Surgical waitlist management: Perspectives from surgeons on surgical prioritization at a paediatric hospital.

Globally exacerbated surgical waitlists have provided the opportunity to reflect on prioritization and resource allocation decisions. The unique circumstances of paediatric surgery and consequences of surgical delay prompted the study reported in this paper. As part of a larger project to attend to prioritization in our surgical waitlists, we conducted a Quality Improvement study, the purpose of which is to understand surgeon's perspectives regarding the ethical and practical realities of surgical prioritization at our institution. The study comprises semi-structured interviews with nine full-time paediatric surgeons from a variety of subspecialties conducted at our institution, which is a tertiary paediatric hospital with ten surgical subspecialties in a publicly funded healthcare system. Participants articulated how they prioritize their waitlists, and how they understand ethical prioritization. These findings resonate with the growing public concern for ethical practice in healthcare delivery and transparency in prioritization and resource allocation practices. Specifically, more transparency, consistency, and support is required in prioritization practices. This work highlights the importance of institutional dialogue regarding surgical case prioritization. Because quality improvement work is necessarily site-specific, concrete generalizations cannot be offered. However, the insights gleaned from these interviews and the process by which they were gleaned are a valuable knowledge-sharing resource for any institution that is interested in ongoing quality improvement work. The objectives here were to clarify the goals of prioritization within the institution, improve prioritization practices, and make them more ethical and transparent.

Visual digital data, ethical challenges, and psychological science.

Digital visual data afford psychologists with exciting research possibilities. It becomes possible to see real-life interactions in real time and to be able to analyze this behavior in a fine-grained and systematic manner. However, the fact that faces (and other personally identifying physical characteristics) are captured as part of these data sets means that this kind of data is at the highest level of sensitivity by default. When this is combined with the possibility of automatic collection and processing, then the sensitivity risks are compounded. Here we explore the ethical challenges that face psychologists wishing to take advantage of digital visual data. Specifically, we discuss ethical considerations around data acquisition, data analysis, data storage, and data sharing. We begin by considering the challenges of securing visual data from both public space security systems and social media sources. We then explore the dangers of bias and discrimination in automatic data processing, as well as the dangers to human analysts. We set out the ethical requirements for secure data storage, the dangers of "function creep," and the challenges of the right of the individual to withdraw from databases. Finally, we consider the tensions that exist between sensitive visual data that require extra protections and the recent open science movement, which advocates data transparency and sharing. We conclude by offering a practical route map for tackling these complex ethical issues in the form of a Privacy and Data Protection Impact Assessment template for researchers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

LUMINA: Using molecular biomarkers to guide decision making for breast radiotherapy.

In this opinion piece, we respond to comments about the LUMINA trial by Meattini and colleagues in the Journal. LUMINA was a prospective cohort study which evaluated the omission of radiotherapy after breast conserving surgery (BCS) in patients treated with endocrine therapy with low risk clinico-pathologic features and luminal A breast cancer. We address their areas of concern including the single cohort design that required careful patient selection, the relatively short follow-up period of 5 years, and the limited follow-up on younger patients. The Ki67 biomarker was key to defining the luminal A phenotype. We clarify the evidence supporting the Ki67 criteria used. The compliance with endocrine therapy was high and similar to other contemporary trials. Based on the results of LUMINA, and mounting evidence from other trials, we feel comfortable offering our patients the option of no radiotherapy after BCS if they fit the trial eligibility criteria from LUMINA and have decided to receive adjuvant endocrine therapy. We concur that a patient-centered approach to treatment decision making should be used to make patients aware of all available information including the results of the LUMINA trial when deciding on post-operative breast radiotherapy.

Evaluating the Outcomes and Trainee Performance of a Canadian Medical Imaging Clinician Investigator Program.

