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Abstract Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.

Abstract Postpartum depression (PPD) affects up to 20% of new mothers and has adverse consequences for the well-being of both mother and child. Exposure to stress during pregnancy as well as dysregulation in the mesolimbic dopamine (DA) reward system and its upstream modulator oxytocin (OT) have been independently linked to PPD. However, no studies have directly examined DA or OT signaling in the postpartum brain after gestational stress. Here we employed a chronic variable stress procedure during pregnancy and evaluated behavioral measures of mood and reward along with assessments of DA and OT signaling in postpartum rats. Our results show that gestational stress induced postpartum depressive-like and anxiety-like behavior in addition to producing reward-related deficits including anhedonia, impaired maternal care, and reduced maternal motivation. Consistent with a hypodopaminergic state, histological analysis revealed reduced expression of tyrosine hydroxylase in the NAc shell and core as well as reduced expression of the dopamine transporter and dopamine D2 receptor in the NAc shell of postpartum females exposed to gestational stress. A reduction in accumbal DA content as determined by liquid chromatography-mass spectrometry was also observed in gestationally-stressed dams. Lastly, we assessed mRNA expression of OT and OT receptors (OTR) and found that gestational stress increased OT expression in the hypothalamus but reduced OTR expression in the postpartum ventral tegmental area (VTA), a target of hypothalamic OT neurons. In the VTA, a reduction in OT-immunoreactive fibers following gestational stress was also seen. Taken together, these data demonstrate that the DA and OT systems within the postpartum reward circuit are sensitive to gestational stress and suggest that mood and maternal disruptions in PPD may arise from dysfunctional oxytocinergic regulation of the dopaminergic reward system.

To comprehend language, we continually use prior context to pre-activate expected upcoming information, resulting in facilitated processing of incoming words that confirm these predictions. But what are the consequences of disconfirming prior predictions? To address this question, most previous studies have examined unpredictable words appearing in contexts that constrain strongly for a single continuation. However, during natural language processing, it is far more common to encounter contexts that constrain for multiple potential continuations, each with some probability. Here, we ask whether and how pre-activating both higher and lower probability alternatives influences the processing of the lower probability incoming word. One possibility is that, similar to language production, there is continuous pressure to select the higher-probability pre-activated alternative through competitive inhibition. During comprehension, this would result in relative costs in processing the lower probability target. A second possibility is that if the two pre-activated alternatives share semantic features, they mutually enhance each others pre-activation. This would result in greater facilitation in processing the lower probability target. To distinguish between these accounts, we recorded ERPs as participants read three-sentence scenarios that constrained either for a single word or for two potential continuations - a higher probability expected candidate and a lower probability second-best candidate. We found no evidence that competitive pre-activation between the expected and second-best candidates resulted in costs in processing the second-best target, either during lexico-semantic processing (indexed by the N400) or at later stages of processing (indexed by a later frontal positivity). Instead, we found only benefits of pre-activating multiple alternatives, with evidence of enhanced graded facilitation on lower-probability targets that were semantically related to a higher-probability pre-activated alternative. These findings are consistent with a previous eye-tracking study by Luke and Christianson (2016, Cogn Psychol) using corpus-based materials. They have significant theoretical implications for models of predictive language processing, indicating that routine graded prediction in language comprehension does not operate through the same competitive mechanisms that are engaged in language production. Instead, our results align more closely with hierarchical probabilistic accounts of language comprehension, such as predictive coding.

