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Background Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing.Methods In this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model.Results The combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in αCD19 ‘stealth’ CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFNγ ELISpot assays performed with T cells from patients previously treated with autologous αCD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes.Conclusions Together, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based αCD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients.

Abstract Background Though financial hardship is a well‐documented adverse effect of standard‐of‐care cancer treatment, little is known about out‐of‐pocket costs and their impact on patients participating in cancer clinical trials. This study explored the financial effects of cancer clinical trial participation. Methods This cross‐sectional analysis used survey data collected in December 2022 and May 2023 from individuals with cancer previously served by Patient Advocate Foundation, a nonprofit organization providing social needs navigation and financial assistance to US adults with a chronic illness. Surveys included questions on cancer clinical trial participation, trial‐related financial hardship, and sociodemographic data. Descriptive and bivariate analyses were conducted using Cramer's V to estimate the in‐sample magnitude of association. Associations between trial‐related financial hardship and sociodemographics were estimated using adjusted relative risks (aRR) and corresponding 95% confidence intervals (CI) from modified Poisson regression models with robust standard errors. Results Of 650 survey respondents, 18% (N = 118) reported ever participating in a cancer clinical trial. Of those, 47% (n = 55) reported financial hardship as a result of their trial participation. Respondents reporting trial‐related financial hardship were more often unemployed or disabled (58% vs. 43%; V = 0.15), Medicare enrolled (53% vs. 40%; V = 0.15), and traveled >1 h to their cancer provider (45% vs. 17%; V = 0.33) compared to respondents reporting no hardship. Respondents who experienced trial‐related financial hardship most often reported expenses from travel (reported by 71% of respondents), medical bills (58%), dining out (40%), or housing needs (40%). Modeling results indicated that respondents traveling >1 h vs. ≤30 min to their cancer provider had a 2.2× higher risk of financial hardship, even after adjusting for respondent race, income, employment, and insurance status (aRR = 2.2, 95% CI 1.3–3.8). Most respondents (53%) reported needing $200–$1000 per month to compensate for trial‐related expenses. Over half (51%) of respondents reported less willingness to participate in future clinical trials due to incurred financial hardship. Notably, of patients who did not participate in a cancer clinical trial (n = 532), 13% declined participation due to cost. Conclusion Cancer clinical trial‐related financial hardship, most often stemming from travel expenses, affected almost half of trial‐enrolled patients. Interventions are needed to reduce adverse financial participation effects and potentially improve cancer clinical trial participation.

The COVID-19 pandemic challenged countries to protect their populations from this emerging disease. One aspect of that challenge was to rapidly modify national surveillance systems or create new systems that would effectively detect new cases of COVID-19. Fifty-five countries leveraged past investments in District Health Information Software version 2 (DHIS2) to quickly adapt their national public health surveillance systems for COVID-19 case reporting and response activities. We provide background on DHIS2 and describe case studies from Sierra Leone, Sri Lanka, and Uganda to illustrate how the DHIS2 platform, its community of practice, long-term capacity building, and local autonomy enabled countries to establish an effective COVID-19 response. With these case studies, we provide valuable insights and recommendations for strategies that can be used for national electronic disease surveillance platforms to detect new and emerging pathogens and respond to public health emergencies.

Background: Hispanic/Latina girls have a low prevalence of moderate-intensity physical activity (PA) compared to their male counterparts and non-Hispanic White girls. Mothers influence their children's activity levels by creating and supporting PA opportunities, modeling PA, and reinforcing children's efforts to be physically active. The Conmigo trial will evaluate a mother-daughter intervention to promote PA and examine potential mechanisms of change including mothers' PA, parenting regarding PA, and mother-daughter communication. Method: This randomized controlled trial examines the feasibility, acceptability, and impact of a 12-week intervention promoting PA in preadolescent Latina girls in San Diego County, CA. Participants (n = 90 dyads) are randomized to the Conmigo PA intervention or to a control group that receive an abbreviated version of the intervention. The intervention was informed by Social Cognitive Theory and Family Systems Theory and emphasize family-level factors to promote PA using an actor-partner model. Mothers and daughters attend weekly 90-min sessions in English or in Spanish via Zoom video conferencing, supported by facilitator follow-ups and WhatsApp supportive chat group for mothers. Objective (accelerometer) and self-report measures at baseline, 3 months, and 6 months capture the frequency and intensity of PA and correlates and predictors of PA. We also examine the impact of the intervention on the bidirectional influence of mother-daughter PA. Implications: The findings from the Conmigo trial will form the basis of a randomized controlled community trial and will move the field forward in identifying targets of change in preventing chronic disease risk in Hispanic/Latino communities.

