Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1-4,7-9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.

Effects of gender-affirming hormone therapy on gray matter density, microstructure and monoamine oxidase A levels in transgender subjects.

MAO-A catalyzes the oxidative degradation of monoamines and is thus implicated in sex-specific neuroplastic processes that influence gray matter (GM) density (GMD) and microstructure (GMM). Given the exact monitoring of plasma hormone levels and sex steroid intake, transgender individuals undergoing gender-affirming hormone therapy (GHT) represent a valuable cohort to potentially investigate sex steroid-induced changes of GM and concomitant MAO-A density. Here, we investigated the effects of GHT over a median time period of 4.5 months on GMD and GMM as well as MAO-A distribution volume. To this end, 20 cisgender women, 11 cisgender men, 20 transgender women and 10 transgender men underwent two MRI scans in a longitudinal design. PET scans using [11C]harmine were performed before each MRI session in a subset of 35 individuals. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Regions showing significant changes of both GMM and GMD were used for the subsequent analysis of MAO-A density. These involved the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: pFWE+Bonferroni < 0.025). In terms of MAO-A distribution volume, no significant effects were found. Additionally, the sexual desire inventory (SDI) was applied to assess GHT-induced changes in sexual desire, showing an increase of SDI scores among transgender men. Changes in the GMD of the bilateral insula showed a moderate correlation to SDI scores (rho = - 0.62, pBonferroni = 0.047). The present results are indicative of a reliable influence of gender-affirming hormone therapy on 1) GMD and GMM following an interregional pattern and 2) sexual desire specifically among transgender men.

Unmet financial needs among patients crowdfunding to support gynecologic cancer care.

BACKGROUND: Patients may use crowdfunding to solicit donations, typically from multiple small donors using internet-based means, to offset the financial toxicity of cancer care. OBJECTIVE: To describe crowdfunding campaigns by gynecologic cancer patients and to compare campaign characteristics and needs expressed between patients with cervical, uterine, and ovarian cancer. STUDY DESIGN: We queried the public crowdfunding forum GoFundMe.com for "cervical cancer," "uterine cancer," and "ovarian cancer." The first 200 consecutive posts for each cancer type fundraising within the United States were analyzed. Data on campaign goals and needs expressed were manually extracted. Descriptive statistics and bivariate analyses were performed. RESULTS: Among the 600 fundraising pages, the median campaign goal was $10,000 [IQR $5000-$23,000]. Campaigns raised a median of 28.6% of their goal with only 8.7% of campaigns reaching their goal after a median of 54 days online. On average, ovarian cancer campaigns had higher monetary goals, more donors, and larger donation amounts than cervical cancer campaigns and raised more money than both cervical and uterine cancer campaigns. Campaigns were fundraising to support medical costs (80-85%) followed by lost wages (36-56%) or living expenses (27-41%). Cervical cancer campaigns reported need for non-medical costs more frequently than uterine or ovarian cancer campaigns. States without Medicaid expansions (31% of the national population) were over-represented among cervical cancer and uterine cancer, but not ovarian cancer campaigns. CONCLUSIONS: Crowdfunding pages reveal patients fundraising for out-of-pocket costs in the thousands of dollars and a wide range of unmet financial needs based on cancer type.

Association between adherence to posttreatment National Comprehensive Cancer Network (NCCN) surveillance guidelines and detection of recurrent uterine cancer.

OBJECTIVE: To identify correlations between disease recurrence and adherence to NCCN posttreatment surveillance guidelines in patients who develop recurrent uterine cancer. METHODS: Retrospective analysis identified patients (n = 60) with recurrent uterine cancer and at least one surveillance visit with a gynecologic oncologist between 2011 and 2020. Adherence to NCCN guidelines and details of recurrence were recorded. RESULTS: Recurrent uterine cancer was identified in 60 patients with an average time to recurrence (TTR) of 25 months. Of those, 39 (65%) were adherent to NCCN surveillance guidelines and 36 (60%) were symptomatic at the time of recurrence diagnosis. Asymptomatic recurrence was diagnosed by imaging in 11 (46%), physical exam in 7 (29%), and blood work in 6 (25%) patients. Patients who were adherent to NCCN guidelines were diagnosed with recurrence on average 11 months earlier (p = 0.0336). Adherence was an independent predictor of TTR for all patients regardless of symptoms. There was no significant effect of age, race, primary language, or stage of disease on adherence. CONCLUSION: Adherence to NCCN posttreatment surveillance guidelines for uterine cancer is independently associated with an earlier diagnosis of recurrence.

