Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption.

SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.

A challenging case of eosinophilic myocarditis leading to heart failure and transplantation.

The large spectrum of etiologies, severities, and histologic appearances of eosinophilic myocarditis (EoM) poses challenges to its diagnosis and management. Endomyocardial biopsy is the current gold standard for diagnosis. However, cardiovascular magnetic resonance imaging is becoming more frequently used to diagnose acute myocarditis because of enhanced sensitivity when compared to histopathologic examination, and its less invasive nature. We report a complicated case of EoM in a male in his mid-thirties that led to fulminant cardiogenic shock that required immunosuppressive therapy on day 5 of admission and implantation of a left ventricular assist device (LVAD) on day 30. EoM was diagnosed on histopathologic examination of the resected fragment of the left ventricular myocardium. Nine months after the initial presentation, the patient ultimately required heart transplantation. The explanted heart showed minimal residual interstitial inflammation with evidence of mildly active intimal arteritis and patchy areas of interstitial fibrosis. In this report, we describe our patient's clinical features and correlate them with imaging and histopathologic findings to illustrate the difficulty in diagnosing EoM, particularly in this complicated patient that ultimately required heart transplantation. The diagnosis can be challenging due to the variable histopathologic features, clinical presentation, and utilization of therapeutic medications and devices.

The learning curve of COVID-19 and organ donation: Potential missed opportunities in the COVID era.

Background: Early in the COVID-19 pandemic, positive COVID-19 status often disqualified potential organ donors due to perceived risks, despite limited evidence. Subsequent studies have clarified that the COVID-19 status of donors, particularly when incidental and not the cause of death, does not adversely affect non-lung transplant outcomes. This study quantifies the potential loss of eligible organ donors and the corresponding impact on organ availability during the initial phase of the pandemic. Methods: In this retrospective analysis, we examined deceased donor referrals to a major organ procurement organization from June 2020 to January 2022. Referrals were categorized as All Referrals, Medically Ruled Out (MRO), or Procured Donors (PD). We used Chi-square tests for categorical comparisons and logistic regression to model additional donors and organs, contrasting COVID-negative and positive cases within age-matched cohorts. Results: Among 9478 referrals, 23.4 % (2221) were COVID-positive. Notably, COVID-positive referrals had a substantially higher MRO rate (80.6 % vs. 29.6 %, p < 0.01) and a markedly lower PD rate (0.2 % vs. 8.2 %, p < 0.01). Potential missed donations of 103 organs from COVID-positive referrals were identified. Conclusion: This OPO-level study demonstrates a substantial impact of COVID-19 status on organ donation rates, revealing significant missed opportunities. Improved management of donor COVID-19 status could potentially increase organ donations nationwide, taking into account evolving evidence and vaccine availability changes.

Hepatic HIF2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency.

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here, we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, though the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.

Beyond prevention: Unveiling the benefits of triple vaccination on COVID-19 severity and resource utilization in solid organ transplant recipients.

