Association of Busulfan Exposure and Outcomes after HCT for Patients with an Inborn Error of Immunity.

Allogeneic HCT is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). Objective of this study was to assess the optimal busulfan exposure prior to allogeneic HCT for patients with an IEI who received an intravenous busulfan-based conditioning regimen between 2000 and 2023. Patients from 17 international centers were included. Main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined-immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (AUCCENTER) and was re-estimated using a validated model (AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) CID, 154 (27.4%) SCID, 101 (18.0%) HLH-related disorders, and 134 (23.8%) neutrophil disorders. Median busulfan AUCNONMEM was 69.0 mg×h/L and correlated poorly with AUCCENTER (r2=0.54). Patients with SCID, HLH-related, and neutrophil disorders were analyzed together (n=389), because CID disease subtype was an effect modifier (p=0.03). Estimated 2-year EFS was 78.5%. In patients with the found optimal busulfan AUCNONMEM of 70-90 mg×h/L, 2-year EFS was superior to <70 mg×h/L (adj-HR 1.97, 95% CI 1.11-3.49, p=0.02), and >90 mg×h/L (adj-HR 5.05, 95% CI 2.43-10.49, p<0.0001). Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg×h/L. For CID patients, optimal AUCNONMEM for donor chimerism was found to be >70 mg×h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg×h/L (range 70-90). Our study stresses the importance to uniformly using a validated population PK-model to estimate the AUCNONMEM.

Correction: The biotoxin BMAA promotes dysfunction via distinct mechanisms in neuroblastoma and glioblastoma cells.

[This corrects the article DOI: 10.1371/journal.pone.0278793.].

International comparison: Spinal cord injury in the USA and UK.

BACKGROUND: Long-term survival after spinal cord injury (SCI) has been extensively studied in the US and UK. OBJECTIVE: To compare SCI epidemiology and survival results between the US and UK for the same time period and patient groups. METHODS: We restricted attention to persons injured at ages 18 and older who had survived at least 2 years post injury and were not ventilator dependent. We performed survival analysis using logistic regression on person-year data with time-dependent covariates. The resulting mortality rates were used to construct life tables in order to obtain life expectancies. RESULTS: The average age at injury, percentage male, and level/grade of injury were rather similar between the two countries. After adjustment for risk factors, UK mortality was 85% of that in the US (95% c.i. 80% to 91%, p < 0.0001). Mortality increased by 0.3% per year over the 1980 to 2012 study period (HR = 1.003); this was not statistically significant (p = 0.44). The US and UK life expectancies are nearly the same percentage of their respective general population values, differing by at most 2%. CONCLUSION: Long-term mortality after SCI in the UK is roughly 15% lower than that in the US. The general population mortality in the UK is also approximately 15% lower, however, and thus the percentages of normal life expectancy in the two countries prove to be strikingly similar.

Manipulative-based Activity Using Pop Beads for Demonstration of Sanger Sequencing.

Sanger sequencing, also known as dideoxy sequencing, is a widely used method for DNA sequencing, particularly for cloned plasmids and clinical samples. This technique requires a combination of essential biochemistry skills, such as a chain-termination reaction, gel electrophoresis, and fluorescence detection. Unfortunately, there is a lack of activities that replicate the Sanger sequencing process for students to learn and practice these skills. To address this issue, a manipulative-based Sanger sequencing activity was developed that incorporates colorful pop beads to demonstrate a chain-termination reaction, separation of products, and fluorescence detection. The beads represent deoxynucleotides and dideoxynucleotides, allowing for a visual representation of DNA fragment generation. This kinesthetic learning activity offers a high visual impact for students, aiding in their understanding of the Sanger sequencing process, and can also be used to illustrate polymerase chain reaction (PCR)-based techniques.

Growth patterns in children and adolescents with cerebral palsy from Argentina and Germany.

