Search

As an increasing number of people with disabilities become pregnant and give birth, understanding their vulnerabilities for poor mental health and life stress can help to improve their health and well-being. We examined whether people with disabilities are more likely to experience stressful life events 12 months before childbirth, postpartum depressive symptoms (PDS), and lack of postpartum partner and social support, and compared these associations by race/ethnicity.Using the Massachusetts Pregnancy Risk Assessment Monitoring System 2016-2020 data (n = 6,483), we used univariate and multivariable logistic regression models to estimate the associations of disability with stressful life events, PDS, and postpartum partner and social support, and calculated risk ratio (RR), adjusted RR, and 95% confidence interval (CI). We also conducted stratified analyses by race/ethnicity.The prevalence of disability was 10.7% overall, and 8.8% among White non-Hispanic people, 14.3% among Black non-Hispanic people, 15.5% among Hispanic people, and 8.3% among Asian non-Hispanic people. Compared with people without disabilities, those with disabilities were more likely to report emotional stress (RR, 1.54; 95% CI, 1.36-1.74), partner-related stress (RR, 2.55; 95% CI, 2.23-2.91), financial stress (RR, 1.55; 95% CI, 1.44-1.68), traumatic stress (RR, 2.27; 95% CI, 1.85-2.79), and PDS (RR, 3.77; 95% CI, 3.13-4.53). People with disabilities were also more likely to lack a partner's emotional support (RR, 2.57; 95% CI, 2.21-2.97), financial support from the newborn's father (RR, 2.89; 95% CI, 2.39-3.51), and social support while feeling tired or frustrated (RR, 2.05; 95% CI, 1.68-2.52). These associations remained statistically significant after adjustment for maternal factors and newborn's birth year. Strong associations of disability with stressful life events (including emotional stress and partner-related stress), PDS, lacking partner's emotional support, and social support existed across racial/ethnic groups.Pregnant people with disabilities may benefit from additional screening for stressful life events and depression during pregnancy and postpartum. Multidisciplinary efforts that combine mental health screening and treatment, peer support groups, increased health care provider training about caring for people with disabilities during pregnancy and better access to care for pregnant people with disabilities are needed to improve their health and support their desire to become parents.

OBJECTIVES: This study examined the performance of a group of adult cochlear implant (CI) candidates (CIC) on visual tasks of verbal learning and memory. Pre-operative verbal learning and memory abilities of the CIC group were compared with a group of older normal-hearing (ONH) control participants. Relations between pre-operative verbal learning and memory measures and speech recognition outcomes after 6 months of CI use were also investigated for a subgroup of the CICs. DESIGN: A group of 80 older adult participants completed a visually presented multi-trial free recall task. Measures of word recall, repetition learning, and the use of self-generated organizational strategies were collected from a group of 49 CICs, prior to cochlear implantation, and a group of 31 ONH controls. Speech recognition outcomes were also collected from a subgroup of 32 of the CIC participants who returned for testing six months after CI activation. RESULTS: CICs demonstrated poorer verbal learning performance compared to the group of ONH control participants. Among the pre-operative verbal learning and memory measures, repetition learning slope and measures of self-generated organizational clustering strategies were the strongest predictors of post-CI speech recognition outcomes. CONCLUSIONS: Older adult CI candidates present with verbal learning and memory deficits compared to older adults without hearing loss, even on visual tasks that are independent from the direct effects of audibility. Pre-operative verbal learning and memory processes reflecting repetition learning and self-generated organizational strategies in free recall were associated with speech recognition outcomes six months after implantation. The pattern of results suggests that visual measures of verbal learning may be a useful predictor of outcomes in post-lingual adult CICs.

Wastewater-based epidemiology is an effective tool for monitoring infectious disease spread or illicit drug use within communities. At the Ohio State University, we conducted a SARS-CoV-2 wastewater surveillance program in the 2020-2021 academic year and compared results with the university-required weekly COVID-19 saliva testing to monitor COVID-19 infection prevalence in the on-campus residential communities. The objectives of the study were to rapidly track trends in the wastewater SARS-CoV-2 gene concentrations, analyze the relationship between case numbers and wastewater signals when adjusted using human fecal viral indicator concentrations (PMMoV, crAssphage) in wastewater, and investigate the relationship of the SARS-CoV-2 gene concentrations with wastewater parameters. SARS-CoV-2 nucleocapsid and envelope (N1, N2, and E) gene concentrations, determined with reverse transcription droplet digital PCR, were used to track SARS-CoV-2 viral loads in dormitory wastewater once a week at 6 sampling sites across the campus during the fall semester in 2020. During the following spring semester, research was focused on SARS-CoV2 N2 gene concentrations at 5 sites sampled twice a week. Spearman correlations both with and without adjusting using human fecal viral indicators showed a significant correlation (p 0.05) between human COVID-19 positive case counts and wastewater SARS-CoV-2 gene concentrations. Spearman correlations showed significant relationships between N1 gene concentrations and both TSS and turbidity, and between E gene concentrations and both pH and turbidity. These results suggest that wastewater signal increases with the census of infected individuals, in which the majority are asymptomatic, with a statistically significant (p-value0.05) temporal correlation. The study design can be utilized as a platform for rapid trend tracking of SARS-CoV-2 variants and other diseases circulating in various communities.