Perceptions of a reduced nicotine policy and predictors of policy support: A nationally representative U.S. survey.

BACKGROUND: The U.S. Food and Drug Administration is considering a policy to reduce nicotine in cigarettes to non-addictive levels. Although current evidence supports the public-health benefits of a reduced-nicotine policy, almost half of people who smoke (∼ 40%) do not support the policy. This study estimates the factors most strongly associated with support or opposition toward the policy, including tobacco use status, perceived effects of a reduced nicotine policy, trust in the FDA, and psychological distress. The study aims to inform messaging campaigns and policy makers. METHODS: Data were collected in 2021 with nationally representative samples of U.S. adults (n = 1763). After receiving information about the reduced nicotine policy, participants indicated their beliefs and support for or opposition to the policy, along with other individual difference characteristics. Univariate population parameters and multinomial logistic regression coefficients were estimated. RESULTS: In adjusted models, people who formerly or never smoked were less likely to oppose the policy compared to those who currently smoke; people with higher psychological distress and those who believe the policy will promote switching to e-cigarettes were more likely to oppose the policy. In addition, people were more likely to support the policy if they believed it would make quitting easier or that the FDA is trustworthy. CONCLUSIONS: Educational campaigns about reduced nicotine policy should expect higher impact by targeting prevalent perceptions and those more strongly associated with policy sentiment. In anticipation of the policy rollout, there may be a critical window to shape public opinion.

Reactions to Messages About a Nicotine Reduction Policy: A Focus Group Study Among People Who Use Little Cigars and Cigarillos.

INTRODUCTION: The U.S. Food and Drug Administration (FDA) has proposed rulemaking to reduce the nicotine content in cigarettes and other combusted tobacco products to non-addictive levels. This qualitative study documents reactions to messages communicating this policy among people who use little cigars and cigarillos (LCCs). AIMS AND METHODS: We conducted eight focus groups with participants from four populations with the highest prevalence of cigar use (African American males and females, white males and females). Participants described their reactions to eight messages about the policy: Three messages about the equal risk of LCCs with regular and low nicotine levels; three quit efficacy messages about low nicotine LCCs being easier to quit; one "compensation" message to correct misperceptions about the policy causing people to smoke more to get desired nicotine; and one message about using alternative nicotine sources (eg, e-cigarettes). RESULTS: Participants perceived risk messages as the most motivating to quit, whereas efficacy messages made some participants feel that the policy would cause former users of LCCs to relapse. Many participants expressed favorable responses to the compensation message. The message about using alternative nicotine sources sparked intense responses, with many participants expressing outrage and mistrust of the message. Participants' beliefs that they were not addicted to LCCs dampened their perceptions of the effectiveness of the policy. CONCLUSIONS: Perceptions of the addictiveness and relative harms of LCCS influenced responses to policy messages. The FDA should consider using different messages to communicate with people who use LCCs because they perceive LCCs as different from cigarettes. IMPLICATIONS: This is the first study to document affective and cognitive responses to the FDA's reduced nicotine policy among people who use LCCs. The false belief that cigar products are less harmful than cigarettes may be influencing people's lack of support for the reduced nicotine policy and difficulty in understanding its potential positive impact. To maximize the public health benefit of the reduced nicotine policy, the FDA should include LCC products in the policy; however, it is crucial that they use educational messaging to clarify misperceptions regarding nicotine and harm as it applies to LCCs.

Independent and combined effects of very low nicotine cigarette messages and e-cigarette messages: a randomised clinical trial.

