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Pedro M Serra, Michael J Cox, Catharine M Chisholm Bradford School of Optometry and Vision Sciences, University of Bradford, Bradford, UK Objective: Astigmatism produces meridional variations in the retinal blur pattern, thus interacting with object spatial detail and altering visual performance as the axis changes. This study investigates the influence of astigmatic axis orientation on visual acuity (VA) for four alphabets used worldwide. Methods: Visual acuity was measured monocularly in 25 Roman alphabet users (mean age: 25.6±7.5 years) using computer-presented logarithm of the minimum angle of resolution (logMAR) charts with letters from four different alphabets (Arabic, Chinese, Roman, and Tamil). VA was assessed under the effect of four optical conditions: best distance correction and three astigmatic conditions (using a +2.00 cylindrical diopter trial case lens with its axis oriented at 180, 45, or 90 degrees). For each alphabet, single optotypes were presented on a monitor viewed from a distance of 4.0 m, and a matching technique was used to identify the letters. Results: The degradation in VA with astigmatic defocus was influenced by the alphabet used (p

Utilizing data from the NICHD Study of Early Child Care, the primary objective of the current report was to examine how avoidant and resistant mother - infant attachment classifications at 15 months were differentially associated with children's interaction with a same-sex friend and exploration during solitary play at 36 months. The added contributions of attachment security at 36 months and maternal sensitivity from 6 to 36 months to the prediction of child outcomes were also explored. As hypothesized, an avoidant attachment history was related to more instrumental aggression during child-friend interaction, whereas a resistant attachment history was associated with less self-assertion/control among friends and less attention and pretend play during exploration. Maternal sensitivity and concurrent attachment security also made unique contributions to the prediction of child outcomes at 36 months, although associations with 15-month attachment remained significant when these subsequent measures of the mother - child relationship were considered. Few differences emerged for the disorganized mother - infant attachment category in this relatively low-risk sample. Results underscore the need to differentiate between avoidant and resistant attachment groups and illustrate how early attachment history and subsequent indices of the mother - child relationship contribute to children's functioning. [ABSTRACT FROM AUTHOR]

Objective. This study tested maternal sensitivity as a moderator of the stability of wary behavior between 15 months and the transition to school. Design. Observational data from 15-month-old children and their mothers, kindergarten teacher reports, and maternal reports during the transition to kindergarten from 215 children from 3 sites (North Carolina, Virginia, and Arkansas) of the National Institute of Child Health and Human Development (NICHD; 1994), Study of Early Child Care are used. Results. Findings indicate significant stability of inhibition from 15 months to the transition to kindergarten and a significant interaction between maternal sensitivity and 15-month wariness in predicting inhibition in the transition to kindergarten. Among children who displayed wariness at 15 months, greater maternal sensitivity was associated with less inhibition during the transition to kindergarten. For children who did not display wariness at 15 months, there was no relation between maternal sensitivity and inhibition in the transition to kindergarten. Conclusions. These findings suggest moderate stability of this early temperamental characteristic and point to the importance of responsive parenting in its modification. [ABSTRACT FROM AUTHOR]

This case study describes a 23-year-old woman who had an unintentional blind placement of a 16 Fr Foley catheter into her right ureter with inflation of the balloon in the right renal pelvis. Pertinent medical history/presentation, clinical interactions, and clinical implications are discussed. [ABSTRACT FROM AUTHOR]

Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8 + CART cells develop signs of exhaustion independently of the presence of CD4 + CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy., (© 2024. The Author(s).)