BackgroundNexImmune is developing highly differentiated immunotherapies to target, activate and expand tumor antigen-specific T cells using the proprietary Artificial Immune Modulation (AIM™) nanotechnology platform. The AIM nanoparticle (AIM-np) technology functions as synthetic dendritic cells capable of directing a specific T cell-mediated immune response. By mimicking natural T cell biology, NexImmune’s non-genetically engineered cellular therapy product candidates (AIM ACT) are designed to combine the attributes of cellular precision, potency, and persistence with reduced potential for undesired toxicities.MethodsHere we present an example of AIM ACT expanded MART-1 specific T cells and their phenotypic and functional characterization in vitro and in vivo. Leukopaks from healthy donors were used to produce AIM ACT T cell products with our proprietary AIM ACT enrichment and expansion (E+E) manufacturing process and antigen peptide-loaded AIM-nanoparticles.ResultsThe final MART1 T cell products include up to 62.8% (20.8% in average) MART-1-specific CD8+ T cells as determined by MART1 peptide (ELAGIGILTV)-loaded multimer staining. MART1-specific T cells were tested in flow cytometry-based and live cell imaging-based cytotoxicity assays using HLA-A2 positive MART1 peptide-loaded target cells. The AIM ACT-generated T cells showed potent cytotoxicity to MART1 peptide-loaded target cells in vitro, while unloaded control cells were not killed. In over 30 independent AIM ACT E+E clinical scale runs, the expanded T cells consisted of a combined average of 91.7% T stem cell like, central and effector memory T cells, as determined by CD62L, CD45RA and CD95 staining. These phenotypes have been associated with long term in vivo persistence and anti-tumor efficacy. In a human melanoma PDX model, we confirmed that transfusion of AIM ACT T cells resulted in long term survival in vivo and significant reduction of tumor growth with complete tumor clearance in 6 out of 15 animals.ConclusionsThe results demonstrate that AIM ACT MART1 T cells have long term persistence and anti-tumor activity in solid tumors such as melanoma, and that the AIM ACT E+E approach is a reproducible clinical scale manufacturing process for non-genetically engineered antigen-specific T cells. The AIM ACT platform is currently being used for generating T cell products for our current clinical trials, NEXI-001 (NCT04284228) and NEXI-002 (NCT04505813), and our pre-clinical development for HPV-associated malignancies. The findings support initiating Phase I trials of adoptive T cell therapy in solid tumors.Ethics ApprovalThe study was approved by the Institutional Animal Care and Use Committee (IACUC).

Introduction Seasonal influenza infects millions annually in Europe. Annual influenza vaccination is the most effective measure to reduce the risk of infection and its complications, especially among young children and older adults. Objective We assessed adverse event (AE) frequency after receiving GSK’s inactivated quadrivalent seasonal influenza vaccine (IIV4). Methods A passive enhanced safety surveillance study was conducted in Belgium, Germany, and Spain. Adults who had received GSK's IIV4 or the parent(s)/guardian(s)/legally acceptable representative(s) of children given the vaccine were invited to complete an adverse drug reaction (ADR) card to document AEs experienced within 7 days post vaccination. Results A total of 1082 participants (51.6% females) received GSK's IIV4, including 115 children 65 years (31.6%). After dose 2, 7.8% reported one or more AE, and GDASC was again the most frequent AE category. There were no serious AEs related to GSK's IIV4 within 7 days post vaccination. Conclusion No serious AEs related to GSK’s IIV4 within 7 days post vaccination were reported. This study supports the favourable risk–benefit safety profile of GSK’s IIV4. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01121-8., Plain Language Summary Seasonal influenza infects millions annually in Europe, especially young children and older adults. Annual influenza vaccination is the most effective measure to reduce the risk of infection and its complications. As the wild influenza virus strains change every year, the composition of the influenza vaccine changes as well. Since the vaccine is produced in the same way over the years, extensive safety studies are no longer required by regulatory authorities. Instead, monitoring of any unwanted medical incidents (adverse events) after vaccination is required. For the 2019/2020 season, we monitored the adverse events reported by a representative sample of people in Belgium, Germany, and Spain within 7 days after receiving GSK's seasonal influenza vaccine. Of the 1082 people who received the first dose of the vaccine, 39% reported at least one adverse event, such as pain and swelling at the injection site, tiredness, fever, headache, or dizziness. A total of 115 children under 9 years of age received two doses 4 weeks apart. After their second dose, few of these children (8%) reported adverse events. The most frequent adverse events were fever, swelling and pain at the injection site, runny nose, or irritability. No serious adverse events were reported after either the first or second dose. No serious adverse events related to GSK’s seasonal influenza vaccine within the 7 days after vaccination were reported. This study supports the favourable risk–benefit safety profile of GSK's seasonal influenza vaccine. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01121-8.

