High-Throughput Assessment of Bile Salt Export Pump Inhibition Using RapidFire-MS and DESI-MS.

The bile salt export pump (BSEP) assay is widely used to evaluate the potential for drug-induced liver injury (DILI) early in the drug discovery process. While traditional liquid chromatography-mass spectrometry (LC-MS)-based approaches have been utilized for BSEP activity testing, they have intrinsic limitations in either throughput or the requirement for sample preparation and are difficult to scale up in order to screen drug candidates. Here we demonstrate the use of two different high-throughput MS methods based on solid-phase extraction (SPE) and desorption electrospray ionization (DESI) for high-throughput BSEP activity assessment in a label-free manner, with minimal needs for sample workup, at sampling rates of ∼11 and ∼5.5 s/sample, respectively. Both approaches were validated, compared, and successfully applied to the evaluation of 96 drug candidates for the inhibition of taurocholic acid (TCA) transport using BSEP vesicles.

Reduced Risk of SARS-CoV-2 Infection Among Household Contacts with Recent Vaccination and Past COVID-19 Infection: Results from Two Multi-Site Case-Ascertained Household Transmission Studies.

Households are a primary setting for transmission of SARS-CoV-2. We examined the role of prior SARS-CoV-2 immunity on the risk of infection in household close contacts. Households in the United States with an individual who tested positive for SARS-CoV-2 during September 2021-May 2023 were enrolled if the index case's illness began ≤6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. The effects of prior SARS-CoV-2 immunity (vaccination, prior infection, or hybrid immunity) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Of 1,532 contacts (905 households), 8% had immunity from prior infection alone, 51% from vaccination alone, 29% hybrid immunity, and 11% had no prior immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The adjusted risk of SARS-CoV-2 infection was lowest among contacts with vaccination and prior infection (aRR: 0.81, 95% CI: 0.70, 0.93, compared with contacts with no prior immunity) and was lowest when the last immunizing event occurred ≤6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). In high-transmission settings like households, immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection.

Does stress from incarceration of family and friends contribute to signs of early vascular ageing in African American women?

BACKGROUND: Early vascular ageing (EVA) contributes to elevated risk of cardiovascular disease (CVD), which disproportionately affects African American women. Incarceration, an event disproportionately impacting African Americans, may be a stressor contributing to EVA in African American women. Further, the subjective perspective, commonly referred to as appraisal, of incarceration may also be important for health. We hypothesised that having family and/or friends incarcerated and appraising the incarceration as upsetting would be associated with indices of EVA. METHODS: In a community-based cohort of African American women aged 30-46 living in Atlanta, Georgia (n=391), participants were asked, at baseline, about family and/or friend incarceration and to appraise how upsetting the incarceration was. Multivariable linear regression examined associations between: (1) family and/or friend incarceration and indices of EVA (pulse wave velocity, augmentation index, central systolic blood pressure (SBP) and pulse pressure amplification) and (2) appraisal of incarceration and EVA indices. RESULTS: 45% of participants (n=174) reported having a loved one incarcerated, and 59% (n=102) reported the incarceration as upsetting. Having a loved one incarcerated was associated with a higher central SBP (b=4.30; 95% CI 1.61, 6.99) and augmentation index (b=2.29; 95% CI 0.26, 4.33). Appraisal of incarceration was only associated with central SBP. CONCLUSIONS: Family or friend incarceration was highly prevalent in this cohort of African American women and associated with indices of EVA. Mass incarceration of others may affect the physical health of African American women which may contribute to CVD disparities.

Predicting relapse in acute lymphoblastic leukemia.

Outcomes in adult and pediatric patients with acute lymphoblastic leukemia (ALL) have improved over successive generations due to rigorously conducted clinical trials and incorporation of novel therapeutic agents. Despite these advances, approximately 20% of high-risk pediatric patients and 50% of adults with ALL will fail to achieve long-term remission with frontline chemotherapy protocols, mostly due to relapse. The ability to predict which patients with ALL are more likely to relapse allows for early intensification of therapy and/or incorporation of novel immunotherapies with the goal of relapse prevention. In this review, we outline the most robust clinical predictors of relapse in ALL with a focus on measurable residual disease (MRD) and genomics. We also discuss application of these prognostic tools in different clinical settings including frontline treatment, pre-/post-allogeneic stem cell transplant, and pre-/post-Chimeric Antigen Receptor T-cell therapy.