Abstract Background Given the high risk of COVID‐19 mortality, patients with cancer may be vulnerable to fear of COVID‐19, adverse psychological outcomes, and health care delays. Methods This longitudinal study surveyed the pandemic's impact on patients with cancer (N= 1529) receiving Patient Advocate Foundation services during early and later pandemic. Generalized estimating equation with repeated measures was conducted to assess the effect of COVID‐19 on psychological distress. Logistic regression with repeated measures was used to assess the effect of COVID‐19 on any delays in accessing health care (e.g., specialty care doctors, laboratory, or diagnostic testing, etc.). Results Among 1199 respondents, 94% considered themselves high risk for COVID‐19. Respondents with more fear of COVID‐19 had a higher mean psychological distress score (10.21; 95% confidence intervals [CI] 9.38–11.03) compared to respondents with less fear (7.55; 95% CI 6.75–8.36). Additionally, 47% reported delaying care. Respondents with more fear of COVID‐19 had higher percentages of delayed care than those with less (56; 95% CI 39%–72% vs. 44%; 95% CI 28%–61%). These relationships persisted throughout the pandemic. For respondents with a COVID‐19 diagnosis in their household (n = 116), distress scores were similar despite higher delays in care (58% vs. 27%) than those without COVID‐19. Conclusions Fear of COVID‐19 is linked to psychological distress and delays in care among patients with cancer. Furthermore, those who are personally impacted see exacerbated cancer care delays. Timely psychosocial support and health care coordination are critical to meet increased care needs of patients with cancer during the COVID‐19 pandemic.

SARS-CoV-2 seroprevalence surveys provide critical information to assess the burden of COVID-19, describe population immunity, and guide public health strategies. Early in the pandemic, most of these surveys were conducted within high-income countries, leaving significant knowledge gaps in low-and middle-income (LMI) countries. To address this gap, the U.S. Centers for Disease Control and Prevention (CDC) is supporting serosurveys internationally. We conducted a descriptive analysis of international serosurveys supported by CDC during May 12, 2020-February 28, 2022, using an internal tracker including data on the type of assistance provided, study design, population surveyed, laboratory testing performed, and status of implementation. Since the beginning of the pandemic, CDC has supported 72 serosurveys (77 serosurvey rounds) in 35 LMI countries by providing technical assistance (TA) on epidemiologic, statistical, and laboratory methods, financial assistance (FA), or both. Among these serosurvey rounds, the majority (61%) received both TA and FA from CDC, 30% received TA only, 3% received only FA, and 5% were part of informal reviews. Fifty-four percent of these serosurveys target the general population, 13% sample pregnant women, 7% sample healthcare workers, 7% sample other special populations (internally displaced persons, patients, students, and people living with HIV), and 18% assess multiple or other populations. These studies are in different stages of implementation, ranging from protocol development to dissemination of results. They are conducted under the leadership of local governments, who have ownership over the data, in collaboration with international partners. Thirty-four surveys rounds have completed data collection. CDC TA and FA of SARS-CoV-2 seroprevalence surveys will enhance the knowledge of the COVID-19 pandemic in almost three dozen LMI countries. Support for these surveys should account for current limitations with interpreting results, focusing efforts on prospective cohorts, identifying, and forecasting disease patterns over time, and helping understand antibody kinetics and correlates of protection.

Abstract Background Given excellent survival outcomes in breast cancer, there is interest in de‐escalating the amount of chemotherapy delivered to patients. This approach may be of even greater importance in the setting of the COVID‐19 pandemic. Methods This concurrent mixed methods study included (1) interviews with patients and patient advocates and (2) a cross‐sectional survey of women with breast cancer served by a charitable nonprofit organization. Questions evaluated interest in de‐escalation trial participation, perceived barriers/facilitators to participation, and language describing de‐escalation. Results Sixteen patient advocates and 24 patients were interviewed. Key barriers to de‐escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for focus on less treatment. Facilitators included trust in physician recommendation, toxicity avoidance, monitoring for progression, perception of good prognosis, and impact on daily life. Participants reported that the COVID‐19 pandemic made them more likely to avoid chemotherapy if possible. Of 91 survey respondents, many (43%) patients would have been unwilling to participation in a de‐escalation clinical trial. The most commonly reported barrier to participation was fear of recurrence (85%). Few patients (19%) considered clinical trials themselves as a barrier to de‐escalation trial participation. The most popular terminology describing chemotherapy de‐escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de‐escalation.” Conclusions Fear of recurrence is a common concern among breast cancer survivors and patient advocates, contributing to resistance to de‐escalation clinical trial participation. Additional research is needed to understand how to engage patients in de‐escalation trials.

