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Virginia’s Readjuster Party was the most successful interracial political coalition in the post-Reconstruction South. Initially arising from a conflict over the payment of Virginia’s massive public debt, the new party became a force of liberal reform and democracy in the Old Dominion. It represented an alternative path before Jim Crow segregation and disfranchisement became the norm. While the Readjusters have long interested historians, the significant work performed by Black Readjusters in building and sustaining the always-tenuous coalition has gone understudied. Knowing their white counterparts were anxious about interracial political alliances, Black Readjusters eased these anxieties by using the Lost Cause. Black Readjusters condemned carpetbaggers as corrupt and repurposed the myth of the faithful slave to strengthen the interracial coalition, press for their own demands, and demonstrate their status as true southerners. The strategy and its seeming contradictions succeeded in some cases and failed in others, and its ultimate effects remain unclear. By shifting focus to Black Readjusters’ coalition-building labors, this article centers Black political activism and challenges the presumptions scholars make about interracial politics and white supremacy.

Abstract Background This study examined the conflicts between different generations working in US emergency departments (ED). We sought to record generational differences involving communication preferences, perceived areas of conflict, work motivations, and attitudes regarding work-life balance. Methods We developed a survey to assess the physician perspective on generational conflict in the ED. The survey was distributed to members of the American College of Emergency Physicians, a professional organization comprising emergency medicine physicians in the USA. Results We received 696 completed responses. Men represented 60% of respondents and the largest proportion of respondents were emergency physicians working in community settings (53%); 11% were residents. Generation representation was smallest for Traditionalist (2%) and largest for Gen X (43%). Seventy percent reported observing conflict due to generational communication with the largest frequency being once a week (26%). In the associated open-ended questions, 247 (33%) provided 316 anecdotal descriptions of observed conflict. Responses clustered into seven themes (ordered by frequency): Work Ethic, Treatment Approach, Technology Application, Entitlement, Professionalism, Work Life/Balance, and Communication Style. Comparing Work Ethic responses, 52–70-year-olds reported that younger providers are less interested in “accomplishing anything” while 26–34-year-olds resented that attitude. Respondents completing the open-ended questions regarding preventing and responding to conflict provided some insight into helpful strategies including actions supportive of clear communication and standardized policies and expectations. Only 5% of respondents reported that they had discussed generational communication in department meetings with the odds of a woman reporting conflict being less than males (p = .01). Conclusion Conflicts in the ED in the USA can be attributed to how an individual views the values of someone from another generation. Understanding the frequency and areas of generational conflict in the ED can help medical leaders find strategies to mitigate negative workplace interactions.

This erratum is created to add an author that was erroneously omitted at the time of submission of Ref. [1]. The author is Cameron Kuchta (ORCID: 0000-0001-5028-4898). Cameron contributed to the publication by way of a supporting role in formal analysis.By K. Bryant; R. P. Young; H. J. LeFevre; C. C. Kuranz; J. R. Olson; K. J. McCollam; Cameron Kuchta and C. B. ForestReported by Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

The primary purpose of the original NAPCHD project was to develop a national Strategic Document of Diabetes Care for Care Homes which has now been completed and well received as a worthwhile, sustainable, and effective guidance for delivering quality diabetes care in the UK. A Working Group of NAPCHD was established to produce a Position Statement on type 1 diabetes in care homes since this area was recommended as a topic to further develop. There are currently limited data on the prevalence and clinical outcomes associated with type 1 diabetes in care homes and management policies have been non‐existent in the UK. Communication among all key stakeholders involved in direct care of residents with type 1 diabetes is generally fragmented and lacks coordination. This is compounded by a slowly growing utilisation of diabetes technology and the absence of a standard/agreed community‐based model of interdisciplinary collaboration. The Rationale and Objectives were defined prior to commencing the work and a work plan with individual tasks was initially set out. After multiple correspondences and Team calls over a period of 9 months, the Group successfully generated a first draft in October 2023. This draft was then finalised the following month and circulated among stakeholders for feedback. Nine chapters have been provided including minimum standards of diabetes care, insulin regimens, avoiding hospitalisation and discharge planning. A scheme for a community‐based model of care for type 1 diabetes has been included. Eight key messages were developed. In addition, an Appendix has been created which includes key assessments such as nutritional assessment, detection of frailty, sick day rules and foot risk stratification (available online). [ABSTRACT FROM AUTHOR]

