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Despite the remarkable success of autologous chimeric antigen receptor (CAR) T cells, some patients relapse due to tumor antigen escape and low or uneven antigen expression, among other mechanisms. Therapeutic options after relapse are limited, emphasizing the need to optimize current approaches. In addition, there is a need to develop allogeneic “off-the-shelf” therapies from healthy donors that are readily available at the time of treatment decision and can overcome limitations of current autologous approaches. To address both challenges simultaneously, we generated a CD20xCD22 dual allogeneic CAR T cell. Herein, we demonstrate that allogeneic CD20x22 CAR T cells display robust, sustained and dose-dependent activity in vitro and in vivo, while efficiently targeting primary B-cell non–Hodgkin lymphoma (B-NHL) samples with heterogeneous levels of CD22 and CD20. Altogether, we provide preclinical proof-of-concept data for an allogeneic dual CAR T cell to overcome current mechanisms of resistance to CAR T-cell therapies in B-NHL, while providing a potential alternative to CD19 targeting.

The present paper reviews the growing body of literature on food insecurity and food bank use in the UK. It provides an overview of food insecurity in this context, followed by a description of the emergence of food banks, highlighting how any role that food banks play in the food insecure population is limited. Data on food insecurity and food bank use suggest many people experiencing food insecurity do not receive help from food banks. To better understand the factors influencing the relationship between food insecurity and food bank use, a conceptual framework is outlined, suggesting the relationship is far from straightforward and contingent on many factors. The nature and availability of food banks and other local support services and individual-level factors influence the likelihood of food banks being used in the context of food insecurity. Then, the extent to which food banks can impact food insecurity is also dependent on the quantity and quality of food distributed, as well as other support services offered from food banks. Closing reflections highlight rising living costs and food banks reporting that they do not have capacity to cope with increasing demand, underscoring the need for policy interventions. Reliance on food banks to respond to food insecurity may ultimately impede formulation of effective policy interventions to reduce food insecurity, giving the illusion of widespread available support, whilst food insecurity persists among those receiving help from food banks and those who experience food insecurity but do not use food banks.

Background: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants. Methods: The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959–1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants’ vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year. Results: Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45–54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03–1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05–1.44]); preterm induced labor (aHR, 1.31 [1.03–1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75–2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97–1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99–1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20–1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00–1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10–2.46]) compared with White (aHR, 1.29 [0.97–1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90–2.90]) compared with Black (aHR, 1.40 [1.00–1.96]) participants. Conclusions: In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

In 2020, in response to major maternity workforce challenges exacerbated by the COVID-19 pandemic, the Victorian Department of Health implemented a number of workforce maximisation strategies, one of which was employment of undergraduate midwifery students called 'Registered Undergraduate Student Of Midwifery' (RUSOM).To evaluate the RUSOM model implemented in a tertiary maternity service in Melbourne, Australia.A cross-sectional online survey was distributed to all RUSOMs and midwives at the study site in August 2021.Twenty of 26 RUSOMs (77%) and 110 of 338 permanent midwives (33%) responded. Both groups considered the model to be a positive workforce strategy that contributed to work readiness of students, and increased confidence and competence to practise. RUSOMS and midwives reported positives for the organisation including improving workload for midwives on the postnatal ward, enhancing quality of care and outcomes for women and babies, and the value of RUSOMs as team members. RUSOMs felt well supported, supervised and clinically and theoretically prepared. Both groups considered RUSOMs were underutilised, and that they could undertake additional duties, and both thought that the RUSOM model should continue.The model was highly valued by both RUSOMs and midwives. There was strong agreement that the model should continue and that the list of duties could be expanded. Given these findings, further research should explore the expansion and sustainability of RUSOMs in the maternity workforce.