BACKGROUND: USA is considering reducing nicotine in cigarettes to non-addictive levels, coupled with promoting alternative nicotine delivery products (eg, e-cigarettes). However, effective communication is needed to reduce misperceptions about very low nicotine cigarettes (VLNCs) being less harmful than regular cigarettes. METHODS: In 2022-2023, we conducted a four-group randomised clinical trial with a national probability sample from an online panel (971 adults who smoked cigarettes exclusively, 472 adults who dual used cigarettes and e-cigarettes and 458 adults aged 18-29 who had never smoked). Participants were randomised (parallel assignment) to one message condition: (1) VLNCs as harmful but easier to quit than regular cigarettes (n=468), (2) those who are not ready to quit should consider switching to e-cigarettes as less harmful alternatives (n=484), (3) combined (VLNC and e-cigarette messages; n=476) or (4) control condition (ie, water ads), n=473. The primary outcome was perceived absolute harm of VLNCs. RESULTS: Perceived harm of VLNCs was higher in the VLNC condition compared with the e-cigarette and control conditions, and higher in the combined condition compared with the e-cigarette condition (adjusted p<0.05). Among adults who dual used, intention to switch to e-cigarettes was higher in the VLNC condition than the e-cigarette, combined or control conditions (adjusted p<0.05). CONCLUSIONS: VLNC messages reduced the misperception that VLNCs are less harmful than cigarettes, but adding messages about e-cigarettes did not enhance desired outcomes. These VLNC messages can be considered during the rollout of a reduced nicotine policy. TRIAL REGISTRATION: NCT05506046.

Vaginal Cuff Dehiscence in Transgender Patients After Minimally Invasive Hysterectomy.

STUDY OBJECTIVE: To compare rates of vaginal cuff dehiscence (VCD) in transgender patients with cisgender patients after minimally invasive hysterectomy (MIH). DESIGN: We performed a single-surgeon, retrospective cohort analysis comparing the rates of VCD in patients undergoing MIH for gender affirmation with other indications (benign, malignant, prophylactic) with our study surgeon between January, 2015, and December, 2021. SETTING: Major, urban, academic tertiary care hospital in the United States. PATIENTS: 166 patients met inclusion criteria with 49 of those patients undergoing MIH (29.5%) for gender affirmation. Of the remaining 117 patients, 92 (78.6%) underwent MIH for cancer, 15 (12.8%) for prophylaxis, and 10 (8.5%) for benign indications. INTERVENTIONS: Not applicable. MEASUREMENTS: We assessed included patients for baseline demographics, presence of risk factors for VCD, details of index hysterectomy, and details of cuff dehiscence events. MAIN RESULTS: Transgender patients tended to be younger at the time of surgery, but demographics were otherwise similar between both groups. Most transgender patients (n = 36, 73.5%) had both ovaries removed at the time of hysterectomy, 100% were on testosterone therapy pre- and postoperatively, and none used supplementary estrogen. Three of the 49 transgender patients (6.1%) experienced postoperative dehiscence of the vaginal cuff compared with 2 of the 117 cisgender patients (1.7%). This failed to reach statistical significance; however, our descriptive analysis showed that all cases of dehiscence in the cisgender group had identifiable precipitating factors (i.e., trauma). By comparison, all cases of dehiscence in the transgender group were spontaneous with few identifiable risk factors. CONCLUSION: Transgender patients undergoing MIH may be at increased risk of VCD, although the rarity of this surgical complication precluded determination of statistical significance in our data set. We propose testosterone exposure as a possible risk factor for VCD, although we cannot exclude other factors, such as young age, as drivers of VCD in this population. Future studies of biospecimens are needed to evaluate for cellular differences in these patients.

Measuring factors affecting honey bee (Hymenoptera: Apidae) attraction to soybeans using bioacoustics monitoring.

