Hypoxanthine in the microenvironment can enable thiopurine resistance in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with relapse being a major obstacle to successful treatment. Our understanding of the mechanisms driving chemotherapy resistance and ultimately relapse in leukemia remains incomplete. Herein, we investigate the impact of the tumor microenvironment on leukemia cell drug responses using human plasma-like media (HPLM), designed to mimic physiological conditions more accurately ex vivo. We demonstrate that while most chemotherapeutics maintain an efficacy in HPLM comparable to standard tissue culture media, the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) exhibit significantly reduced potency and efficacy against both B- and T- leukemia cells in HPLM. By merging our understanding of thiopurines' mechanism of action with the metabolites supplemented in HPLM compared to standard media, we proposed and subsequently validated the hypothesis that hypoxanthine, a purine derivative, is responsible for conferring resistance to the thiopurines. Importantly, the concentration of hypoxanthine required for resistance is comparable to physiological levels found in vivo, supporting clinical relevance. Our findings demonstrate the utility of a more physiologic media in identifying and characterizing mechanisms by which the microenvironment can enable resistance. Understanding such interactions may inform strategies to overcome drug resistance and improve therapeutic outcomes in pediatric leukemia.

Narrative Ability in Autism and First-Degree Relatives.

Narrative is an important communication skill for sharing personal experiences and connecting with others. Narrative skills are often impacted in autism spectrum disorder (ASD) and have important consequences for social interactions and relationships. Subtle differences in narrative have also been reported among first-degree relatives of autistic individuals, suggesting that narrative may also be an etiologically important language-related skill that is influenced by genes associated with ASD. This study examined narrative ability and related visual attention during narration in ASD and first-degree relatives of individuals with ASD (siblings and parents) to understand how narrative and related attentional styles may be variably impacted across the spectrum of ASD genetic influence. Participants included 56 autistic individuals, 42 siblings of autistic individuals, 49 controls, 161 parents of autistic individuals, and 61 parent controls. Narratives were elicited using a wordless picture book presented on an eye tracker to record concurrent gaze. Findings revealed parallel patterns of narrative differences among ASD and sibling groups in the use of causal language to connect story elements and the use of cognitive and affective language. More subtle differences within the domain of causal language were evident in ASD parents. Parallel patterns in the ASD and sibling groups were also found for gaze during narration. Findings implicate causal language as a critical narrative skill that is impacted in ASD and may be reflective of ASD genetic influence in relatives. Gaze patterns during narration suggest similar attentional mechanisms associated with narrative among ASD families.

A trans-eyebrow zig-zag approach for frontal bone fractures✰.

Frontal bone fractures are amongst the most common facial fractures and surgical management, which has traditionally involved access via a coronal flap, can result in unsightly scarring, alopecia, paraesthesia, facial nerve weakness and temporal hollowing. Alternative approaches include use of endoscopically-assisted surgery, often through the eyebrow, which minimises the risk of unsightly scarring but may also sacrifice access in the process. In this technical note, we discuss a surgical technique for open reduction and internal fixation of fractures of the bone overlying the frontal sinus and supra-orbital rim, which the authors have not found in the literature, which involves the making of a "zig-zag" incision through the eyebrow in a trichophytic manner which reduces the risk of unsightly scarring whilst simultaneously allowing for sufficient surgical access to the fracture site.

Get2PrEP2-A Provider Messaging Strategy to Improve PrEP Uptake: A Randomized Controlled Quality Improvement Project.

Introduction: HIV preexposure prophylaxis (PrEP), a key strategy for preventing HIV transmission, requires awareness and access to PrEP services. Although all patients should be made aware of HIV PrEP; the diagnosis of bacterial sexually transmitted infections (STIs) is an important indicator of potential HIV PrEP need. In a previous evaluation of Get2PrEP (G2P), we found that an electronic medical record laboratory comments did not increase the frequency of PrEP discussions between patients and providers. In Get2PrEP2 (G2P2), we hypothesized that active, personalized messaging to providers about HIV PrEP would increase the documentation of PrEP discussions, referrals, and/or provision of HIV PrEP to individuals diagnosed with an STI. Methods: G2P2 was a parallel 3-arm, unblinded, randomized controlled design. Participants were allocated 2:1 to intervention or control. Participants in the intervention arm were further allocated to receive provider messaging through the electronic medical record chat message or e-mail. Results: The 191 randomized encounters resulted in a modest 7.8% (odds ratio, 1.078; confidence interval, 1.02-1.13) increase in documented PrEP discussions in intervention encounters versus none in the standard care group. There was no statistical difference by intervention modality. All documented discussions occurred in the outpatient or emergency department and were more frequent in women and those aged <25 years. Discussion: An e-mail or electronic medical record chat message sent to providers of patients testing positive for an STI had a small but significant effect on documented patient-provider PrEP discussions. Further investigation is required to determine whether provider messaging can increase PrEP uptake among eligible patients and longer-term outcomes.