Background: Medication disposal programs have been promoted as one solution to the opioid crisis, but uptake by community members has been minimal. Objectives: To clarify perceptions of medication disposal options among people who have been prescribed an opioid analgesic in North Carolina to inform interventions that can facilitate the disposal of unused opioids. Methods: In 2022, we conducted focus groups with participants who received an opioid medication in the past year to gain information to develop an intervention related to the disposal of unused opioid medication (12 focus group discussions (FGDs); total N  = 37; 30 identified as female, 6 as male, and 1 as another gender). Participants were shown a slide with the Food and Drug Administration's recommended disposal options and asked about their perceptions of each option. Themes were derived using an inductive, thematic, qualitative approach. Results: Seven themes about perceptions of medication disposal programs emerged from the data. Four of the themes reflect potential barriers to medication disposal: failed disposal attempts, lack of sufficient education on proper disposal, unclear meaning of specific disposal language, and concerns about existing disposal options. Three of the themes provide insight on potential facilitators of medication disposal: preference of low-cost disposal options, ease and accessibility among disposal methods, and preferred disposal methods. Conclusion: Patients should be provided clear and consistent guidance from prescribers and dispensing pharmacists on when and how to dispose of unused medications and opportunities to dispose of medications at no cost to the patient.

Introduction: The presence of cannabinoid products in the home may increase the likelihood of unintended adverse consequences for children and adolescents. Secure storage of these products is one prevention method to decrease the risk of diversion and use of cannabinoid products among youth. We sought to examine cannabis, delta-8 tetrahydrocannabinol (THC), and cannabidiol (CBD) storage practices among a sample of adults 18-64 years old residing in the USA., Methods: In December 2021, we conducted an online cross-sectional survey of 1042 current (past 30 day) users of cannabinoid products (88.3% cannabis, 49.0% delta-8 THC, and 67.2% CBD). Participants were asked about where they typically keep products in their home (ie, in a locked container, unlocked container, or out in the open). We conducted multinomial regression analyses to examine the relationship between sociodemographic characteristics and cannabinoid use behaviours with home storage practices., Results: For all products, participants more frequently reported locking, followed by storing the product in an unlocked but not visible location. Storing the product in an unlocked and visible location was endorsed the least across all three products. Participants reported more frequent endorsement of locking cannabis products as compared with delta-8-THC and CBD. Storage practices varied by biological sex, sexual orientation, ethnicity, educational attainment, having a child who lives in the home, frequency of use, possession of a medical cannabis card and exposure to advertising., Conclusions: Increasing the prevalence of secure storage practices of cannabinoid products may facilitate prevention of unanticipated consequences associated with diversion of these products., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Secure storage and disposal is a critical strategy to reduce prescription opioid misuse. We sought to develop effective messages to promote secure storage and disposal of unused opioid medications that can be used in interventions designed to reduce diversion of opioid medications for nonmedical use., Methods: We used a mixed-method design to develop and evaluate messages. First, we pretested 34 messages in focus group discussions (FGDs; n = 12 FGDs, n = 2-5 participants per FGD; 37 total participants). Then, we tested the 12 most salient messages in an online survey with a nationally representative Qualtrics ® panel (n = 1520 participants). A pretest-posttest design was conducted to assess change in beliefs about storage and disposal of opioid medication following message exposure., Results: All 12 messages favorably influenced participants' perceptions related to concerns and risks of retaining unused opioid medications and the importance of and self-efficacy in securely storing and disposing of unused opioid medications. Storage and disposal messages that included the sentence-"Your prescription can become someone else's addiction."-outperformed other messages in encouraging people to safely store or dispose of opioid medication., Conclusions: This study informs the development of a universal text message intervention using multimodal feedback from the target population that the intervention seeks to serve. The next step is to conduct a randomized controlled trial to assess efficacy of the intervention., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: We systematically reviewed the literature to assess the association between use of alcohol protective behavioral strategies (PBS) and young adult heavy drinking and alcohol-related consequences., Method: We followed the preferred reporting items for systematic review and meta-analysis guidelines to select and review research studies that were comprised of a sample of young adults ages 18-26, included PBS derived from one of 10 validated scales as an independent variable, measured heavy alcohol use or alcohol consequences as the dependent variable, and tested the direct association between the two. Studies were gathered via PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature, APA PsycInfo, and Global Health. All identified study records underwent a two-step screening process and risk of bias assessment., Results: Data were extracted from 94 studies that met inclusion criteria; 16 studies (17%) examined associations with heavy alcohol use and 91 studies (97%) tested effects of PBS on alcohol consequences. All studies that measured a total effect of PBS use (summations across all strategies) found significant negative associations with heavy alcohol use and 91% were negatively associated with alcohol consequences. Most studies that examined subscales of PBS found at least one significant, negative relation with heavy alcohol use (73%) and alcohol-related consequences (78%), though effects varied across type of subscale (e.g., manner of drinking)., Conclusions: Our results support the use of PBS to address heavy alcohol consumption and related harms among young adults. Opportunities for refinement of current PBS in preventive interventions are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution of somatic mutations in the hematopoietic compartment, the restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof of principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow., Significance: CH occurs commonly in humans and can predispose to hematologic malignancy. Although well characterized in blood, it is poorly understood how clones are spatially distributed in the bone marrow. To answer this, we developed methods for spatially aware somatic mutation profiling to describe clonal heterogeneity in human bone marrow. See related commentary by Austin and Aifantis, p. 139., (©2024 The Authors; Published by the American Association for Cancer Research.)