Simulation-based education (SBE) has revolutionized health care training by enhancing skills and addressing systemic issues. This article explores how SBE can bridge the gap between recognizing health care disparities and implementing actionable steps to address them. The immersive nature of SBE, combined with structured debriefing, sets the foundation for a "brave space" that fosters critical discussions on crucial topics, such as health equity. SBE enables health care professionals to develop cultural humility, confront biases, and practice upstander skills. This approach not only addresses hidden curricula but also integrates equity into clinical practice through practical scenarios and community engagement. Despite the potential benefits, challenges such as unintentional harm and the need for thoughtful implementation persist. To maximize effectiveness, SBE initiatives must be aligned with organizational goals and include interdisciplinary team commitment. Ongoing research and robust evaluation are essential to measure SBE's impact on health equity and patient outcomes. [ Pediatr Ann . 2024;53(11):e414-e419.] .

Mutations in protein tyrosine phosphatase non-receptor type 11 ( PTPN11 ) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of PTPN11 mutations, we utilized single-cell DNA sequencing and identified that PTPN11 mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The co-driver role of PTPN11 mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice. This immune diversity was reconstituted from early precursor cells when engrafted into immunodeficient mice. Moreover, immune diversity was also observed in the blast component of patient samples with NPM1 and PTPN11 mutations, providing novel antigen targets for immune based approaches in this subset of AML that is resistant to multiple targeted therapies.

Background: While the cognitive hallmark of typical Alzheimer disease (AD) is impaired memory consolidation, increasing evidence suggests that the frontal lobes and associated executive functions are also impacted., Objective: We examined two neurobehavioral executive function tasks and associations with cortical thickness in patients diagnosed with mild cognitive impairment (MCI), suspected AD dementia, and a healthy control group., Methods: First, we compared group performances on a go/no-go (GNG) task and on Luria's Fist-Edge-Palm (FEP) motor sequencing task. We then examined correlations between neurobehavioral task performance and the thickness of frontal cortical regions, AD signature regions, broader unbiased brain regions, and white matter hyperintensities (WMH)., Results: Participants with MCI performed worse than healthy controls, but better than participants with suspected AD dementia on both tasks. Both GNG and FEP (to a slightly greater extent) tasks showed diffuse associations with most AD signature regions and multiple additional regions within the temporal, parietal, and occipital cortices. Similarly, both tasks showed significant associations with all other cognitive tasks examined. Of the frontal regions examined, only the middle frontal gyrus and pars opercularis were associated with performance on these tasks. Interactions between the precuneus and transtemporal gyri were most predictive of GNG task performance, while the interaction between superior temporal and lingual gyri was most predictive of FEP task performance., Conclusion: This study replicates difficulties with both GNG and FEP tasks in participants with MCI and AD dementia. Both tasks showed widespread associations with the cortical thickness of various brain structures rather than localizing to frontal regions, consistent with the diffuse nature of AD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Wounds are a significant source of morbidity among people who use substances (PWUS). This project sought to identify the incidence and severity of wounds among PWUS in the South Bronx, a region of New York City with one of the highest morbidities of substance use disorder., Methods: This study recruited PWUS within the past 30 days. Research staff were trained to document the presence and severity of wounds. The primary outcome measure was the incidence of wounds. Acceptability of on-the-street wound care was assessed by the number of participants encountered. The association between participant characteristics and wounds was also evaluated., Results: In total, 586 PWUS were assessed (19.4 % female: 69 % Hispanic; 23 % Black; 5 % White). Heroin (65.7 %) and psychostimulants (58.3 %) were the most commonly used drugs. Approximately 23 % of outreach recipients disclosed a wound. Among those with a wound, 60.9 % reported one wound, 27.8 % had two wounds, and 11.3 % had three or more wounds. Small wounds (approximately the size of a cherry) were the most common (78.6 %). Recent use of stimulants or heroin, along with intravenous use of any substance were significantly associated with having a wound., Conclusions: This study found that drug-related wounds were common among PWUS. Toxicology data from other sources indicate that xylazine was present in the NYC market at the time, though its prevalence among the current sample is difficult to determine. The occurrence and severity of substance-related wounds in NYC should continue to be monitored as a function of changes in the xylazine adulteration., Competing Interests: Declaration of Competing Interest In the past three years, Dr. Jones has received compensation in the form of partial salary support from studies supported by BioXcel Therapeutics, is the recipient of an investigator-initiated grant from Merck Pharmaceuticals and the Peter McManus Charitable Trust, along with honoraria from the World Health Organization. The other authors have no interests to declare., (Copyright © 2024. Published by Elsevier B.V.)