Abstract: The Cross-Hosgri slope is a bathymetric lineament that crosses the main strand of the Hosgri fault offshore Point Estero, central California. Recently collected chirp seismic reflection profiles and sediment cores provide the basis for a reassessment of Cross-Hosgri slope origin and the lateral slip rate of the Hosgri fault based on offset of the lower slope break of the Cross-Hosgri slope. The Cross-Hosgri slope is comprised of two distinct stratigraphic units. The lower unit (unit 1) overlies the post–Last Glacial Maximum transgressive erosion surface and is interpreted as a Younger Dryas (ca. 12.85–11.65 ka) shoreface deposit based on radiocarbon and optically stimulated luminescence (OSL) ages, Bayesian age modeling, seismic facies, sediment texture, sediment infauna, and heavy mineral component. The shoreface was abandoned and partly eroded during rapid sea-level rise from ca. 11.5 to 7 ka. Unit 2 consists of fine sand and silt deposited in a midshelf environment when the rate of sea-level rise slowed between ca. 7 ka and the present. Although unit 2 provides a thin, relatively uniform cover over the lower slope break of the older shoreface, this feature still represents a valuable piercing point, providing a Hosgri fault slip rate of 2.6 ± 0.8 mm/yr. Full-waveform processing of chirp data resulted in significantly higher resolution in coarser-grained strata, which are typically difficult to interpret with more traditional envelope processing. Our novel combination of offshore radiocarbon and OSL dating is the first application to offshore paleoseismic studies, and our results indicate the utility of this approach for future marine neotectonic investigations.

A sample of 116 university students enrolled in developmental psychology courses participated in a study examining whether playing interactive video games with older adults would reduce students' misconceptions and negative stereotypes about older adults and increase their willingness to interact with older adults in the future. A service-learning group (n = 84) spent 10 hours playing interactive video games with older adults, while a comparison group (n = 32) participated in alternate activities. Results indicated that the service-learning group endorsed fewer negative stereotypes and had an increased desire to interact with older adults in the future than the comparison group.

Rurality has served as a key concept in popular and scientific understandings of the US overdose crisis, with White, rural, and low-income areas thought to be most heavily affected. However, we observe that overdose trends have risen nearly uniformly across the urban-rural designations employed in most research, implying that their importance has likely been overstated or incorrectly conceptualized. Nevertheless, urbanicity/rurality does serve as a key axis to understand inequalities in overdose mortality when assessed with more nuanced modalities-employing a more granular analysis of geography at the sub-county level, and intersecting rurality sociodemographic indices such as race/ethnicity. Using national overdose data from 1999-2021, we illustrate the intersectional importance of rurality for overdose surveillance. Finally, we offer recommendations for integrating these insights into drug overdose surveillance moving forward.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) characterized by a hallmark translocation of t (11; 14). CD10 negativity has been used to differentiate MCL from other NHL types; however, recently, there has been an increase in the number of reported cases of CD10-positive MCL. This warrants further investigation into this rarer immunophenotype and its clinical significance. BCL6, which is a master transcription factor for the regulation of cell proliferation and key oncogene in B cell lymphomagenesis, has been reported to have co-expression with CD10 in MCL. The clinical significance of this aberrant antigen expression remains unknown. We conducted a systematic review by searching four databases and selected five retrospective analyses and five case series. Two survival analyses were conducted to determine if BCL6 positivity conferred a survival difference: 1. BCL6+ vs. BCL6- MCL. 2. BCL6+/CD10+ vs. BCL6-/CD10+ MCL. Correlation analysis was conducted to determine if BCL6 positivity correlated with the Ki67 proliferation index (PI). Overall survival (OS) rates were performed by the Kaplan-Meier method and log-rank test. Our analyses revealed that BCL6+ MCL had significantly shorter overall survival (median OS: 14 months vs. 43 months; p = 0.01), BCL6+/CD10+ MCL had an inferior outcome vs. BCL6+/CD10- MCL (median OS: 20 months vs. 55 months p = 0.1828), BCL6+ MCL had significantly higher percentages of Ki67% (Ki67% difference: 24.29; p = 0.0094), and BCL6 positivity had a positive correlation with CD10+ status with an odds ratio 5.11 (2.49, 10.46; p = 0.0000286). Our analysis showed that BCL6 expression is correlated with CD10 positivity in MCL, and BCL6 expression demonstrated an inferior overall survival. The higher Ki67 PI in BCL6+ MCL compared to BCL6- MCL further supports the idea that the BCL6+ immunophenotype may have prognostic value in MCL. MCL management should consider incorporating prognostic scoring systems adjusted for BCL6 expression. Targeted therapies against BCL6 may offer potential therapeutic options for managing MCL with aberrant immunophenotypes.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Purpose: To compare the biomechanical properties of quadriceps tendon (QT) graft stitch methods using 3 different suture systems for anterior cruciate ligament reconstruction. Methods: A total of 48 QTs were harvested from cadaveric knee specimens (age: 73 ± 7 years; range, 66-86 years). Samples were randomly divided into 3 groups where different suture needle systems were used to create 2 stitch methods: whipstitch (WS) and locking stitch (LS). Surgeons performed each technique to 5 stitches, each 0.5 cm apart. Stitching time was recorded. Samples were preconditioned and then underwent cyclic loading, followed by load to failure. Stiffness (N/mm), ultimate failure load (N), peak-to-peak displacement (mm), elongation (mm), and failure displacement (mm) were recorded. Results: WS and LS were equivalent across stiffness, ultimate load, and peak-to-peak displacement within groups 2 and 3. In group 1, the LS was stiffer than the WS, but the WS achieved a higher ultimate load. For all groups, the LS achieved lower elongation and failure displacement than the WS, with significant differences in groups 1 and 2. Within each stitching method, equivalence was determined for total elongation and ultimate failure load for all 3 suture system groups. For WS samples, group 1 all failed from suture breakage, and both groups 2 and 3 had instances of failure from suture pull-through. All LS samples failed from suture breakage. Conclusions: Both LS and WS provide adequate mechanical properties in each of the 3 suture systems. Differences in performance do exist; however, each method shows equivalent total elongation and ultimate failure load for all 3 suture systems. LS may be preferred over WS due to lower mean elongation and failure displacement. Clinical Relevance: There is an increased use of QT grafts in for anterior cruciate ligament reconstruction. However, there have been a limited number of studies comparing various stitching methods and optimizing techniques for QT graft fixation. This study may provide important information to surgeons about which suture techniques have better biomechanical profiles.

