Evaluation of early fluoropyrimidine toxicity in solid organ cancer patients: a retrospective observational study in Australia.

BACKGROUND: Despite common global usage, fluoropyrimidine (FP; 5-flurouracil and capecitabine)-related chemotherapy toxicity is poorly reported in the literature, with serious toxicity ranging from 10% to 40% and early toxicity (within 60 days of exposure) quoted at 14%. Data reflecting the incidence of Grades 3-5 FP-related toxicity in Australian cancer patients is scant, despite the significant impact of toxicity on patients (hospitalisations, intensive care unit (ICU) admissions and even death). AIMS: This retrospective audit evaluated Grades 3-5 toxicities in a contemporaneous cohort of 500 patients receiving FP chemotherapies within the Hunter-New England Local Health District from June 2020 to June 2022. Data were extracted from public hospital records and oncology-specific e-records to determine rates of toxicity and associated hospitalisations, intensive care admissions and deaths that occurred within 60 days of first exposure to FP chemotherapy-containing regimens. RESULTS: One hundred and fifty incidents of Grades 3-4 toxicity in the first 60 days led to 87 patients presenting to hospital (87/500, 17.4%). The most common serious toxicities were diarrhoea (39.3%), nausea and vomiting (22.7%) and febrile neutropaenia (10%). Four patients were admitted to the ICU, and four patients died of toxicity. Within the first 60 days, 22.2% of patients required treatment delays, 21.4% required dose reductions, and 7.8% of patients ceased treatment because of toxicities. DISCUSSION AND CONCLUSION: Our experience reflects international reports and is likely generalisable to the Australian population. These data are a basis to understand the potential benefits of precision medicine strategies such as pharmacogenomic screening to improve patient tolerability and the cost-effectiveness of FP chemotherapy prescribing.

Intersections of climate change, migration, and health: experiences of first-generation migrants from Latin America to the Atlanta-metropolitan area.

Climate change is an important driver of migration, but little research exists on whether migrant communities in the U.S. identify climate change-related factors as reasons for migrating. In 2021, we conducted a multidisciplinary, collaborative project to better understand the nexus of climate change and immigrant health in the Atlanta area. This paper presents one arm of this collaboration that explored both the role of climate change in decisions to immigrate to Georgia and the ways that climate change intersects with other possible drivers of migration. First generation migrants from Latin America were recruited primarily through CPACS Cosmo Health Center and were invited to participate in an intake survey and an in-depth interview. Results were analyzed using descriptive statistics and thematic analysis. Findings suggest that while participants may not have explicitly identified climate change as a primary reason for migration, in both surveys and in-depth interviews, participants reported multiple and intersecting social, economic, political, and environmental factors that are directly or indirectly influenced by climate change and that are involved in their decisions to migrate. The narratives that emerged from in-depth interviews further contextualised survey data and elucidated the complex nexus of climate change, migration, and health.

Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro.

Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer's disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

Compensation for Board of Pharmacy members in the United States.

BACKGROUND: No published data exist regarding per diem pay differences between the 50 United States Boards of Pharmacy. OBJECTIVES: The purpose of this study was to quantify and compare the per diem pay rate of Board of Pharmacy members for each state in the U.S. Compensation for mileage and meals, as well as demographic information regarding U.S. Board of Pharmacy members, was also evaluated. METHODS: In June 2022, each state Board of Pharmacy was contacted to gather data including per diem pay, mileage and meal compensation, number of meetings per year, number and gender of Board members, length of appointment, and regulatory statutes. RESULTS: The average per diem pay for Board members was $75.86 (median = $50.00, range = $0.00-$250.00, n = 48 states). Most states report paying Board members for mileage (95.1%, n = 39 of 41) and meals (80.0%, n = 28 of 35). On average, Boards are composed of 8.3 members (median = 7.5, range = 5-17, n = 50), meet 8.3 times annually (median = 8, range = 3-16, n = 47), and have a 4.5-year length of appointment (median = 4, range = 3-6, n = 47). Men represented 61.2% of occupied Board positions, and pharmacists accounted for 74.2% of all positions. The average year for per diem pay statute update was 2002. CONCLUSION: The per diem pay for U.S. Board of Pharmacy members varies from state to state, ranging from unpaid (n = 8 states) up to $250.00 per diem. Fair compensation, increased pharmacy technician and women representation, and more timely pharmacy statute updates are necessary in order to achieve inclusion, diversity, and equity across state Boards of Pharmacy.

Burnout reduction in acute care surgeons: Impact of faculty schedule change at a level 1 trauma and tertiary care center.