To analyze growth patterns of children with CP between countries; to examine differences in growth; and to assess the fit of growth charts. Cross-sectional study in children with CP from 2 to 19 years old, 399 from Argentina and 400 from Germany. Growth measures were converted into z-scores and compared to WHO reference and US CP growth charts. Generalized Linear Model was used to analyze the growth expressed as mean z-scores. 799 children. Mean age 9 years (± 4). Compared to the WHO reference, the decrease in Height z-scores (HAZ) with age in Argentina (- 0.144/year) was double that in Germany (- 0.073/year). For children in GMFCS IV-V, BMI z-scores (BMIZ) decreased with age (- 0.102/year). Using the US CP charts, both countries showed decreasing HAZ with age, in Argentina (- 0.066/year) and in Germany (- 0.032/year). BMIZ increased more among children with feeding tubes (0.062/year), similar in both countries. Argentinian children with oral feeding decrease their Weight z-score (WAZ) by - 0.553 compared to their peers. With WHO charts BMIZ presented an excellent fit for GMFCS I-III. HAZ presents a poor fit to growth references. BMIZ and WAZ presented a good fit to US CP Charts. Growth differences due to ethnicity also act in children with CP, and are related to motor impairment, age and feeding modality, possibly reflecting differences in environment or health care.

The biotoxin BMAA promotes dysfunction via distinct mechanisms in neuroblastoma and glioblastoma cells.

Chronic exposure to the Cyanobacteria biotoxin Beta-methylamino-L-alanine (BMAA) has been associated with development of a sporadic form of ALS called Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), as observed within certain Indigenous populations of Guam and Japan. Studies in primate models and cell culture have supported the association of BMAA with ALS/PDC, yet the pathological mechanisms at play remain incompletely characterized, effectively stalling the development of rationally-designed therapeutics or application of preventative measures for this disease. In this study we demonstrate for the first time that sub-excitotoxic doses of BMAA modulate the canonical Wnt signaling pathway to drive cellular defects in human neuroblastoma cells, suggesting a potential mechanism by which BMAA may promote neurological disease. Further, we demonstrate here that the effects of BMAA can be reversed in cell culture by use of pharmacological modulators of the Wnt pathway, revealing the potential value of targeting this pathway therapeutically. Interestingly, our results suggest the existence of a distinct Wnt-independent mechanism activated by BMAA in glioblastoma cells, highlighting the likelihood that neurological disease may result from the cumulative effects of distinct cell-type specific mechanisms of BMAA toxicity.

Evidence Suggests a Decrease in the Incidence of Kernicterus in California.

We identified children diagnosed with kernicterus in the California Department of Developmental Services and estimated an incidence of 0.42 per 100 000 births from 1988 to 2014, significantly decreasing to 0.04 per 100 000 births after 2009. We also examined national infant kernicterus mortality from 1979 to 2016 using CDC data. It did not decrease significantly.

Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation.

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

Rapid Detection of Staphylococcus aureus Using Paper-Derived Electrochemical Biosensors.

Several groups have recently explored the idea of developing electrochemical paper-based wearable devices, specifically targeting metabolites in sweat. While these sensors have the potential to provide a breadth of analytical information, there are several key challenges to address before these sensors can be widely adopted for clinical interventions. Toward this goal, we describe the development of a paper-based electrochemical sensor for the detection of Staphylococcus aureus. Enabling the application, this report describes the use of paper-derived carbon electrodes, which were modified with a thin layer of sputtered gold (that minimizes lateral resistivity and significantly improves the electron transfer process) and with chitosan (used as a binder, to offer flexibility). The resulting material was laser-patterned and applied for the development of an electrochemical biosensor controlled (via a wireless connection) by a custom-built, portable potentiostat. As no interference was observed when exposed to other bacteria or common metabolites, this wearable system (paper-derived electrodes + potentiostat) has the potential to detect the presence of S. aureus in the skin, a commonly misdiagnosed and mistreated infection.

Life expectancy in multiple sclerosis by EDSS score.

