Acute Promyelocytic Leukemia With Torque Teno Mini Virus::RARA Fusion: An Approach to Screening and Diagnosis.

Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.

Health Care Access and COVID-19 Vaccination in the United States: A Cross-Sectional Analysis.

BACKGROUND: Although federal legislation made COVID-19 vaccines free, inequities in access to medical care may affect vaccine uptake. OBJECTIVE: To assess whether health care access was associated with uptake and timeliness of COVID-19 vaccination in the United States. DESIGN: A cross-sectional study. SETTING: 2021 National Health Interview Survey (Q2-Q4). SUBJECTS: In all, 21,532 adults aged≥18 were included in the study. MEASURES: Exposures included 4 metrics of health care access: health insurance, having an established place for medical care, having a physician visit within the past year, and medical care affordability. Outcomes included receipt of 1 or more COVID-19 vaccines and receipt of a first vaccine within 6 months of vaccine availability. We examined the association between each health care access metric and outcome using logistic regression, unadjusted and adjusted for demographic, geographic, and socioeconomic covariates. RESULTS: In unadjusted analyses, each metric of health care access was associated with the uptake of COVID-19 vaccination and (among those vaccinated) early vaccination. In adjusted analyses, having health coverage (adjusted odds ratio [AOR] 1.60; 95% CI: 1.39, 1.84), a usual place of care (AOR 1.58; 95% CI: 1.42, 1.75), and a doctor visit within the past year (AOR 1.45, 95% CI: 1.31, 1.62) remained associated with higher rates of COVID-19 vaccination. Only having a usual place of care was associated with early vaccine uptake in adjusted analyses. LIMITATIONS: Receipt of COVID-19 vaccination was self-reported. CONCLUSIONS: Several metrics of health care access are associated with the uptake of COVID-19 vaccines. Policies that achieve universal coverage, and facilitate long-term relationships with trusted providers, may be an important component of pandemic responses.

Highly efficient Ca2+ chelation activated by visible light.

Calcium ion (Ca2+) control is an essential tool in neuronal research. Herein, we report three thiocoumarin-based, visible light-activated Ca2+ chelators with quantum yields of 0.39, 0.52, and 0.83. The chelators demonstrated an over 105-fold increase in Ca2+ binding affinity upon irradiation. These chelators are efficiently triggered by biologically safer wavelengths, rendering them excellent candidates for use in neurological research and medicine.

Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.

Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy3-6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness7,8. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.

Publisher Correction: Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.

In this Letter, author Xing Du was incorrectly listed as Du Xing; this has been corrected online.

The Risk of Kidney Injury in Patients With Sickle Cell Disease Treated With Ketorolac for Acute Pain.

Ketorolac, a nonsteroidal anti-inflammatory drug, is used in combination with opioids to manage vaso-occlusive episodes (VOEs). The relationship between ketorolac use and kidney injury in pediatric patients with sickle cell disease (SCD) remains incompletely understood. We hypothesize that ketorolac is associated with acute kidney injury (AKI) in patients with SCD presenting with pain. All nonsurgical hospitalizations for VOEs treated with ketorolac between January 2014 and December 2022 were included. We used optimal matching methodology to identify control admissions (2:1 ratio) and used nonparametric tests to compare ketorolac administration between cases and controls. A total of 1319 encounters/253 patients were included in this study. AKI was noted in 1.1% of encounters and 5.5% of patients. Cases had significantly higher initial BUN than controls (9.0 vs. 6.0 mg/dL, P =0.012). In cases versus controls, there was significantly lower serum sodium (136.0 vs. 138.0 mmol/L, P =0.021). There was no association between ketorolac dose and development of AKI among children with SCD. Higher BUN and lower sodium in cases suggest that patients with AKI were more volume depleted on admission than controls. This highlights the need for strict assessment of fluid status upon admission for VOE.

Sexual Consent Norms in a Sexually Diverse Sample.