Travel-time barriers to specialized cancer care for adolescents and young adults with acute lymphoblastic leukemia.

BACKGROUND: Prior studies demonstrate that 20%-50% of adolescents and young adults (age 15-39 years) with acute lymphoblastic leukemia (ALL) receive care at specialty cancer centers, yet a survival benefit has been observed for patients at these sites. Our objective was to identify patients at risk of severe geographic barriers to specialty cancer center-level care. METHODS: We used data from the North American Association of Central Cancer Registries Cancer in North America database to identify adolescent and young adult ALL patients diagnosed between 2004 and 2016 across 43 US states. We calculated driving distance and travel time from counties where participants lived to the closest specialty cancer center sites. We then used multivariable logistic regression models to examine the relationship between sociodemographic characteristics of counties where adolescent and young adult ALL patients resided and the need to travel more than 1 hour to obtain care at a specialty cancer center. RESULTS: Among 11 813 adolescent and young adult ALL patients, 43.4% were aged 25-39 years, 65.5% were male, 32.9% were Hispanic, and 28.7% had public insurance. We found 23.6% of adolescent and young adult ALL patients from 60.8% of included US counties would be required to travel more than 1 hour one way to access a specialty cancer center. Multivariable models demonstrate that patients living in counties that are nonmetropolitan, with lower levels of educational attainment, with higher income inequality, with lower internet access, located in primary care physician shortage areas, and with fewer hospitals providing chemotherapy services are more likely to travel more than 1 hour to access a specialty cancer center. CONCLUSIONS: Substantial travel-related barriers exist to accessing care at specialty cancer centers across the United States, particularly for patients living in areas with greater concentrations of historically marginalized communities.

Gender Parity Analysis of the Editorial Boards of Influential Dermatology Journals: Cross-Sectional Study.

This study underscores the persistent underrepresentation of women in academic dermatology leadership positions by examining the gender composition of editorial boards across top dermatology journals, emphasizing the urgent need for proactive strategies to promote diversity, equity, and inclusion.

Treated versus self-reported prevalence of chronic pain and costs of patients' health services utilization: a population-based study of health administrative databases.

Objectives: To compare treated to self-reported prevalence of chronic pain (CP) and to estimate health services utilization (HSU) costs of patients treated for CP in Alberta, Canada. Methods: Patients treated for CP were identified by the physician billing codes of health services for CP from the practitioner claims database in fiscal year 2021/22. The treated prevalence of CP (number of these patients divided by the population) was compared to the self-reported prevalence of CP previously estimated (doi:10.1371/journal.pone.0272638). Costs of patients' HSU included costs for general practitioner (GP), specialist, inpatient, emergency department, outpatient clinic services, and prescription drugs. Results: The treated prevalence of CP was 6.0% (4.4% among males and 7.8% among females) which was 30% to 41% of the self-reported prevalence. The highest treated prevalence (7.2%) was found in the age group of 18-64 years, followed by age groups of >64 years (7.0%) and <18 years (2.1%). The average cost per patient per year was $5096 ($5878 for males and $4652 for females), of which hospitalizations accounted for 65.0%, outpatient clinic visits 16.4%, ED visits 9.5%, prescription drugs 4.7%, GP visits 3.9%, and specialist visits 0.4%. The total cost of patients with CP for the health system was $1.37 billion (∼7% of total health expenditure), of which males accounted for 41.7% and females for 58.3%. Discussion: Our findings suggest that the economic burden of CP is considerable and that many people with self-reported CP do not use the public healthcare services. This can be multifactorial, including lack of availability and accessibility of publicly funded services, people's lack of awareness of available services, lower utilization due to COVID-19 pandemic, and reliance on self-management, private services, and alternative treatments. Further studies are warranted to inform future policies and health system initiatives aiming to reduce the burden of CP and improve lives of people living with it.

Traumatic telson avulsion and attempted external stabilization in Atlantic horseshoe crabs (Limulus polyphemus).