The median survival time of newly-diagnosed MS patients without severe disabilities is approximately 30-35 years. The prognosis after the onset of severe disability has not been reported. Based on Harding et al.'s 2018 study of the Southeast Wales MS registry, we calculated life expectancies according to the Expanded Disability Status Scale (EDSS). Upon loss of independent ambulation (EDSS 6-6.5; mean age 51.2) life expectancy was 13.3 additional years. At EDSS 9-9.5 (mean age 70.8) life expectancy was 1.1 additional years. These figures provide an empirical basis for discussions of advanced MS care planning.

The differential impact of COVID-19 on mental health: Implications of ethnicity, sexual orientation, and disability status in the United States.

The COVID-19 pandemic's effects on mental health interact with preexisting health risks and disparities to impact varying populations differently. This study explored the relationship between demographic variables (e.g., ethnicity, sexual orientation, and disability status), distress and mental health (e.g., depression, anxiety, somatic complaints, and pandemic distress), and vulnerability factors for COVID-19 (e.g., personal health vulnerabilities, community members' health vulnerabilities, and environmental exposure risks at work or home). An online cross-sectional study was conducted from 18 June to 17 July 2020, reflecting the impact of early phase COVID-19 pandemic and related shelter-in-place measures in the United States. Participants were adults residing in the United States (N = 594), with substantial subsamples (N ≥ 70) of American Indian, Asian American, African-American, and Hispanic and/or Latinx participants, as well as people with disabilities and sexual minorities. Outcomes measured were depression, hopelessness, somatic complaints, anxiety-related disorders, locus of control (LOC), and a novel measure of pandemic-related distress. Data were analyzed using analyses of covariance (ANCOVA), chi-square test, and correlation coefficients. Generally, younger individuals, and those with less financial power-across all identities-suffered more distress. When controlling for age, lower financial power was associated with higher scores on the Center for Epidemiologic Studies Depression Scale-Revised (CESD-R; r = -0.21, p = < 0.001), Beck Hopelessness Scale (BHS; r = -0.17, p < 0.001), Patient Health Questionnaire-15 (PHQ-15; r = -0.09, p = 0.01), Screen for Child Anxiety Related Emotional Disorders for Adults Panic Disorder (SCARED-A PD; r = -0.14, p < 0.001), SCARED-A generalized anxiety disorder (GAD; r = -0.13, p = 0.002), SCARED-A obsessive-compulsive disorder (OCD; r = -0.08, p = 0.04), and the COVID-19 Pandemic Distress restriction/disconnection scale (C19PDS; r = -0.10, p = 0.009). In addition, disparities were found, in general, for marginalized identities by gender, sexual orientation, and disability status. Importantly, each ethnicity subsample showed a unique pattern of relationships between COVID-19 risk variables and mental health symptoms. The results support the hypothesis that any pandemic may amplify preexisting social and financial disparities. Overall, interventions at the clinical, governmental, or health equity level should take into consideration the needs of vulnerable groups.

Impact of an auditory hallucination simulation coupled with a speaker diagnosed with schizophrenia on mental illness stigma in pharmacy students.

INTRODUCTION: Hallucination simulations improve student empathy but increase desired social distance from individuals with schizophrenia, while direct contact reduces social distance. This study describes the implementation of combining an auditory hallucination simulation with a speaker diagnosed with schizophrenia and its impact on mental illness stigma. METHODS: Pharmacy students in their last year of didactic instruction (N = 346) attended a presentation by a speaker diagnosed with schizophrenia then participated in a hallucination simulation. Mental illness stigma was measured before and after the intervention using the Opening Minds Survey for Health Care Professionals (OMS-HC). Related-samples Wilcoxon-signed rank tests were used to evaluate changes in OMS-HC scores. An inductive qualitative analysis was conducted on student perceptions of patients with psychosis. RESULTS: OMS-HC total scores were reduced by an average of 2.0 ± 5.6 (P = .005) for the first-year pilot and 2.3 ± 7.0 (P < .001) for the subsequent year. OMS-HC attitudes (P = .005) and disclosure/help-seeking (P < .005) subscales decreased both years. There was no significant change in the social distance subscale (P = .205) the first year and a significant decrease (P = .015) the second year. The themes identified from the open-ended comments were increased awareness, sympathy, empathy, inspiration/admiration, discomfort, and change to patient care. CONCLUSIONS: The combination of a speaker with schizophrenia and auditory hallucination simulation effectively reduced mental illness stigma. The combination is likely effective for reducing stigmatizing attitudes and willingness to disclose mental illness with variable reduction in desired social distance.