This paper presents Metrinome, a tool for performing automatic path complexity analysis of C functions. The path complexity of a function is an expression that describes the number of paths through the function up to a given execution depth. Metrinome constructs the control flow graph (CFG) of a C function using LLVM utilities, analyzes that CFG using algebraic graph theory and analytic combinatorics, and produces a closed-form expression for the path complexity as well as the asymptotic path complexity of the function. Our experiments show that path complexity predicts the growth rate of the number of execution paths that Klee, a popular symbolic execution tool, is able to cover within a given exploration depth. Metrinome is open-source, available as a Docker image for immediate use, and all of our experiments and data are available in our repository and included in our Docker image.

Summary: Patients with chronic kidney disease (CKD) and end-stage renal disease experience high pain and symptom burden, but management of chronic pain in this population remains challenging. Recent studies have shown a high rate of opioid prescription and use in patients with kidney disease. However, the concern for opioid-related morbidity and mortality suggests a need to reconsider the safety and efficacy of opioid use in patients with CKD. In this review, we describe the current approaches to pain management in CKD, highlight the evolving opioid-related risks and kidney-specific concerns, and offer both pharmacologic and nonpharmacologic nonopioid strategies for pain management in patients with kidney disease, emphasizing the importance of using a multimodal approach to optimize pain control.

本研究目的在檢視臺北市國小資源班學生個別化教育計畫設計與執行情形。由研究者與五名評定者以自編之「個別化教育計畫評鑑檢核表」評鑑72 名資源班學生103 與104 學年度之IEP。主要發現有： 1.85% 以上之IEP 均能具備特教法令規範之基本要項，且與學生之需求達到適配性。 2. 兩年度之IEP 設計與執行情形較理想之向度為「行政管理與執行」。待改善之處包括評量記錄多為一年以上的資料；較少敘明學生所需之教學和評量調整內容；部分學習領域之學習節數無法與學年教育目標配合；教育目標之可測量性/ 可觀察性、類化性、可行性等待改善；相關專業服務、行為功能介入方案說明不完整，且轉銜服務多以六年級學生為主。 The main purpose of this study was to evaluate the contents and qualities of Individualized Educational Plans (IEPs) of elementary students with disabilities in Taipei City. The researcher and five co-raters employed a self-designed “IEP Evaluation Checklist” to analyze students’ IEPs from 2014 to 2015, covering 72 elementary students with disabilities who had participated in resource programs. The main findings are as follows. 1. About 85% of “IEP-required content” met the requirements of the related special education laws and matched students’ special needs. 2. The best area of quality rating from 2014 to 2015 was “administrative management and execution”. The area needing improvement included stated assessment records of more than one year. However, there lacked adaptations of instructional designs and assessments. Moreover, the number of lessons of some areas/subjects provided did not match annual education goals; the qualities of the observability, generalization, and accessibility of goals/ objectives were in need of improvement; the contents of related services and behavior intervention programs of IEPs were not stated clearly; and IEPs were mainly developed for the 6 graders with transition needs.

ImportancePreliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described.ObjectiveTo provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients.DesignObservational, retrospective study.SettingAdmitted to hospital between February 27 and April 15, 2020.ParticipantsPatients aged ≥18 years with laboratory confirmed COVID-19ExposuresAKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline).Main Outcomes and MeasuresFrequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation.ResultsA total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test.Conclusions and RelevanceAKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.Key PointsQuestionWhat is incidence and outcomes of acute kidney injury (AKI) in patients hospitalized with COVID-19?FindingsIn this observational study of 3,235 hospitalized patients with COVID-19 in New York City, AKI occurred in 46% of patients and 20% of those patients required dialysis. AKI was associated with increased mortality. 44% of patients discharged alive had residual acute kidney disease. A machine learned predictive model using baseline features for dialysis requirement had an AUC Of 0.79.MeaningAKI was common in patients with COVID-19, associated with increased mortality, and nearly half of patients had acute kidney disease on discharge.

Patients with chronic kidney disease (CKD) experience a high pain and symptom burden. Concurrently, opioid prescription and use in patients with CKD continues to increase, leading to concern for opioid-related risks. Nephrologists increasingly face challenging clinical situations requiring further evaluation and treatment of pain, for which opioid use may be indicated. However, nephrologists are not commonly trained in pain management and may find it difficult to compile the necessary information and tools to effectively assess and treat potentially multidimensional pain. In these situations, they may benefit from using an evidence-based stepwise approach proposed in this article. We address current approaches to opioid use for pain management in CKD and offer a stepwise approach to individualized opioid assessment, focusing on kidney-specific concerns. This includes thorough evaluation of the pain experience, opioid use history, and treatment goals. We subsequently discuss considerations when initiating opioid therapy, strategies to reduce opioid-related risks, and recommended best practices for opioid stewardship in CKD. Using this sequential approach to opioid management, nephrologists can thereby gain a broad overview of key patient considerations, the foundation for understanding implications of opioid use, and a patient-tailored plan for opioid therapy.