To evaluate the associations between preconception sleep characteristics and shift work with fecundability and live birth.Secondary analysis of the Effects of Aspirin in Gestation and Reproduction study, a preconception cohort.Four US academic medical centers.Women aged 18-40 with a history of 1-2 pregnancy losses who were attempting to conceive again.Not applicable.We evaluated baseline, self-reported sleep duration, sleep midpoint, social jetlag, and shift work among 1,228 women who were observed for ≤6 cycles of pregnancy attempts to ascertain fecundability. We ascertained live birth at the end of follow up via chart abstraction. We estimated fecundability odds ratios (FORs) using discrete, Cox proportional hazards models and risk ratios (RRs) for live birth using log-Poisson models.Sleep duration ≥9 vs. 7 to8 hours (FOR: 0.81, 95% confidence interval [CI], 0.61; 1.08), later sleep midpoints (3rd tertile vs. 2nd tertile: FOR: 0.85; 95% CI, 0.69, 1.04) and social jetlag (continuous per hour; FOR: 0.93, 95% CI: 0.86, 1.00) were not associated with reduced fecundability. In sensitivity analyses, excluding shift workers, sleep duration ≥9 vs. 7 to8 hours (FOR: 0.62; 95% CI, 0.42; 0.93) was associated with low fecundability. Night shift work was not associated with fecundability (vs. non-night shift work FOR: 1.17, 95% CI, 0.96; 1.42). Preconception sleep was not associated with live birth.Overall, there does not appear to be a strong association between sleep characteristics, fecundability, and live birth. Although these findings may suggest weak and imprecise associations with some sleep characteristics, our findings should be evaluated in larger cohorts of women with extremes of sleep characteristics.Clinicaltrials.gov NCT00467363.

Retrotransposons are gene segments that proliferate in the genome, and the Long INterspersed Element 1 (LINE-1 or L1) retrotransposon is active in humans. Although older mammals show enhanced skeletal muscle L1 expression, exercise generally reverses this trend. We hypothesize skeletal muscle L1 expression influences muscle physiology, and additional innovative investigations are needed to confirm this hypothesis.

BackgroundThe effectiveness of vaccines against the severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2) B.1.1.529 Omicron variant in immunosuppressed solidorgan and islet transplant (SOT) recipients is unclear.MethodsNational registries in England were linked to identify SARS-CoV-2 positive tests, noninjuryhospitalisation within 14 days, and deaths within 28 days between 7 December2020 and 31 March 2022 in adult SOT recipients. Incidence rate ratios (IRRs) forinfection, and hospitalisation or death, were adjusted for recipient demographics andcalendar month for the Omicron-dominant period (20 December 2021 to 31 March2022). Mortality risk following SARS-CoV-2 infection was adjusted for recipientdemographics and dominant variant using a Cox proportional-hazards model for theentire time period.ResultsDuring the Omicron-dominant period, infection IRRs (95% confidence intervals) werehigher in those receiving two, three and four vaccine doses compared to unvaccinated patients (1·25 (1·08-1·45), 1·46 (1·28-1·67), and 1·79 (1·54-2·06), respectively).However, hospitalisation or death IRRs during this period were lower in those receivingthree or four vaccine doses compared to unvaccinated patients (0·62 (0·45-0·86) and0·39 (0·26-0·58), respectively). Risk-adjusted analyses for deaths after SARS-CoV-2infection between 7 December 2020 to 31 March 2022 found hazard ratios (95%confidence intervals) of 0·67 (0·46-0·98), 0·46 (0·30-0·69), 0·18 (0·09-0·35) for thosewith two, three, and four vaccine doses, respectively, when compared to theunvaccinated group.ConclusionsIn immunosuppressed SOT recipients, vaccination is associated with incremental,dose-dependent protection against hospitalisation or death after SARS-CoV-2infection, including against the Omicron variant.

Innovation, and the creative thinking that provides the basis for innovation, is of great value for organizations. In this article we describe what is needed for people to think creatively, noting that creative thinking is a complex, albeit voluntary, activity involving performance on certain types of problems. The ways leaders influence peoples’ willingness to engage in, and ability to solve, creative problems are then described. Leaders of creative efforts must not only motivate creative work but also actively contribute to creative problem-solving both by engaging followers in creative problem-solving and by establishing the conditions that allow creative problem-solving at the individual, team, and firm levels. The implications of these observations for leader assessment and leader development are discussed.

Gallium as a solvent liquid metal catalyst is used in an energy efficient, high yield and controlled reaction between lithium and CO2. A liquid metal electrode and the naturally formed surface products are used as a supercapacitor.