Atlantic horseshoe crabs (Limulus polyphemus) are prevalent in public aquarium touch pools. Despite their popularity, the literature concerning medical management under managed care is sparse. Noninfectious conditions include trauma to the exoskeleton and compound eyes; however, injury to the soft tissue connecting the telson and opisthosoma has not been previously reported. This report describes telson avulsion in three Atlantic horseshoe crabs at a public aquarium and attempted external stabilization with a vascular silicone tie in two of three affected animals. The horseshoe crab that received no veterinary intervention suffered a complete telson amputation 1 month after the initial injury. Although the two other horseshoe crabs did well postoperatively, and external stabilization prevented further avulsion or amputation, they still could not right themselves if flipped into dorsal recumbency. All three horseshoe crabs were ultimately euthanized due to animal welfare concerns. To avoid potentially serious telson ligament injury, horseshoe crabs should never be picked up by the telson. The authors recommend that telson ligament injuries be addressed promptly, any inciting cause be mitigated, and external stabilization be considered earlier.

Single-center randomized trial of T-reg graft alone vs T-reg graft plus tacrolimus for the prevention of acute GVHD.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T-regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10-matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n = 12) or T-reg graft plus single-agent GVHD prophylaxis (n = 12) to determine whether T-reg graft alone was noninferior in preventing acute GVHD. All patients developed full-donor myeloid chimerism. Patients with T-reg graft alone vs with prophylaxis had incidences of grade 3 to 4 acute GVHD of 58% vs 8% (P = .005) and grade 3 to 4 of 17% vs 0% (P = .149), respectively. The incidence of moderate-to-severe chronic GVHD was 28% in the T-reg graft alone arm vs 0% with prophylaxis (P = .056). Among patients with T-reg graft and prophylaxis, CD4+ T-cell-to-Treg ratios were reduced after transplantation, gene expression profiles showed reduced CD4+ proliferation, and the achievement of full-donor T-cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred over T-reg graft alone for the prevention of acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT01660607.

Loss of Muscle Mass and Strength After Hip Fracture: an Intervention Target for Nutrition Supplementation.

PURPOSEOF REVIEW: To summarize what is known about the deleterious effect of hip fracture on muscle mass and strength as well as the scientific evidence for post-surgical nutrition supplementation to maintain muscle and improve function. RECENT FINDINGS: This review provides a discussion of the relationship between muscle mass, strength, and physical function following hip fracture, briefly describes the approaches to measuring lean mass, discusses prevalence of sarcopenia and malnutrition among older men and women with hip fracture, and reviews the effects of essential amino acids on muscle. Loss of muscle mass and strength following hip fracture is substantial with consequences for recovery of functional independence. EAA-based nutrition supplementation, which directly effects muscle, has potential to improve outcomes.

History of Finding Genes and Mutations Causing Inherited Retinal Diseases.

This is a brief history of the work by many investigators throughout the world to find genes and mutations causing inherited retinal diseases (IRDs). It largely covers 40 years, from the late-1980s through today. Perhaps the best reason to study history is to better understand the present. The "present" for IRDs is exceptionally complex. Mutations in hundreds of genes are known to cause IRDs; tens of thousands of disease-causing mutations have been reported; clinical consequences are highly variable, even within the same family; and genetic testing, counseling, and clinical care are highly advanced but technically challenging. The aim of this review is to account for how we have come to know and understand, at least partly, this complexity.

Impact of Specialized Treatment Setting on Survival in Adolescent and Young Adult ALL.

PURPOSE: Unlike children with ALL who receive cancer care primarily at specialized cancer centers (SCCs; National Cancer Institute and/or Children's Oncology Group centers), adolescents and young adults (AYAs; 15-39 years) receive care in a variety of settings. Using population-based data, we describe where AYAs with ALL receive treatment and determine associations with overall survival (OS). METHODS: Data from the 2004 to 2018 California (CA, n = 2,283), New York (NY, n = 795), and Texas (TX, n = 955) state cancer registries were used to identify treatment setting of AYAs with newly diagnosed ALL. Multivariable Cox proportional hazards regression models evaluated associations with OS. RESULTS: Seventy percent were older than 18 years, and 65% were male. A majority in CA (63%) and TX (64%) were Hispanic while most in NY were non-Hispanic White (50%). Treatment at an SCC occurred in 48.2% (CA), 44.4% (NY), and 19.5% (TX). Across states, AYAs who were older or uninsured were less likely to receive treatment at an SCC. Treatment at an SCC was associated with superior OS in CA (hazard ratio [HR], 0.73; 95% CI, 0.63 to 0.85) and TX (HR, 0.61; 95% CI, 0.45 to 0.83); a nonsignificant association was seen in NY (HR, 0.83; 95% CI, 0.64 to 1.08). CONCLUSION: Only 20%-50% of AYA patients with ALL received frontline treatment at SCCs. Treatment of ALL at an SCC was associated with superior survival, highlighting the importance of policy efforts to improve access and reduce inequities in AYA ALL care.

