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Strategic investment(s) in vehicle automation technologies led to the rapid development of technology that revolutionised transport services and reduced fatalities on a scale never seen before. Technological advancements and their integration in Connected Autonomous Vehicles (CAVs) increased uptake and adoption and pushed firmly for the development of highly supportive legal and regulatory and testing environments. However, systemic threats to the security and privacy of technologies and lack of data transparency have created a dynamic threat landscape within which the establishment and verification of security and privacy requirements proved to be an arduous task. In CAVs security and privacy issues can affect the resilience of these systems and hinder the safety of the passengers. Existing research efforts have been placed to investigate the security issues in CAVs and propose solutions across the whole spectrum of cyber resilience. This paper examines the state-of-the-art in security and privacy solutions for CAVs. It investigates their integration challenges, drawbacks and efficiencies when coupled with distributed technologies such as Blockchain. It has also listed different cyber-attacks being investigated while designing security and privacy mechanism for CAVs.

Many corporate tax practitioners are familiar with Code Sec. 338 , (1) which permits a purchasing corporation to elect asset acquisition treatment with respect to certain purchases of target corporation [...]

•In the context of our recent conference, INSPIRED (Insights in Pediatric CAR T-cell Immunotherapy: Recent Advances and Future Directions), we reviewed published chimeric antigen receptor (CAR) T cell therapy (CAR-T) trials and consortium/collaborative outcomes to establish variables associated with optimal response to this therapy in pediatric patients with B cell acute lymphoblastic leukemia (B-ALL).•Key factors associated with increased risk of CAR-T failure include high bone marrow disease burden, prior blinatumomab nonresponse, active non-central nervous system extramedullary disease, and subthreshold fludarabine exposure.•Ongoing data collection from patients receiving commercial and investigational CAR-T products and collaboration among different groups is critical to advancing outcomes in children and young adults with B-ALL.

ABSTRACTThe neighboring cities of El Paso, USA and Juárez, Mexico share a 440-year history. In the almost 100 years since radio came to both cities, listeners have found their favorite stations with little regard for which side of the Rio Grande in which it is licensed. This article starts with how radio developed in the region, a court case that set a US precedent, and the use of early Mexican stations to reach immigrants in the US. It then looks at the contemporary situation where cross-border targeted stations balance US and Mexican regulations. It will be shown that border agnostic listening continues. It also considers how recent changes would allow a Mexican firm to own U.S. stations and a U.S. firm to own Mexican stations.

No TV station today would send a crew to a news conference with a 16 mm film camera. Today's radio reporter would think you were crazy if issued a reel-to-reel [...]

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.

•Currently, patients receive a single dose of tisagenlecleucel across a wide dose range.•Clinicians could choose to give a higher dose of tisagenlecleucel upfront, within the approved dose range, to optimize response.

Poor graft function (PGF) is a life-threatening complication after allogeneic stem cell transplantation (alloSCT). Historically, outcomes of patients with PGF have been very poor, and there are no standardized approaches to treatment. Furthermore, few outcomes after CD34-selected stem cell boost (CD34+SCB) for PGF in pediatric alloSCT recipients have been reported. Here we report on a single center experience with CD34+SCB for PGF after alloSCT in patients treated on the Pediatric Transplant and Cellular Therapy Service at MSK Kids, Memorial Sloan Kettering Cancer Center. A retrospective analysis of patients transplanted for malignant and nonmalignant disorders who received a CD34+SCB between 2008 to 2020 for treatment of PGF defined as the need for granulocyte colony-stimulating factor (G-CSF) and/or packed red blood cell or platelet transfusion support with bone marrow donor chimerism ≥85%. Peripheral blood stem cells from the original donor were the source for CD34+SCB. Durable complete recovery (durable CR) was defined as recovery of peripheral blood counts without recurrent need for G-CSF or transfusion support. The main outcomes of interest were recovery of hematopoiesis and overall survival. Development of graft versus host disease (GVHD) was an additional outcome of interest. Fourteen patients with PGF received a boost. Six patients had no known infection, while 8 patients had PGF associated with an infection. The probability of CR at 60 days was 79% (95% confidence interval [CI], 57%-100%). The overall survival at both 2 and 5 years was 78% (95% CI, 56%-100%). One patient developed GVHD, which was fatal. No other CD34+SCB-related toxicities were observed. While including patients with PGF as recently defined by the American Society for Transplantation and Cellular Therapy, as well as PGF in patients with concomitant infections, we demonstrate that CD34+SCB is safe and can provide for durable trilineage hematopoietic recovery and long-term survival in pediatric patients after alloSCT.