Life Expectancy after Liver Transplantation for NASH.

Introduction: Non-Alcoholic Steatohepatitis is an increasing reason for liver transplantation in the western world. Knowledge of recipient life expectancy may assist in prudent allocation of a relatively scarce supply of donor livers. Research Questions: We calculated life expectancies for Non-alcoholic steatohepatitis (NASH) patients both at time of transplant and one year later, stratified by key risk factors, and examined whether survival has improved in recent years. Design: Data on 6635 NASH patients who underwent liver transplantation in the MELD era (2002-2018) from the United States OPTN database were analyzed using the Cox proportional hazards regression model and life table methods. Results: Factors related to survival were age, presence of diabetes or hepatic encephalopathy (HE), and whether the patient required dialysis in the week prior to transplant. Other important factors were whether the patient was working, hospitalization prior to transplant, ventilator support, and length of hospital stay (LOS). Survival improved over the study period at roughly 4.5% per calendar year during the first year posttransplant, though no improvement was observed in those who had survived one year. Conclusion: Life expectancy in NASH transplant patients was much reduced from normal, and varied according to age, medical factors, status at transplant, and post transplant course. Over the 17-year study period, patient survival improved markedly during the first year posttransplant, though not thereafter. The results given here may prove helpful in medical decision-making regarding treatment for both liver disease and other medical conditions, as they provide both clinicians and their patients with evidence-based information on prognosis.

Life Expectancy of 1-Year Survivors of Traumatic Brain Injury, 1988-2019: Updated Results From the TBI Model Systems.

OBJECTIVE: To update the life expectancy estimates according to age, sex, mobility, and feeding skills reported in the 2015 study of Brooks et al. To examine trends in survival over the past decade. DESIGN: Observational cohort study. SETTING: Poisson regression and life table analysis applied to long-term follow-up data on United States (US) Traumatic Brain Injury (TBI) Model Systems patients recorded in the national database. Functional mobility and feeding skills were assessed with FIM. PARTICIPANTS: A total of 14,803 persons with TBI during the years 1988-2019 who underwent inpatient rehabilitation and provided at least 1 long-term assessment of functional skills 1 year or more postinjury (N=14,803). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Survival, mortality rates, and life expectancy. RESULTS: Life expectancy was lower than that of the age- and sex-matched general population. Older age and severity of functional impairments were risk factors for mortality (both P<.0001 in regression models). Among ambulatory individuals, mortality was 51% (95% confidence interval, 35%-69%) higher in men than women. Life expectancy of 20-year-old women who walked well (FIM ambulation score 7) was 55 (SE=0.8) additional years to age 75, representing a reduction of 6.9 years from the normal general population figure. For 20-year-old men who walked well, the life expectancy was 49 (SE=0.5) additional years, representing a reduction of 8.1 years from normal. Life expectancies for men and women who did not walk and were fed by others were much lower. There was no significant change in mortality rates during the study period (hazard ratio, 1.008; P=.07). CONCLUSIONS: There has been no significant change in the long-term survival of persons with TBI in the US since the late 1980s. The life expectancies reported here are similar to those reported in the 2015 study of Brooks et al, although they are more precise because of the larger sample size and longer follow-up.

Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation.