A Druggable FOXA1-Glucocorticoid Receptor Transcriptional Axis Drives Tumor Growth in a Subset of Non-Small Cell Lung Cancer.

The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone-dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as estrogen receptor (ER) and androgen receptor (AR) to activate lineage-specific growth programs. FOXA1 is also highly expressed in non-small cell lung cancer (NSCLC), but whether and how it regulates tumor growth in this context is not known. Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1 dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein, we identified chromatin-localized interactions between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. In these FOXA1-dependent models, FOXA1 and GR cooperate to regulate gene targets involved in EGF signaling and G1-S cell-cycle progression. To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand-binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo. Taken together, our findings point to a subset of NSCLCs harboring a dependence on the FOXA1/GR growth program and provide rationale for its therapeutic targeting. Significance: NSCLC is the leading cause of cancer deaths worldwide. There is a need to identify novel druggable dependencies. We identify a subset of NSCLCs dependent on FOXA1-GR and sensitive to GR antagonism.

Pinna Edge Biopsy of 7 and 21 Day Old C57BL/6 Mice as a Method for Identification and Genotyping.

Identifying and genotyping mice prior to weaning can be useful for mouse colony management. Mice of an undesired genotype can be identified prior to weaning and removed from further study, resulting in a reduction of housing costs, and labor time. We hypothesized that a pinna edge biopsy (PEB) performed by removing a portion of its edge with scissors is a reliable method for identifying and genotyping mice on postnatal day (PND) 7 consistent with PND 21, weaned mice. The pinnae of 54 C57BL/NCrl6 mice were biopsied on PND 7, and another 54 were biopsied on PND 21. Nine pinna patterns were tested. The accuracy of pattern identification was assessed on PND 7, 14, 21, 30, and 63. The mean times were compared for performing the biopsy on PND 7 and PND 21 mice, and the average time taken to identify the patterns were determined. Weight, milk spot presence, pup rejection, morbidity, and mortality were examined at various time points. During the biopsy, bleeding of the pinna, urination, vocalization, and flinching were assessed. No significant differences were detected in DNA quality, relative DNA quantity, genotyping reliability, or body weight (P ≥ 0.05) between mice biopsied on PND 7 and PND 21. Flinching at the time of PEB was significantly higher in PND 21 mice as compared with PND 7 mice (P < 0.00001). Pinna pattern identification accuracy for mice biopsied on PND 7 and PND 21 were 96% and 98%, respectively. This study validates the use of PEB for simultaneous identification and genotyping of PND 7 mice.

Effects of a hydropower project on a high-value Asian elephant population.

Habitat loss and fragmentation are leading contributors to the endangered status of species. In 2006, the Nakai Plateau contained the largest known Asian elephant (Elephas maximus) population in the Lao People's Democratic Republic (Lao PDR), and the population was among those with the highest genetic diversity reported for Asian elephants. In 2008, completion of the Nam Theun 2 hydroelectric dam inundated much of the Plateau, resulting in the loss of 40% of elephant habitat. We studied elephant presence, movements, and the incidence of human-elephant conflict (HEC) on the Nakai Plateau and surrounding areas from 2004 to 2020, before and for 12 years after dam completion. To examine contemporary population dynamics in the Nakai elephants, we used genetic sampling to compare minimum population numbers, demography, and levels of genetic diversity from the wet and dry seasons in 2018/2019, 10 years after dam completion, with those reported in a pre-dam-completion genetic survey. After dam completion, we found a major increase in HEC locally and the creation of new, serious, and persistent HEC problems as far as 100 km away. While we were unable to compare estimated population sizes before and after dam completion, our data revealed a decrease in genetic diversity, a male-biased sex ratio, and evidence of dispersal from the Plateau by breeding-age females. Our results raise concerns about the long-term viability of this important population as well as that of other species in this region. Given that hydropower projects are of economic importance throughout Laos and elsewhere in southeast Asia, this study has important implications for understanding and mitigating their impact.

