What every Intensivist should know about ... Ammonia in liver failure.

PURPOSE: Acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) patients have high short-term mortality and morbidity. In the context of liver failure, increased serum ammonia is associated with worse neurological outcomes, including high-grade hepatic encephalopathy (HE), cerebral edema, and intracranial hypertension. Besides its neurotoxicity, hyperammonemia may contribute to immune dysfunction and the risk of infection, a frequent trigger for multi-organ failure in these patients. MATERIAL AND METHODS: We performed a literature-based narrative review. Publications available in PubMed® up to June 2023 were considered. RESULTS: In the ICU management of liver failure patients, serum ammonia may play an important role. Accordingly, in this review, we focus on recent insights about ammonia metabolism, serum ammonia measurement strategies, hyperammonemia prognostic value, and ammonia-targeted therapeutic strategies. CONCLUSIONS: Serum ammonia may have prognostic value in liver failure. Effective ammonia targeted therapeutic strategies are available, such as laxatives, rifaximin, L-ornithine-l-aspartate, and continuous renal replacement therapy.

Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice.

Iron overload (IOL) is hypothesized to contribute to dysplastic erythropoiesis. Several conditions, including myelodysplastic syndrome, thalassemia and sickle cell anemia, are characterized by ineffective erythropoiesis and IOL. Iron is pro-oxidant and may participate in the pathophysiology of these conditions by increasing genomic instability and altering the microenvironment. There is, however, lack of in vivo evidence demonstrating a role of IOL and oxidative damage in dysplastic erythropoiesis. NRF2 transcription factor is the master regulator of antioxidant defenses, playing a crucial role in the cellular response to IOL in the liver. Here, we crossed Nrf2-/- with hemochromatosis (Hfe-/-) or hepcidin-null (Hamp1-/-) mice. Double-knockout mice developed features of ineffective erythropoiesis and myelodysplasia including macrocytic anemia, splenomegaly, and accumulation of immature dysplastic bone marrow (BM) cells. BM cells from Nrf2/Hamp1-/- mice showed increased in vitro clonogenic potential and, upon serial transplantation, recipients disclosed cytopenias, despite normal engraftment, suggesting defective differentiation. Unstimulated karyotype analysis showed increased chromosome instability and aneuploidy in Nrf2/Hamp1-/- BM cells. In HFE-related hemochromatosis patients, NRF2 promoter SNP rs35652124 genotype TT (predicted to decrease NRF2 expression) associated with increased MCV, consistent with erythroid dysplasia. Our results suggest that IOL induces ineffective erythropoiesis and dysplastic hematologic features through oxidative damage in Nrf2-deficient cells.

Cellular iron governs the host response to malaria.

Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4+ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.

Candida auris in Intensive Care Setting: The First Case Reported in Portugal.

Candida auris is an opportunistic human pathogen that has rapidly spread to multiple countries and continents and has been associated with a high number of nosocomial outbreaks. Herein, we report the first case of C. auris in Portugal, which was associated with a patient transferred from Angola to an ICU in Portugal for liver transplantation after a SARS-CoV-2 infection. C. auris was isolated during the course of bronchoalveolar lavage, and it was subjected to antifungal susceptibility testing and whole-genome sequence analysis. This isolate presents low susceptibility to azoles and belongs to the genetic clade III with a phylogenetic placement close to African isolates. Although clade III has already been reported in Europe, taking into account the patient's clinical history, we cannot discard the possibility that the patient's colonization/infection occurred in Angola, prior to admission in the Portuguese hospital. Considering that C. auris is a fungal pathogen referenced by WHO as a critical priority, this case reinforces the need for continuous surveillance in a hospital setting.