Background: With a notably narrow therapeutic window and wide intra- and interindividual pharmacokinetic (PK) variability, initial weight-based dosing along with routine therapeutic drug monitoring of tacrolimus are employed to optimize its clinical utilization. Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes, thus tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism, and excretion among children of various sizes and at different stages of development. The primary goals of the current study were to develop a population PK (PopPK) model for tacrolimus IV continuous infusion in the pediatric and young adult hematopoietic cell transplant (HCT) population and implement the PopPK model in a clinically available Bayesian forecasting tool. Methods: A retrospective chart review was conducted of 111 pediatric and young adult patients who received IV tacrolimus by continuous infusion early in the post-transplant period during HCT from February 2016 to July 2020 at our institution. PopPK model building was performed in NONMEM. The PopPK model building process included identifying structural and random effects models that best fit the data and then identifying which patient-specific covariates (if any) further improved model fit. Results: A total of 1,648 tacrolimus plasma steady-state trough concentrations were included in the PopPK modeling process. A 2-compartment structural model best fit the data. Allometrically-scaled weight was a covariate that improved estimation of both clearance and volume of distribution. Overall, model predictions only showed moderate bias, with minor under-prediction at lower concentrations and minor over-prediction at higher predicted concentrations. The model was implemented in a Bayesian dosing tool and made available at the point-of-care. Discussion: Novel therapeutic drug monitoring strategies for tacrolimus within the pediatric and young adult HCT population are necessary to reduce toxicity and improve efficacy in clinical practice. The model developed presents clinical utility in optimizing the use of tacrolimus by enabling model-guided, individualized dosing of IV, continuous tacrolimus via a Bayesian forecasting platform.

Life Expectancy After Liver Transplantation for Alcoholic Cirrhosis.

BACKGROUND: Alcohol-associated liver disease is the leading cause of liver transplantation in the western world. For these patients we calculated life expectancies both at time of transplant and several years later, stratified by key risk factors, and determined if survival has improved in recent years. METHODS: Data on 14 962 patients with alcohol-associated liver disease who underwent liver transplantation in the MELD era (2002-2018) from the United States Organ Procurement and Transplantation Network database were analyzed using the Cox proportional hazards regression model and life table methods. RESULTS: Demographic and past medical history factors related to survival were patient age, presence of diabetes or severe hepatic encephalopathy, and length of hospital stay. Survival improved over the study period, at roughly 3% per calendar year during the first 5 years posttransplant and 1% per year thereafter. CONCLUSIONS: Life expectancy in transplanted patients with alcohol-associated liver disease was much reduced from normal, and varied according to age, medical risk factors, and functional status. Survival improved modestly over the study period. Information on patient longevity can be helpful in making treatment decisions.

A Guidance for Concomitant Drug Reconciliation Prior to Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults.

Pediatric diseases treated by allogeneic hematopoietic stem cell transplantation (alloHCT) are complex and associated with significant comorbidities and medication requirements that can complicate the transplant process. It is critical to reconcile pre-transplant concomitant medications (pcon-meds) in the weeks prior to alloHCT and to consider the potential for pcon-meds to cause harmful drug-drug interactions (DDIs) or overlapping toxicities with conditioning agents. In this perspective, we describe a systematic process to review pcon-meds and determine the drug modifications needed to avoid DDIs with conditioning regimens. We provide an extensive appendix with timelines for discontinuation or modification of common pcon-meds that patients are taking when presenting to the HCT medical team. The timelines are based on the pharmacokinetic (PK) properties of both the pcon-meds and the planned conditioning medications, as well as anticipated DDIs. They also account for the ages seen at pediatric transplant centers (0-30 years old). Common scenarios, such as when pcon-med discontinuation is not an option, are discussed. Since alloHCT patients are often dependent upon psychiatric medications with problematic DDIs, a table of alternative, non-interacting psychiatric medications is also presented. The appendix provides details regarding how to adjust pcon-meds prior to the start of chemotherapy for children and young adults undergoing alloHCT, however patient-specific circumstances always need to be taken into account. Careful attentiveness to pcon-meds at the time the decision is made to pursue transplant will result in more consistent HCT outcomes, with lower toxicity and increased efficacy of conditioning agents.