BACKGROUND: Acute care surgeons are prone to burnout because of heavy workload, concurrent clinical responsibilities, and busy in-house call. Modifiable burnout factors have been identified, but few studies have looked for longitudinal effects after change is implemented. We hypothesized that optimizing faculty workflow could decrease burnout without compromising productivity. METHODS: We streamlined the faculty schedule at our institution to eliminate 24-hour call by creating weekly blocks of 12-hour day and night call, free from other clinical obligations. Protected academic time was added. The Maslach Burnout Inventory and Areas of Worklife Survey for health care providers were given to faculty, as well as close friends or family, at baseline, 6 months, and 12 months. Maslach Burnout Inventory and Areas of Worklife Survey proprietary formulas were used to assess change in factors contributing to burnout. Our primary outcome measure was the presence of factors contributing to burnout. Chart delinquency, relative value units, and academic projects were secondary outcome measures assessing clinical productivity change. RESULTS: Survey completion rates were 92% for faculty and 80% for family. All burnout risk factors improved at 6 and 12 months. In surgeon and family groups, the following improvements were noted in the mean scores of risk factors at 1 year: workload (74%, 68%), control (38%, 16%), reward (14%, 24%), fairness (69%, 22%), emotional exhaustion (27.5%, 24%), depersonalization (37.5%, 14%), personal accomplishment (12.5%, 2%), community (3%, 5%), values (10%, 15%), and over-all burnout (12.5%, 23.3%). There was a reduction in charts reaching delinquent status. Relative value unit production did not decrease. CONCLUSION: This study demonstrates that implementing a weekly, 12-hour call schedule can improve factors leading to burnout. Improvements were noted in surgeon and family groups alike, signifying both subjective improvements and observed change in the surgeons' behavior, without compromising clinical productivity. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping.

Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.

Chimpanzee Extraversion scores vary with epigenetic modification of dopamine receptor gene D2 (DRD2) and early rearing conditions.

Chimpanzees have consistent individual differences in behaviour, also referred to as personality. Similar to human personality structure, five dimensions are commonly found in chimpanzee studies that show evidence for convergent and predictive validity (Dominance, Openness, Extraversion, Agreeableness, and Reactivity/Undependability). These dimensions are to some extent heritable, indicating a genetic component that explains part of the variation in personality scores, but are also influenced by environmental factors, such as the early social rearing background of the individuals. In this study, we investigated the role of epigenetic modification of the dopamine receptor D2 gene (DRD2) as a potential mechanism underlying personality variation in 51 captive chimpanzees. We used previously collected personality trait rating data and determined levels of DRD2 CpG methylation in peripheral blood samples for these same individuals. Results showed that DRD2 methylation is most strongly associated with Extraversion, and that varying methylation levels at specific DRD2 sites are associated with changes in Extraversion in nursery-reared, but not mother-reared, individuals. These results highlight the role of dopaminergic signalling in chimpanzee personality, and indicate that environmental factors, such as social experiences early in life, can have long-lasting behavioural effects, potentially through modification of the epigenome. These findings add to the growing evidence demonstrating the importance of the experience-dependent methylome for the development of complex social traits like personality.

Examination of Intersectionality and the Pipeline for Black Academic Surgeons.

IMPORTANCE: The lack of underrepresented in medicine physicians within US academic surgery continues, with Black surgeons representing a disproportionately low number. OBJECTIVE: To evaluate the trend of general surgery residency application, matriculation, and graduation rates for Black trainees compared with their racial and ethnic counterparts over time. DESIGN, SETTING, AND PARTICIPANTS: In this nationwide multicenter study, data from the Electronic Residency Application Service (ERAS) for the general surgery residency match and Graduate Medical Education (GME) surveys of graduating general surgery residents were retrospectively reviewed and stratified by race, ethnicity, and sex. Analyses consisted of descriptive statistics, time series plots, and simple linear regression for the rate of change over time. Medical students and general surgery residency trainees of Asian, Black, Hispanic or Latino of Spanish origin, White, and other races were included. Data for non-US citizens or nonpermanent residents were excluded. Data were collected from 2005 to 2018, and data were analyzed in March 2021. MAIN OUTCOMES AND MEASURES: Primary outcomes included the rates of application, matriculation, and graduation from general surgery residency programs. RESULTS: Over the study period, there were 71 687 applicants, 26 237 first-year matriculants, and 24 893 graduates. Of 71 687 applicants, 24 618 (34.3%) were women, 16 602 (23.2%) were Asian, 5968 (8.3%) were Black, 2455 (3.4%) were Latino, and 31 197 (43.5%) were White. Women applicants and graduates increased from 29.4% (1178 of 4003) to 37.1% (2293 of 6181) and 23.5% (463 of 1967) to 33.5% (719 of 2147), respectively. When stratified by race and ethnicity, applications from Black women increased from 2.2% (87 of 4003) to 3.5% (215 of 6181) (P < .001) while applications from Black men remained unchanged (3.7% [150 of 4003] to 4.6% [284 of 6181]). While the matriculation rate for Black women remained unchanged (2.4% [46 of 1919] to 2.3% [52 of 2264]), the matriculation rate for Black men significantly decreased (3.0% [57 of 1919] to 2.4% [54 of 2264]; P = .04). Among Black graduates, there was a significant decline in graduation for men (4.3% [85 of 1967] to 2.7% [57 of 2147]; P = .03) with the rate among women remaining unchanged (1.7% [33 of 1967] to 2.2% [47 of 2147]). CONCLUSIONS AND RELEVANCE: Findings of this study show that the underrepresentation of Black physicians at every stage in surgical training pipeline persists. Black men are especially affected. Identifying factors that address intersectionality and contribute to the successful recruitment and retention of Black trainees in general surgery residency is critical for achieving racial and ethnic as well as gender equity.