Iron metabolism in colorectal cancer: a balancing act.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second deadliest malignancy worldwide. Current dietary habits are associated with increased levels of iron and heme, both of which increase the risk of developing CRC. The harmful effects of iron overload are related to the induction of iron-mediated pro-tumorigenic pathways, including carcinogenesis and hyperproliferation. On the other hand, iron deficiency may also promote CRC development and progression by contributing to genome instability, therapy resistance, and diminished immune responses. In addition to the relevance of systemic iron levels, iron-regulatory mechanisms in the tumor microenvironment are also believed to play a significant role in CRC and to influence disease outcome. Furthermore, CRC cells are more prone to escape iron-dependent cell death (ferroptosis) than non-malignant cells due to the constitutive activation of antioxidant genes expression. There is wide evidence that inhibition of ferroptosis may contribute to the resistance of CRC to established chemotherapeutic regimens. As such, ferroptosis inducers represent promising therapeutic drugs for CRC. CONCLUSIONS AND PERSPECTIVES: This review addresses the complex role of iron in CRC, particularly in what concerns the consequences of iron excess or deprivation in tumor development and progression. We also dissect the regulation of cellular iron metabolism in the CRC microenvironment and emphasize the role of hypoxia and of oxidative stress (e.g. ferroptosis) in CRC. Finally, we underline some iron-related players as potential therapeutic targets against CRC malignancy.

A randomised controlled feasibility study of food-related computerised attention training versus mindfulness training and waiting-list control for adults with overweight or obesity: the FOCUS study.

BACKGROUND: In a feasibility randomised controlled trial in people with overweight/obesity with and without binge eating disorder (BED) symptoms, we assessed eight weekly sessions of attention bias modification training (ABMT) and mindfulness training (MT) versus waiting list (WL) and explored potential mechanisms. METHODS: 45 participants were randomly allocated to one of three trial arms. Primary outcomes were recruitment, retention and treatment adherence rates. Secondary outcomes included measures of eating behaviour, mood, attention and treatment acceptability. Assessments were conducted at baseline, post-intervention (week 8), and follow-up (week 12). RESULTS: Participant retention at follow-up was 84.5% across groups. Session completion rates in the laboratory were 87% for ABMT and 94% for MT, but home practice was much poorer for ABMT. Changes in BMI and body composition were small between groups and there was a medium size BMI reduction in the MT group at follow-up. Effect sizes of eating disorder symptom changes were not greater for either intervention group compared to WL, but favoured ABMT compared to MT. Hedonic hunger and mindful eating scores favoured MT compared to ABMT and WL. ABMT reduced attention biases towards high-calorie food cues, which correlated with lower objective binge eating days at post-intervention. No significant changes were observed in the MT, or WL conditions. CONCLUSIONS: Both ABMT and MT have potential value as adjuncts in the treatment of obesity and BED, and a larger clinical trial appears feasible and indicated. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN15745838. Registered on 22 May 2018.

In this small research study, people who were classified as overweight or living with obesity (with or without symptoms of binge eating disorder) received either a mindfulness intervention, a "subconscious" attention-based intervention called attention bias modification training (ABMT) or were put on a waiting list for 8 weeks. People in the mindfulness group experienced improvements in emotional eating, mindful eating, and "impulsive" eating. Those who received the attention-based training paid less attention to highly caloric food after the intervention which correlated with fewer binge eating episodes. Results from this study suggest that both types of interventions have potential as add-on treatments for obesity and binge eating disorder, but larger studies are necessary to assess their clinical impact.

[The Impact of the COVID-19 Pandemic on the Intensive Care Residency Program in Portugal]. / Impacto da Pandemia COVID-19 na Formação Especializada do Internato Médico de Medicina Intensiva em Portugal.