The Role of the Multidisciplinary HIV Care Center in Mitigating Social Isolation Among Patients with HIV During the Early COVID-19 Pandemic.

As the COVID-19 pandemic began in 2020, significant public health mitigation efforts were vital to combat an unprecedented health crisis. These efforts, which involved social distancing and self-quarantine, likely worsened a public health crisis of social isolation and loneliness in the U.S., particularly among people with HIV (PWH). Multidisciplinary HIV care centers, which served as the main source of clinical care for PWH and in some cases the only point of social contact, faced evolving dynamics of in-person visits during the COVID-19 pandemic, as well as a shift to telehealth services. Using in-depth interviews, we explored the role that multidisciplinary HIV care centers and providers played in the experience of social isolation among PWH in New York City. We recruited participants (n = 30) from a multidisciplinary HIV care center in NYC between October 2020 and June 2021. We conducted semi-structured interviews to understand the specific domains of social isolation that were mitigated. In this cohort, the major theme that drove both in-person and telehealth care continuity was the strength of the patient-provider relationship. We found that participants saw members of the HIV care center as part of their social network, and providers served both as a source of emotional support and provided important social resources and benefits. Thus, in times of heightened social isolation, HIV care centers can play a critical role in providing social support in addition to clinical care.

Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Enabling a Learning Public Health System:Enhanced Surveillance of HIV and Other Sexually Transmitted Infections.

Sexually transmitted infections (STIs) continue to pose a substantial public health challenge in the United States (US). Surveillance, a cornerstone of disease control and prevention, can be strengthened to promote more timely, efficient, and equitable practices by incorporating health information exchange (HIE) and other large-scale health data sources into reporting. New York City patient-level electronic health record data between January 1, 2018 and June 30, 2023 were obtained from Healthix, the largest US public HIE. Healthix data were linked to neighborhood-level information from the American Community Survey. In this casecontrol study, chlamydia, gonorrhea, and HIV-positive cases were compared to controls to estimate the odds of receiving a specific laboratory test or positive result using generalized estimating equations with logit function and robust standard errors. Among 1,519,121 tests performed for chlamydia, 1,574,772 for gonorrhea, and 1,200,560 for HIV, 2%, 0.6% and 0.3% were positive for chlamydia, gonorrhea, and HIV, respectively. Chlamydia and gonorrhea co-occurred in 1,854 cases (7% of chlamydia and 21% of gonorrhea total cases). Testing behavior was often incongruent with geographic and sociodemographic patterns of positive cases. For example, people living in areas with the highest levels of poverty were less likely to test for gonorrhea but almost twice as likely to test positive compared to those in low poverty areas. Regional HIE enabled review of testing and cases using granular and complementary data not typically available given existing reporting practices. Enhanced surveillance spotlights potential incongruencies between testing patterns and STI risk in certain populations, signaling potential under- and over-testing. These and future insights derived from HIE data may be used to continuously inform public health practice and drive further improvements in provision and evaluation of services and programs.

Effects of age and word frequency on Korean visual word recognition: Evidence from a web-based large-scale lexical-decision task.

The present study examined age differences in word-frequency effects in Korean visual word recognition through a large-scale, web-based lexical-decision task. Four hundred ninety-seven adult Korean speakers in their 20s through 60s participated in the task, in which they decided the lexicality of 120 Korean words varying in frequency and 120 nonwords. Overall, both lexical-decision accuracy and response times increased with age, and more frequent words were recognized more rapidly than less frequent words. We also found significant effects of participants' reading skill as well as age of acquisition of words. Crucially, despite older adults' generally slower reaction times, there was no hint of any interaction between participant age and word frequency on lexical-decision times. This result adds to the literature on age-related changes in visual word recognition and provides evidence for stable word-frequency effect across the adult age spectrum. These findings are discussed with different hypotheses of lexical access and aging proposed in the literature. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Examining Patient Preferences for Express, Telemedicine, and Standard Visits in a Sexual Health Clinic in New York City.