Abstract: Chimeric antigen receptor (CAR) T cells (CARTs) have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CART therapy of MM to date, but not all remissions are sustained. Emergence of BCMA escape variants has been reported under the selective pressure of monospecific anti-BCMA CART treatment. Thus, there is a clinical need for continuous improvement of CART therapies for MM. Here, we show that a novel trimeric APRIL (a proliferation-inducing ligand)–based CAR efficiently targets both BCMA+ and BCMA− MM. Modeled after the natural ligand-receptor pair, APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CART activity against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.

Abstract: Fms-like tyrosine kinase 3 (Flt3) is expressed on progenitor cells and acute myeloid leukemia (AML) blasts. Fms-like tyrosine kinase 3 ligand (Flt3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Conversely, Flt3+ AML is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering complete remission (CR) but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the bone marrow. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 140 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib or placebo. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney UP < .0001). Day 26 Flt3L was also associated with survival; Flt3L ≤291 pg/mL was associated with inferior event-free survival (EFS), and Flt3L >1185 pg/mL was associated with higher overall survival (OS; P = .0119). The separation of EFS and OS curves increased when minimal residual disease (MRD) status was combined with Flt3L measurement, and Flt3L retained a near-significant association with survival after adjusting for MRD in a proportional hazards model. Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML illustrates the potential value of monitoring Flt3L to identify relapse. Measurement of Flt3L is a noninvasive test with the potential to inform clinical decisions in patients with AML.

Interleukin-6 (IL-6) has been linked to several life-threatening disease processes. Developing a point-of-care testing platform for the immediate and accurate detection of IL-6 concentrations could present a valuable tool for improving clinical management in patients with IL-6-mediated diseases. Drawing on an available biobank of samples from 35 patients hospitalized with COVID-19, a novel quantum-magnetic sensing platform is used to determine plasma IL-6 concentrations. A strong correlation was observed between IL-6 levels measured by QDTI10x and the Luminex assay (r = 0.70, p-value < 0.001) and between QDTI80x and Luminex (r = 0.82, p-value < 0.001). To validate the non-inferiority of QDTI to Luminex in terms of the accuracy of IL-6 measurement, two clinical parameters—the need for intensive care unit admission and the need for mechanical intubation—were chosen. IL-6 concentrations measured by the two assays were compared with respect to these clinical outcomes. Results demonstrated a comparative predictive performance between the two assays with a significant correlation coefficient. Conclusion: In short, the QDTI assay holds promise for implementation as a potential tool for rapid clinical decision in patients with IL-6-mediated diseases. It could also reduce healthcare costs and enable the development of future various biomolecule point-of-care tests for different clinical scenarios.

Rebel groups employ a number of strategies beyond violence, and these alternative tactics are often thought to improve the reputation and legitimacy of rebel actors. How powerful states (and their publics) view rebels can affect their chances of international recognition, inclusion in peace talks, and whether they are eventually successful at achieving their objectives. This study employs two experiments to test the link between rebel tactics and opinions of these rebels held by external audiences. We examine the impact of six rebel behaviors on American public opinion: (a) nonviolent demonstrations, (b) nonviolent interventions (such as blockades and sit ins), (c) social noncooperation (such as hunger strikes), (d) terrorism, (e) stone throwing, and (f) the use of local democratic practice (elections) in rebel groups. We find that the use of elections within rebel actors, demonstrations, and hunger strikes improve positive perceptions of rebels, whereas rebel use of terrorism decreases support.