The NEXI-002 study is a prospective, multicenter, open-label phase 1/2 trial designed to characterize the safety, immunologic, and preliminary anti-myeloma activity of the NEXI-002 antigen specific CD8+ T cell product. Multiple myeloma (MM) is an incurable malignancy that occurs predominantly in older patients and is characterized by the growth of malignant plasma cells in the bone marrow. Despite substantial advances in therapy, virtually all patients relapse after treatment, emphasizing the unmet medical need for additional effective treatments. The NEXI-002 product is an autologous non-genetically engineered therapy of CD8+ T cells that recognize HLA 02.01-restricted peptides from the WT1, CD138, CS1, and NY-ESO-1 antigens. This T-cell product includes key memory phenotypes such as stem-like memory, central memory, and effector memory cells. Eligible patients have relapsed or refractory multiple myeloma (RRMM) who have received at least three prior lines of treatment that included at least an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 agent. Three patients were enrolled into the Safety Evaluation phase and received a single infusion of 80 million (M) to 100M cells of NEXI-002 product. In this phase of the study the primary endpoint is safety and secondary endpoints include expansion, persistence, and trafficking of the NEXI-002 cells. Bridging anti-MM treatment was permitted during the manufacture of the cellular product with a wash-out period of at least 14 days prior to lymphodepletion (LD) chemotherapy (intravenous fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2), which was administered on Days -5, -4, and -3 prior to the infusion of the NEXI-002 product up to 72 hours later (Day1). Treatment-related adverse events, including infusion reactions, events that prolong hospitalization post infusion, CRS, and neurotoxicity (ICANS) have not developed in these patients who received the NEXI-002 product. Lymphocyte recovery to baseline levels occurred within a few days after the infusion of the NEXI-002 product, demonstrating robust CD4 and CD8 T cell reconstitution following LD chemotherapy. NEXI-002 antigen specific T cells were detected in peripheral blood (PB) by multimer staining and proliferated over time and trafficked to the bone marrow (BM). The phenotype composition of detectable antigen specific T cells at both sites maintained that of the infused product. These NEXI-002 T cells persisted in PB and BM during follow-up. T-cell receptor (TCR) sequencing assays revealed T cell clones in the NEXI-002 product that were not detected in PB of patients tested at baseline. These clones subsequently expanded and persisted over time in the PB and BM. In conclusion, these results show that infusion of the NEXI-002 product is safe, well tolerated, and capable of generating a cell-mediated immune response that may lead to clinical activity. RNA Seq transcriptional profiling of the CD8+ T cells is planned. Additional patients have recently received NEXI-002 infusions and the trial will continue to be expanded to gain additional safety, immunologic, and clinical activity experience. Disclosures Knight: Neximmune, Inc: Current Employment. Varela: Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Speakers Bureau. Edavana: Neximmune, Inc: Current Employment. Lu: Neximmune, Inc: Current Employment. Kim: Neximmune, Inc: Current Employment. Suarez: Neximmune, Inc: Current Employment. Oelke: Neximmune, Inc: Current Employment. Bednarik: Neximmune, Inc: Current Employment.