ABSTRACT: This study, completed at an sexually transmitted infection (STI) clinic in 2019 to 2020, evaluated patient preferences for telemedicine, express, and standard visits. Active PrEP users preferred telemedicine and express visits, patients with prior STIs preferred express visits, and cisgender women preferred standard visits. Configuring STI clinic visit types requires shared decision making and individualization.

The lab discovered: Place-for-institution metonyms appearing in subject position are processed as agents.

"Hospital" can refer to a physical place or more figuratively to the people associated with it. Such place-for-institution metonyms are common in everyday language, but there remain several open questions in the literature regarding how they are processed. The goal of the current eyetracking experiments was to investigate how metonyms are interpreted when they appear as sentence subjects in structures that are temporarily syntactically ambiguous versus unambiguous (e.g., "The hospital [that was] requested by the doctor…"). If comprehenders have a bias to interpret metonyms in subject position as agents (Fishbein & Harris, 2014), they should initially access the figurative (institutional) sense of the metonym. This interpretation is rendered incorrect at the disambiguating by-phrase, which should lead to reanalysis (i.e., garden-path effects). In Experiment 1, larger garden-path effects were observed for metonyms compared to inanimate control nouns that did not have a figurative sense. In Experiment 2, garden-path effects were equivalent for metonyms and animate sentence subjects. In addition, there was some evidence that readers exhibited initial difficulty at the verb (e.g., "requested") when it immediately followed the metonym compared to the inanimate control nouns in Experiment 1. Overall, the results suggest that the subject-as-agent heuristic is a powerful cue during sentence processing, which can prompt the comprehender to access a figurative interpretation of a metonym. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Using a Health Information Exchange to Characterize Changes in HIV Viral Load Suppression and Disparities During the COVID-19 Pandemic in New York City.

Background: HIV viral suppression requires sustained engagement in care. The COVID-19 pandemic challenged care accessibility for many people living with HIV (PLWH). We used health information exchange data to evaluate the effect of pandemic-related disruptions in HIV care on viral load suppression (VLS) and to examine racial/ethnic disparities in VLS. Methods: We performed a retrospective observational cohort study of PLWH using data from a regional health information exchange in the New York City region between 1 January 2018 and 31 December 2022. We established 2 cohorts: PLWH who received HIV care in 2020 (cohort A) and PLWH who did not receive HIV care in 2020 (cohort B). We categorized HIV VLS outcomes as suppressed or not suppressed and calculated the prevalence of VLS between 2018 and 2022. We compared proportions using chi-square tests and used unadjusted and adjusted logistic regression to estimate the association among variables, including race/ethnicity, cohort, and VLS. Results: Of 5 301 578 patients, 34 611 met our inclusion criteria for PLWH, 11 653 for cohort A, and 3141 for cohort B. In 2019, cohort B had a lower prevalence of VLS than cohort A (86% vs 89%, P < .001). Between 2019 and 2021, VLS dropped significantly among cohort B (86% to 81%, P < .001) while staying constant in cohort A (89% to 89%, P = .62). By 2022, members of cohort B were less likely than cohort A to be receiving HIV care in New York City (74% vs 88%, P < .001). Within both cohorts, Black and Hispanic patients had lower odds of VLS than White patients. Conclusions: In New York City, VLS remained high among PLWH who continued to receive care in 2020 and dropped among PLWH who did not receive care. VLS was lower among Black and Hispanic patients even after controlling for receipt of care.

Inhalation Dosage Forms: A Focus on Dry Powder Inhalers and Their Advancements.

In this review, an extensive analysis of dry powder inhalers (DPIs) is offered, focusing on their characteristics, formulation, stability, and manufacturing. The advantages of pulmonary delivery were investigated, as well as the significance of the particle size in drug deposition. The preparation of DPI formulations was also comprehensively explored, including physico-chemical characterization of powders, powder processing techniques, and formulation considerations. In addition to manufacturing procedures, testing methods were also discussed, providing insights into the development and evaluation of DPI formulations. This review also explores the design basics and critical attributes specific to DPIs, highlighting the significance of their optimization to achieve an effective inhalation therapy. Additionally, the morphology and stability of 3 DPI capsules (Spiriva, Braltus, and Onbrez) were investigated, offering valuable insights into the properties of these formulations. Altogether, these findings contribute to a deeper understanding of DPIs and their development, performance, and optimization of inhalation dosage forms.