Strategies to reduce the onset of sleeve gastrectomy associated bone loss (STRONG BONES): Trial design and methods.

Background: Despite recognized improvements in obesity-related comorbidities, mounting evidence implicates surgical weight loss in the onset of skeletal fragility. Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure and is associated with 3-7% axial bone loss in the year following surgery. Bisphosphonates are FDA-approved medications for the prevention and treatment of age-related bone loss and may represent a strategy to reduce bone loss following SG surgery. Methods: The Strategies to Reduce the Onset of Sleeve Gastrectomy Associated Bone Loss (STRONG BONES) trial (NCT04922333) is designed to definitively test whether monthly administration of the bisphosphonate, risedronate, for six months can effectively counter SG-associated bone loss. Approximately 120 middle-aged and older (≥40 years) SG patients will be randomized to six months of risedronate or placebo treatment, with skeletal outcomes assessed at baseline, six, and 12-months post-surgery. The primary outcome of the trial is 12-month change in total hip areal bone mineral density (aBMD), measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and quantitative computed tomography (QCT) derived changes in bone quality. Change in muscle mass and function will also be assessed, as well as biomarkers of bone health, turnover, and crosstalk, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Discussion: Results from the STRONG BONES trial have the potential to influence current clinical practice by determining the ability of bisphosphonate use to mitigate bone loss and concomitant fracture risk in middle-aged and older SG patients.

Standing on the shoulders of a giant: The legacy of Robert M. Sellers.

Robert M. Sellers, PhD, most known for his influential and highly cited Multidimensional Model of Racial Identity (MMRI), is one of the most prolific and foundational Black scholars in psychology. From racial identity theory development and measurement to conceptual and methodological innovations in studying the lived experiences of Black people, Sellers' scholarship centers on the lives of Black communities. Sellers' mentorship and contributions to the professional development of scholars and professionals of color have supported and catalyzed new intergenerational knowledge building by these scholars, ensuring a perpetuating and far-reaching legacy in psychology. In this article, we: (a) celebrate Sellers' enduring contribution to the racial identity literature and its profound impact on psychology as a discipline as well as numerous subfields of psychology, (b) outline his contributions to the racial socialization literature, (c) describe methodological innovations in racial identity and racial socialization research advanced through his scholarship, and (d) summarize his contributions in professional development and mentorship and his leadership roles. Sellers' scholarly contributions and mentorship have transformed the discipline of psychology and the social sciences broadly speaking, making him one of the most influential psychologists in the modern era. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Total serum and ionized magnesium concentrations in healthy and hospitalized dogs.

OBJECTIVE: To determine if an association between ionized magnesium (iMg) and total magnesium (tMg) exists in healthy and hospitalized dogs admitted through an emergency service and to assess the associations between iMg and tMg with total protein, albumin, ionized calcium, and total calcium. DESIGN: Prospective cohort study. SETTING: Veterinary teaching hospital. ANIMALS: Sixty-nine dogs were enrolled. The healthy control group (group 1) included 24 dogs, and the hospitalized group (group 2) included 45 dogs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For both groups, signalment, a venous blood gas, and serum biochemistry were obtained. In addition, the presumptive diagnosis was recorded for group 2. Blood was obtained prior to any therapeutic interventions. Group 1 tMg was within the reference interval (RI), and the values for iMg were used to provide a healthy group range (HGR) of 0.44-0.50 mmol/L. Group 2 tMg was within the RI, but iMg was below the calculated HGR range (group 2 median iMg = 0.4 mmol/L; range = 0.27-0.70). There was a significant positive correlation between iMg and tMg in each group (group 1: r = 0.6713, P = 0.0003; group 2: r = 0.5312, P = 0.0002). Ionized Mg and tMg were not significantly associated with any of the other evaluated variables in either group. CONCLUSIONS: Ionized Mg and tMg were significantly associated in both healthy and hospitalized dogs, but the relationship was weaker in the hospitalized dogs compared with the healthy population. For hospitalized dogs, the relationship was weak enough to question the validity of using iMg and tMg interchangeably to track magnesium status.