Aims: To explore UK healthcare professionals' practice and attitudes towards asking women with diabetes about sexual health problems, including symptoms of female sexual dysfunction (FSD)., Methods: An online questionnaire to address the study aims was developed, piloted by ten healthcare professionals (HCPs) and completed by 111 eligible HCPs, recruited via professional networks and social media. Free text data were analysed and reported thematically. Two questions were analysed to test the hypothesis of differences between men's and women's responses., Results: The majority of respondents did not ask women with diabetes about sexual problems. Multiple barriers to inquiry were reported, including inadequate training, time constraints, competing priorities, the perceived likelihood that questions will cause surprise or distress (especially for certain groups of women), the belief that sexual problems are to be expected as women age, and the belief that FSD is complex or untreatable, with unclear management pathways. Exploratory findings indicated significant differences in men and women's responses (men disagreed more strongly with prioritisation, and fewer reported routine inquiry about sexual problems in their usual practice)., Conclusions: HCPs reported not asking women with diabetes about sexual problems during routine care. They described multiple factors reinforcing the silence about sexual health, including inadequate education and perceived social risk for individual HCPs who deviate from the patterns of topics usually discussed in diabetes consultations., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Introduction: Hospital-acquired adverse drug reactions (HA-ADRs) are common in older adults. However, there is limited knowledge regarding the association between HA-ADRs and adverse clinical outcomes., Objective: To investigate the incidence and characteristics of HA-ADRs in older adults, and any association with mortality, length of stay, and readmissions., Design: Prospective cohort study., Setting and Participants: Flinders Medical Centre, a large tertiary referral hospital in Adelaide, South Australia. Older adults admitted under the General Medicine and Acute Care of the Elderly units with no previous diagnosis of dementia., Methods: All patients had a Multidimensional Prognostic Index (MPI) assessment performed within 3 days of the admission. Data collected included age, gender, estimated glomerular filtration rate (eGFR), length of stay, readmissions, and mortality. HA-ADRs were identified by review of individual discharge summaries. Univariate and multivariate analyses were performed to investigate associations with clinical outcomes including mortality, length of stay, and readmissions. Exploratory analyses were performed for HA-ADR groups based on Medical Dictionary for Regulatory Activities System Organ Class and World Health Organization Anatomical Therapeutic Chemical classifications that accounted for ≥10% of all HA-ADRs., Results: There were 737 patients in the cohort with 72 having experienced a HA-ADRs (incidence = 9.8%). Patients with an HA-ADR had increased length of stay and 30-day readmissions compared with those without an HA-ADR. In multivariate analysis, the number of HA-ADRs was associated with in-hospital mortality and length of stay but not post-discharge mortality or readmissions within 30 days. In exploratory analyses, patients with an HA-ADR to antibacterial drugs had significantly higher rates of in-hospital mortality compared with those without these reactions., Conclusions and Implications: The number of HA-ADRs are associated with in-hospital mortality and length of stay in older Australian inpatients. The occurrence of HA-ADRs may be a trigger to offer advice to prescribers to prevent future ADRs to similar agents and proactively manage disease to improve health outcomes., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)