The only curative approach for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising in patients with Fanconi anemia (FA) is allogeneic hematopoietic stem cell transplantation (HCT); however, HCT approaches are inconsistent and limited data on outcomes exist. We retrospectively evaluated outcomes of thirty patients with FA and MDS/AML who underwent first allogeneic HCT with a T-cell depleted (TCD) graft at our institution. Patients were transplanted on successive protocols with stepwise changes in cytoreduction and GVHD prophylaxis. All but two patients (93%) experienced durable hematopoietic engraftment. With median follow-up of 8.7 years, 5-year OS was 66.8% and DFS 53.8%. No significant differences in survival were found in patients with high-risk prognostic features (age ≥20 years, AML diagnosis, alternative donor graft) or when stratified by conditioning regimen. The 5-year cumulative incidences of relapse and NRM were 24.3% and 21.9%, respectively. NRM was higher in patients ≥20 years at HCT but did not otherwise differ. We herein demonstrate promising outcomes following allogeneic HCT for patients with FA and MDS/AML using TCD grafts, particularly in a cohort of high-risk patients with 50% ≥20 years and a majority receiving mismatched grafts. Future prospective studies are needed to compare this approach with other HCT platforms.

Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children <3 years of age were excluded from licensing studies. We retrospectively evaluated data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n = 14). Sixty-four percent of patients (n = 9) achieved minimal residual disease-negative remission after CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.

The buzz around IoT has been palpable for several years and the potential of the technology is undeniable. A variety of devices are now being connected to the internet from [...]

Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range, <1-25 years), and in the non-CNS EM cohort it was 13 years (range, 2-26 years). In patients with CNS disease, 88% (35 of 40) achieved a complete response vs only 66% (10 of 15) with non-CNS EM disease. Patients with CNS disease (both with and without BM involvement) had 24-month OS outcomes comparable to those of non-CNS EM or BM only (P = .41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM-only patients (P = .92). No increased toxicity was seen with CNS or non-CNS EM disease (P = .3). Active CNS disease at time of infusion did not affect outcomes. Isolated CNS disease trended toward improved OS compared with combined CNS and BM (P = .12). R/R EM disease can be effectively treated with tisagenlecleucel; toxicity, relapse, and survival rates are comparable to those of patients with BM-only disease. Outcomes for isolated CNS relapse are encouraging.

Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell–depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.

Augmenting the cytotoxic potential of natural killer (NK) cells through the expression of a chimeric antigen receptor (CAR) promises to overcome many of the limitations of CAR-modified T cells, notably T cell-associated toxicities and difficulties with off-the-shelf allogeneic use. However, to date, the clinical efficacy of CAR-modified NK cells has been limited to CD19-expressing B cell malignancies. Toward translating this success to myeloid malignancies, we report the generation and optimization of membrane-proximal CD33-targeted CAR-modified NK cells produced by gammaretroviral transduction of peripheral blood-derived primary NK cells. The CD33-targeted CD28/CD3ζ-based CAR is derived from a high-affinity binder obtained through membrane-proximal fragment immunization, and it has demonstrated superior preclinical functionality compared to the current best-in-class CAR T cell binders that target membrane-distal CD33 epitopes with high affinity or membrane-proximal epitopes with low affinity.

We recently showed in a large pediatric tri-institutional cohort of patients receiving a first allogeneic hematopoietic cell transplantation (allo-HCT) for a hematologic malignancy, that, in addition to recovery of CD4 > 50 cells/uL, also recovery of B cells > 25 cells/uL was found to be a predictor for outcomes. The impact of B cell immune reconstitution (IR) in a purely ex vivoT-cell depleted (TCD) setting has not been described.

Acute Graft-versus-Host Disease (aGvHD) is a potentially life-threatening complication following hematopoietic cell transplantation (HCT). Early CD4+ T-cell reconstitution (>50 cells/microliter) is associated with improved survival for moderate to severe (grade 2-4) aGvHD, but the underlying mechanisms remain unclear. CD4+ regulatory T cells (Tregs) play a key role in maintaining immune tolerance and regulating immune reactions. Here, we explored potential associations between Treg frequencies (Treg/CD4 ratio) and 90-day onset of aGvHD in pediatric and young adult HCT recipients.

Recent thymic emigrants (RTEs) are immature naïve T cells originating in the thymus, crucial for immune reconstitution after hematopoietic cell transplantation (HCT). Thymic damage may delay or permanently impair immune reconstitution. This study investigates variables influencing RTE reconstitution after HCT, aiming to identify factors essential for de novo immune reconstitution.

Hematotoxicity is the most frequent grade ≥3 toxicity following chimeric antigen receptor (CAR) T therapy. The CAR-HEMATOTOX score has been validated for prediction of post-CAR T hematotoxicity in adults with lymphoma, but risk factors in children and young adults (CAYA) with B-ALL are not well-defined.

Tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel) are approved CD19 CAR T products for adolescents and young adults (AYAs) with r/r B-ALL. These products have not previously been compared, yet overlap in age range presents a choice in therapy for AYAs. We describe real world efficacy and safety in AYAs with r/r B-ALL receiving tisa-cel or brexu-cel.

Network Proxies and Virtual Private Networks (VPN) are tools that are used every day to facilitate various business functions. However, they have gained popularity amongst unintended userbases as tools that can be used to hide mask identities while using websites and web-services. Anonymising Proxies and/or VPNs act as an intermediary between a user and a web server with a Proxy and/or VPN IP address taking the place of the user’s IP address that is forwarded to the web server. This paper presents computational models based on intelligent machine learning techniques to address the limitations currently experienced by unauthorised user detection systems. A model to detect usage of anonymising proxies was developed using a Multi-layered perceptron neural network that was trained using data found in the Transmission Control Protocol (TCP) header of captured network packets

The detection of unauthorised users can be problematic for techniques that are available at present if the nefarious actors are using identity hiding tools such as anonymising proxies or Virtual Private Networks (VPNs). This work presents computational models to address the limitations currently experienced in detecting VPN traffic. The experiments conducted to classify OpenVPN usage found that the Neural Network was able to correctly identify the VPN traffic with an overall accuracy of 93.71%. These results demonstrate a significant advancement in the detection of unauthorised user access with evidence showing that there could be further advances for research in this field particularly in the application of business security where the detection of VPN usage is important to an organization.

The limited liability company (LLC) has become an important component of federal and state tax planning for many U.S. companies. Converting a state law corporation to an LLC may cause [...]

How many times does your radio station run a liner that says, 'Find us on the app,' or 'Listen on your computer at work'? Now, how often have you put [...]

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post–CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post–CAR T progression. Thirty patients (79%) received salvage treatment of post–CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post–CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.

The integrity of wireless networks that make up the clear majority of IoT networks lack the inherent security of their wired counterparts. With the growth of the internet of things (IoT) and its pervasive nature in the modern home environment, it has caused a spike in security concerns over how the network infrastructure handles, transmits, and stores data. New wireless attacks such as KeySniffer and other attacks of this type cannot be tracked by traditional solutions. Therefore, this study investigates if wireless spectrum frequency monitoring using interference analysis tools can aid in the monitoring of device signals within a home IoT network. This could be used enhance the security compliance guidelines set forth by OWASP and NIST for these network types and the devices associated. Active and passive network scanning tools are used to provide analysis of device vulnerability and as comparison for device discovery purposes. The work shows the advantages and disadvantages of this signal pattern testing technique compared to traditional network scanning methods. The authors demonstrate how RF spectrum analysis is an effective way of monitoring network traffic over the air waves but also possesses limitations in that knowledge is needed to decipher these patterns. This article demonstrates alternative methods of interference analysis detection.

A company organized under the laws of a foreign country that does not conduct business in the United States still may be "relevant" for purposes of U.S. taxation. Therefore, it [...]

Whether it was CONELRAD, the Emergency Broadcast System or today's Emergency Alert System, broadcasters have been tasked with responsibility for mass notification for 66 years. You can count me among [...]

SURFACE-MOUNT ADHESIVE (SMA) Used in both wave and reflow soldering processes to maintain component positioning on the PCB, the SMA's greatest challenge is to survive the thermal shock of transitioning [...]

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.

Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell immune reconstitution (IR; CD4+ IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+ IR, defined as ≥50 CD4+ T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+ IR within 100 days after HCT was 30% vs 80% (P = .02) at UMC/PMC and 5% vs 67% (P = .02) at MSK. This was associated with lower OS without CD4+ IR (UMC/PMC, 61% vs 20%; P = .04; MSK, 75% vs 33%; P = .12). Inadequate CD4+ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P < .001) and inferior OS (24% vs 78%; P < .001). In this retrospective analysis, we demonstrate that early CD4+ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.

Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+T-cell immune reconstitution (IR; CD4+IR) predicts survival after HCT. Here, we studied the relation between CD4+IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+IR, defined as ≥50 CD4+T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+IR within 100 days after HCT was 30% vs 80% (P= .02) at UMC/PMC and 5% vs 67% (P= .02) at MSK. This was associated with lower OS without CD4+IR (UMC/PMC, 61% vs 20%; P= .04; MSK, 75% vs 33%; P= .12). Inadequate CD4+IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P< .001) and inferior OS (24% vs 78%; P< .001). In this retrospective analysis, we demonstrate that early CD4+IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.

For as long as there has been broadcasting, the North American nations of Canada, the United States and Mexico have closely guarded their domestic radio and, later, television, industries. The [...]