Soybean (Glycine max (L.) Merr.) is an important agricultural crop around the world, and previous studies suggest that honey bees (Apis mellifera Linnaeus) can be a component for optimizing soybean production through pollination. Determining when bees are present in soybean fields is critical for assessing pollination activity and identifying periods when bees are absent so that bee-toxic pesticides may be applied. There are currently several methods for detecting pollinator activity, but these existing methods have substantial limitations, including the bias of pan trappings against large bees and the limited duration of observation possible using manual techniques. This study aimed to develop a new method for detecting honey bees in soybean fields using bioacoustics monitoring. Microphones were placed in soybean fields to record the audible wingbeats of foraging bees. Foraging activity was identified using the wingbeat frequency of honey bees (234 ±â€…14 Hz) through a combination of algorithmic and manual approaches. A total of 243 honey bees were detected over 10 days of recording in 4 soybean fields. Bee activity was significantly greater in blooming fields than in non-blooming fields. Temperature had no significant effect on bee activity, but bee activity differed significantly between soybean varieties, suggesting that soybean attractiveness to honey bees is heavily dependent on varietal characteristics. Refinement of bioacoustics methods, particularly through the incorporation of machine learning, could provide a practical tool for measuring the activity of honey bees and other flying insects in soybeans as well as other crops and ecosystems.

Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection.

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.

The influence of season on glutamate and GABA levels in the healthy human brain investigated by magnetic resonance spectroscopy imaging.

Seasonal changes in neurotransmitter systems have been demonstrated in imaging studies and are especially noticeable in diseased states such as seasonal affective disorder (SAD). These modulatory neurotransmitters, such as serotonin, are influencing glutamatergic and GABAergic neurotransmission. Furthermore, central components of the circadian pacemaker are regulated by GABA (the suprachiasmatic nucleus) or glutamate (e.g., the retinohypothalamic tract). Therefore, we explored seasonal differences in the GABAergic and glutamatergic system in 159 healthy individuals using magnetic resonance spectroscopy imaging with a GABA-edited 3D-MEGA-LASER sequence at 3T. We quantified GABA+/tCr, GABA+/Glx, and Glx/tCr ratios (GABA+, GABA+ macromolecules; Glx, glutamate + glutamine; tCr, total creatine) in five different subcortical brain regions. Differences between time periods throughout the year, seasonal patterns, and stationarity were tested using ANCOVA models, curve fitting approaches, and unit root and stationarity tests, respectively. Finally, Spearman correlation analyses between neurotransmitter ratios within each brain region and cumulated daylight and global radiation were performed. No seasonal or monthly differences, seasonal patterns, nor significant correlations could be shown in any region or ratio. Unit root and stationarity tests showed stable patterns of GABA+/tCr, GABA+/Glx, and Glx/tCr levels throughout the year, except for hippocampal Glx/tCr. Our results indicate that neurotransmitter levels of glutamate and GABA in healthy individuals are stable throughout the year. Hence, despite the important correction for age and gender in the analyses of MRS derived GABA and glutamate, a correction for seasonality in future studies does not seem necessary. Future investigations in SAD and other psychiatric patients will be of high interest.

Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies.

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 cytokine release syndrome, 9%; grade ≥3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

Direct Measurement of Hexacontatetrapole, E6 γ Decay from

The only proposed observation of a discrete, hexacontatetrapole (E6) transition in nature occurs from the T_{1/2}=2.54(2)-min decay of ^{53m}Fe. However, there are conflicting claims concerning its γ-decay branching ratio, and a rigorous interrogation of γ-ray sum contributions is lacking. Experiments performed at the Australian Heavy Ion Accelerator Facility were used to study the decay of ^{53m}Fe. For the first time, sum-coincidence contributions to the weak E6 and M5 decay branches have been firmly quantified using complementary experimental and computational methods. Agreement across the different approaches confirms the existence of the real E6 transition; the M5 branching ratio and transition rate have also been revised. Shell model calculations performed in the full fp model space suggest that the effective proton charge for high-multipole, E4 and E6, transitions is quenched to approximately two-thirds of the collective E2 value. Correlations between nucleons may offer an explanation of this unexpected phenomenon, which is in stark contrast to the collective nature of lower-multipole, electric transitions observed in atomic nuclei.

"I'm Bored and I'm Stressed": A Qualitative Study of Exclusive Smokers, ENDS Users, and Transitioning Smokers or ENDS Users in the Time of COVID-19.