Widespread access to an increasing number of technology-enhanced communications channels multiplies the potential for abusive interactions (i.e., technology-facilitated abuse [TFA]). Practitioners will be better prepared to respond to the problem of TFA if more is known about how commonly victims seek help, and from whom. Through a cross-sectional, U.S. nationally representative survey of n = 1,215 young adults aged 18 to 35, respondents completed the TFA scale of the Cyber-Abuse Research Initiative. We calculated the percentage of TFA survivors who sought help for their most damaging experience of TFA, and used logistic regression to model help-seeking for health services, victim services, technological assistance, and/or criminal justice/legal assistance. For each help source, we examined risk markers including sociodemographic characteristics, online activity, the number of different forms of TFA experience, and the perpetrator’s relationship to the victim. Use of a broader range of social media sites/platforms, and several indicators of more severe TFA experiences, predicted help-seeking from health services, victim services, and justice/legal assistance. Young adults who identified the TFA perpetrator as a current or ex-intimate partner were less likely than other survivors to seek two forms of help: technological assistance and/or criminal justice/legal assistance. Survivors who self-identified as Black were more likely than White survivors to seek victim services. Professionals who support survivors of interpersonal aggression may use these results to enhance their screening protocols and form cross-disciplinary partnerships to address the harms associated with TFA.

Fisheries management needs to ensure that resources are exploited sustainably, and the risk of depletion is at an acceptable level. However, often uncertainty about resource dynamics exists, and data availability may differ substantially between fish stocks. This situation can be addressed through tiered systems, where tiers represent different data limitations, and tier-specific stock assessment methods are defined, aiming for risk equivalence across tiers. As case studies, we selected stocks of European plaice, Atlantic cod and Atlantic herring, where advice is provided by the International Council for the Exploration of the Sea (ICES). We conducted a closed-loop simulation to compare risk equivalence between the data-rich ICES MSY rule, based on a quantitative stock assessment, and the revised data-limited empirical management procedures of the ICES advice framework. The simulations indicated that the data-limited approaches were precautionary and did not lead to a higher risk of depletion than the data-rich approach. Although the catch based on generic data-limited approaches was lower, stock-specific optimisation improved management performance with catch levels comparable with the data-rich approach. Furthermore, the simulation indicated the ICES MSY rule can fail to meet management objectives due to increased depletion risk when management reference points are set suboptimally. We conclude that the recent revisions of the ICES system explicitly account for risk equivalence for data-limited fisheries management and are a major step forward. Finally, we advocate further consideration of simple empirical management procedures irrespective of data limitations due to their ability to meet fisheries management objectives with greater simplicity.

Optimism and loneliness, which reflect the expected inverse associations with excess morbidity and mortality, are theoretically and empirically associated with early adversities and offer potential avenues for clinical support. The current study first estimates latent classes of adverse childhood experiences and, second, assesses the role of these experiences on later reports of optimism and loneliness in late adolescence and emerging adulthood, and the role of emotional regulation and common mental disorders. Surveys were conducted in a longitudinal household sample of adolescents recruited in 2013 (average age of 20 at wave 6 follow-ups). The analytic sample included 1177 female and male respondents representative of their age group in the USA at baseline. Latent classes were estimated based on 10 indicators of childhood adversity. Respondents were assigned to classes using posterior probabilities of latent class membership, and class membership was used to predict psychological outcomes in multivariable models. Three latent classes of childhood adversity were identified in the current sample, representing low childhood adversity (81.5%), higher probability of family dysfunction with lower levels of interpersonal abuse (13.4%), and high adversity including higher probabilities of parental discord and violence as well as child abuse (5.1%). Both classes of respondents who faced greater childhood adversity were more likely to report greater loneliness and lower optimism in emerging adulthood. Results were attenuated by measures of emotional well-being. Addressing adolescent loneliness and supporting optimistic outlooks in emerging adulthood are two pathways with potential benefits to reduce mental and physical morbidities.

This video essay places Bit (Brad Michael Elmore, 2019, US) and Seance (Simon Barrett, 2021, US) in conversation. I show how both of these queer horror films move beyond the questions of representation and investigate how the very genre of horror can be utilised to reflect ideas of queerness. I incorporate Robin Wood’s psychoanalytical perspective on the monster reflecting what society represses. However, unlike the films Wood analysed in the 70s/80s, these modern films do not just relegate queerness to subtext. Queerness is now present, alive, in the text. And here, I interrogate how the role of the monster in both films reflects ideas of queer lived experience.

Eyebrows and eyelashes serve important anatomical and social functions, and hair loss at these sites can impact patients significantly. Acquired eyebrow and eyelash loss (madarosis) may be due to a variety of underlying local or systemic disease processes; in other cases it may be idiopathic. There is a dearth of literature relating to eyebrow and eyelash loss, and there is limited guidance to help clinicians treat these clinical presentations in comparison with scalp alopecia. Here, we discuss the acquired causes of eyebrow and eyelash alopecia, our clinical approach to diagnosis and review treatment options for clinicians.