Patients who relapse after allogeneic HCT have a poor prognosis and few effective treatment options. Responses to salvage therapy with donor lymphocyte infusions (DLI) are driven by a graft versus leukemia (GvL) effect. However, relapses and moderate to severe graft versus host disease (GVHD) are common. Therapies that increase the GvL effect without inducing GVHD are needed. The NEXI-001 study is a prospective, multicenter, open-label phase 1/2 trial designed to characterize the safety, immunogenic, and antitumor activity of the NEXI-001 antigen specific T-cell product. This product is a donor-derived non-genetically engineered therapy that consists of populations of CD8+ T cells that recognize HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. These T cells consist of populations with key memory phenotypes, including stem-like memory, central memory, and effector memory cells, with a low proportion ( In conclusion, these results show that infusion of the NEXI-001 product is safe and capable of generating a cell-mediated immune response with early signs of clinical activity. A second infusion is associated with increasing the level of antigen specific CD8+ T cells and their persistence in PB and BM. TCR sequencing and RNA Seq transcriptional profiling of the CD8+ T cells are planned, and these data will be available for presentation during the ASH conference. At least two cycles of 200M NEXI-001 cells weekly x 3 weeks of a 4-week cycle is planned for the next dose-escalation cohort. Early data suggest that the NEXI-001 product has the potential to enhance a GvL effect with minimal GVHD-associated toxicities. Disclosures Al Malki: Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Modi: MorphoSys: Membership on an entity's Board of Directors or advisory committees; Seagen: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Perales: Sellas Life Sciences: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Merck: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; MorphoSys: Honoraria; Kite/Gilead: Honoraria, Other; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medigene: Honoraria; NexImmune: Honoraria; Cidara: Honoraria; Nektar Therapeutics: Honoraria, Other; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other. Edavana: Neximmune, Inc: Current Employment. Lu: Neximmune, Inc: Current Employment. Kim: Neximmune, Inc: Current Employment. Suarez: Neximmune, Inc: Current Employment. Oelke: Neximmune, Inc: Current Employment. Bednarik: Neximmune, Inc: Current Employment. Knight: Neximmune, Inc: Current Employment. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Relapse after allo-HSCT is the leading cause of death in patients with AML. While donor lymphocyte infusions (DLI) achieve modest graft-versus-leukemia (GVL) effects in a small group of responders, responses are often accompanied by significant morbidity and mortality from graft-versus host disease (GVHD). Therefore, there is a significant need for cellular approaches that enhance the benefit of GVL while decoupling toxicities associated with GVHD. Herein, we report initial results from a first-in-human study of a non-genetically engineered adoptive cellular therapy product, NEXI-001, which contains populations of anti-leukemia antigen-specific CD8+ T cells. NEXI-001is generated using a novel technology platform referred to as Artificial Immune Modulation (AIM). Specifically, nano-artificial Antigen Presenting Cells are used in combination with a proprietary cellular expansion system to isolate and expand populations of CD8+ T cells that recognize five specific HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens, each of which is commonly over-expressed on AML blasts and leukemic stem cells. The ability to direct T cells against multiple leukemic antigens may reduce potential for tumor escape via target down-regulation. The AIM manufacturing process is optimized to consistently produce cellular products that contain T cell subtypes which combine anti-tumor potency with long-term persistence. Each NEXI-001 product is comprised of >95% memory T cells, and include stem-like central memory (Tscm), central memory (Tcm) and effector memory (Tem) cells - those T cell subtypes with potential to provide long lasting GVL effects. Importantly, each product also contains very low proportions of naïve T cells with allo-reactive potential (Tn), which may further reduce the risk of GVHD. (Table 1) Patients underwent bridging therapy to control leukemic burden while NEXI-001 T cells were manufactured for 14 days. After a 14-day wash out period, lymphodepleting therapy (fludarabine 30mg/m2, Cytoxan 300mg/m2 D-5 to D-3) was given followed by two rest days before NEXI-001 cell infusion. Dose levels for Phase 1 patients enrolled include safety D-1 (50 million T cells, n=1); followed by two additional dose-escalating safety cohorts {100 million T cells (n=3); and 200 million T cells, (n=3)}, and expansion cohort (n=16). A total of 7 AML patients (median age 43) with HLA-02:01 who had relapsed after allo-HSCT have been enrolled to-date. The same HLA-matched donor PBMCs are used for NEXI-001 manufacturing. Median time from previous SCT to relapse was 10 months, median bone marrow blast at relapse was 9%. and all patients were determined as poor risk category. To-date, there have been no infusion reactions, CRS or ICANS events observed for any patient treated. Significantly, there is no evidence of GVHD in any patient (n=3). Analysis of primary end point demonstrates a safe and well tolerated profile. Analyses of secondary end points support early signs of clinical response. We observed early and significant in vivo T cell proliferation as early as Day 5 (Figure 1). This may suggest that NEXI- T cells are actively engaging leukemic targets. Multimer staining confirmed the presence of NEXI-001 T cells in peripheral blood (Figure 2). Uniquely, the CD8+ T cells in peripheral blood maintain the phenotype subsets of the infused product over all time points measured (Figure 3). Despite complete lymphodepletion, CD4 reconstitution is robust, earlier than expected and consistent with increased levels of IL2. Evidence of cytotoxic activity, likely mediated by CD8+ T cells, was evident with increased serum levels of IFNg, TNFa, Granzymes A and B, and sFas. Additionally, we observed recruitment and trafficking of CD4 T cells to the bone marrow which may contribute to the initiation of a more robust cell-mediated immune response. Maintaining populations of T-stem cell and T-central memory subtypes may provide marrow-resident effector T cells with a source of continued replenishment over time, providing potential for a durable anti-tumor response. In conclusion, early results suggest that infusion of NEXI-001 product, is safe, well tolerated and capable of generating an early and robust cell-mediated immune response in patients with relapsed AML post allo-HSCT. As a novel cellular therapy, NEXI-001 may have potential to enhance the benefit of GVL while decoupling the toxicities associated with GVHD. Disclosures Al Malki: Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Perales:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Research Funding; Miltenyi Biotec: Research Funding; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Modi:MorphoSys: Membership on an entity's Board of Directors or advisory committees. Vasu:Janssen: Membership on an entity's Board of Directors or advisory committees; Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Omeros: Membership on an entity's Board of Directors or advisory committees. Kim:Neximmune: Current Employment. Wang:Neximmune: Current Employment. Lu:Neximmune: Current Employment. Oelke:Neximmune: Current Employment. Myint:Neximmune: Current Employment, Current equity holder in private company; BMS: Current equity holder in publicly-traded company; Celgene: Ended employment in the past 24 months. Varela:Neximmune: Consultancy, Current equity holder in private company.