Transgender persons have an increased vulnerability to HIV infection yet have not been well-represented in past clinical trials for pre-exposure prophylaxis (PrEP). Because of this, there are few data available to understand whether gender-affirming hormone concentrations are influenced by PrEP agents in transgender men (TM) and transgender women (TW). The objective of this study was to compare gender-affirming hormone concentrations with versus without emtricitabine (F, FTC)-tenofovir disoproxil fumarate (TDF). TM and TW without HIV, aged 15-24 years, were enrolled for 1 month of directly observed daily F/TDF. Participants were required to be receiving a stable hormone dose (estradiol or testosterone) for at least 1 month or three consecutive doses, whichever was longer, before enrollment and willing to continue the same dose. Intensive pharmacokinetic (PK) sampling for gender-affirming hormones was collected before and 2-3 weeks after daily F/TDF. Serum estradiol and total testosterone were determined by liquid chromatography-tandem mass spectrometry; free testosterone by equilibrium dialysis. Maximum concentrations (Cmax) and area under the curve (AUClast) were log-transformed and compared between baseline and on F/TDF using geometric mean ratios (GMRs) with 95% confidence intervals (CIs). Twenty-five TW and 24 TM were enrolled (median age: 20 and 21 years, respectively). In TW, estradiol Cmax (GMR [95% CI]: 0.85 [0.65-1.11]) and AUClast (GMR [95% CI]: 0.87 [0.73-1.03]) were comparable on F/TDF versus baseline. In TM, similar comparability was observed for PrEP versus baseline including total testosterone Cmax (GMR [95% CI]: 0.91 [0.80-1.03]) and AUClast (GMR [95% CI]: 0.91 [0.81-1.04]) and free testosterone Cmax (GMR [95% CI]: 0.89 [0.74-1.07]) and AUClast (GMR [95% CI]: 0.88 [0.74-1.03]). Estradiol and testosterone exposures in young TW and TM did not significantly differ on F/TDF versus baseline. These findings should reassure patients and providers that F/TDF can be used as PrEP without concern for altering gender-affirming hormone PK. ClinicalTrials.gov (NCT03652623).