Background: Diet is increasingly recognized as an important determinant of human fertility, with most research focused on specific nutrients or food groups. However, there has been limited assessment of the effect of dietary patterns on fertility. Objectives: We evaluated the association between 4 dietary patterns [the alternative Mediterranean Diet (aMed), the Healthy Eating Index-2010 (HEI-2010), the Danish Dietary Guidelines (DDGI), and the Dietary Inflammatory Index (DII)] and fecundability in 2 preconception cohorts of couples trying to conceive: SF (SnartForaeldre.dk) in Denmark and PRESTO (Pregnancy Study Online) in North America. Methods: Participants completed a baseline questionnaire on sociodemographic, anthropometric, and lifestyle factors and, 10 d later, a validated cohort-specific FFQ. We used data from these respective FFQs to calculate adherence to each dietary pattern. Participants completed bimonthly follow-up questionnaires for ≤12 mo or until pregnancy, whichever came first. We restricted analyses to 3429 SF and 5803 PRESTO participants attempting pregnancy for ≤6 cycles at enrollment. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusting for potential confounders. Results: Greater DII, indicative of a less anti-inflammatory diet (i.e., poorer diet quality), was associated with reduced fecundability in both SF and PRESTO (DII ≥ -1.5 compared with < -3.3: FR: 0.83; 95% CI: 0.71, 0.97 and FR: 0.82; 95% CI: 0.73, 0.93, respectively). In PRESTO, greater adherence to the aMed or to the HEI-2010 was associated with greater fecundability. In SF, there was no appreciable association between the aMed and fecundability, whereas greater adherence to the DDGI was associated with greater fecundability. Conclusions: In prospective preconception cohort studies from Denmark and North America, higher-quality diets, including diets lower in inflammatory effects, were associated with greater fecundability.

To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability.Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort.Four US reproductive endocrinology and infertility care study centers, 2013-2017.Couples (n = 2,369) seeking fertility consultations at 4 US infertility care study centers.Semen volume, pH, sperm viability, morphology, progressive and total motility, concentration, count, and total and progressive motile count assessed at baseline and at 2, 4, and 6 months after enrollment.Log-binomial models stratified by fertility treatment received (in vitro fertilization [IVF], intrauterine insemination [IUI], ovulation induction [OI], or no treatment) estimated risk differences (RDs) between semen parameter quartiles and live birth and accounted for multiple semen assessments per person. We accounted for abstinence time, the biological interdependence of semen parameters, and potential selection bias because of loss to follow-up.Among couples using OI only or no treatment, 39% had a live birth, and relative to the highest quartile, the lowest quartiles of morphology (RD, -19 [95% CI, -23 to -15] per 100 couples), motility (RD, -13 [95% CI, -17 to -9]), concentration (RD, -22 [95% CI, -26 to -19]), and total motile count (RD, -18 [95% CI, -22 to -14]) were associated with fewer live births. For IUI, 26% had a live birth, and the lowest quartiles of volume (RD, -6 [95% CI, -11 to -0.4]), concentration (RD, -6 [95% CI, -11 to -0.1]), count (RD, -10 [95% CI, -15 to -4]), and total motile count (RD, -7 [95% CI, -13 to -1]) were associated with fewer live births. For IVF, 61% had a live birth, and only morphology (Q1 RD, -7 [95% CI, -14 to 0.2]; Q2 RD, -10 [95% CI, -17 to -2.2]) was associated with live birth.Semen parameters are critical in couples undergoing OI/IUI. Only low morphology was important for live birth after IVF. Although data supporting the use of semen parameters are fragmented across differing populations, current findings are generalizable across the range of male fertility and couple fertility treatments, providing evidence about which semen parameters are most relevant in which settings.NCT#01857310.

Background California’s South Coast has experienced peak burned area in autumn. Following typically dry, warm summers, precipitation events and Santa Ana winds (SAWs) each occur with increasing frequency from autumn to winter and may affect fire outcomes. Aims We investigate historical records to understand how these counteracting influences have affected fires. Methods We defined autumn precipitation onset as the first 3 days when precipitation ≥8.5 mm, and assessed how onset timing and SAWs were associated with frequency of ≥100 ha fires and area burned during 1948–2018. Key results Timing of autumn precipitation onset had negligible trend but varied considerably from year to year. A total of 90% of area burned in autumn through winter occurred from fires started before onset. Early onset autumns experienced considerably fewer fires and area burned than late onset autumns. SAWs were involved in many of the large fires before onset and nearly all of the lesser number after onset. Conclusions Risk of large fires is reduced after autumn precipitation onset, but may resurge during SAWs, which provide high risk weather required to generate a large fire. Implications During autumn before onset, and particularly during late onset autumns, high levels of preparation and vigilance are needed to avoid great fire impacts.