Rationale: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation., Objectives: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits., Methods: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome., Measurements and Main Results: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing., Conclusions: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www., Clinicaltrials: gov, ID: NCT02410772. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes., Methods: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression., Results: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events., Conclusions: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Molecules and cytokines can be targeted in cancer therapy. Transforming growth factor-beta (TGF-β) is a cytokine that acts on protein kinase receptors in the plasma membrane. The signaling pathway of TGF-β can trigger the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, a signal transduction pathway important in cancer growth and development. However, this PI3K/AKT cascade can be inhibited by phosphatase and tensin homolog (PTEN) tumor suppressor genes., Aim: To determine the inhibitory effect of Holothuria scabra methanol extract (HSE) on breast cancer growth through the TGF-β/PI3K pathways and PTEN tumor suppressor gene on a breast cancer (BC) mice model., Materials and Methods: Female C57BL6 mice were subcutaneously injected with carcinogen DMBA 1 mg/kg body weight (BW) and fed a high-fat diet (HFD). Mice were randomly divided into five groups (n = 6): negative control (NC) administered with a standard diet, positive control (PC) administered with DMBA and HFD, and three treatment groups (T1, T2, and T3) treated with HSE doses of 0.33, 0.66, and 0.99 g/kg BW for 12 weeks. TGF-β concentration in the blood serum of mice was assessed by ELISA and the PIK3CA and PTEN gene expression by qRT-PCR., Results: The treatment with HSE resulted in a significant decrease in TGF-β concentrations in the blood sera of treatment groups T1 (35.31 ± 17.33), T2 (43.31 ± 17.42), and T3 (48.67 ± 20.94) pg/mL compared to the PC group (162.09 ± 11.60) pg/mL (p < 0.001). However, only HSE at a dose of 0.99 g/kg BW decreased the PIK3CA gene expression (p = 0.026), and at a dose of 0.66 g/kg BW increased the PTEN expression up to 4.93-fold., Conclusion: HSE is capable of inhibiting the TGF-β/PIK3CA pathway and increasing the PTEN gene expression.