INTRODUCTION: In 2020, critical care departments underwent profound changes imposed by the COVID-19 pandemic. The aim of this study was to evaluate the impact of the pandemic on the intensive care residency program in Portugal. MATERIAL AND METHODS: The Association of Critical Care Residents (AIMINT) prepared a questionnaire using the Google Forms® tool, which was applied during August 2020 to the Critical Care residents in Portugal. A descriptive analysis was performed with the data collected. RESULTS: Eighty-five residents participated in the questionnaire, yieldinga response rate of 62%. Three-quarters of all participants provided care to COVID-19 patients. More than 80% of the surveyed participants were on rotations, and these were canceled in 59% of cases. Seventy-eight percent reported a workload greater than 40 hours per week. CONCLUSION: The COVID-19 pandemic had an impact on the Critical Care Residency program in Portugal. Most residents surveyed provided care to COVID-19 patients and not only saw their rotations suspended but also experienced difficulties in rescheduling them.

Introdução: No ano de 2020, os serviços de medicina intensiva sofreram profundas adaptações e reestruturações impostas pela pandemia de COVID-19. Este estudo teve como objetivo avaliar o impacto desta pandemia na formação especializada do internato médico de medicina intensiva em Portugal.Material e Métodos: A Associação de Internos de Medicina Intensiva elaborou um questionário usando a ferramenta Google Forms®, e que foi aplicado durante o mês de agosto de 2020 aos internos de formação especializada de medicina intensiva, em Portugal. Com base na informação recolhida realizou-se uma análise descritiva.Resultados: Oitenta e cinco médicos internos responderam ao questionário, perfazendo uma taxa de resposta de 62%. Três quartos dos participantes no estudo contactaram com doentes com COVID-19. Oitenta e seis por cento dos médicos internos inquiridos encontravam-se em estágios, tendo os mesmos sido cancelados em 59% dos casos. Setenta e oito por cento referiram uma carga assistencial superior a 40 horas semanais.Conclusão: A pandemia de COVID-19 teve impacto na formação especializada do internato médico de medicina intensiva em Portugal. A maioria dos internos inquiridos contactaram com doentes com COVID-19, com suspensão dos seus estágios e com prejuízo na remarcação dos mesmos.

Measurement of Tissue Non-Heme Iron Content using a Bathophenanthroline-Based Colorimetric Assay.

Iron is an essential micronutrient. Both iron overload and deficiency are highly detrimental to humans, and tissue iron levels are finely regulated. The use of experimental animal models of iron overload or deficiency has been instrumental to advance knowledge of the mechanisms involved in the systemic and cellular regulation of iron homeostasis. The measurement of total iron levels in animal tissues is commonly performed with atomic absorption spectroscopy or with a colorimetric assay based on the reaction of non-heme iron with a bathophenanthroline reagent. For many years, the colorimetric assay has been used for the measurement of the non-heme iron content in a wide range of animal tissues. Unlike atomic absorption spectroscopy, it excludes the contribution of heme iron derived from hemoglobin contained in red blood cells. Moreover, it does not require sophisticated analytical skills or highly expensive equipment, and can thus be easily implemented in most laboratories. Finally, the colorimetric assay can be either cuvette-based or adapted to a microplate format, allowing higher sample throughput. The present work provides a well-established protocol that is suited for the detection of alterations in tissue iron levels in a variety of experimental animal models of iron overload or iron deficiency.

Hemodialysis catheter heparin lock related bleeding: Hemorrhagic shock every other day.

Catheter dysfunction is an important cause of catheter loss. In order to prevent this, locking solutions with minimal risk of systemic anticoagulation are used to ensure catheter patency. At present the most commonly used solutions are either heparin or sodium citrate. According to the literature use of sodium citrate may be advantageous in reducing bleeding events. We report a case of hemorrhagic shock following hemodialysis catheter lock with heparin, reversed after switching solution to sodium citrate.

Macrophage Resistance to Ionizing Radiation Exposure Is Accompanied by Decreased Cathepsin D and Increased Transferrin Receptor 1 Expression.