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin + colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients., (© The Author(s), 2024.)

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance., (© 2024. The Author(s).)

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F-knockin mice with α-KG supplementation significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte, and platelet counts. Finally, α-KG treatment significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling that contributes to platelet hyperreactivity in MPN patients.

Objective: This study examined how young adults' likelihood to engage in protective behavioral strategies (PBS) to reduce alcohol harms varies across physical and social contexts for drinking., Method: We conducted an online survey with 514 heavy drinking young adults (M age = 22.4 years, 52% women, 30% Hispanic/Latin(x), 40% non-White). Participants were asked to rate their likelihood to engage in 26 PBS generally, and specifically in six physical contexts (e.g., bar/club), and six social contexts (e.g., in a large group). We conducted regression analyses to examine the overall effect of context on the likelihood to engage in each PBS and post-hoc Tukey tests to assess pairwise comparisons of the differences in likelihood to engage in each PBS across response options for physical and social context. Analyses were conducted using the full sample, and for men and women separately., Results: There were significant differences in six strategies across physical contexts; likelihood to engage in PBS varied across public and private spaces for different strategies. We also found significant differences in five strategies across social contexts; participants were more likely to engage in PBS among larger numbers of people and those who are intoxicated. There were numerous differences in pairwise comparisons of PBS engagement across physical and social contexts for women, while men demonstrated only two differences in PBS across physical context., Conclusions: Results suggest that alcohol interventions for young adults that include PBS should consider tailoring strategies to the individual and the specific context of the drinking event.

Background: Protective behavioral strategies (PBS) are specific harm reduction behaviors which mitigate alcohol-related consequences among young adults. Prior work indicates PBS utilization varies according to drinking context and gender, suggesting a need for further research assessing whether young adults employ unidentified PBS according to such factors. Objectives: This study examined alcohol PBS young adults suggest using across drinking contexts and gender to inform alcohol-related harm reduction interventions. Methods: An online survey with 514 young adult heavy drinkers ( n  = 269 female, M age  = 22.36 years) assessed PBS use generally, and across 12 physical and social contexts. We utilized qualitative content analysis methods to code and derive themes from open-ended responses from a prompt asking participants to state additional PBS used per context. The frequency of each theme's appearance was calculated across the overall sample, by gender, and within each context. Results: PBS endorsement varied across context and gender within each theme. Young adults who reported PBS use most frequently endorsed utilizing strategies related to drink content (18.30%), social support (12.36%), and engaging in other activities (10.34%). Participants infrequently endorsed strategies related to awareness of time (0.23%), standards of behavior (0.78%) and avoiding environments (0.87%). Conclusions: Young adults endorse utilizing additional PBS in varying frequency according to drinking context and gender. Given PBS are often a key component of alcohol harm reduction interventions, monitoring trends in young adult PBS use is crucial to ensure continued relevance and efficacy of such interventions to minimize harms associated with young adult heavy alcohol use.

The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)-cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages., (©2023 American Association for Cancer Research.)