The relationship between size and performance of collaborative human small groups has been studied broadly across management, psychology, economics, sociology, and engineering disciplines. However, empirical research findings on this question remain equivocal. Many of the earlier studies centered on empirical human-subject experiments, which inevitably involved many confounding factors. To obtain more theory-driven mechanistic explanations of the linkage between group size and performance, we developed an agent-based simulation model that describes the complex process of collaborative group decision-making on problem-solving tasks. To find better solutions to a problem with given complexity, these agents repeatedly explore and share solution candidates, evaluate and respond to the solutions proposed by others, and update their understanding of the problem by conducting individual local search and incorporating others’ proposals. Our results showed that under a condition of ineffective information sharing, group size was negatively related to group performance at the beginning of discussion across each level of problem complexity (i.e., low, medium, and high). However, in the long run, larger groups outperformed smaller groups for the problem with medium complexity and equally well for the problem with low complexity because larger groups developed higher solution diversity. For the problem with high complexity, the higher solution diversity led to more disagreements which in turn hindered larger groups’ collaborative problem-solving ability. Our results also suggested that, in small collaborative team settings, effective information sharing can significantly improve group performance for groups of any size, especially for larger groups. This model provides a unified, mechanistic explanation of the conflicting observations reported in the existing empirical literature.

Mindfulness-based interventions are widely used to target pain, yet their neural mechanisms of action are insufficiently understood. The authors studied neural and subjective pain response in a randomized active-control trial of mindfulness-based stress reduction (MBSR) alongside long-term meditation practitioners.Healthy participants (N=115) underwent functional neuroimaging during a thermal acute pain task before and after random assignment to MBSR (N=28), an active control condition (health enhancement program [HEP]) (N=32), or a waiting list control condition (N=31). Long-term meditators (N=30) completed the same neuroimaging paradigm. Pain response was measured via self-reported intensity and unpleasantness, and neurally via two multivoxel machine-learning-derived signatures: the neurologic pain signature (NPS), emphasizing nociceptive pain processing, and the stimulus intensity independent pain signature-1 (SIIPS1), emphasizing stimulus-independent neuromodulatory processes.The MBSR group showed a significant decrease in NPS response relative to the HEP group (Cohen's d=-0.43) and from pre- to postintervention assessment (d=-0.47). The MBSR group showed small, marginal decreases in NPS relative to the waiting list group (d=-0.36), and in SIIPS1 relative to both groups (HEP group, d=-0.37; waiting list group, d=-0.37). In subjective unpleasantness, the MBSR and HEP groups also showed modest significant reductions compared with the waiting list group (d=-0.45 and d=-0.55). Long-term meditators reported significantly lower pain than nonmeditators but did not differ in neural response. Within the long-term meditator group, cumulative practice during intensive retreat was significantly associated with reduced SIIPS1 (r=-0.65), whereas daily practice was not.Mindfulness training showed associations with pain reduction that implicate differing neural pathways depending on extent and context of practice. Use of neural pain signatures in randomized trials offers promise for guiding the application of mindfulness interventions to pain treatment.

We study the joint effects of motivation and workload on human servers’ service time. Using operational and survey data from a call center with a pooled queue structure and limited financial incentives, we examine how individual differences between servers’ trait intrinsic motivation (IM) and extrinsic motivation (EM) impact their average offline, online, and total service times in response to changing workloads. We find significant differences in the patterns of workload and service time relationships across different stages of the service request between servers possessing different combinations of trait motivation. For example, servers with a combination of high IM and low EM were approximately 15% (161%) faster in processing the offline portion of service requests than their peers with the opposite combination (low and high) when workload levels were low (high), respectively. In contrast, servers with high IM-low EM were approximately 35% (5%) slower in processing the online portion of service requests than their low IM-high EM counterparts when workload levels were low (high), respectively. Our findings suggest important nuances in how servers with different trait motivation types respond to changing workload across different stages of the service request. The behavioral pattern shown by high IM-low EM servers is consistent with the preferences of productivity-seeking call center managers who favor speedup and slowdown at certain stages of the service request, conditional to workload. These findings underscore the importance of accounting for trait-based individual differences for a more complete understanding of the complex relationship between workload and service time. This paper was accepted by Charles Corbett, operations management.