Sexual consent has received increased attention in mainstream media, educational, and political settings since the rise of the #MeToo movement in 2017. However, long before #MeToo, sexual consent has been a core practice among people who engage in Bondage and Discipline, Dominance and Submission, Sadism, and Masochism (BDSM). This study examined sexual consent norms among a sexually diverse sample, including people who practice BDSM (n = 116), people who identify with another sexual minority group, such as swingers and sex workers (n = 114), and people who did not identify with a sexual minority group, termed sexual majority group members (n = 158). Explicit consent for both BDSM- and non-BDSM-related activities was rated as more common (descriptively normative) among people who were a member of the BDSM community compared to majority participants. Further, BDSM participants rated consent discussions as less sexually disruptive compared to majority participants. We found no significant group differences in the extent to which people thought sexual consent should be discussed. We also discuss findings from an open-ended question asking participants to recall a recent sexual experience with a new partner. This study demonstrates variability in consent norms between groups and points to the potential to shift sexual consent behaviors among majority participants.

Causal Attributions of Low Sexual Desire in Women Partnered with Men.

Low sexual desire in women partnered with men has been the subject of controversy and research over the past decades, including both as construct and diagnosis. Despite discussion surrounding the causes of low desire, there is a gap in research about how women themselves understand the causes of their low desire and the potential consequences of these causal attributions. In the current study, we investigated this by asking 130 women who had low desire and were partnered with men about their attributions for low desire. Through content analysis, we identified five attribution categories: psychological/individual, relational, biological, sociocultural, and/or sexual orientation/identity/status. Many participants chose more than one category, indicating a multifaceted nature of women's causes of low desire. We then quantitatively assessed women's feelings of responsibility for, and emotions surrounding, their low desire. Our findings indicate that the majority-but not all-of women have negative feelings about their low desire. However, the specific emotions they experience are related to their attribution patterns. This underscores the significance of investigating various facets of women's attributions regarding low desire in order to gain a more comprehensive understanding of their emotional experiences and desire overall.

Utilization of an ITP quality improvement pathway improves adherence to management guidelines.

Despite availability of epidemiologic studies and national guidelines for the management of newly diagnosed pediatric immune thrombocytopenia (ITP), practice variation exists among and within hematology practices. We previously described the development of an ITP pathway guiding management based on bleeding symptoms. Over an 8-year period, integration of this iterative ITP pathway into management of newly diagnosed ITP increased observation rates in children with no or mild bleeding symptoms and improved consistency of laboratory evaluation and treatment strategies without increasing adverse outcomes. This quality improvement initiative has been sustainable, acceptable to providers, and increased adherence to guidelines.

Ketamine use for management of vaso-occlusive pain in pediatric sickle cell disease.

BACKGROUND: Typical sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. OBJECTIVES: This study aimed to characterize ketamine use for VOE management in pediatric SCD. METHOD: This retrospective case series summarizes a single-center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. RESULTS: Continuous low-dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0 µg/kg/min; median maximum dose 3.0 µg/kg/min). Ketamine was started a median of 13.7 hours after admission. Median ketamine infusion duration was 3 days. In most encounters, ketamine infusion was discontinued prior to opioid patient-controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was associated with side effects noted in 21.8% (n = 34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. CONCLUSION: Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.

Does Sexual Desire Fluctuate More Among Women than Men?

There is a lay assumption that women's sexual desire varies substantially over time, whereas men's is stable. This assumption is mirrored in prominent theories of desire, which posit that women are more variable than men in the extent to which they desire sex, and that women's sexual desire is more contextually sensitive than men's. We tested this assumption across three longitudinal studies. Study 1 assessed desire at 3 time points spanning 13 years (Nobservations = 5562), and Studies 2 and 3 (Nobservations = 11,282) assessed desire moment-to-moment over 7 days. When desire was measured over years, women were more variable in their sexual desire than men (Study 1). However, we found a different pattern of results when desire was measured over the short term. In Studies 2 and 3, we found no significant differences in women's and men's desire variability. The extent to which desire varied as a function of affective states (e.g., happiness) and relationship-oriented states (e.g., partner closeness) was similar for women and men, with some exceptions; women's desire was more negatively associated with tiredness and anger in Study 2. These data qualify existing assumptions about sex differences in sexual desire variability.