Objectives Data on the potential effect of dental cleaning and community water fluoridation (CWF) on pregnancy outcomes are scarce. While numerous studies confirm the cost-effectiveness of fluoride in preventing dental caries, the benefit of CWF during pregnancy has not been well established. Methods This cross-sectional study used data from 2009 to 2016 Massachusetts Pregnancy Risk Assessment Monitoring System and restricted to singleton live births (n = 9234, weighted response rate = 64.3%). Our exposures were: (1) dental cleaning alone during pregnancy; (2) CWF alone; and (3) dental cleaning and CWF combined (DC-CWF). Women without dental cleaning during pregnancy and CWF comprised our reference group. The outcome was preterm birth, (birth < 37 weeks gestation). This study used multivariate logistic regression modeling, controlling for maternal sociodemographic characteristics, previous medical risk and behavioral factors, and calculated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs). Results During 2009-2016, the prevalence of preterm birth among women with a singleton live birth was 8.5% in Massachusetts. Overall, 58.7% of women had dental cleaning during pregnancy, and 63.6% lived in CWF. After adjusting for potential confounders, the associations between dental cleaning alone and preterm birth (aRR = 0.74 [95% CI 0.55-0.98]), and DC-CWF and preterm birth (aRR = 0.74 [95% CI 0.57-0.95]) were significant, while the association between CWF alone and preterm birth was not significant (aRR = 0.81 [95% CI 0.63-1.05]), compared to women without dental cleaning and CWF. Conclusions for Practice This study shows that the prevalence of preterm birth was lower among women with DC only and DC-CWF.

Increasing prostaglandin E2 by knocking out its inhibitor 15-hydroxyprostaglandin dehydrogenase (15-PDGH) or administering a compound that inhibits 15-PDGH was recently found to improve healing in hematopoietic stem cell transplants, colitis recovery, and hepatogenesis after transection in mice. These results are suggestive of pharmacologic therapies or even genetic therapy that could improve patient outcomes, especially since the excess PGE2 and the 15-PDGH inhibitor have proven to be non-toxic. However, elevated levels of PGE2 are associated with increased risk of cancer and blood clotting problems. It would be unacceptable to treat a cancer patient with chemotherapy and replenish the hematopoietic stem cells with the help of PGE2, only to have increased expression of PGE2 and induce another cancer. Therefore, to assess the most therapeutic aspects of PGE2, it is important to consider effects that could induce disease.

Aiming at CMP (Chemical Mechanical Polisher) pad thickness uniformity optimization and pad lifetime extension, we performed optimal design to do experiments finding the optimal process condition. We obtained much longer using time of pad and better pad uniformity on CMP tool from wafer stay time distribution on pad by zone. Base on the results of DOE (Design of Experiment), we get the best setting of stay time ratio by zone for optimal pad thickness uniformity is 18%/ 20% (zone1/ zone10). Also we estimated a mechanism of pad thickness uniformity maintenance after polish in CMP process.

Recognizing the gap between high quality care and the care actually provided, health care providers across the country are under increasing institutional and payer pressures to move towards more high quality care. This pressure is often leveraged through data feedback on provider performance; however, feedback has been shown to have only a variable effect on provider behavior. This study examines the cognitive behavioral factors that influence providers to participate in feedback interventions, and how feedback interventions should be implemented to encourage more provider engagement and participation.

Objectives The aim of this study was to evaluate the in vitro biocompatibility and in vivo osseointegration of three novel bioactive glass fiber reinforced composite (GFRC) implants and to compare these with metal (Ti6Al4V) implants. Methods The surfaces of these experimental substrates were characterized by scanning electron microscopy (SEM), a 2D profilometer and by contact angle measurement. In vitro biological performance was assessed using MG-63 human osteoblast-like cell morphology, cell proliferation assays and the alkaline phosphatase (ALP) activity testing. Furthermore, in vivo osseointegration performance was examined by installing samples into rabbit femurs and evaluated the results using micro-CT, histology and histomorphometrical analysis; these assessments were carried out after 1, 2, 4 and 8 weeks of healing. Results The results showed that moderate surface roughness, moderate hydrophilic exposure and moderate homogenous exposure of bioactive glass fibers were present for all of the GFRC substrates. Furthermore, MG-63 cells, when cultured on all of the GFRC substrates, grew well and exhibited a more differentiated phenotype than cells grown on titanium alloy (Ti6Al4V) substrate. Histological evaluation revealed more newly-formed bone regeneration within the thread of the GFRC implants during the initial healing period. In addition, the novel GFRC implants with a bioactive Bio-fiber structure and glass particles within the epoxy resin matrix showed better bone volume/tissue volume (BV/TV) values at 4 weeks and this was accompanied by bone-implant contact (BIC) values at 8 weeks comparable to the Ti6Al4V group. Significance These findings demonstrated that novel GFRC implants seem to show improved osteogenesis and osseointegration functionality and have potential as a substitute for Ti6Al4V, or other metal-based materials, when used for clinically dental and orthopedic applications.

In this paper, the solution to optimize poly etch condition on different type tool was studied. In this course, we investigated the potentiality of recipe optimization on different type tool by applying an optimal experiment design (OED) to the poly etch step. In our case, the experiments were carried out with four factors/three levels response surface method (RSM). Base on experiences, we select a, b, c, d parameter as four factors to do the design of experiment. After DOE (design of experiment) data analysis, we finally take the process condition of 64/56/130/6.6 (a / b / c / d) as the optimal poly etch condition for the different type tool.

