arm) after LITT. The overall survival (OS), local progression-free survival (PFS), and any PFS were compared to historical controls treated with bevacizumab salvage therapy (n = 50) or LITT with standard BBB-permeable salvage therapy (n = 28). Cox proportional-hazards models examined the contribution of age, gender, MGMT promoter status, and IDH-mutation status on any PFS and OS. Adverse events were also cataloged. Results The Late Arm and all patients (Early Arm + Late Arm) demonstrated significant improvement in OS compared to historical controls treated with bevacizumab (p < 0.001) and LITT with standard salvage therapy (p < 0.05). No significant difference in any PFS was observed between either arm and historical controls. Low-dose doxorubicin was well tolerated with comparable adverse event rates between the arms. Conclusions Low-dose doxorubicin given after LITT is well tolerated and correlated with higher OS compared to historical controls treated with bevacizumab or LITT with standard salvage chemotherapy. A larger study is needed to further characterize survival and progression patterns.