Despite the remarkable success of autologous chimeric antigen receptor (CAR) T cells, some patients relapse due to tumor antigen escape and low or uneven antigen expression, among other mechanisms. Therapeutic options after relapse are limited, emphasizing the need to optimize current approaches. In addition, there is a need to develop allogeneic “off-the-shelf” therapies from healthy donors that are readily available at the time of treatment decision and can overcome limitations of current autologous approaches. To address both challenges simultaneously, we generated a CD20xCD22 dual allogeneic CAR T cell. Herein, we demonstrate that allogeneic CD20x22 CAR T cells display robust, sustained and dose-dependent activity in vitro and in vivo, while efficiently targeting primary B-cell non–Hodgkin lymphoma (B-NHL) samples with heterogeneous levels of CD22 and CD20. Altogether, we provide preclinical proof-of-concept data for an allogeneic dual CAR T cell to overcome current mechanisms of resistance to CAR T-cell therapies in B-NHL, while providing a potential alternative to CD19 targeting.

Supplementary Tables 1-4, supplementary Figures 1-10 and legends

Pattern similarity analysis, which uses correlation to examine similarities between neural activation patterns evoked by different trials or conditions, are often leveraged to test hypotheses not easily answerable with univariate comparisons, such as how events are represented or processed and the relationships between representations or processing of events. In principle, univariate analyses of global activation and multivariate analyses of pattern similarity can be used to answer substantively different questions about psychological and neural processing. For this to hold, it is necessary that pattern similarity estimates are not contaminated by differences in global activation across experimental events. Here, we report simulated data that demonstrate that global activation and pattern similarity (as assessed by correlation), although theoretically independent, are often intertwined. We present two plausible scenarios that illustrate how condition-specific changes in global activation can elicit condition-specific increases in pattern similarity by interacting with underlying across-voxel activation patterns. First, we consider a scenario in which a target region contains subpopulations of voxels such that only some voxels in a region are sensitive to a psychological variable and the remaining voxels are not modulated by this variable. In this scenario, this spatial pattern of responsive and unresponsive voxels adds new, shared across-voxel variability for events in the "active" condition, thereby increasing pattern similarity between these events. Second, we consider a scenario in which trials from all conditions elicit a shared across-voxel pattern of activation, but this shared across-voxel pattern is amplified for trials within one condition due to greater global activation. In this scenario, the change in activation for a given condition increases the ability to detect pre-existing, shared across-voxel variability across events in that condition, thereby increasing pattern similarity between these events. Given the observed influence of global activation on pattern similarity, we then assess whether it is possible to statistically separate the contributions of global activation and pattern similarity to observed activation patterns (using regression approaches, matching activation across conditions, and inclusion of control conditions). Additional simulations demonstrate that use of these techniques is not always effective in removing the influence of global activation on pattern similarity -- the efficacy of these techniques depends on a variety of signal parameters that will likely vary across experiments and participants, highlighting the need for tailored control analyses that are targeted at addressing the particular hypotheses and potential global activation confounds of a given experiment.

Understanding how per- and poly-fluoroalkyl substances (PFAS) are transported is critical to site characterization, monitoring, risk assessment, and remediation planning. This includes an understanding of PFAS retention and release at air-water interfaces. These interfaces exist throughout the vadose zone, but can also exist as trapped air bubbles created by water table fluctuations, recharge, and biogenic gas production. In addition to being directly applicable to transport through trapped gas zones at PFAS-impacted sites, laboratory experiments using emplaced trapped gas (quasi-saturated conditions) provide a controlled method to investigate PFAS behavior, including the effects of different PFAS, concentrations, and mixtures. In this study, a series of laboratory experiments was conducted using one-dimensional sand-packed columns (20 cm × 7 cm dia.). Trapped air was emplaced by sequential drainage and imbibition to create quasi-saturated conditions. Each experiment included separate injections of non-reactive tracer (NaCl) and PFAS solutions through both water-saturated and quasi-saturated columns. A clean, low organic carbon sand was used to eliminate solid-phase sorption (verified through comparison of non-reactive tracer and PFAS breakthrough in the water-saturated columns) and to isolate the effect of air-water interfaces. Experiments were conducted using single-component solutions of PFOA, PFOS and 6:2 FTS, as well as mixtures of those PFAS, at concentrations of 0.1-1 mg/L. Experiments were also conducted using diluted aqueous film-forming foam (AFFF) solutions. Measured retardation factors in triplicate experiments were used to estimate air-water partitioning coefficients.The results showed that PFAS breakthrough was significantly delayed in the presence of trapped air bubbles. Breakthrough delay was greater for PFOS than for PFOA or 6:2 FTS, and was greater for lower PFAS concentrations, for the range of concentrations used in these experiments. For PFAS mixtures, differences in retention were sufficient to completely separate breakthrough (i.e., PFOA and 6:2 FTS achieved complete breakthrough prior to any PFOS arrival) even over short (20 cm) distances. However, the behavior of each PFAS tested was altered by the presence of other PFAS, with PFOA and 6:2 FTS experiencing earlier breakthrough at higher concentrations (concentration overshoot) in the presence of PFOS. Mixture effects were also observed for branched and linear PFOS isomers, and for AFFF solutions, which was further complicated by the presence of hydrocarbon surfactants. The experimental results will be presented along with numerical simulations of PFAS transport subject to air-water partitioning, both to interpret the behavior of PFAS mixtures in experimental systems and to explore the implications of mixture transport in more complex field scenarios.

Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability to migrate to sites of neuroinflammation and respond to paracrine signaling in those sites by secreting cytokines, growth factors, and other neuromodulators. We potentiated this ability by stimulating MSCs with inflammatory molecules, improving their migratory and secretory properties. We investigated the use of intranasally delivered adipose-derived MSCs (AdMSCs) in combating prion disease in a mouse model. Prion disease is a rare, lethal neurodegenerative disease that results from the misfolding and aggregation of the prion protein. Early signs of this disease include neuroinflammation, activation of microglia, and development of reactive astrocytes. Later stages of disease include development of vacuoles, neuronal loss, abundant aggregated prions, and astrogliosis. We demonstrate the ability of AdMSCs to upregulate anti-inflammatory genes and growth factors when stimulated with tumor necrosis factor alpha (TNFα) or prion-infected brain homogenates. We stimulated AdMSCs with TNFα and performed biweekly intranasal deliveries of AdMSCs on mice that had been intracranially inoculated with mouse-adapted prions. At early stages in disease, animals treated with AdMSCs showed decreased vacuolization throughout the brain. Expression of genes associated with Nuclear Factor-kappa B (NF-κB) and Nod-Like Receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling were decreased in the hippocampus. AdMSC treatment promoted a quiescent state in hippocampal microglia by inducing changes in both number and morphology. Animals that received AdMSCs showed a decrease in both overall and reactive astrocyte number, and morphological changes indicative of homeostatic astrocytes. Although this treatment did not prolong survival or rescue neurons, it demonstrates the benefits of MSCs in combatting neuroinflammation and astrogliosis.

Meeting the contraceptive needs of women of reproductive age is beneficial for the health of women and children, and the economic and social empowerment of women. Higher rates of contraceptive coverage have been linked to the availability of a more diverse range of contraceptive methods. We present estimates of the contraceptive prevalence rate (CPR), modern contraceptive prevalence rate (mCPR), demand satisfied, and the method of contraception used for both partnered and unpartnered women for 5-year age groups in 204 countries and territories between 1970 and 2019.We used 1162 population-based surveys capturing contraceptive use among women between 1970 and 2019, in which women of reproductive age (15-49 years) self-reported their, or their partner's, current use of contraception for family planning purposes. Spatiotemporal Gaussian process regression was used to generate estimates of the CPR, mCPR, demand satisfied, and method mix by age and marital status. We assessed how age-specific mCPR and demand satisfied changed with the Socio-demographic Index (SDI), a measure of social and economic development, using the meta-regression Bayesian, regularised, trimmed method from the Global Burden of Diseases, Injuries, and Risk Factors Study.In 2019, 162·9 million (95% uncertainty interval [UI] 155·6-170·2) women had unmet need for contraception, of whom 29·3% (27·9-30·6) resided in sub-Saharan Africa and 27·2% (24·4-30·3) resided in south Asia. Women aged 15-19 years (64·8% [62·9-66·7]) and 20-24 years (71·9% [68·9-74·2]) had the lowest rates of demand satisfied, with 43·2 million (95% UI 39·3-48·0) women aged 15-24 years with unmet need in 2019. The mCPR and demand satisfied among women aged 15-19 years were substantially lower than among women aged 20-49 years at SDI values below 60 (on a 0-100 scale), but began to equalise as SDI increased above 60. Between 1970 and 2019, the global mCPR increased by 20·1 percentage points (95% UI 18·7-21·6). During this time, traditional methods declined as a proportion of all contraceptive methods, whereas the use of implants, injections, female sterilisation, and condoms increased. Method mix differs substantially depending on age and geography, with the share of female sterilisation increasing with age and comprising more than 50% of methods in use in south Asia. In 28 countries, one method was used by more than 50% of users in 2019.The dominance of one contraceptive method in some locations raises the question of whether family planning policies should aim to expand method mix or invest in making existing methods more accessible. Lower rates of demand satisfied among women aged 15-24 years are also concerning because unintended pregnancies before age 25 years can forestall or eliminate education and employment opportunities that lead to social and economic empowerment. Policy makers should strive to tailor family planning programmes to the preferences of the groups with the most need, while maintaining the programmes used by existing users.BillMelinda Gates Foundation.