The distribution of motion between the radiocarpal and midcarpal joints in scapholunate instability is poorly understood. This has potential implications in predicting degenerative changes and in selecting salvage procedures. We studied 19 healthy wrists and 19 wrists with scapholunate instability using dynamic computed tomography during wrist extension to flexion and ulnar to radial deviation. Radiocarpal and midcarpal kinematics of the scaphoid and the lunate were computed. In scapholunate instability, in the radial column, there was increased motion in the radiocarpal joint when the wrist was radially deviating beyond 10° or moving from 70° to 40° extension. In both groups, the capitolunate joint was the dominant articulation in the central column. In scapholunate instability, there was significantly more capitolunate motion during 70° to 30° extension. These changes may predict the development of radioscaphoid arthritis and enable identifying a kinematically abnormal wrist. The motion distribution in scapholunate instability was abnormal beyond 10° of radial deviation and between 70° and 40° of wrist extension. Level of evidence: III., Competing Interests: Declaration of conflicting interestsThe author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Management of hypertension, dyslipidemia, diabetes and other modifiable factors may mitigate the cardiovascular disease (CVD) risk in people with human immunodeficiency virus (HIV, PWH) compared with people without HIV (PWoH)., Methods: This was a retrospective cohort study of 8285 PWH and 170 517 PWoH from an integrated health system. Risk factor control was measured using a novel disease management index (DMI) accounting for amount/duration above treatment goals (0% to 100% [perfect control]), including 2 DMIs for hypertension (diastolic and systolic blood pressure), 3 for dyslipidemia (low-density lipoprotein, total cholesterol, triglycerides), and 1 for diabetes (HbA1c). CVD risk by HIV status was evaluated overall and in subgroups defined by DMIs, smoking, alcohol use, and overweight/obesity in adjusted Cox proportional hazards models., Results: PWH and PWoH had similar DMIs (80%-100%) except for triglycerides (worse for PWH) and HbA1c (better for PWH). In adjusted models, PWH had an elevated risk of CVD compared with PWoH (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.31). This association was attenuated in subgroups with controlled dyslipidemia and diabetes but remained elevated for PWH with controlled hypertension or higher total cholesterol. The strongest HIV status association with CVD was seen in the subgroup with frequent unhealthy alcohol use (HR, 2.13; 95% CI, 1.04-4.34)., Conclusions: Control of dyslipidemia and diabetes, but not hypertension, attenuated the HIV status association with CVD. The strong association of HIV and CVD with frequent unhealthy alcohol use suggests enhanced screening and treatment of alcohol problems in PWH is warranted., Competing Interests: Potential conflicts of interest. M. C. reports research grants from Gilead, MSD, and ViiV (paid to institution); payment for expert testimony from Gilead, MSD, and ViiV Healthcare (paid to institution); and support for attending meetings and/or travel from Gilead (paid to institution). C. B. H. reports grants or contracts from Gilead (payments to institution for unrelated research). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Musculoskeletal (MSK) causes of chest pain are considered common in emergency care, yet management is limited, reported outcomes are poor and prevalence data in New Zealand are lacking. The present study aims to estimate the prevalence of MSK chest pain in New Zealand EDs and describe the characteristics of MSK chest pain cases., Methods: A retrospective chart review was conducted based on de-identified clinical notes extracted from four hospitals within the South Island of New Zealand from 3 months spanning 1 March to 31 May 2021. Individual cases were categorised to the single best-fitting cause of chest pain using systems-based categorisation, based primarily on the doctors' documented final impression., Results: A total of 1344 cases were categorised in the present study. MSK chest pain had a prevalence of 15% (range 11-31%) of chest pain presentations across all study sites. This represented the second most common system responsible for chest pain, after the cardiovascular system. The mean age of MSK chest pain cases was 46.9 (standard deviation [SD] 19.1) years, compared to 55.5 (SD 19.7) years in all cases. Age and gender-specific data, data from rural hospitals and MSK sub-type data are presented., Conclusions: These data provide a conservative estimate of MSK chest pain prevalence in EDs within the South Island of New Zealand. The findings highlight MSK chest pain as common in emergency care, providing a basis and justification for further research to improve management and outcomes for people with MSK chest pain., (© 2023 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Background: To estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain., Methods: We conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks., Results: Participants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively. Pain interference decreased for all three arms. Mean differences in change in pain interference for gabapentin vs. placebo, and naltrexone vs. placebo was 0.16 (95% CI -1.38, 1.71; p = 0.83) and 0.40 (95% CI -1.18, 1.99; p = 0.83), respectively., Conclusion: Neither gabapentin nor low-dose naltrexone appeared to improve pain more than placebo among PWH with chronic pain and past-year heavy alcohol use., Clinical Trial Registration: ClinicalTrials.gov (NCT4052139)., Competing Interests: Employees of the funder NIH (K. Bryant and M. Backonja) are co-authors on this manuscript and helped guide analysis, interpretation and presentation of data and participated in the decision to submit the manuscript for publication. The funder provided support in the form of salaries for authors [K. Bryant, M. Backonja], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. D. Cheng serves on Data Safety Monitoring Boards for Janssen Research & Development. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors report no conflicts of interest., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a supplementary intervention that can be incorporated into the Pre-Exposure Prophylaxis (PrEP) Care Continuum, complementing initiatives and endeavors focused on Human Immunodeficiency Virus (HIV) prevention in clinical care and community-based work. Referencing the Transtheoretical Model of Change and the PrEP Awareness Continuum, this conceptual analysis highlights how SBIRT amplifies ongoing HIV prevention initiatives and presents a distinct chance to address identified gaps. SBIRT's mechanisms show promise of fit and feasibility through (a) implementing universal Screening (S), (b) administering a Brief Intervention (BI) grounded in motivational interviewing aimed at assisting individuals in recognizing the significance of PrEP in their lives, (c) providing an affirming and supportive Referral to Treatment (RT) to access clinical PrEP care, and (d) employing client-centered and destigmatized approaches. SBIRT is uniquely positioned to help address the complex challenges facing PrEP awareness and initiation efforts. Adapting the SBIRT model to integrate and amplify HIV prevention efforts merits further examination., 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., (Copyright © 2024 Harris, Kerr, Skidmore, Ghare, Reyes-Vega, Remenik-Zarauz, Samanapally, Anwar, Rijal, Bryant, Hall and Barve.)