Early implementation learnings on acceptability and feasibility of "V": a multi-level PrEP intervention designed with and for adolescent girls and young women in Zimbabwe.

INTRODUCTION: Adolescent girls and young women (AGYW) remain disproportionately affected by HIV in Zimbabwe. Several HIV prevention options are available, including oral tenofovir-based pre-exposure prophylaxis (PrEP), however AGYW face unique barriers to PrEP uptake and continuation and novel approaches are therefore needed to empower AGYW to use PrEP. The objective of this study was to characterize early learnings from implementing a multi-level intervention consisting of fashionable branding (including a "V Starter Kit"), service integration, and peer education and support throughout a young woman's journey using oral PrEP across four phases of implementation, from creating demand, preparing for PrEP, initiation of PrEP, and adherence to PrEP. METHODS: A mixed methods implementation research study was undertaken, including site observations and interviews to explore the acceptability of "V" and its relevance to target users, as well as the feasibility of integrating "V" with existing service delivery models. Interviews (n = 46) were conducted with healthcare workers, Brand Ambassadors, and young women purposively sampled from four implementation sites. Interview data was analyzed thematically using the framework method for qualitative data management and analysis. Project budgets and invoices were used to compile unit cost and procurement data for all "V" materials. RESULTS: "V" was acceptable to providers and young women due to attractive branding coupled with factual and thought-provoking messaging, establishing "a girl code" for discussing PrEP, and addressing a gap in communications materials. "V" was also feasible to integrate into routine service provision and outreach, alongside other services targeting AGYW. Cost for the "V" branded materials ranked most essential-FAQ insert, pill case, makeup bag, reminder sticker-were $7.61 per AGYW initiated on PrEP. CONCLUSION: "V" is a novel approach that is an acceptable and feasible multi-level intervention to improve PrEP access, uptake, and continuation among AGYW, which works through empowering AGYW to take control of their HIV prevention needs. In considering "V" for scale up in Zimbabwe, higher volume procurement and a customized lighter package of "V" materials, while still retaining V's core approach, should be explored.

Using the Project ECHO Model to Increase Pediatric Primary Care Provider Confidence to Independently Treat Adolescent Depression.

OBJECTIVE: The model for the Extension for Community Healthcare Outcomes (Project ECHO®) was used to extend specialist support to the pediatric medical home for the treatment of adolescent depression by taking a comprehensive, disease-specific approach. METHODS: Child and adolescent psychiatrists constructed a course to train community pediatric primary care providers (PCPs) to screen patients for depression, initiate evidence-based interventions, and provide ongoing management. Participants were assessed for changes in clinical knowledge and self-efficacy. Secondary measures included self-reported practice change and emergency department (ED) mental health referrals 12 months pre- and post-course completion. RESULTS: Sixteen out of 18 participants in cohort 1 and 21 out of 23 participants in cohort 2 completed the pre- and post-assessments. Clinical knowledge and self-efficacy showed statistically significant improvement pre- and post-course completion. ED mental health referrals from participant PCPs decreased by 34% (cohort 1) and 17% (cohort 2) after course completion. CONCLUSIONS: These findings indicate that utilizing the Project ECHO format to provide subspecialist support and education on the treatment of depression can improve pediatric PCPs' clinical knowledge and confidence in their ability to independently treat depression. Secondary measures suggest that this can translate into practice change and improved treatment access with decreased ED referrals for mental health assessments by participant PCPs. Future directions include more robust outcomes measurement and developing more courses with an in-depth approach to a single or similar cluster of mental health diagnoses such as anxiety disorders.