Purpose: To measure the research productivity of trainees from the University of Toronto's Medical Imaging Clinician Investigator Program (MI-CIP) and comparing it with the research productivity of trainees from MI-non-CIP and General Surgery (GSx) Clinician Investigator Program. Methods: We identified residents who completed an MI-CIP, MI-non-CIP and GSx-CIP from 2006-2016. In each group of trainees, we assessed 3 research productivity outcomes with non-parametric tests before residency and at 7 years post-CIP completion/post-graduation. Research productivity outcomes include the number of total publications, the number of first-author publications, and the publication's average journal impact factor (IF). Results: We identified 11 MI-CIP trainees (male/female: 9 [82%]/2 [18%]), 74 MI-non-CIP trainees (46 [62%]/28 [38%]) and 41 GSx-CIP trainees (23 [56%]/18 [44%]). MI-CIP trainees had statistically significant higher research productivity than MI-non-CIP in all measured outcomes. The median (interquartile range, IQR) number of total publications of MI-CIP vs MI-non-CIP trainees was 5.0 (8.0) vs 1.0 (2.0) before residency and 6.0 (10.0) vs .0 (2.0) at 7 years post-CIP completion/post-graduation. The median (IQR) first-author publications of MI-CIP vs MI-non-CIP trainees was 2.0 (3.0) vs .0 (1.0) before residency and 2.0 (4.0) vs (.0) (1.0) at 7 years post-CIP completion/post-graduation. The median (IQR) average journal IF of MI-CIP vs MI-non-CIP trainees was 3.2 (2.0) vs .3 (2.4) before residency and 3.9 (3.2) vs .0 (2.6) at 7 years post-CIP completion/post-graduation. Between MI-CIP and GSx-CIP trainees, there were no significant differences in research productivity in all measured outcomes. Conclusion: MI-CIP trainees actively conducted research after graduation. These trainees demonstrated early research engagement before residency. The similar research productivity of MI-CIP vs GSx-CIP trainees shows initial success of MI-CIP trainees.

"Are we in this together?": embedding social identity detection in drones improves emergency coordination.

Autonomous systems, such as drones, are critical for emergency mitigation, management, and recovery. They provide situational awareness and deliver communication services which effectively guide emergency responders' decision making. This combination of technology and people comprises a socio-technical system. Yet, focusing on the use of drone technology as a solely operational tool, underplays its potential to enhance coordination between the different agents involved in mass emergencies, both human and non-human. This paper proposes a new methodological approach that capitalizes on social identity principles to enable this coordination in an evacuation operation. In the proposed approach, an adaptive drone uses sensor data to infer the group membership of the survivors it encounters during the operation. A corpus of 200 interactions of survivors' talk during real-life emergencies was computationally classified as being indicative of a shared identity or personal/no identity. This classification model, then, informed a game-theoretic model of human-robot interactions. Bayesian Nash Equilibrium analysis determined the predicted behavior for the human agent and the strategy that the drone needs to adopt to help with survivor evacuation. Using linguistic and synthetic data, we show that the identity-adaptive architecture outperformed two non-adaptive architectures in the number of successful evacuations. The identity-adaptive drone can infer which victims are likely to be helped by survivors and where help from emergency teams is needed. This facilitates effective coordination and adaptive performance. This study shows decision-making can be an emergent capacity that arises from the interactions of both human and non-human agents in a socio-technical system.

Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).

Vitamin C Urinary Loss and Deficiency in Human Immunodeficiency Virus (HIV): Cross-sectional Study of Vitamin C Renal Leak in Women With HIV.