PURPOSE: To identify a molecular signature of macrophages exposed to clinically relevant ionizing radiation (IR) doses, mirroring radiotherapy sessions. METHODS: Human monocyte-derived macrophages were exposed to 2 Gy/ fraction/ day for 5 days, mimicking one week of cancer patient's radiotherapy. Protein expression profile by proteomics was performed. RESULTS: A gene ontology analysis revealed that radiation-induced protein changes are associated with metabolic alterations, which were further supported by a reduction of both cellular ATP levels and glucose uptake. Most of the radiation-induced deregulated targets exhibited a decreased expression, as was the case of cathepsin D, a lysosomal protease associated with cell death, which was validated by Western blot. We also found that irradiated macrophages exhibited an increased expression of the transferrin receptor 1 (TfR1), which is responsible for the uptake of transferrin-bound iron. TfR1 upregulation was also found in tumor-associated mouse macrophages upon tumor irradiation. In vitro irradiated macrophages also presented a trend for increased divalent metal transporter 1 (DMT1), which transports iron from the endosome to the cytosol, and a significant increase in iron release. CONCLUSIONS: Irradiated macrophages present lower ATP levels and glucose uptake, and exhibit decreased cathepsin D expression, while increasing TfR1 expression and altering iron metabolism.

Mortalidade por suicídio na cidade de São Paulo: caracterização, tendências e análise de efeito idade-período-coorte (1996-2018) / Suicide mortality in the city of São Paulo: characterization, trends, and age-period- cohort effect analysis (1996-2018)

Introdução - Globalmente, o suicídio é a causa de morte violenta mais frequente. No Brasil, a taxa de suicídio está crescendo. Para a saúde pública, é fundamental conhecer a magnitude e tendência dos suicídios para criar estratégias de prevenção, visando à diminuição desses óbitos evitáveis. Objetivo - Descrever a mortalidade por suicídio no Município de São Paulo entre 1996 e 2018, analisando tendências temporais e os efeitos independentes de idade, período e coorte de nascimento. Métodos - Foram calculadas taxas de mortalidade por suicídio brutas, específicas e padronizadas por idade. A mortalidade proporcional foi descrita segundo sexo, idade, raça/cor, escolaridade, estado civil, meios utilizados, regiões de residência e períodos. Modelos lineares generalizados foram ajustados para avaliar a tendência temporal do suicídio segundo sexo, idade e meios utilizados e estimar a Variação Percentual Anual das taxas. Análises de idade-período-coorte estratificadas por sexo foram realizadas para estimar separadamente os efeitos do tempo calendário, da idade e da coorte de nascimento sobre o suicídio. Resultados - Foram registrados 11.204 óbitos por suicídio no período. A taxa de mortalidade por suicídio foi de 5,2 óbitos (por 100 mil habitantes), e a razão de taxas entre sexos foi de 3,7. A região Centro apresentou a maior taxa, e a região Sul, a menor. Em ambos os sexos, as taxas por enforcamento, envenenamento e precipitação cresceram no período, e as por meios não especificados tiveram queda. Para os homens, o meio mais comum utilizado foi o enforcamento, independentemente de idade, estado civil, escolaridade, raça/cor ou período. O uso das armas de fogo foi o segundo mais frequente, mas as taxas por esse meio tiveram queda de -11,3% ao ano (IC 95% -15,7 : -6,6) até 2001, crescimento de 4,9% (IC 95% 0,4 : 9,6) até 2006 e queda de -5,6% (IC 95% -7,4 : -3,7) até 2018. Não foi identificada tendência nas taxas de homens de 10 a 19 anos (p = 0,74). Em homens adultos, houve tendência de queda de -5,6% ao ano (IC 95% -7,3 : -4,0) até 2002, crescimento de 2,6% (IC 95% 1,7 : 3,5) até 2012 e queda de -3,1% (IC 95% -4,7 : -1,5) até 2018. Em homens idosos, houve tendência de queda de -2,8% (IC 95% -4,1 : -1,5) até 2012, seguida de crescimento de 4,6% (IC 95% 0,8 : 8,5). Em homens adultos e idosos, foram identificados efeitos significativos de idade e período, mas não de coorte de nascimento. Para as mulheres, enforcamento, envenenamento e precipitação foram os meios mais comuns, e os suicídios por armas de fogo caíram -6,6% (IC 95% -9,0 : -4,1) em todo o período. Houve tendência de queda de -4,2% (IC 95% -6,9 : -1,4) nas mulheres da faixa de 10 a 19 anos e de - 1,1% (IC 95% -2,1 : -0,1) nas demais faixas até 2008. Idosas tiveram queda permanente nas taxas. Nas mulheres de 10 a 59 anos, as taxas cresceram 8,7% (IC 95% 5,3 : 12,3) entre 2008 e 2012. Houve queda no período final de -1,1% (IC 95% -2,1 : -0,1) nas mulheres de 10 a 39 anos e de -9,4% (IC 95% -13,2 : -5,6) nas de 40 a 59 anos. Em mulheres adultas, houve efeitos de idade, período e coorte, com crescimento linear no risco de suicídio a partir das gerações nascidas após 1970. Em mulheres idosas, houve efeitos significativos apenas de idade. Conclusões - Em geral, houve uma queda no suicídio de homens e mulheres. Homens idosos são o único grupo etário com tendência recente de crescimento. Além destes, as populações com maior risco atualmente são as mulheres entre 20 e 39 anos, bem como as nascidas após 1970. Suicídios por armas de fogo tiveram expressiva redução após mudança legislativa dos anos 2000. Recomenda-se mais pesquisas na área da epidemiologia do suicídio no Brasil, considerando a subnotificação desse tipo de óbito e o crescimento de suas taxas no país.