Effect of Fluoride Release on Enamel Demineralization Adjacent to Orthodontic Brackets.

INTRODUCTION AND AIM: This study aimed to evaluate the ability of fluoride-releasing adhesives to inhibit enamel demineralization surrounding orthodontic brackets. METHODS: Two groups of 40 sound human premolars were sectioned mesio-distally. The halves were varnished, and orthodontic brackets were bonded with different adhesive materials. An area 1 mm wide surrounding the brackets was left exposed. Each specimen was immersed daily in a pH cycle for 28 days. In the second group, the specimens were exposed daily to a fluoride solution (250 ppm F-) at 37°C. The fluoride release from different groups was measured. Quantitative light-induced fluorescence (QLF) was used to quantify fluorescence loss of enamel surfaces adjacent to the brackets. Results were statistically analyzed using ANOVA at (p<0.05). RESULTS: Fluoride released from the three fluoride-releasing adhesives was significantly higher (p<0.001) in the group with daily fluoride exposures than in the group without fluoride exposures. Enamel adjacent to brackets bonded with Fuji Ortho LC, Ketac Cem, and Dyract Cem showed significantly less (p<0.001) changes in (ΔQ) value (less demineralization) than enamel bonded with Transbond, the control adhesive material. CONCLUSIONS: Using fluoride-releasing adhesives significantly reduced the level of demineralization adjacent to orthodontic brackets.

Integrating a Resilience Framework to Assess Implementation of a Novel HIV Care Re-Engagement Model in NYC.

BACKGROUND: The Bottom Up Project, a collaboration of clinical, community, and academic partners, consists of 7 major steps that leverage a health information exchange, a system for sharing patient health information, with real-time alerts to mobilize peer outreach workers to find and re-engage persons with HIV disconnected from care. Bottom Up faced implementation challenges in its start-up phase and produced effective responses leading to Project maturation, which we explore using a novel implementation science framework incorporating resilience. METHODS: We conducted semistructured interviews with implementation staff (N = 6) and meeting minutes and protocols document reviews (N = 35). The Consolidated Framework for Implementation Research and a novel resilience framework guided thematic and process analyses. The resilience framework consisted of the following 3 resilience types: absorptive to cope with adversity, adaptive to adjust as short-term solutions, and transformative to structurally change. RESULTS: The Project experienced 20 major challenges, 2-5 challenges per step. Challenges were multilevel and of chronic and crisis intensities. Implementers overcame challenges by leveraging multilevel factors that were absorptive, adaptive (most common), and transformative. DISCUSSION: Bottom Up matured by practicing consistency and flexibility. The Project maintained core operations while under crisis-level stress by strategically simplifying or "downshifting" activities. Transformational responses suggest that specific initiatives can catalyze organizational change. CONCLUSIONS: Bottom Up implementation demonstrates using diverse tactics to respond to challenges, thereby shaping Project development and in turn organizations. Applying resilience to Consolidated Framework for Implementation Research helps build awareness of active and dynamic processes promoting or impeding the growth and success of intervention-oriented Projects.

Predictors of missed HIV screening opportunities among newly diagnosed individuals at an urban medical center in New York City, 2018-2022.

OBJECTIVE: To identify demographic and clinical factors predictive of having a missed opportunity (MO) for HIV screening. DESIGN: Retrospective cohort study. METHODS: Electronic medical records were queried for individuals newly diagnosed with HIV in different sites within a large urban academic medical center in New York City between 2018 and 2022. The primary outcome was having one or more MO for HIV screening within the institution, defined as any encounter at which screening was not performed in the 365 days preceding the HIV diagnosis. RESULTS: Over one third of new diagnoses had at least one MO in the preceding year. Older individuals, cisgender women and those assigned female sex at birth, and heterosexual individuals were more likely to have at least one MO. An initial CD4 < 200 cells/ul was more likely among men who have sex with women specifically. Most MOs occurred in the emergency department and outpatient settings, with minimal HIV prevention discussions documented during each MO. CONCLUSIONS: These findings suggest that populations perceived to be at lower risk for HIV are more likely to have MOs and possibly late diagnoses, and that universal HIV screening must be implemented into the workflows of emergency department and outpatient settings to facilitate early diagnosis and reduce the incidence of HIV.