The Colibrí™ is a new instrument that automates picking and placement of colonies on target plates for MALDI identification. This study compared the performance of the Colibrí™ to standard manual spotting using the VITEK® MS for bacterial identification. Colonies were selected from cultures of urine, wound, respiratory, and positive blood cultures. The Colibrí™ sampled the colonies, transferred them to a MALDI target slide, and overlayed each spot with matrix. Manual spotting was then performed using the same or similar colonies. A total of 444 bacteria were compared. Identification was achieved with both methods for 432 organisms with only 2 discrepant results, overall agreement of 99.54%. Twelve organisms (2.70%) gave no identification using Colibrí™. The Colibrí™ provides automation to a manual process with a high accuracy. Use of the Colibrí™ instrumentation provides an opportunity to reallocate technologist time to more complicated tasks and provides complete traceability from plating to organism identification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Alcohol use is common among people with HIV and is a risk factor for tuberculosis disease and non-adherence to isoniazid preventive therapy (IPT). Few interventions exist to reduce alcohol use and increase IPT adherence in sub-Saharan Africa. The aim of this study was to test the hypothesis that financial incentives conditional on point-of-care negative urine alcohol biomarker testing and positive urine isoniazid testing would reduce alcohol use and increase isoniazid adherence, respectively, in people with HIV who have latent tuberculosis infection and hazardous alcohol use., Methods: We conducted an open-label, 2×2 factorial randomised controlled trial in Uganda. Eligible for the study were non-pregnant HIV-positive adults (aged ≥18 years) prescribed antiretroviral therapy for at least 6 months, with current heavy alcohol use confirmed by urine ethyl glucuronide (biomarker of recent alcohol use) and a positive Alcohol Use Disorders Identification Test-Consumption (AUDIT-C; ≥3 for women, ≥4 for men) for the past 3 months' drinking, no history of active tuberculosis, tuberculosis treatment, or tuberculosis preventive therapy, and a positive tuberculin skin test. We randomly assigned participants (1:1:1:1) initiating 6 months of IPT to: no incentives (group 1); or incentives for recent alcohol abstinence (group 2), isoniazid adherence (group 3), or both (group 4). Escalating incentives were contingent on monthly point-of-care urine tests negative for ethyl glucuronide (groups 2 and 4), or positive on IsoScreen (biomarker of recent isoniazid use; groups 3 and 4). The primary alcohol outcome was non-hazardous use by self-report (AUDIT-C <3 for women, <4 for men) and phosphatidylethanol (PEth; past-month alcohol biomarker) <35 ng/mL at 3 months and 6 months. The primary isoniazid adherence outcome was more than 90% bottle opening of days prescribed. We performed intention-to-treat analyses. This trial is registered with ClinicalTrials.gov (NCT03492216), and is complete., Findings: From April 16, 2018, to Aug 2, 2021, 5508 people were screened, of whom 680 were randomly assigned: 169 to group 1, 169 to group 2, 170 to group 3, and 172 to group 4. The median age of participants was 39 years (IQR 32-47), 470 (69%) were male, 598 (90%) of 663 had HIV RNA viral loads of less than 40 copies per mL, median AUDIT-C score was 6 (IQR 4-8), and median PEth was 252 ng/mL (IQR 87-579). Among 636 participants who completed the trial with alcohol use endpoint measures (group 1: 152, group 2: 159, group 3: 161, group 4: 164), non-hazardous alcohol use was more likely in the groups with incentives for alcohol abstinence (groups 2 and 4) versus no alcohol incentives (groups 1 and 3): 57 (17·6%) of 323 versus 31 (9·9%) of 313, respectively; adjusted risk difference (aRD) 7·6% (95% CI 2·7 to 12·5, p=0·0025). Among 656 participants who completed the trial with isoniazid adherence endpoint measures (group 1: 158, group 2: 163, group 3: 168, group 4: 167), incentives for isoniazid adherence did not increase adherence: 244 (72·8%) of 335 in the isoniazid incentive groups (groups 3 and 4) versus 234 (72·9%) of 321 in the no isoniazid incentive groups (groups 1 and 2); aRD -0·2% (95% CI -7·0 to 6·5, p=0·94). Overall, 53 (8%) of 680 participants discontinued isoniazid due to grade 3 or higher adverse events. There was no significant association between randomisation group and hepatotoxicity resulting in isoniazid discontinuation, after adjusting for sex and site., Interpretation: Escalating financial incentives contingent on recent alcohol abstinence led to significantly lower biomarker-confirmed alcohol use versus control, but incentives for recent isoniazid adherence did not lead to changes in adherence. The alcohol intervention was efficacious despite less intensive frequency of incentives and clinic visits than traditional programmes for substance use, suggesting that pragmatic modifications of contingency management for resource-limited settings can have efficacy and that further evaluation of implementation is merited., Funding: National Institute on Alcohol Abuse and Alcoholism., Translation: For the Runyankole translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Developing a diverse talent pool starting at the high-school level, while students are making future education and career decisions, should be a national priority, given the need to build a diverse health-care workforce. This article describes a 6-week immersive simulation-based summer program to introduce 20 junior high-school students (13-15 years old) to the range of health professions. Because precollege students typically receive limited exposure to clinical settings, high-fidelity simulation is an excellent surrogate for providing realistic experiences in health care. Students heard lectures on health careers, earned basic life support certification, learned to perform basic vital signs measurement, practiced the management of acute asthma, and received an introduction to the daily activities in the life of a nurse and an anesthesiologist. They researched, developed, and presented public service announcement videos about a health-care issue affecting their community. Participants reported being excited about health careers. Future programs will focus on longitudinal support and mentoring, essential for mitigating the higher rates of attrition from health professions among minoritized individuals.