Abstract Background Rubella is a common mild rash illness caused by rubella virus. The majority of infections occur in children and young adults. The infection is the cause of a serious birth defect known as Congenital Rubella Syndrome (CRS) when a woman acquires infection early in pregnancy. Ethiopia has not yet established rubella virus surveillance and has not yet introduced rubella vaccine into the routine immunization program. We characterize the epidemiology of laboratory confirmed rubella virus cases collected through measles surveillance from 2009 to 2015 to better understand the burden of the disease in the country. Methods A descriptive analysis was made to characterize rubella cases reported through the national measles case based surveillance system. The measles case definition was used to capture potential rubella cases. A suspected measles case was a person with generalized rash and fever with cough, or coryza or conjunctivitis. Those cases whose sera were negative for measles IgM antibodies were tested for rubella IgM antibody. A confirmed rubella case was a person who tested positive for rubella IgM. Only laboratory confirmed rubella cases were analyzed in this article. Results Between 2009 and 2015, a total of 28,284 serum/plasma samples were collected and tested for measles IgM antibody and 11,151 (39.4%) were found positive. A total of 17,066 measles IgM negative or indeterminate samples were tested for rubella virus IgM and 2615 (15.3%) were found positive during the same period. Of 2615 confirmed rubella cases, 52.2% were females. The age of confirmed cases ranged from one month to 42 years with a mean age of 7.3 years. Three-fourth of all confirmed rubella cases were aged less than 10 years. The number of laboratory confirmed rubella cases linearly increased from 83 in 2009 to 856 in 2013 but dropped to 222 and 319 in 2014 and 2015 respectively. Higher number of cases occurred in the hot dry season (January through June) and in the central and western part of Ethiopia with 127 lab-confirmed outbreaks in the study period. Conclusions Based on our analysis, rubella was found to be endemic throughout Ethiopia. Children below the age of 10 years were the most affected. The burden of rubella cases varied from year to year but had a seasonal peak in March. To better understand the magnitude of rubella prior to vaccine introduction, establishing rubella surveillance system, conducting sero-prevalence studies among child bearing age females and establishing CRS sentinel surveillance among young infants are critical.

This paper considers the social role of collaborative ethnographic research amid our current intersecting social, political and ecological crises. It investigates how the multi-sited, arts-based, ethnographic study, "Global Youth (Digital) Citizen-Artists and their Publics: Performing for Socio-Ecological Justice (2019-2024)," adopts drama as a tool to at once respond compassionately and imaginatively to crisis, and envision alternative social, political and ecological futures in its wake. A "metho-pedagogical" paradigm is mobilized as a framework to consider how drama is put to work, methodologically and pedagogically, at a time of climate emergency and pandemic. This framework is illustrated across two vignettes, which attend to the social challenges and impacts of emergent drama-based ethnographic research across two years of the study, in varying geographic locations with different cultural orientations, in live classrooms and in virtual theatre spaces. Attention, risk, desire, trust and reciprocity emerge as important proposals for engaging in arts-led research with youth in these times.

In this article, we examine the fraught task of doing drama-based work on the climate crisis with youth in schools at a time of increasing climate fatalism. We focus on what a virtual, speculative fiction writing and performance workshop achieved with students in Coventry, Kaohsiung and Bogotá by inviting them to rewrite the futures of local environments. We harness the concepts of agency, memory, desire, repair and care as part of a deeply situated yet expansive aesthetics in which youth can imagine more hopeful futures in their worlds.

Surveillance for hepatitis C virus infection in 6 US sites identified 20,285 newly reported cases in 12 months (report rate 69 cases/100,000 population, range 25–108/100,000). Staff reviewed 4 laboratory reports per new case. Local surveillance data can document the effects of disease, support linkage to care, and help prevent secondary transmission.

En el proceso de purificación de la 5,7-dimetil-1-(metilen-metil-éter)-2- carboxicromona, separada previamente a partir del líquen Alectoóa scrobiculata se logró aislar un compuesto sólido blanco, soluble en DMSO y etanol, para el cual se propone la estructura de 3-a-hidroxi-5'-metil-4-0-demetilbarbatato de metilo, en base a su comportamiento cromatográfico y sus datos espectrales IR, 1 H-NMR y 13C-NMR.

A partir del liquen Usnea sp. de la zona de Ingenio, Huancayo, se logró aislar, aplicanmdo técnicas de extracción, recristalización y cromatografía CCD y CC, seis compuestos: ácido (-) - úsnico (compuesto mayoritario), ácido 5-(B-oxopropil)-4-0-dimetilbarbático, 1´-oxo-4´-hidroxi-Filoquinona, 1´-oxo-4´-hidroxi-6`-eno-Filoquinona, un pigmento de naturaleza 1,4-naftoquinónica y un posible derivado ácido del orcinol. Todos ellos fueron analizados por sus propiedades físicas, cromotográficas y espectroscópicas.

Why do governments make concessions to some rebels but not others? We argue that the origins of rebel groups influence the bargaining process, and the government's willingness to make concessions in particular. Rebel groups inherit different resource endowments – community ties and military expertise – from pre-existing "parent" organizations. These resource endowments are visible to the government, and they provide critical information about the likely durability of the rebellion. We expect that rebel group origins facilitating these endowments are associated with the state offering concessions earlier in the conflict. Employing original data on rebel group origins, as well as information on government concessions during post-Cold War African conflicts, we find general support for our expectations, although not all types of parent organizations are equally beneficial to rebel groups when it comes to extracting concessions from the state. [ABSTRACT FROM AUTHOR]