Background: Efficient ex-vivo generation of functional tumor-specific T cells with an optimal memory phenotype remains a significant hurdle to the broad application of adoptive cell transfer (ACT) protocols for the treatment of cancer. Genetically engineered T cells represent a currently available option, but the genetic manipulation of T cells presents significant challenges in terms of manufacturing, cost and addressing tumor escape mechanisms. Here, we describe a novel nanoparticle-based approach for generating tumor-specific T cells at clinical grade and scale from the endogenous T cell repertoire using artificial antigen presenting cells (aAPC). Methods: aAPC consist of a paramagnetic nanoparticle to which humanized HLA-A2-Ig dimer-molecules and anti-CD28 antibodies are covalently linked. aAPC are loaded with multiple HLA-A2 restricted peptides and used to magnetically enrich and expand tumor-specific CD8+ T cells. Using peptide loaded aAPC, a fully enclosed and automated GMP T cell expansion platform has been developed that consistently generates clinically relevant numbers of tumor-specific, T stem cell, central and effector memory CD8+ T cells in 14 days, providing an alternative to genetically manipulated T cells. Results: Starting from a healthy donor leukopak, tumor-specific CD8+ T cells were generated using an aAPC cocktail loaded with 5 HLA-A2 epitopes from AML tumor antigens WT1, PRAME and Cyclin A1. On average, 1-2 x109 T cells were generated that were >90% of the memory phenotype that averaged 18% T stem cells, 40% central memory and 35% effector memory CD8+ T cells. AML-specific T cells were expanded 500 to >5000-fold from low frequency precursor populations. The system has also been used to generate MM specific T cells of the same quality from both from fresh leukopacks and cryopreserved PBL. All generated T cells were fully functional, as demonstrated by intra-cellular cytokine analysis and tumor cell killing. Conclusion: AIM ACT is a novel nanoparticle-based T cell platform developed for the rapid, streamlined generation of clinically-relevant numbers of tumor-specific, T stem cell, central and effector memory CD8+ T cells from donor PBMC in 14 days. The platform described here will be used to generate multi-antigen specific CD8+ T cell products that will be evaluated in multi-center P1/2 clinical trials. These trials will enroll r/r MM patients and r/r AML patients pre- and post-allogeneic hematopoietic stem cell transplant. The flexibility of the AIM ACT system, as shown has potential for clinical evaluation in other hematological tumors and can be used for targeting neo-epitopes. Citation Format: Sojung Kim, Lauren Suarez, Emily Lu, Celine Walmacq, Daniel Dembrow, Juan Varela, Dan Bednárik, Kenneth Carter, Naimish Pandya, Kristi Jones, Mathias Oelke. AIM ACT, a novel nanoparticle-based technology that generates therapeutic numbers of functional tumor-specific CD8+ T cells with T stem cell, central and effector memory phenotype in 14 days [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1423.

This study explores how weight status is related to mental health status among Massachusetts children, aged 10-17 years. We used data from the 2007 National Survey of Children's Health to examine the association between weight status (body mass index-for-age) and parent-reported mental health status among Massachusetts children (N = 827). Multivariable log binomial regression was performed to calculate the adjusted prevalence ratios (aPR) of three mental health outcomes (behavioral, emotional, and social) as related to weight status, after controlling for covariates including physical activity, sex, race/ethnicity, maternal education, poverty status, special health needs, and neighborhood safety. Almost one-third (32.5 %) of Massachusetts children were either overweight or obese. Sex was a significant effect modifier of the association between weight status and negative emotions. After stratifying by sex and controlling for covariates, the relationship between weight status and negative emotions remained significant among girls (aPR = 1.8, 95 % CI 1.3-2.6). Children who did not exercise at all were significantly more likely to exhibit negative behaviors (aPR = 1.3, 95 % CI 1.0-1.6), negative emotions (boys' aPR = 3.3, 95 % CI 1.6-6.9; girls' aPR = 2.6, 95 % CI 1.5-4.5), and fewer social skills (aPR = 1.9, 95 % CI 1.3-2.9) than those who exercised at least 20 min every day of the week. Overweight/obese children, especially girls, were more likely than children of normal weight to have parent-reported negative emotions, suggesting an association between weight status and mental health. Lower levels of physical activity were associated with negative mental health outcomes, supporting the benefits of physical activity for all children.

Purpose The purpose of this study was to examine the prevalence of smoking before, during, and after pregnancy among a representative sample of Massachusetts women with and without disabilities. Methods Data from the 2007 to 2009 Massachusetts Pregnancy Risk Assessment Monitoring System survey were used to estimate the prevalence of smoking by disability status. Main findings Disability prevalence was 4.8% (n = 204) among Massachusetts women giving birth during 2007 through 2009. The prevalence of smoking during the 3 months before pregnancy among women with disabilities was 37.3% (95% CI, 28.3-47.2%) compared with 18.3% (95% CI, 16.6-20.1%) among women without disabilities. Similarly, 25.2% (95% CI, 17.3-35.2%) of women with disabilities, compared with 9.4% of women without disabilities (95% CI, 8.1-10.8%), smoked during the last trimester of their pregnancy, and 32.1% of women with disabilities (95% CI, 23.5-42.1%) compared with 12.5% of women without disabilities (95% CI, 11.1-14.1%), smoked after pregnancy. In the multivariate logistic regression models, women with disabilities had significantly higher risks of smoking before, during and after pregnancy than women without disabilities (adjusted relative risk [aRR], 1.7 [95% CI, 1.2-2.2]; aRR, 1.9 [95% CI, 1.3-2.8]; aRR, 1.8 [95% CI, 1.3-2.5], respectively) while adjusting for race/Hispanic ethnicity, marital status, education, age, household poverty status, and infant's birth year. Implications Women with disabilities are more likely to smoke before, during, and after their pregnancy and less likely to quit smoking during pregnancy. Efforts to integrate and target pregnant women with disabilities in smoking-cessation programs are vital.