Background: Fungal-bacterial cocolonization and coinfections pose an emerging challenge among patients suspected of having pulmonary tuberculosis (PTB); however, the underlying pathogenic mechanisms and microbiome interactions are poorly understood. Understanding how environmental microbes, such as fungi and bacteria, coevolve and develop traits to evade host immune responses and resist treatment is critical to controlling opportunistic pulmonary fungal coinfections. In this project, we propose to study the coexistence of fungal and bacterial microbial communities during chronic pulmonary diseases, with a keen interest in underpinning fungal etiological evolution and the predominating interactions that may exist between fungi and bacteria., Objective: This is a protocol for a study aimed at investigating the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections through determining and characterizing the burden, etiological profiles, microbial communities, and interactions established between fungi and bacteria as implicated among patients with presumptive PTB., Methods: This will be a laboratory-based cross-sectional study, with a sample size of 406 participants. From each participant, 2 sputa samples (one on-spot and one early morning) will be collected. These samples will then be analyzed for both fungal and bacterial etiology using conventional metabolic and molecular (intergenic transcribed spacer and 16S ribosomal DNA-based polymerase chain reaction) approaches. We will also attempt to design a genome-scale metabolic model for pulmonary microbial communities to analyze the composition of the entire microbiome (ie, fungi and bacteria) and investigate host-microbial interactions under different patient conditions. This analysis will be based on the interplays of genes (identified by metagenomics) and inferred from amplicon data and metabolites (identified by metabolomics) by analyzing the full data set and using specific computational tools. We will also collect baseline data, including demographic and clinical history, using a patient-reported questionnaire. Altogether, this approach will contribute to a diagnostic-based observational study. The primary outcome will be the overall fungal and bacterial diagnostic profile of the study participants. Other diagnostic factors associated with the etiological profile, such as incidence and prevalence, will also be analyzed using univariate and multivariate schemes. Odds ratios with 95% CIs will be presented with a statistical significance set at P<.05., Results: The study has been approved by the Mbarara University Research Ethic Committee (MUREC1/7-07/09/20) and the Uganda National Council of Science and Technology (HS1233ES). Following careful scrutiny, the protocol was designed to enable patient enrollment, which began in March 2022 at Mbarara University Teaching Hospital. Data collection is ongoing and is expected to be completed by August 2023, and manuscripts will be submitted for publication thereafter., Conclusions: Through this protocol, we will explore the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections among patients with presumptive PTB. Establishing key fungal-bacterial cross-kingdom synergistic relationships is crucial for instituting fungal bacterial coinfecting etiology., Trial Registration: ISRCTN Registry ISRCTN33572982; https://tinyurl.com/caa2nw69., International Registered Report Identifier (irrid): DERR1-10.2196/48014., (©Israel Kiiza Njovu, Pauline Petra Nalumaga, Lucas Ampaire, Edwin Nuwagira, James Mwesigye, Benson Musinguzi, Kennedy Kassaza, Kabanda Taseera, James Kiguli Mukasa, Joel Bazira, Jacob Stanley Iramiot, Andrew Baguma, Felix Bongomin, Richard Kwizera, Beatrice Achan, Michael J Cox, Jason S King, Robin May, Elizabeth R Ballou, Herbert Itabangi. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 15.08.2023.)

Introduction: The hygiene hypothesis identified a relationship between living in rural areas and acquiring protective environmental factors against the development of asthma and atopy. In our previous study, we found a correlation between particular bacterial species and early-onset wheezing in infants from the rural tropics of Ecuador who were corticosteroid-naïve and had limited antibiotic exposure. We now describe a longitudinal study of infants conducted to determine the age-related changes of the microbiome and its relationship with wheezing., Methods: We performed an amplicon sequencing of the 16S rRNA bacterial gene from the oropharyngeal samples obtained from 110 infants who had a history of recurrent episodic wheezing sampled at different ages (7, 12, and 24 months) and compared it to the sequencing of the oropharyngeal samples from 150 healthy infants sampled at the same time points. Bioinformatic analyses were conducted using QIIME and R., Results: As expected, the microbiota diversity consistently increased as the infants grew older. Considering age-based microbiota changes, we found that infants with wheeze had significantly lower species richness than the healthy infants at 7 months, but not at 12 or 24 months. Most of the core and accessory organisms increased in abundance and prevalence with age, except for a few which decreased. At 7 months of age, infants with wheeze had notably higher levels of a single Streptococcus operational taxonomic unit and core microbiota member than controls., Conclusions: In a cohort with limited antibiotic and corticosteroid use, a progressively more complex and diverse respiratory microbial community develops with age. The respiratory microbiota in early life is altered in infants with wheeze, but this does not hold true in older infants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Cardenas, Cox, Willis-Owen, Moffatt, Cookson and Cooper.)

Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first-line therapeutic agents. However, despite all having potent capacity to suppress JAK-STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA-approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2-mutant in vitro models, all four inhibitors demonstrated similar anti-proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient-derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA-sequencing and gene set enrichment analyses, differential suppressive degrees of JAK-STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy., (© 2023 Wiley Periodicals LLC.)

Raw acoustic data were collected in East Antarctica from the RSV Aurora Australis during two surveys: the Krill Availability, Community Trophodynamics and AMISOR Surveys (KACTAS) and the Krill Acoustics and Oceanography Survey (KAOS) in the East Antarctic (centre coordinate 66.5° S, 63° E). The KACTAS survey was conducted between 14th to 21st January and 2001, and the KAOS survey was conducted between 16 January and 1 February 2003. We examine the Antarctic krill (Euphausia superba) component of these surveys and provide scientific echosounder (EK500 and EK60) data collected at 38, 120 and 200 kHz, cold water (-1 °C) echosounder calibration parameters and accompanying krill length frequency distributions obtained from trawl data. We processed the acoustic data to apply calibration values and remove noise. The processed data were used to isolate echoes arising from swarms of krill and to estimate metrics for each krill swarm, including internal density and individual swarm biomass. The krill swarm data provide insights to a predators' views of krill distribution and density., (© 2023. Crown.)

Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models and sAML PDXs without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and highlight the DUSP6-RSK1 axis as a vulnerable, druggable pathway in myeloid malignancies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diabetes and skin cancers have emerged as threats to public health worldwide. However, their association has been less intensively studied. In this narrative review, we explore the common risk factors, molecular mechanisms, and prognosis of the association between cutaneous malignancies and diabetes. Hyperglycemia, oxidative stress, low-grade chronic inflammation, genetic, lifestyle, and environmental factors partially explain the crosstalk between skin cancers and this metabolic disorder. In addition, diabetes and its related complications may interfere with the appropriate management of cutaneous malignancies. Antidiabetic medication seems to exert an antineoplastic effect, however, future large, observation studies with a prospective design are needed to clarify its impact on the risk of malignancy in diabetes. Screening for diabetes in skin cancers, as well as close follow-up for the development of cutaneous malignancies in subjects suffering from diabetes, is warranted., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: While tobacco and alcohol co-use is highly prevalent across the United States, little experimental research has examined ways to counter such dual use. We developed and tested messages about the risks of co-using tobacco and alcohol among adults who used a combustible tobacco product and drank alcohol within the 30 days., Methods: In an online experiment, 1,300 participants were randomly assigned to read different messages about tobacco and alcohol co-use (e.g., Alcohol and tobacco cause throat cancer). Three between-subjects experiments manipulated the presence of: 1) a marker word (e.g., Warning), 2) text describing the symptoms of health effects and a quitting self-efficacy cue, and 3) an image depicting the health effect. Participants rated each message using a validated Perceived Message Effectiveness (PME) scale. We used independent samples t-tests to examine differences between experimental conditions. Results include effect sizes (Cohen's d) to compare standardized mean differences., Results: Our sample was 64% male, 70% white, 23% Black, and 17% Hispanic/Latino with a mean age of 42.4 (SD = 16.4) years. Messages that described the symptoms of the health effect (d = 0.17, p = 0.002) and included an image (d = 0.11, p = 0.04) were rated significantly higher in PME compared with messages that did not describe symptoms and were text-only. We found no significant effects of a marker word or self-efficacy cue on PME., Conclusions: Messages that describe the symptoms of health effects and include text and images may be particularly effective for communicating the risks of tobacco and alcohol co-use and decreasing adverse health effects from co-use., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Dental task trainer simulators using haptics (virtual touch) offers a cost-effective method of teaching certain clinical skills. The purpose of this study is to evaluate students' performance in removing artificial caries after training with either a haptic dental chair simulator with virtual reality or a traditional dental chair simulator with a mannequin head. Cluster Randomized Controlled Trials in two cohorts, both Year 1 dental students. Students taught using traditional dental chair simulators were compared with students taught using haptic-based simulators on their ability to cut a cavity in a plastic tooth following training. Across both cohorts, there was no difference in the quality of cavity cut, though students' technique differed across the two simulator groups in some respects. No difference was seen across both cohorts in the quality of cavity cut for a simple preparation, though students in the haptic condition performed less well in the more demanding task. Moreover, students in the haptic group were also less likely to be perceived to be 'holding the instrument appropriately'. These findings suggest further investigation is needed into the differences in handling of instruments and level of clinical task difficulty between the simulators.