Natural and Synthetic Suppressor Mutations Defy Stability-Activity Tradeoffs.

Thermodynamic stability represents one important constraint on protein evolution, but the molecular basis for how mutations that change stability impact fitness remains unclear. Here, we demonstrate that a prevalent global suppressor mutation in TEM ß-lactamase, M182T, increases fitness by reducing proteolysis in vivo. We also show that a synthetic mutation, M182S, can act as a global suppressor and suggest that its absence from natural populations is due to genetic inaccessibility rather than fundamental differences in the protein's stability or activity.

Characteristics and outcomes of autoimmune hemolytic anemia after pediatric allogeneic stem cell transplant.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplant (HSCT) is a rare but complex and serious complication. Detailed descriptions of cases and management strategies are needed due to lack of prospective trials. OBJECTIVES: Describe the incidence, clinical characteristics, and management of AIHA after HSCT in a pediatric cohort. METHODS: This is a retrospective cohort study of 33 pediatric patients with AIHA after HSCT at an academic tertiary care center from 2003 to 2019. RESULTS: The overall incidence of AIHA after allogeneic HSCT was 3.8% (33/868). AIHA was significantly more common after transplant for nonmalignant versus malignant diagnoses (7.0% [26/370] vs. 1.4% [7/498], p < .0001). AIHA developed at a median of 4.7 months (range 1.0-29.7) after transplant. Sixteen of 33 patients (48.5%) required new AIHA-directed pharmacologic therapy; 17 (51.5%) were managed on their current immunosuppression and supportive care. Patients managed without additional therapy were significantly older, more likely to have a malignant diagnosis, and tended to develop AIHA at an earlier time point after transplant. Patients received a median of two red blood cell transfusions within the first 2 weeks of diagnosis and a median of one AIHA-directed medication (range one to four), most commonly corticosteroids and rituximab. CONCLUSIONS: AIHA after HSCT is rare but occurs more commonly in patients transplanted for nonmalignant diagnoses. While some pediatric patients who develop AIHA after transplant can be managed on current immunosuppression and supportive care, many require AIHA-directed therapy including second-line medications.

Benevolent Sexism and the Traditional Sexual Script as Predictors of Sexual Dissatisfaction in Heterosexual Women from the U.S.

Women report lower sexual satisfaction than men. Given that sexual dissatisfaction adversely impacts health and well-being, it is imperative that we investigate why women are sexually dissatisfied. In the present study, we explored whether women's benevolently sexist attitudes might predict their sexual dissatisfaction. In a sample of 308 (Mage = 38.09) heterosexual American women who had previously had sex with a man, we hypothesized that women's benevolent sexism would be associated with an increased adoption of the traditional sexual script (i.e., an increased propensity for submissiveness and passivity during sex) and that this, in turn, would be associated with increased sexual dissatisfaction. We also hypothesized that the relationship between the adoption of the traditional sexual script and sexual dissatisfaction would be moderated by the degree to which participants enjoy submissiveness. Overall, we did not find support for our model: benevolent sexism did not predict sexual dissatisfaction. However, we did find that adopting the traditional sexual script was predictive of sexual dissatisfaction for women who do not enjoy submissiveness. These findings contribute to an emerging literature pertaining to women's sexual health. Specifically, results suggest that benevolent sexism does not contribute to women's experiences of sexual dissatisfaction. Instead, they suggest that sexual dissatisfaction in women may (in part) be driven by their engagement in sexual roles that do not align with their sexual preferences. Theoretical and clinical implications for these findings are discussed.

Gender Inequities in Household Labor Predict Lower Sexual Desire in Women Partnered with Men.