Next-generation sequencing results from bead-based aptamer libraries have demonstrated that traditional DNA/RNA alignment software is insufficient. This is particularly true for X-aptamers containing specialty bases (W, X, Y, Z, ...) that are identified by special encoding. Thus, we sought an automated program that uses the inherent design scheme of bead-based X-aptamers to create a hypothetical reference library and Markov modeling techniques to provide improved alignments. Aptaligner provides this feature as well as length error and noise level cutoff features, is parallelized to run on multiple central processing units (cores), and sorts sequences from a single chip into projects and subprojects.

e15001Background: CCAs are often aggressive tumors of the bile duct system with a poor prognosis. Immune cells that infiltrate these tumors might have a prognostic value for patients who have had s...

310 Background: HCC is the sixth most common cancer and the second leading cause of cancer-related death worldwide. Most HCCs develop in severely damaged liver. Methods: The effect of multiple treatment options on liver function (LF) and disease outcome of patients (pts) with HCC (n = 380) were examined retrospectively. Pt LF (Child Pugh score [CPS]) was assessed at time of diagnosis (dx) and then after treatment. Kaplan Meier with log rank and Chi square test was used for comparisons. Results: Our cohort of 380 pts had the following demographics: 74% were male and 26% female; 42% were African American, 26% Caucasian, 13% Asian, and 8% undetermined. The mean age at dx was 62.7 yrs; 17% and 61% of pts were between 40-55 and 56-70 yrs, respectively. Only 2% were below 40 yrs, and 19.6% were above 70 yrs of age. About half of pts smoked (55%) or drank (54%). Regarding viral infection, 17% had Hep B, 52% Hep C, 3% both, and 26% neither. Risky behavior correlated with age of dx: pts aged 56-70 yrs of age had the highest of both (p < 0.05). Cirrhosis and vascular invasion were seen in 66% and 40% of pts, respectively. Stage I/II HCC was seen in 38% and stage III/IV in 68% of pts. Median OS was significantly higher for stage I/II pts (p < 0.001). Pts who had no change or improvement in LF had longer median OS vs. pts who had declining LF (p < 0.001). Considering all treatment scenarios including local and systemic therapy, LF improved in 13%, did not change in 41%, and worsened in 46% of pts. LF decline in pts receiving various treatments was as follows: 53%, sorafenib (SFB); 39%, TACE; 53% radiation; 58% TACE/Y-90/SFB; and 32%, immunotherapy independent of prior treatment. However the degree in LF decline, as dictated by a ΔCPS of > 4, 3 to 4, or 1 to 2 points, did not by itself correlate with significant changes in median OS. Conclusions: The outcome of pts with HCC depends on disease stage and LF. Most pts experience LF decline during treatment. The degree of LF decline is independent of median OS, but maintaining LF is significantly beneficial for OS. Balancing survival benefit with liver toxicities is critical to the successful treatment of pts with advanced HCC.

Objective.Nationally, infertility therapies (IFTs) are increasingly used to overcome fecundity issues. However, it is unclear to what extent noninvasive IFTs are used compared with assisted reproductive technology. To better understand outcomes related to the increasing use of all types of IFTs, we compared self-reported IFT use from a Massachusetts pilot Pregnancy Risk Assessment Monitoring System (MA-PRAMS) to IFT use recorded on birth certificates (BCs).Methods.In 2005, Massachusetts conducted a three-month pilot study modeled after the Centers for Disease Control and Prevention's PRAMS, a population-based surveillance system that monitors pregnancy experiences. Descriptive and bivariate analyses compared responses to MA-PRAMS survey questions regarding IFT use with data collected on BCs from the same women sampled.Results.According to MA-PRAMS, 6.1% of live births were conceived using IFTs compared with 3.1% reported on BCs. Reported IFT use varied by maternal age and plurality. For women aged 18–34 years, IFT use reported on MA-PRAMS (5.0%) was 2.5 times higher than that reported on BCs (2.0%). For women aged 35 years or older, reported IFT use was comparable in both systems. For women giving birth to singletons, IFT use reported on MA-PRAMS (5.5%) was three times higher than that reported on BCs (1.8%).Conclusions.Higher use of IFTs was reported by MA-PRAMS than on BCs, particularly among younger women and those having singleton births. These findings suggest that self-reported IFT use might be a more sensitive method for states to use in assessing population-based IFT usage among women and monitoring trends in adverse birth outcomes.

Objectives— An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action. Methods and Results— We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor–mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor–mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-α or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin. Conclusions— The inhibition of Fc receptor–mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids.

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.