BACKGROUND: To better understand the various influences of COVID-19 on tobacco use, we examined three different tobacco user groups using qualitative methods. METHODS: Ten online focus groups with 61 adults from the Atlanta, GA area were held in October-November 2020: four with exclusive smokers (n = 16), three with Electronic Nicotine Delivery System (ENDS) users (dual and exclusive, n = 22), and three with transitioning (recently quit or currently quitting) smokers and/or ENDS users (n = 23). RESULTS: Exclusive smokers reported smoking more frequently, driven by COVID-19-related stress, time at home, and boredom. They were not motivated to quit during the pandemic, and some considered smoking to be protective against COVID-19. ENDS users reported vaping less, with dual users often increasing their smoking; many were concerned about health effects of smoking and ENDS use during the pandemic. Transitioning smokers/ENDS users worried about their health and wanted to quit, but many found the stress of COVID-19 unbearable without tobacco use. CONCLUSIONS: There were some similarities among the groups, but also pronounced differences. Educational campaigns should capitalize on the teachable moment of COVID-19 to increase perceived risk of smoking. Smokers need access to more adaptive ways to deal with stress (such as mindfulness training) in lieu of smoking and systems-level approaches should address structural determinants of health that cause high levels of stress. The proposed policy to lower nicotine in combusted tobacco products might help smokers choose other means of coping instead of cigarettes by reducing the stress-relieving properties of smoking particularly salient during the pandemic. IMPLICATIONS: Smokers believe that cigarettes help them deal with the stresses and challenges of the COVID-19 pandemic. This needs to be counteracted by educational campaigns to increase perceived harm of smoking, alternative stress-relief strategies, and mandated changes to the combusted tobacco products to make them less appealing.

Slow Binocular Reading in Amblyopic Children Is a Fellow Eye Deficit.

SIGNIFICANCE: Amblyopic children read 25% slower than their peers during binocular silent reading. PURPOSE: We compared binocular reading to fellow eye reading to determine whether slow reading in amblyopic children is due to binocular inhibition; that is, the amblyopic eye is interfering during binocular reading. METHODS: In a cross-sectional study, 38 children with amblyopia and 36 age-similar control children who completed grades 1 to 6 were enrolled. Children silently read grade-appropriate paragraphs during binocular reading and fellow eye reading while wearing ReadAlyzer eye-tracking goggles (Compevo AB, Stockholm, Sweden). Reading rate, number of forward saccades, number of regressive saccades, and fixation duration were analyzed between groups and between viewing conditions. We also examined whether sensory factors (amblyopia severity, stereoacuity, suppression) were related to slow reading. RESULTS: For amblyopic children, binocular reading versus fellow eye reading did not differ for reading rate (176 ± 60 vs. 173 ± 53 words per minute, P = .69), number of forward saccades (104 ± 35 vs. 97 ± 33 saccades/100 words, P = .18), number of regressive saccades (21 ± 15 vs. 22 ± 13 saccades/100 words, P = .75), or fixation duration (0.31 ± 0.06 vs. 0.32 ± 0.07 seconds, P = .44). As expected, amblyopic children had a slower reading rate and more forward saccades than control children during binocular reading and fellow eye reading. Slow reading was not related to any sensory factors. CONCLUSIONS: Binocular reading did not differ from fellow eye reading in amblyopic children. Thus, binocular inhibition is unlikely to play a role in slow binocular reading and is instead a fellow eye deficit that emerges from a disruption in binocular visual experience during development.

Automated Item Generation: impact of item variants on performance and standard setting.