BACKGROUND: Reduced plasma vitamin C (vitC) concentrations in human immunodeficiency virus (HIV) may result from abnormal urinary excretion: a renal leak. VitC renal leak indicates underlying nutritional dysregulation independent of diet. We hypothesized that increased renal leak prevalence in HIV would be associated with deficient vitC concentrations. METHODS: We conducted an outpatient cross-sectional study of 96 women (40 HIV [PWH] and 56 without HIV [PWOH]) at the National Institutes of Health and Georgetown University. Renal leak was defined as abnormal urinary vitC excretion at fasting plasma concentrations <43.2µM, 2 SDs below vitC renal threshold in healthy women. To determine the primary outcome of renal leak prevalence, matched urine and plasma samples were collected the morning after overnight fast. Secondary outcomes assessed group differences in mean plasma vitC concentrations and prevalence of vitC deficiency. Exploratory outcomes assessed clinical parameters associated with renal leak. VitC was measured by high-performance liquid chromatography with coulometric electrochemical detection. RESULTS: PWH had significantly higher renal leak prevalence (73%vs14%; OR (odds ratio):16; P<.001), lower mean plasma vitC concentrations (14µMvs50µM; P<.001), and higher prevalence of vitC deficiency (43%vs7%; OR:10; P<.001) compared with PWOH, unchanged by adjustments for confounding factors. Significant predictors of renal leak included antiretroviral therapy (ART), Black race, older age, and metabolic comorbidities but not viral load or CD4 count. When compared with other chronic disease cohorts, PWH had the highest prevalence of renal leak and vitC deficiency (P<.001). CONCLUSIONS: High prevalence of vitC renal leak in HIV was associated with vitC deficiency, ART use, and race/ethnicity differences.

Impact of 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Versus Conventional Staging in Patients With Locally Advanced Breast Cancer.

PURPOSE: Patients with locally advanced breast cancer (LABC) typically undergo staging tests at presentation. If staging does not detect metastases, treatment consists of curative intent combined modality therapy (neoadjuvant chemotherapy, surgery, and regional radiation). Positron emission tomography-computed tomography (PET-CT) may detect more asymptomatic distant metastases, but the evidence is based on uncontrolled studies. METHODS: For inclusion, patients had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1). Consenting patients from six regional cancer centers in Ontario were randomly assigned to 18F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of the chest/abdomen and pelvis). The primary end point was upstaging to stage IV. A key secondary outcome was receiving curative intent combined modality therapy (ClinicalTrials.gov identifier: NCT02751710). RESULTS: Between December 2016 and April 2022, 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging. Forty-three (23%) PET-CT patients were upstaged to stage IV compared with 21 (11%) conventional staged patients (absolute difference, 12.3% [95% CI, 3.9 to 19.9]; P = .002). Consequently, treatment was changed in 35 (81.3%) of 43 upstaged PET-CT patients and 20 (95.2%) of the 21 upstaged conventional patients. Subsequently, 149 (81%) patients in the PET-CT group received combined modality treatment versus 165 (89.2%) patients in the conventional staging group (absolute difference, 8.2% [95% CI, 0.1 to 15.4]; P = .03). CONCLUSION: In patients with LABC, PET-CT detected more distant metastases than conventional staging, and fewer PET-CT patients received combined modality therapy. Our randomized trial demonstrates the utility of the PET-CT staging strategy.

Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice.

BACKGROUND: Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements. OBJECTIVES: We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver. METHODS: C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet. RESULTS: The Vit E-fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05). CONCLUSIONS: Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.

Vitamin C Urinary Loss in Fabry Disease: Clinical and Genomic Characteristics of Vitamin C Renal Leak.

BACKGROUND: Reduced plasma vitamin C concentrations in chronic diseases may result from abnormal urinary excretion of vitamin C: a renal leak. We hypothesized that vitamin C renal leak may be associated with disease-mediated renal dysregulation, resulting in aberrant vitamin C renal reabsorption and increased urinary loss. OBJECTIVES: We investigated the prevalence, clinical characteristics, and genomic associations of vitamin C renal leak in Fabry disease, an X-linked lysosomal disease associated with renal tubular dysfunction and low plasma vitamin C concentrations. METHODS: We conducted a non-randomized cross-sectional cohort study of men aged 24-42 y, with Fabry disease (n = 34) and controls without acute or chronic disease (n = 33). To match anticipated plasma vitamin C concentrations, controls were placed on a low-vitamin C diet 3 wk before inpatient admission. To determine the primary outcome of vitamin C renal leak prevalence, subjects were fasted overnight, and matched urine and fasting plasma vitamin C measurements were obtained the following morning. Vitamin C renal leak was defined as presence of urinary vitamin C at plasma concentrations below 38 µM. Exploratory outcomes assessed the association between renal leak and clinical parameters, and genomic associations with renal leak using single nucleotide polymorphisms (SNPs) in the vitamin C transporter SLC23A1. RESULTS: Compared with controls, the Fabry cohort had 16-fold higher odds of renal leak (6% vs. 52%; OR: 16; 95% CI: 3.30, 162; P < 0.001). Renal leak was associated with higher protein creatinine ratio (P < 0.01) and lower hemoglobin (P = 0.002), but not estimated glomerular filtration rate (P = 0.54). Renal leak, but not plasma vitamin C, was associated with a nonsynonymous single nucleotide polymorphism in vitamin C transporter SLC23A1 (OR: 15; 95% CI: 1.6, 777; P = 0.01). CONCLUSIONS: Increased prevalence of renal leak in adult men with Fabry disease may result from dysregulated vitamin C renal physiology and is associated with abnormal clinical outcomes and genomic variation.