Background: Severe early-onset childhood obesity is diagnosed by having a BMI >120% of the 95th percentile before age 5 years. Treatment for early-onset obesity is frequently unsuccessful. Prior studies have shown parents of children with obesity often face stigmatization and those who experience weight bias also experience poorer medical care. Home environment influences many risk factors, and parents are crucial for intervention. Research on the parental perspective of care is lacking and greater understanding could increase the effectiveness of treatment. We sought to understand the common stressors and obstacles parents encounter caring for a child with early-onset severe obesity. Methods: Parents of children with early-onset severe obesity participated in semistructured interviews. Interviews were digitally recorded, transcribed verbatim, coded, and analyzed using hybrid thematic analysis. Results: We identified a global theme of "Isolation in a sea of 'experts'," supported by three organizing themes: (i) Facing barriers at every turn; (ii) Carrying all the burdens; and (iii) Struggling to get their child seen as an individual. Within each organizing theme, subthemes emerged that highlighted the struggles that parents encountered. These included significant conflict with others when attempting to implement dietary changes ( e.g. , spouses, other children, and extended family), protecting their child's self-esteem, perceived weight bias from medical staff, lack of experienced obesity clinicians, lack of access to weight management services, and judgment from others ( e.g. , family, friends, and strangers). Conclusions: This study highlighted that many parents of children with early-onset severe obesity felt significant struggles, both internal and external. Understanding the barriers parents face when caring for their children is critical to improving relationships and medical care.

Amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) dementia are characterized by pathological changes to the medial temporal lobes, resulting in explicit learning and retention reductions. Studies demonstrate that implicit/procedural memory processes are relatively intact in these populations, supporting different anatomical substrates for differing memory systems. This study examined differences between explicit and procedural learning and retention in individuals with aMCI and AD dementia relative to matched healthy controls. We also examined anatomical substrates using volumetric MRI. Results revealed expected difficulties with explicit learning and retention in individuals with aMCI and AD with relatively preserved procedural memory. Explicit verbal retention was associated with medial temporal cortex volumes. However, procedural retention was not related to medial temporal or basal ganglia volumes. Overall, this study confirms the dissociation between explicit relative to procedural learning and retention in aMCI and AD dementia and supports differing anatomical substrates.

Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03278886.

Objective: The scaphoid is proposed to be driven by the distal carpal row in scapholunate instability (SLI) as it is dissociated from the proximal row. The aim of this study was to describe the 6 degrees of freedom kinematics of the scaphoid using dynamic CT in the normal and SLI wrists. We hypothesised that the SLI scaphoid would demonstrate kinematic evidence conforming to distal row motion., Materials and Methods: We studied dynamic CT scans of 17 SLI and 17 normal wrists during ulnar to radial deviation and extension to flexion. The radio-scaphoid angles in three anatomic planes were calculated in the wrist neutral position and during wrist motion. The centroid position was also calculated in the wrist neutral position and during wrist motion. The scapho-capitate motion index (SCI) was calculated as a ratio between the scaphoid and the capitate motion., Results: In the neutral position of the wrist, the SLI scaphoid was flexed, internally rotated, and radially translated compared to the normal scaphoid. During wrist motion, the SLI scaphoid had more 'in-plane' motion and less 'out-of-plane' motion with a higher SCI during wrist neutral to radial deviation and extension to neutral., Conclusion: We have described the malalignment of the SLI scaphoid in the neutral position of the wrist and 6 degrees of freedom kinematics during wrist motion of the SLI scaphoid compared to the normal. The SLI scaphoid conformed more to the distal row motion than the normal scaphoid. This information may help define the surgical reconstruction techniques for SLI., (© 2023. The Author(s).)