OBJECTIVE: Despite the widespread reduction in COVID-19-related morbidity and mortality attributed to vaccination in the general population, vaccine efficacy in solid organ transplant recipients (SOTR) remains under-characterized. This study aimed to investigate clinically relevant outcomes on double and triple-vaccinated versus unvaccinated SOTR with COVID-19. STUDY DESIGN AND SETTING: A retrospective propensity score-matched cohort study was performed utilizing data from the US Collaborative Network Database within TriNetX (n = 117,905,631). We recruited vaccinated and unvaccinated (matched controls) SOTR with COVID-19 over two time periods to control for vaccine availability: December 2020 to October 2022 (bi-dose, double-dose vaccine effectiveness) and December 2020 to April 2023 (tri-dose, triple-dose vaccine effectiveness). A total of 42 factors associated with COVID-19 disease severity were controlled for including age, obesity, diabetes, and hypertension. We monitored 30-day outcomes including acute respiratory failure, intubation, and death following a diagnosis of COVID-19. RESULTS: Subjects were categorized into two cohorts based on the two time periods: bi-dose cohort (vaccinated, n = 462; unvaccinated, n = 20,998); tri-dose cohort (vaccinated, n = 517; unvaccinated, n = 23,061).Compared to unvaccinated SOTR, 30-day mortality was significantly lower for vaccinated subjects in both cohorts: tri-dose (2.0% vs 7.5%, HR = 0.22 [95% CI: 0.11, 0.46]); bi-dose (3.7% vs 8.2%, HR = 0.43 [95% CI: 0.24, 0.76]). Hospital admission rates were similar between bi-dose vaccinated and unvaccinated subjects (33.1% vs 28.6%, HR = 1.2 [95% CI: 0.95, 1.52]). In contrast, tri-dose vaccinated subjects had a significantly lower likelihood of hospital admission (29.4% vs 36.6%, HR = 0.74 [95% CI: 0.6, 0.91]). Intubation rates were significantly lower for triple-vaccinated- (2.3% vs 5.2%, p < 0.05), but not double-vaccinated subjects (3.0% vs 5.2%, p > 0.05). CONCLUSION: In solid organ transplant recipients with COVID-19, triple vaccination, but not double vaccination, against SARS-CoV-2 was associated with significantly less hospital resource utilization, decreased disease severity, and fewer short-term complications. These real-world data from extensively matched controls support the protective effects of COVID-19 vaccination with boosters in this vulnerable population.

AAV-mediated hepatic expression of SLC30A10 and the Thr95Ile variant attenuates manganese excess and other phenotypes in Slc30a10-deficient mice.

The manganese (Mn) export protein SLC30A10 is essential for Mn excretion via the liver and intestines. Patients with SLC30A10 deficiency develop Mn excess, dystonia, liver disease, and polycythemia. Recent genome-wide association studies revealed a link between the SLC30A10 variant T95I and markers of liver disease. The in vivo relevance of this variant has yet to be investigated. Using in vitro and in vivo models, we explore the impact of the T95I variant on SLC30A10 function. While SLC30A10 I95 expressed at lower levels than T95 in transfected cell lines, both T95 and I95 variants protected cells similarly from Mn-induced toxicity. Adeno-associated virus 8-mediated expression of T95 or I95 SLC30A10 using the liver-specific thyroxine binding globulin promoter normalized liver Mn levels in mice with hepatocyte Slc30a10 deficiency. Furthermore, Adeno-associated virus-mediated expression of T95 or I95 SLC30A10 normalized red blood cell parameters and body weights and attenuated Mn levels and differential gene expression in livers and brains of mice with whole body Slc30a10 deficiency. While our in vivo data do not indicate that the T95I variant significantly compromises SLC30A10 function, it does reinforce the notion that the liver is a key site of SLC30A10 function. It also supports the idea that restoration of hepatic SLC30A10 expression is sufficient to attenuate phenotypes in SLC30A10 deficiency.

Supervised weight loss requirements disproportionately affect Black patients seeking weight loss surgery.

BACKGROUND: We use our high-volume institutional experience with a majority Black population to examine the role of supervised weight loss (SWL) requirements perpetuating disparities in bariatric surgery. OBJECTIVE: To determine if there are racial disparities in the required amount of supervised weight loss prior to approval for bariatric surgery. SETTING: University hospital. METHODS: A retrospective review was conducted of all patients seen at our institution's bariatric surgery clinic in 2018. Odds of undergoing surgery within 1 year and mean number of SWL requirements were determined using descriptive statistics for Black patients as compared with non-Hispanic White patients. Finally, a logistic model was constructed to examine likelihood of undergoing an operation within 1 year for patients of varying SWL requirements. RESULTS: A total of 335 patients were included (75% Black, 25% White). Within 1 year, 37% of Black patients compared with 53% of White patients had undergone an operation (relative risk .7, P = .01). Mean insurance-mandated SWL sessions were significantly higher for Black patients (3.6 ± 2.8) versus non-Hispanic White patients (2.2 ± 2.7) (P < .01). Mean program-mandated SWL sessions were also significantly higher for Black patients (2.5 ± 2.6) versus non-Hispanic White patients (.8 ± 1.8) (P < .01). Increasing SWL requirements significantly reduced the odds of undergoing surgery at 1 year within the entire cohort (odds ratio .86, P < .01). CONCLUSIONS: Black patients are disproportionally affected by SWL requirements, which strongly correlate with decreased likelihood of undergoing a bariatric operation as compared with their White counterparts. Even after overcoming barriers to see a bariatric surgery provider, Black patients still face disproportionally more barriers to surgery. Bariatric centers must be sensitive to the effect of SWL requirements, as it is negatively associated with the likelihood of a patient receiving a bariatric operation.