Patient reported symptom burden amongst immigrant and Canadian long-term resident women undergoing breast cancer surgery.

PURPOSE: Immigrants are susceptible to marginalization due to social isolation, economic disadvantage and systemic bias. Our goal was to compare symptom burden between immigrant and long-term resident women undergoing breast cancer surgery in Ontario, Canada. METHODS: A population-level retrospective cohort-study using administrative databases was conducted. Women who underwent surgery for newly diagnosed breast cancer and were treated at regional cancer centers between 2010 and 2016 were included. The primary outcome was a moderate or severe (≥ 4) symptom score on the Edmonton Symptom Assessment System Scale (ESAS). RESULTS: There were 12,250 (87.2%) long-term Canadian residents and 1,806(12.8%) immigrants. Immigrants were younger (mean age 53 vs. 61 years); had a higher proportion residing in a lowest income quintile neighbourhood (22.2% vs 15.4%); were less often on a primary-care physician roster (83.7% vs. 90.4%); and were less often diagnosed with Stage I/II disease (80.9% vs. 84.6%) (all p < 0.01). The proportion of women with scores ≥ 4 was significantly higher amongst immigrant women for 7/9 symptom categories; with the largest differences for depression (24.9% vs. 20.2%, p < 0.01) and pain (28.0% vs. 22.4%, p < 0.01). On multivariable regression analysis, immigration status was associated with scores ≥ 4 for pain (OR 1.13, 95% CI 1.02-1.23). There was an association between moderate/severe pain and region of origin, but not length of stay in Canada or immigration class. CONCLUSIONS: This is the first study comparing symptom burden amongst immigrant and non-immigrant women with breast cancer at a population-level. Immigrant women with breast cancer undergoing surgery were found to have a higher burden of pain.

Developing a Data and Analytics Platform to Enable a Breast Cancer Learning Health System at a Regional Cancer Center.

PURPOSE: This study documents the creation of automated, longitudinal, and prospective data and analytics platform for breast cancer at a regional cancer center. This platform combines principles of data warehousing with natural language processing (NLP) to provide the integrated, timely, meaningful, high-quality, and actionable data required to establish a learning health system. METHODS: Data from six hospital information systems and one external data source were integrated on a nightly basis by automated extract/transform/load jobs. Free-text clinical documentation was processed using a commercial NLP engine. RESULTS: The platform contains 141 data elements of 7,019 patients with newly diagnosed breast cancer who received care at our regional cancer center from January 1, 2014, to June 3, 2022. Daily updating of the database takes an average of 56 minutes. Evaluation of the tuning of NLP jobs found overall high performance, with an F1 of 1.0 for 19 variables, with a further 16 variables with an F1 of > 0.95. CONCLUSION: This study describes how data warehousing combined with NLP can be used to create a prospective data and analytics platform to enable a learning health system. Although upfront time investment required to create the platform was considerable, now that it has been developed, daily data processing is completed automatically in less than an hour.

Red Blood Cell Vitamin C Concentration and Its Effect on Deformability in Pediatric Sickle Cell Disease.