Low sexual desire in women is usually studied as a problem, one that is located within women. However, other possibilities exist, including known gender inequities related to heteronormative gender roles. In this study, we provide the first test of the theory that heteronormativity is related to low sexual desire in women partnered with men, focusing specifically on inequities in the division of household labor. In two studies with women who were partnered with men and had children (Study 1, N = 677; Study 2, N = 396), performing a large proportion of household labor was associated with significantly lower sexual desire for a partner. Together, the results suggest that this association was mediated by both perceiving the partner as a dependent and perceiving the division of labor as unfair. These results support the heteronormativity theory of low sexual desire in women partnered with men, and show that gender inequities are important, though understudied, contributors to low desire in women partnered with men.

The Heteronormativity Theory of Low Sexual Desire in Women Partnered with Men.

Low sexual desire in women partnered with men is typically presumed to be a problem-one that exists in women and encourages a research agenda on causation and treatment targeting women. In this paper, we present a distinct way forward for research on low sexual desire in women partnered with men that attends to a more structural explanation: heteronormativity. A heteronormative worldview assumes that relationships and structures are heterosexual, gender (usually conflated with sex) is binary and complementary, and gender roles fit within narrow bounds including nurturant labor for women. We propose the heteronormativity theory of low sexual desire in women partnered with men, arguing that heteronormative gender inequities are contributing factors. We outline four hypotheses and their predictions related to: inequitable divisions of household labor, blurring of partner and mother roles, objectification of women, and gender norms surrounding sexual initiation. We discuss some mechanisms-social, physiological, and otherwise-for the heteronormativity theory, especially related to stress, objectification, and nurturance. We close by noting some limitations of our paper and the ways that the heteronormativity theory of low sexual desire in women partnered with men provides a rigorous, generative, and empirical way forward.

Sexual Orientation Across Porn Use, Sexual Fantasy, and In-Person Sexuality: Visualizing Branchedness and Coincidence via Sexual Configurations Theory.

Sexual orientation describes sexual interests, approaches, arousals, and attractions. People experience these interests and attractions in a number of contexts, including in-person sexuality, fantasy, and porn use, among others. The extent to which sexual orientation is divergent (branched) and/or overlapping (coincident) across these, however, is unclear. In the present study, a gender/sex and sexually diverse sample (N = 30; 15 gender/sex/ual minorities and 15 majorities) manipulated digital circles representing porn use, in-person sexuality, and fantasy on a tablet during in-person interviews. Participants used circle overlap to represent the degree of shared sexual interests across contexts and circle size to indicate the strength and/or number of sexual interests within contexts. Across multiple dimensions of sexual orientation (gender/sex, partner number, and action/behavior), we found evidence that sexual interests were both branched and coincident. These findings contribute to new understandings about the multifaceted nature of sexual orientations across contexts and provide a novel way to measure, conceptualize, and understand sexual orientation in context.

Barriers to Working with Patients Who Misuse Opioids and Physician Burnout: Implications for Medical Education.

BACKGROUND: Physicians are on the front lines of the U.S. opioid epidemic, providing care in multiple treatment settings. Very little is known, however, about whether this experience has contributed to physician burnout. This information is critical for guiding efforts to expand the relatively low level of training on opioid misuse currently available in medical education. METHODS: We surveyed 408 board-certified physicians practicing in Ohio about their experiences working with patients who misuse opioids. We also collected quantitative measures of physicians' burnout and their level of contact with this patient population. We coded and analyzed open-ended responses and calculated a partial correlation between contact and burnout, controlling for relevant factors. RESULTS: Physicians experienced three primary barriers when working with patients who misuse opioids: inadequate knowledge and training, limited external resources and partnerships in their communities, and an incomplete context for understanding problematic patient behaviors. 70% of physicians experienced negative emotions when working with this patient population and 19% mentioned experiencing burnout specifically. Contact with patients who misuse opioids was significantly and positively associated with burnout scores. CONCLUSIONS: Our findings underscore the need for medical educators to take a proactive approach to equipping physicians with the knowledge, skills, and resources needed to effectively work with patients who misuse opioids.