BACKGROUND: Automated Item Generation (AIG) uses computer software to create multiple items from a single question model. There is currently a lack of data looking at whether item variants to a single question result in differences in student performance or human-derived standard setting. The purpose of this study was to use 50 Multiple Choice Questions (MCQs) as models to create four distinct tests which would be standard set and given to final year UK medical students, and then to compare the performance and standard setting data for each. METHODS: Pre-existing questions from the UK Medical Schools Council (MSC) Assessment Alliance item bank, created using traditional item writing techniques, were used to generate four 'isomorphic' 50-item MCQ tests using AIG software. Isomorphic questions use the same question template with minor alterations to test the same learning outcome. All UK medical schools were invited to deliver one of the four papers as an online formative assessment for their final year students. Each test was standard set using a modified Angoff method. Thematic analysis was conducted for item variants with high and low levels of variance in facility (for student performance) and average scores (for standard setting). RESULTS: Two thousand two hundred eighteen students from 12 UK medical schools participated, with each school using one of the four papers. The average facility of the four papers ranged from 0.55-0.61, and the cut score ranged from 0.58-0.61. Twenty item models had a facility difference > 0.15 and 10 item models had a difference in standard setting of > 0.1. Variation in parameters that could alter clinical reasoning strategies had the greatest impact on item facility. CONCLUSIONS: Item facility varied to a greater extent than the standard set. This difference may relate to variants causing greater disruption of clinical reasoning strategies in novice learners compared to experts, but is confounded by the possibility that the performance differences may be explained at school level and therefore warrants further study.

Review: the risks of spray adjuvants to honey bees.

Pesticide applications are often made as tank mixes containing multiple pesticide products and may include spray adjuvants to enhance pesticidal activities. The primary aim of adjuvant products is to increase the spreading and sticking of spray droplets and to increase the penetration of active ingredients through the cuticles of leaves or targeted pests, which can reduce the amount of active ingredient needed for effective pest control. Adjuvants are made up of compounds drawn from the "inert ingredient" list maintained by EPA but are identified as "principal functioning agents" when used in adjuvant products. These inert compounds do not undergo the same testing and risk assessment process that is required of pesticide active ingredients and generally have no mitigation measures that prevent application onto crops during bloom at times of day when bees are foraging. Honey bees (Apis mellifera;Hymenoptera:Apidae) are at an increased risk of exposure to adjuvant tank mixtures while providing agricultural pollination services. Colony losses attributed to pesticide applications thought to have low risk to honey bees have been reported, highlighting the need to better understand the toxicity of adjuvants included in pesticide tank mixtures. This review summarizes current literature on the risks posed to honey bees by agricultural adjuvants and tank mix combinations of adjuvants with pesticides. Based on the current state of knowledge, we make recommendations to pesticide applicators, product manufacturers, regulatory agencies, and researchers regarding adjuvant toxicity to honey bees with the goal of reducing risks that adjuvants pose to honey bees and other beneficial insects.

Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure.

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.

Perceptions of Nicotine Reduction Policy in the United States: A Qualitative Study.

INTRODUCTION: Several countries are considering a reduced nicotine policy that would make cigarettes minimally or nonaddictive. This qualitative study documents reactions to the policy that should be addressed by future communication efforts. METHODS: In 2020, we recruited participants in Atlanta, GA and San Francisco, CA (27 people who exclusively smoke, 25 who dual use cigarettes and e-cigarettes, 32 who formerly smoked, and 31 young adults who do not smoke). We held 16 focus groups: 2 focus groups for each smoking status in each city. Participants viewed messages about very low nicotine content cigarettes (VLNCs) and were asked about their reactions to each message and their overall response to the reduced nicotine policy. RESULTS: While responses to the policy were predominantly positive, focus group discussion also revealed concerns, questions, and misunderstandings (referred to here collectively as "perceptions") that may need to be addressed if a reduced nicotine policy is enacted. Participants expressed perceptions related to the policy intent, including that the FDA has ulterior motives, adoption/ implementation, including that nicotine would have to be replaced with other chemicals if removed or that the policy would be unfeasible to implement, and effectiveness, including concern that VLNCs would still be addictive or the policy would backfire. CONCLUSIONS: Addressing perceptions about reduced nicotine policy intent, adoption/implementation, and effectiveness could be key in creating public support and political motivation to move forward with such a policy. Countries contemplating adopting such a policy should consider pairing it with communications that address these perceptions. IMPLICATIONS: This study is one of very few to use qualitative methods to explore potentially problematic perceptions about nicotine reduction policy among US adults. Results illuminated new policy-specific concerns, questions, and misunderstandings about the reduced nicotine policy intent, adoption/implementation, and effectiveness. Identifying, studying, and addressing relevant perceptions may play a key role in generating support in countries contemplating such a policy.