Red cell rigidity is common in sickle cell disease (SCD). The contribution of oxidative stress on deformability remains unknown. This study investigated red blood cell (RBC) vitamin C concentrations in pediatric SCD (n=43) compared with healthy controls ( n =23) and developed a protocol to raise RBC vitamin C concentrations to measure the effect on deformability. Sickle cell RBC vitamin C concentrations seem low (20.5 µM, SD: 16.2 vs. 51.7 µM, SD: 15.8; P <0.0001). Vitamin C can be successfully loaded into sickle cell RBCs but seems to have minimal effect on deformability. Future studies are needed to understand the clinical implications of vitamin C deficiency in pediatric SCD.

Use of population-based electronic databases for the identification of patients with synchronous colorectal cancer and liver metastases potentially eligible for a surgical trial.

BACKGROUND: Some population-based recruitment methods, such as registries and databases, have been used to increase enrolment in clinical trials by identifying eligible participants based on baseline characteristics; however; these methods have not been tested in surgical trials, in which accrual occurs before surgery. We evaluated the use of population-based electronic databases to identify patients who potentially could be accrued to the Simultaneous Resection of Colorectal Cancer with Synchronous Liver Metastases (RESECT) trial and compared it to the traditional methods used to accrue patients (e.g., multidisciplinary rounds, letters to community surgeons) for that same trial during the same period. METHODS: An electronic database (ePath) was interrogated every 2 weeks for patients diagnosed with colorectal cancer from Feb. 1, 2017, to Mar. 30, 2019. A radiologic image database (OneView) was reviewed to identify those with liver metastases (level 1 screening). Reports were interrogated to identify potentially eligible patients for the RESECT trial (level 2 screening). A hepatobiliary surgeon reviewed radiology images to identify eligible patients for the trial (level 3 screening). The primary outcome was patient eligibility for the ongoing RESECT trial. RESULTS: The population-based method identified 90 (11.2%) of 803 patients diagnosed with colorectal cancer over the study period. Among the 90 patients, level 2 screening identified 60 (67%) potentially eligible patients for the RESECT trial. Of the 90 patients, 18 (20%) were eligible after radiographic image review (level 3 screening). Traditional accrual methods identified 38 patients with liver metastases, 27 (71%) of whom were identified as potentially eligible on level 2 screening, and 14 (37%) of whom were deemed to be eligible on level 3 screening. Twenty-six patients were identified by both methods. Twelve patients were identified by population-based methods alone, and 8 patients by traditional methods alone. Six eligible patients were identified by both methods. Baseline characteristics were similar between the 2 groups. CONCLUSION: A population-based electronic database method of patient accrual was able to identify eligible participants for the RESECT trial. However, optimal accrual likely requires the use of traditional methods as well.

Collective self-understanding: A linguistic style analysis of naturally occurring text data.

Understanding what groups stand for is integral to a diverse array of social processes, ranging from understanding political conflicts to organisational behaviour to promoting public health behaviours. Traditionally, researchers rely on self-report methods such as interviews and surveys to assess groups' collective self-understandings. Here, we demonstrate the value of using naturally occurring online textual data to map the similarities and differences between real-world groups' collective self-understandings. We use machine learning algorithms to assess similarities between 15 diverse online groups' linguistic style, and then use multidimensional scaling to map the groups in two-dimensonal space (N=1,779,098 Reddit comments). We then use agglomerative and k-means clustering techniques to assess how the 15 groups cluster, finding there are four behaviourally distinct group types - vocational, collective action (comprising political and ethnic/religious identities), relational and stigmatised groups, with stigmatised groups having a less distinctive behavioural profile than the other group types. Study 2 is a secondary data analysis where we find strong relationships between the coordinates of each group in multidimensional space and the groups' values. In Study 3, we demonstrate how this approach can be used to track the development of groups' collective self-understandings over time. Using transgender Reddit data (N= 1,095,620 comments) as a proof-of-concept, we track the gradual politicisation of the transgender group over the past decade. The automaticity of this methodology renders it advantageous for monitoring multiple online groups simultaneously. This approach has implications for both governmental agencies and social researchers more generally. Future research avenues and applications are discussed.

Vitamin C deficiency reveals developmental differences between neonatal and adult hematopoiesis.