Introduction: Discrepancies between parental and child perceptions of problems and their therapeutic expectations can negatively impact mental health treatment efficacy. Aims: We sought to explore concordance and discrepancy in families receiving brief, client-centered, and strengths-based mental health services, specifically by contrasting parents’ and children’s perceptions of the child’s presenting issues; treatment expectations; and levels of concern pre- and post-treatment. We also examined the psychometric properties of a therapeutic scaling question on the level of concern, by examining associations with scores from the Strengths and Difficulties Questionnaire. Methods: Using a mixed-methods approach, we examined data from openand closed-ended questions, some used as part of the treatment. This included brief descriptions of perceived presenting issues and treatment expectations, and levels of concern on a scale of 1 to 10. Results: Parent and child descriptions of issues were judged generally congruent 66% of the time. Respectively, minor and major non-congruence was observed 25% and 9% of the time. In terms of treatment expectations, parents were more likely to express a desire to understand the issues and improve communication in the family. Children were more likely to express no expectancies or respond with simple statements (e.g., feel better). Parents initially rated their children’s problems as more severe than did their children. We found that the scaling question demonstrated a modest association with the level of concern from the Strength and Difficulties Questionnaire (SDQ). Conclusions: Even though most parents and their children broadly agree on presenting mental health issues for which they seek counseling, important differences manifest in how they perceive them and what they want accomplished during sessions. Practitioners need to consider, assess, and accommodate such discrepancies.

The Great Salt Lake (GSL) is the largest saline lake in the Western Hemisphere. It supports billion-dollar industries and recreational activities, and is a vital stopping point for migratory birds. However, little is known about the spatiotemporal variation of phytoplankton biomass in the lake that supports these resources. Spectral reflectance provided by three remote sensing products was compared relative to their relationship with field measurements of chlorophyll a (Chl a). The MODIS product MCD43A4 with a 500 m spatial resolution provided the best overall ability to map the daily distribution of Chl a. The imagery indicated significant spatial variation in Chl a, with low concentrations in littoral areas and high concentrations in a nutrient-rich plume coming out of polluted embayment. Seasonal differences in Chl a showed higher concentrations in winter but lower in summer due to heavy brine shrimp (Artemia franciscana) grazing pressure. Twenty years of imagery revealed a 68% increase in Chl a, coinciding with a period of declining lake levels and increasing local human populations, with potentially major implications for the food web and biogeochemical cycling dynamics in the lake. The MCD43A4 daily cloud-free images produced by 16-day temporal composites of MODIS imagery provide a cost-effective and temporally dense means to monitor phytoplankton in the southern (47% surface area) portion of the GSL, but its remaining bays could not be effectively monitored due to shallow depths, and/or plankton with different pigments given extreme hypersaline conditions.

The transgender community has expressed concerns regarding drug-drug interactions between HIV-pre-exposure prophylaxis (PrEP) and gender-affirming hormones. In this study, we evaluated emtricitabine (F, FTC)/tenofovir (TFV) disoporoxil fumarate (TDF) pharmacokinetics (PK) among adolescent and young adult transgender persons receiving gender-affirming hormone therapy (GAHT). This was a prospective, observational study among transgender women (TW) and men (TM) without HIV, 15-24 years of age, receiving GAHT (estradiol with/without spironolactone, or testosterone). Participants received 1 month of directly observed daily F/TDF. Weekly convenience blood samples were collected for plasma TFV and FTC, and intracellular TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in peripheral blood mononuclear cells (PBMC) and dried blood spots (DBS). After 2-3 weeks of F/TDF dosing, intensive PK sampling was conducted. PK parameters were estimated using noncompartmental methods. Data were log-transformed and compared between TM and TW, and to historical data among cisgender adults. Plasma TFV exposures were similar between TM and TW [geometric mean ratio (GMR); confidence interval (95% CI): 1.06 (0.89-1.28)], whereas FTC plasma exposures were 21% higher in TM versus TW (95% CI: 1.07-1.38). TFV-DP in PBMC and DBS and FTC-TP in DBS did not differ between TM versus TW after controlling for creatinine clearance (CrCl), but FTC-TP in PBMC remained 46% (95% CI: 1.15-1.86) higher in TM versus TW. All PK exposures were within expected ranges based on historical studies. TM had higher FTC exposures compared with TW, but overall plasma and intracellular exposures for both drugs were within the range of historical studies, suggesting high PrEP efficacy will be retained in adolescent and young adult transgender persons. Registered at ClinicalTrials.gov (NCT03652623).