Mobile Health Technologies Are Essential for Reimagining the Future of Water, Sanitation, and Hygiene.

The new Lancet Commission on water, sanitation, and hygiene (WASH) hopes to reimagine and guide global WASH efforts. This comes at a time when unequal living conditions and global disparities in response and recovery have been highlighted by the COVID-19 pandemic and recent large impact trials have delivered mostly disappointing results suggesting the need for radically more effective interventions to improve global public health. We find ourselves at an inflection point in global WASH with an opportunity to build new approaches with potentially more equitable, cost-effective, and scalable solutions. Mobile health (mHealth) technology is an important and innovative tool for WASH advances. Yet, the use of mHealth has not been equally distributed in terms of its benefits nor is its impact guaranteed. In resource-constrained settings, where technology can increase inequalities, special attention should be paid to structural and systemic hierarchies during the development of mHealth programs along with the acknowledgment and understanding how these systems can reinforce the systematic exclusion of those most vulnerable. The WASH sector needs to adapt to a future that is innovative and inclusive with a commitment to rethinking the resources needed to enhance scope and impact. We highlight urban sanitation in Brazil as a case study to demonstrate that mHealth can support and enhance publicly funded infrastructure and to help reimagine WASH for postpandemic and beyond.

Effective use of weight-based enoxaparin for deep vein thrombosis chemoprophylaxis in patients with traumatic brain injury.

BACKGROUND: Enoxaparin is the recommended agent for deep vein thrombosis (DVT) chemoprophylaxis in trauma patients. Current literature suggests weight-based dosing is superior to standard dosing for adequate chemoprophylaxis. Literature regarding the use of weight-based enoxaparin in the setting of traumatic brain injury (TBI) however is limited. METHODS: A retrospective analysis of adult trauma patients admitted between January 1, 2018 to February 28, 2019 was performed. Sixty-six patients with TBI receiving weight-based enoxaparin met inclusion criteria. Incidence of intracranial hemorrhage (ICH) expansion was the primary endpoint. Newly diagnosed venous thromboembolism (VTE) and death were secondary endpoints. RESULTS: Two patients, out of sixty-six, had progression of their TBI requiring surgical intervention. Newly diagnosed VTE occurred in one patient. No deaths were due to ICH expansion or VTE. CONCLUSIONS: Use of weight-based enoxaparin dosing in the setting of TBI shows promise without an increased incidence of ICH expansion when compared to other studies. Level of Evidence and Study Type: Level IV, Therapeutic.

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature.

Pharmacogenomic screening can identify patients with gene variants that predispose them to the development of severe toxicity from fluoropyrimidine (FP) chemotherapy. Deficiency of the critical metabolic enzyme dihydropyrimidine dehydrogenase (DPD) leads to excessive toxicity on exposure to fluoropyrimidine chemotherapy. This can result in hospitalisation, intensive care admissions and even death. Upfront screening of the gene that encodes for DPD (DPYD) has recently been implemented in regions throughout Europe and the United Kingdom. Current screening evaluates DPYD variants that are well described within Caucasian patient populations and provides genotyped-guided dose adjustment recommendations based upon the presence of these variants. This article reviews the differences in DPYD gene variants within non-Caucasian populations compared to Caucasian populations, with regard to the implications for clinical tolerance of fluoropyrimidine chemotherapies and genotype guided dose adjustment guidelines.

Achievement of goal anti-Xa activity with weight-based enoxaparin dosing for venous thromboembolism prophylaxis in trauma patients.