Hematopoiesis, a process that results in the differentiation of all blood lineages, is essential throughout life. The production of 1x1012 blood cells per day, including 200x109 erythrocytes, is highly dependent on nutrient consumption. Notably though, the relative requirements for micronutrients during the perinatal period, a critical developmental window for immune cell and erythrocyte differentiation, have not been extensively studied. More specifically, the impact of the vitamin C/ascorbate micronutrient on perinatal as compared to adult hematopoiesis has been difficult to assess in animal models. Even though humans cannot synthesize ascorbate, due to a pseudogenization of the L-gulono-γ-lactone oxidase (GULO) gene, its generation from glucose is an ancestral mammalian trait. Taking advantage of a Gulo-/- mouse model, we show that ascorbic acid deficiency profoundly impacts perinatal hematopoiesis, resulting in a hypocellular bone marrow (BM) with a significant reduction in hematopoietic stem cells, multipotent progenitors, and hematopoietic progenitors. Furthermore, myeloid progenitors exhibited differential sensitivity to vitamin C levels; common myeloid progenitors and megakaryocyte-erythrocyte progenitors were markedly reduced in Gulo-/- pups following vitamin C depletion in the dams, whereas granulocyte-myeloid progenitors were spared, and their frequency was even augmented. Notably, hematopoietic cell subsets were rescued by vitamin C repletion. Consistent with these data, peripheral myeloid cells were maintained in ascorbate-deficient Gulo-/- pups while other lineage-committed hematopoietic cells were decreased. A reduction in B cell numbers was associated with a significantly reduced humoral immune response in ascorbate-depleted Gulo-/- pups but not adult mice. Erythropoiesis was particularly sensitive to vitamin C deprivation during both the perinatal and adult periods, with ascorbate-deficient Gulo-/- pups as well as adult mice exhibiting compensatory splenic differentiation. Furthermore, in the pathological context of hemolytic anemia, vitamin C-deficient adult Gulo-/- mice were not able to sufficiently increase their erythropoietic activity, resulting in a sustained anemia. Thus, vitamin C plays a pivotal role in the maintenance and differentiation of hematopoietic progenitors during the neonatal period and is required throughout life to sustain erythroid differentiation under stress conditions.

Correction: Coppock et al. Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial. Life 2022, 12, 453.

The authors wish to make a change to the author names (deleting one author-Constantine Daskalakis) for this paper [...].

Artichoke phytocomplex modulates serum microRNAs in patients exposed to asbestos: a first step of a phase II clinical trial.

BACKGROUND: Malignant pleural mesothelioma is a highly aggressive tumor associated with asbestos exposure. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis. Mesothelioma has the potential to represent an appropriate disease to prevent because of its strong association with asbestos exposure and the long latency from exposure to the disease on-set. METHODS: In the present study, we tested biological activity and toxicity of an artichoke freeze-dried extract (AWPC) as potential complementary preventive/early stage treatment agent for mesothelioma. This phase II clinical study then was conducted in 18 male-patients with evidence of radiographic characteristics related to asbestos exposure such as asbestosis or benign pleural disease as surrogate disease for mesothelioma clinical model. RESULTS: We investigate AWPC biological activity assessing its effect on mesothelin serum level, a glycoprotein with low expression in normal mesothelial cells and high expression in mesothelioma and asbestos related diseases. We also assess the AWPC effect on circulating miRNAs, as novel biomarkers of both cancer risk and response to therapeutic targets. While we found a small and not significant effect of AWPC on mesothelin serum levels, we observed that AWPC intake modulated 11 serum miRNAs related to gene-pathways connected to mesothelioma etiology and development. In terms of toxicity, we also did not observe any severe adverse effects associated to AWPC treatment, only gastro-intestinal symptoms were reported by five study participants. CONCLUSIONS: We observed an interesting AWPC effect on miRNAs which targets modulate mesothelioma development. New and much larger clinical studies based on follow-up of workers exposed to asbestos are needed to corroborate the role of AWPC in prevention and early treatment of mesothelioma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02076672 . Registered 03/03/2014.