Background: People aging with and without HIV (PWH and PWoH) want to avoid neurocognitive dysfunction, especially delirium. Continued use of alcohol in conjunction with neurocognitively active medications (NCAMs) may be a largely underappreciated cause, especially for PWH who experience polypharmacy a decade earlier than PWoH. We compare absolute and relative risk of delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs., Methods: Using the VACS cohort, we compare absolute and relative risk of inpatient delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs between 2007 and 2019. We matched each case based on age, race/ethnicity, sex, HIV, baseline year, and observation time with up to 5 controls. The case/control date was defined as date of admission for cases and the date corresponding to the same length of time on study for controls. Level of alcohol use was defined using Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Medication exposure was measured from 45 to 3 days prior to index date; medications were classified as anticholinergic NCAM, non-anticholinergic NCAM, or non NCAM and counts generated. We used logistic regression to determine odds ratios (ORs) for delirium associated with medication counts stratified by HIV status and adjusted for demographics, severity of illness, and related diagnoses., Results: PWH experienced a higher incidence of delirium (5.6, [95% CI 5.3-5.9/1000 PY]) than PWoH (5.0, [95% CI 4.8-5.1/1000 PY]). In multivariable analysis, anticholinergic and non-anticholinergic NCAM counts and level of alcohol use demonstrated strong independent dose-response associations with delirium., Conclusions: Decreasing alcohol use and limiting the use of neurocognitively active medications may help decrease excess rates of delirium, especially among PWH., (© 2023 The American Geriatrics Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Alcohol use has been linked to worse human immunodeficiency virus (HIV) immunologic/virologic outcomes, yet few studies have explored the effects of alcohol use disorder (AUD). This study assessed whether AUD severity is associated with HIV viral suppression and CD4 count in the three cohorts of the Uganda Russia Boston Alcohol Network for Alcohol Research Collaboration on HIV/AIDS (URBAN ARCH) Consortium., Methods: People with HIV (PWH) in Uganda (n = 301), Russia (n = 400), and Boston (n = 251), selected in-part based on their alcohol use, were included in analyses. Logistic and linear regressions were used to assess the cross-sectional associations between AUD severity (number of DSM-5 diagnostic criteria) and (1) HIV viral suppression, and (2) CD4 count (cells/mm 3 ) adjusting for covariates. Analyses were conducted separately by site., Results: The proportion of females was 51% (Uganda), 34% (Russia), and 33% (Boston); mean age (SD) was 40.7 (9.6), 38.6 (6.3), and 52.1 (10.5), respectively. All participants in Uganda and all but 27% in Russia and 5% in Boston were on antiretroviral therapy. In Uganda, 32% met criteria for AUD, 92% in Russia, and 43% in Boston. The mean (SD) number of AUD criteria was 1.6 (2.4) in Uganda, 5.6 (3.3) in Russia, and 2.4 (3.1) in Boston. Most participants had HIV viral suppression (Uganda 92%, Russia 57%, Boston 87%); median (IQR) CD4 count was 673 (506, 866), 351 (201, 542), and 591 (387, 881), respectively. In adjusted models, there were no associations between AUD severity and HIV viral suppression: adjusted odds ratios (AOR) (95%CI) per 1 additional AUD criterion in Uganda was 1.08 (0.87, 1.33); Russia 0.98 (0.92, 1.04); and Boston 0.95 (0.84, 1.08) or CD4 count: mean difference (95%CI) per 1 additional criterion: 5.78 (-7.47, 19.03), -3.23 (-10.91, 4.44), and -8.18 (-24.72, 8.35), respectively., Conclusions: In three cohorts of PWH, AUD severity was not associated with HIV viral suppression or CD4 count. PWH with AUD in the current era of antiretroviral therapy can achieve virologic control., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)