College completion rates declined from the 1970s to the 1990s. We document that this trend has reversed--since the 1990s, college completion rates have increased. The authors investigate the reasons for the increase in college graduation rates. Collectively, student characteristics, institutional resources, and institution attended do not explain much of the change. However, they show that grade inflation can explain much of the change in graduation rates. They also show that GPA is a strong predictor of graduation rates and that GPAs have been rising since the 1990s. They find that increases in college GPAs cannot be explained by student demographics, ability, and school factors. Further, they show that at a public liberal arts college, grades have increased over time conditional on final exam performance. Annenberg Institute at Brown University

Moderately data-limited fisheries can be managed with simple empirical management procedures without analytical stock assessments. Often, control rules adjust advised catches by the trend of an abundance index. We explored an alternative approach where a relative harvest rate, defined by the catch relative to a biomass index, is used and the target level derived from analysing historical catch length data. This harvest rate rule was tested generically with management strategy evaluation. A genetic algorithm was deployed as an optimisation procedure to tune the parameters of the control rule to meet maximum sustainable yield and precautionary management objectives. Results indicated that this method could outperform trend-based strategies, particularly when optimised, achieving higher long-term yields while remaining precautionary. However, optimum harvest rate levels can be narrow and challenging to find because they depend on historical exploitation and life history characteristics. Misspecification of target levels can have a detrimental impact on management. Nevertheless, harvest rates appear to be a suitable management option for moderately data-limited resources, and their application has modest data requirements. Harvest rate strategies are especially suitable for stocks for which case-specific analyses can be conducted.

This article presents the study of ambiguity as the essence of hybrid warfare to reconcile it with the international political context. It addresses the gaps in the literature in an effort to elucidate the essence of hybrid warfare not as a separate concept, but rather as the symptom of a changing political environment. The analysis of the literature is reinforced by two case studies: the war in eastern Ukraine of 2014 and the South China Sea dispute. Both these case studies express ambiguity in the combination of kinetic and non-kinetic means used to achieve political objectives. The article rests on three pillars that constitute the architecture of the central argument. The first pillar will address the gap in the current literature on hybrid warfare and how the current debate is too concerned with conflict dynamics rather than its political nature. The second pillar will delineate the essence, characteristics, and value of ambiguity in hybrid warfare. The third pillar will address the practice of hybrid warfare as the conduct of war by great powers.

Stemming intimate partner violence among adults demands earlier education and skill-building supportive of healthy youth and young adult dating relationships. The current U.S.-based study examines a spectrum of youth and young adult relationship dynamics (RDs), inclusive of abusive interactions. In a nationally representative cohort of youth aged 10–18 at baseline and one parent or caregiver, survey responses regarding RDs from 618 participants ages 15–23 at wave 5 follow-up were analyzed. Latent class analysis of four positive dynamics, six problematic dynamics, and three scales of adolescent relationship abuse (ARA) were estimated, yielding four latent profiles of dating RDs. Relationships characterized by Unhealthy and Intense RDs both exhibited high probability of ARA but differed from each other in terms of other positive and problematic dynamics. Relationships characterized by Disengaged RDs had lower probability of ARA but elevated probability of awkward communications, negative feelings, social liability, and other challenging dynamics. Several baseline covariates were significantly associated with profiles of dating RDs approximately 5 years later. Younger participants were more likely to subsequently fall in an Intense or Disengaged RDs profile, as were participants with baseline emotional health problems. Further, classification in the Unhealthy RDs profile was less likely for participants reporting a better baseline relationship with their parents and more likely for those exposed to violence in childhood. These findings suggest that in addition to developmental maturity, youth and young adults would benefit from closer investigation and processing of past emotional and relational issues and traumas to foster healthier dating relationships.