Mask-related costs in measuring preview benefit: Evidence from a distributional analysis based on target word reading times.

Skilled reading involves processing the upcoming word in parafoveal vision before it is fixated, leading to shorter fixations on that word. This phenomenon, parafoveal preview benefit, is a key component of theoretical models of reading; it is measured using the invisible boundary paradigm, in which reading times on a target word are compared for instances when preview is accurate and when the target word is masked while in the parafovea. However, parafoveal masks have been shown to induce unintentional processing costs, thereby inflating measures of preview benefit. The degraded mask has been explored as a potential solution to this problem, leading to mixed results. While previous work has analyzed the preview effect by comparing mean reading times on the target word, the present study provides a more comprehensive analysis by examining the distribution of the preview effect across target word fixation times for unrelated and degraded masks. Participants read sentences containing target words whose preview was either identical, unrelated, or degraded, and their eye movements were recorded. Analyses revealed that although there were no mean differences between reading times for the unrelated and degraded conditions, the pattern of the effects varied as a function of target word fixation times. Unrelated masks resulted in positively sloped generally linear delta plots, while degraded masks resulted in relatively flat delta plots for fixations longer than 200 ms. These differences suggest that different cognitive mechanisms are involved in the processing of the two mask types. Implications for understanding and measuring preview benefit are discussed.

Rapid or Immediate ART, HIV Stigma, Medical Mistrust, and Retention in Care: An Exploratory Mixed Methods Pilot Study.

Rapid or immediate antiretroviral therapy (iART) after HIV diagnosis improves linkage to care and time to viral suppression. However, iART may affect or be affected by HIV-related stigma and medical mistrust. In this mixed-methods pilot study, we examined the bi-directional role of HIV stigma, medical mistrust, and visit adherence (VA) in the context of iART in a diverse, newly diagnosed patient population. Participants were recruited from an HIV clinic in New York City and we utilized a convergent parallel design integrating quantitative data from demographic surveys, the HIV Stigma Survey (HIVSS), the Medical Mistrust Index (MMI) and electronic medical records, and qualitative data from in-depth interviews. Among the sample (N = 30), 26% (N = 8) initiated ART same-day or within 3 days, while the majority (N = 17) initiated between 4 and 30 days, and 17% (N = 5) initiated ART > 30 days. The median (range) age was 35, and most were English-speaking, Black or Hispanic men and identified as gay. Time to ART initiation was associated with time to linkage to care and time to viral suppression. Day 0-3 group's major theme was iART as stigma prevention, and they had the highest mean HIVSS, lowest MMI score, and a visit adherence of 0.86. Day 4-30 group's major theme was alleviation of internalized stigma, and they had the lowest mean HIVSS score, and highest visit adherence of 0.91. Day > 30 group's major theme was exacerbation of perceived or anticipated stigma, had the highest MMI score and a visit adherence of 0.85. iART implementation requires equitable strategies that address HIV-stigma and mistrust.

CXCR4 antagonists disrupt leukaemia-meningeal cell adhesion and attenuate chemoresistance.

The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge. Developing novel and more effective CNS-directed therapies has been hampered, in part, by our limited understanding of the leukaemia niche in the CNS relative to the bone marrow. Accordingly, defining the molecular and cellular components critical for the establishment and maintenance of the CNS leukaemia niche may lead to new therapeutic opportunities. In prior work we showed that direct intercellular interactions between leukaemia and meningeal cells enhance leukaemia chemoresistance in the CNS. Herein, we show that the CXCR4/CXCL12 chemokine axis contributes to leukaemia-meningeal cell adhesion. Importantly, clinically tested CXCR4 antagonists, which are likely to cross the blood-brain and blood-cerebral spinal fluid barriers and penetrate the CNS, effectively disrupted leukaemia-meningeal cell adhesion. Moreover, by disrupting these intercellular interactions, CXCR4 antagonists attenuated leukaemia chemoresistance in leukaemia-meningeal cell co-culture experiments and enhanced the efficacy of cytarabine in targeting leukaemia cells in the meninges in vivo. This work identifies the CXCR4/CXCL12 axis as an important regulator of intercellular interactions within the CNS leukaemia niche and supports further testing of the therapeutic efficacy of CXCR4 antagonists in overcoming CNS niche-mediated chemoresistance.