Background: Drinking events are characterized by social and physical contexts that are associated with level of alcohol consumption. Ecologically valid data is needed to delineate aspects of the drinking context that are most likely to precipitate excessive alcohol consumption., Methods: We utilized event-level data from a longitudinal study that included repeated daily surveys administered in two 28-day bursts. Data from 341 college student past-month alcohol and cannabis users (Mage=19.79; 53 % women; 74 % White) produced a total of 4107 alcohol use days. Generalized linear mixed effects models were used to predict drinking level (moderate: 1-3/1-4 for women/men; heavy-episodic drinking (HED): 4-7/5-9; high-intensity drinking (HID), 8+/10+) by social (e.g., with friends) and physical (e.g., at a party) contexts. We conducted analyses for the first and last drink reported, controlling demographic and study characteristics., Results: Being at a party, friend's house, or with strangers at the last drink reported were associated with HID compared to HED, while being at home, alone, or with family were protective for HID. No first drink contexts were associated with HID relative to HED. Witnessing others who were intoxicated was consistently associated with HID., Conclusions: Social settings such as parties and those with intoxicated persons were associated with risk for HID. The context of drinks at the end of an event are salient signals of level of alcohol consumption. Preventive interventions, particularly those that deliver strategies in real time, should consider accounting for contextual risk factors to reduce harms associated with excessive alcohol consumption., Competing Interests: Conflict of interest No conflict declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Regular monitoring is an important component of the successful management of pelagic animals of interest to commercial fisheries. Here we provide a biomass estimate for Antarctic krill (Euphausia superba) in the eastern sector of the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) Division 58.4.2 (55°E to 80°E; area = 775,732 km2) using data collected during an acoustic-trawl survey carried out in February and March 2021. Using acoustic data collected in day-time and trawl data, areal biomass density was estimated as 8.3 gm-2 giving a total areal krill biomass of 6.48 million tonnes, with a 28.9% coefficient of variation (CV). The inaccessibility of the East Antarctic makes fisheries-independent surveys of Antarctic krill expensive and time consuming, so we also assessed the efficacy of extrapolating smaller surveys to a wider area. During the large-scale survey a smaller scale survey (centre coordinates -66.28°S 63.35°E, area = 4,902 km2) was conducted. We examine how representative krill densities from the small-scale (Mawson box) survey were over a latitudinal range by comparing krill densities from the large-scale survey split into latitudinal bands. We found the small scale survey provided a good representation of the statistical distribution of krill densities within its latitudinal band (KS-test, D = 0.048, p-value = 0.98), as well as mean density (t-test p-value = 0.44), but not outside of the band. We recommend further in situ testing of this approach., Competing Interests: The authors have declared that no competing interests exist.