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.

To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1–20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0–37%), 20% (95% CI: 0–40%), and 80% (95% CI: 60–100%), respectively. Severe toxicity following CAR T cells did not impact OS (p= 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n= 9) vs unmodified (n= 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0–49%) vs 0% (p= 0.14), 0% vs 50% [95% CI: 10–90%] (p= 0.02) and 100% vs 50% [95% CI: 10–90%] (p= 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.

The detection of unauthorized users can be problematic for techniques that are available at present if the nefarious actors are using identity hiding tools such as anonymising proxies or virtual private networks (VPNs). This work presents computational models to address the limitations currently experienced in detecting VPN traffic. A model to detect usage of VPNs was developed using a multi-layered perceptron neural network that was trained using flow statistics data found in the transmission control protocol (TCP) header of captured network packets. Validation testing showed that the presented models are capable of classifying network traffic in a binary manner as direct (originating directly from a user's own device) or indirect (makes use of identity and location hiding features of VPNs) with high degrees of accuracy. The experiments conducted to classify OpenVPN usage found that the neural network was able to correctly identify the VPN traffic with an overall accuracy of 93.71%. The further work done to classify Stunnel OpenVPN usage found that the Neural Network was able to correctly identify VPN traffic with an overall accuracy of 97.82% accuracy when using 10-fold cross validation. This final experiment also provided an observation of 3 different validation techniques and the different accuracy results obtained. These results demonstrate a significant advancement in the detection of unauthorised user access with evidence showing that there could be further advances for research in this field particularly in the application of business security where the detection of VPN usage is important to an organization.

The authors implement common attacks on a DNS server and demonstrate that DNSSEC is an effective solution to counter DNS security flaws. This research demonstrates how to counter the zone transfer attack via the generation of DNSSEC keys on the name servers which prevent attackers from obtaining a full zone transfer as its request for the transfer without the keys was denied by the primary server. This article also provides a detailed scenario of how DNSSEC can be used as a mechanism to protect against the attack if an attacker tried to perform Cache Poisoning. The authors ultimately show that a DNSSEC server will not accept responses from unauthorised entities and would only accept responses which are authenticated throughout the DNSSEC chain of trust.

The article to assesses whether it may be possible to recommend a solution to enable automation of the process of detection and fault management of common conclusive loss-of-connectivity last-mile outages, within the access network. To ascertain the utility of the research, UK based MPLS VPN managed service providers, their fault management staff and their business customers, were surveyed using online questionnaires for their views. UK public Internet users were additionally surveyed via five UK Internet forums. UK communication providers offering MPLS VPN solutions were characterised. Access network connectivity technologies and fault management functions were compared, contrasted and analysed. An aspiration for the solution to be beneficial to the largest potential population, meant that current non-proprietary Internet Standard technologies were selected, justified and identified which could be recommended for use. It was found that of the participating survey respondents, two-thirds were in favour of automation. Many current communication provider processes were found to be mostly automated. The article concludes with recommendations of how an automated solution could potentially be enabled. This involves further use of business-to-business interfacing between communication providers, automation of their Fault Management Systems and introducing Bi-Directional forwarding for detection between last-mile active network elements.

Anti-thymocyte globulin (ATG) is used in the conditioning for pediatric hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure (GF). Toxicity includes poor T-cell recovery, associated with viral reactivations and higher mortality. The PARACHUTE-trial1(non-randomized prospective trial investigating model-based dosing [MBD] compared to historical fixed dose of ATG Thymoglobulin) showed that MBD of ATG improves T-cell recovery compared to fixed dosing, while maintaining an anti-GvHD effect. We now evaluated outcome after 5-year follow-up combined with real-world data.

Ex vivoCD34-selected allo-HCT is associated with favorable CRFS but limited by delayed immune reconstitution (IR) and in some trials higher non-relapse mortality (NRM) (BMT CTN 1301, JCO 2023). We recently reported that the use of traditional weight-based ATG dosing in this setting led to high post-HCT ATG pharmacokinetic (PK) exposure that was associated with delayed CD4+ T cell IR (CD4+IR) and increased NRM risk (Lakkaraja et al., Blood Adv 2022).

•Routine bone marrow aspirates after alloHCT assessed for minimal residual disease by multiparameter flow cytometry and/or level of donor chimerism are poor predictors for relapse in pediatric and young adult patients with leukemia or MDS.•The median time between MFC-MRDnegrBMA and relapse in these patients was 4.6 months.•Complete blood count every 1 to 4 weeks after alloHCT may suffice for monitoring as relapse most frequently presents with peripheral blood blasts and/or cytopenias.•Absolute Neutrophil Count and platelet count at 1-year were highly predictive of disease-free survival (DFS).