STUDY OBJECTIVE: The purpose of this study was to evaluate the utility of routine anti-Xa peak monitoring for trauma patients initiated on weight-based enoxaparin for venous thromboembolism (VTE) prophylaxis and identify patient populations where monitoring is necessary. DESIGN: Retrospective study. SETTING: Augusta University (AU) Medical Center in Augusta, Georgia, a level 1 trauma center. PATIENTS: Adult patients admitted to the trauma surgery service requiring chemical VTE prophylaxis. INTERVENTION: At least three consecutive doses of enoxaparin 0.5 mg/kg subcutaneously every 12 hour for VTE prophylaxis prior to an anti-Xa peak as the initial chemical VTE prophylaxis strategy. MEASUREMENTS: The primary end point was the percentage of patients who achieved goal anti-Xa peak of 0.2-0.6 unit/ml. The incidence of newly diagnosed VTE and clinically significant bleeding were assessed as secondary end points. MAIN RESULTS: From January 1, 2018, through February 28, 2019, 300 patients met inclusion criteria. Anti-Xa peaks were within goal in 91% of all patients, 7.7% were below goal, and 1.3% were above goal. For patients who did not meet the goal, dose adjustments were made in 70.4% of patients. New levels were obtained in 73.7% of those patients, and all repeat levels was within goal. Clinically significant bleeding occurred in 5.3% of patients. Newly diagnosed VTE occurred in 1.7% of patients. CONCLUSIONS: The use of initial weight-based enoxaparin dosing in trauma patients routinely achieved the prespecified target anti-Xa goal. In conclusion, anti-Xa levels are not necessary for routine monitoring of weight-based enoxaparin for VTE prophylaxis in trauma patients. Incidence of clinically significant bleeding and newly diagnosed VTE were similar to previous studies.

VIP interneurons in mouse primary visual cortex selectively enhance responses to weak but specific stimuli.

Vasoactive intestinal peptide-expressing (VIP) interneurons in the cortex regulate feedback inhibition of pyramidal neurons through suppression of somatostatin-expressing (SST) interneurons and, reciprocally, SST neurons inhibit VIP neurons. Although VIP neuron activity in the primary visual cortex (V1) of mouse is highly correlated with locomotion, the relevance of locomotion-related VIP neuron activity to visual coding is not known. Here we show that VIP neurons in mouse V1 respond strongly to low contrast front-to-back motion that is congruent with self-motion during locomotion but are suppressed by other directions and contrasts. VIP and SST neurons have complementary contrast tuning. Layer 2/3 contains a substantially larger population of low contrast preferring pyramidal neurons than deeper layers, and layer 2/3 (but not deeper layer) pyramidal neurons show bias for front-to-back motion specifically at low contrast. Network modeling indicates that VIP-SST mutual antagonism regulates the gain of the cortex to achieve sensitivity to specific weak stimuli without compromising network stability.

Age-associated epigenetic change in chimpanzees and humans.

Methylation levels have been shown to change with age at sites across the human genome. Change at some of these sites is so consistent across individuals that it can be used as an 'epigenetic clock' to predict an individual's chronological age to within a few years. Here, we examined how the pattern of epigenetic ageing in chimpanzees compares with humans. We profiled genome-wide blood methylation levels by microarray for 113 samples from 83 chimpanzees aged 1-58 years (26 chimpanzees were sampled at multiple ages during their lifespan). Many sites (greater than 65 000) showed significant change in methylation with age and around one-third (32%) of these overlap with sites showing significant age-related change in humans. At over 80% of sites showing age-related change in both species, chimpanzees displayed a significantly faster rate of age-related change in methylation than humans. We also built a chimpanzee-specific epigenetic clock that predicted age in our test dataset with a median absolute deviation from known age of only 2.4 years. However, our chimpanzee clock showed little overlap with previously constructed human clocks. Methylation at CpGs comprising our chimpanzee clock showed moderate heritability. Although the use of a human microarray for profiling chimpanzees biases our results towards regions with shared genomic sequence between the species, nevertheless, our results indicate that there is considerable conservation in epigenetic ageing between chimpanzees and humans, but also substantial divergence in both rate and genomic distribution of ageing-associated sites. This article is part of the theme issue 'Evolution of the primate ageing process'.

'Zero Leprosy' and other endgame strategies: Rhetoric vs. realism in public health campaigns.

For over half a century, many public health campaigns related to infectious disease have focused on disease 'eradication,' rather than 'control' or 'management.' In this article, I will focus on the example of a recent global leprosy (Hansen's Disease) control campaign, Triple Zero. Drawing on examples from other public health initiatives, this article explores how the language of 'zero disease' or 'endgame strategies' is appealing to certain audiences but how it can also be misleading and have unexpected and unintended consequences. Depending on the specific characteristics of the disease, the disease vectors, and the circumstances of transmission, 'zero' disease is rarely an achievable goal. In addition, when a disease is said to reach 'zero,' it is important to consider the possible implications for people with social, physical, or emotional sequeläe from the disease and who still may require follow-up treatment and care.