Hypoxia-inducible factor 2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency.

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane transport protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to severe manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess, but the basis of erythropoietin excess in SLC30A10 deficiency has yet to be established. Here we demonstrate that erythropoietin expression is increased in liver but decreased in kidneys in Slc30a10-deficient mice. Using pharmacologic and genetic approaches, we show that liver expression of hypoxia-inducible factor 2 (Hif2), a transcription factor that mediates the cellular response to hypoxia, is essential for erythropoietin excess and polycythemia in Slc30a10-deficient mice, while hypoxia-inducible factor 1 (HIF1) plays no discernible role. RNA-seq analysis determined that Slc30a10-deficient livers exhibit aberrant expression of a large number of genes, most of which align with cell cycle and metabolic processes, while hepatic Hif2 deficiency attenuates differential expression of half of these genes in mutant mice. One such gene downregulated in Slc30a10-deficient mice in a Hif2-dependent manner is hepcidin, a hormonal inhibitor of dietary iron absorption. Our analyses indicate that hepcidin downregulation serves to increase iron absorption to meet the demands of erythropoiesis driven by erythropoietin excess. Finally, we also observed that hepatic Hif2 deficiency attenuates tissue manganese excess, although the underlying cause of this observation is not clear at this time. Overall, our results indicate that HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency.

Multisite biologic tissue SARS-CoV-2 PCR testing in kidney transplantation from a COVID-positive donor.

With a high community transmission rate, SARS-CoV-2 has profoundly exacerbated the shortage of organs. Although the risk of donor-recipient transmission of SARS-CoV-2 is anecdotally low, an organ-specific infection analysis of procured organs from SARS-CoV-2 positive donors has yet to be established. Using a combination of clinically available and research-only polymerase chain reaction methods, organ preservation fluid and renal parenchymal tissues were tested for SARS-CoV-2 from the kidney of a SARS-CoV-2-positive donor prior to transplantation. The recipient has remained SARS-CoV-2 negative and clinically well, with excellent graft function 120 days post-transplantation.

Circulating Small Extracellular Vesicles May Contribute to Vaso-Occlusive Crises in Sickle Cell Disease.

We previously found that the plasma of patients with sickle cell disease (SCD) contains large numbers of small extracellular vesicles (EVs) and that the EVs disrupt the integrity of endothelial cell monolayers (especially if obtained during episodes of acute chest syndrome, ACS). The present study was designed to test the generality of this finding to other complications of SCD, specifically to evaluate the possibility that circulating EVs isolated during a vaso-occlusive crises (VOC) also cause damage to the intercellular connections between endothelial cells. Plasma was obtained from nine pediatric subjects at baseline and during VOC episodes. EVs isolated from these samples were added to cultures of microvascular endothelial cells. Immunofluorescence microscopy was employed to assess monolayer integrity and to localize two intercellular junction proteins (VE-cadherin and connexin43). The EVs isolated during VOC caused significantly greater monolayer disruption than those isolated at baseline. The extent of disruption varied between different episodes of VOC or ACS in the same patient. The VOC EVs disrupted the integrity of both junction proteins at appositional membranes. These results suggest that circulating EVs may be involved in modulating endothelial integrity contributing to the pathogenesis of different complications of SCD.