Introduction - Globally, suicide is the most frequent cause of violent death. The suicide rate is growing in Brazil. It is essential to know the magnitude and trends of suicide for prevention strategies, aiming to reduce these preventable deaths. Objective - To describe suicide mortality in the city of São Paulo between 1996 and 2018, analyzing temporal trends and the independent effects of age, period and birth cohort. Methods - Crude, age-specific, and agestandardized suicide mortality rates were calculated. Proportional mortality was described according to sex, age, race/color, education, marital status, suicide methods, city regions and periods. Generalized linear models were fitted to assess the temporal trend of suicide according to sex, age, and methods, and to estimate the Annual Percent Change of the rates. Sex-stratified age-period-cohort analyzes were performed to estimate the effects of calendar time, age, and birth cohort on suicide. Results - There were 11,204 deaths from suicide in the period. Suicide mortality rate was 5.2 deaths (per 100,000 inhabitants), and sex rate ratio was 3.7. The central region had the highest rate and the southern region the lowest. Suicide rates by hanging, poisoning and precipitation increased over the period, and decreased for unspecified methods, for both sexes. For men, the most common method was hanging, regardless of age, marital status, education, race/color or period. Firearms were the second most frequent method, but firearmspecific rates decreased -11.3% per year (95% CI -15.7 : - 6.6) until 2001, increased 4.9% (95% CI 0.4 : 9.6) until 2006, and decreased -5.6% (95% CI - 7.4 : -3.7) until 2018. No trend was identified in the rates for 10 to 19-year-old men (p = 0.74). Adult men rates decreased -5.6% per year (95% CI -7.3 : -4.0) until 2002, increased 2.6% (95% CI 1.7 : 3.5) until 2012, and decreased -3.1% (95% CI -4.7 : -1.5) until 2018. Elderly men rates decreased -2.8% (95% CI -4.1 : -1.5) until 2012, followed by a 4.6% increase (95% CI 0.8 : 8.5). Significant age and period effects were identified for adult and elderly men suicide, but no birth cohort effect. For women, hanging, poisoning and precipitation were the most common methods, and firearmspecific rates decreased -6.6% (95% CI -9.0 : -4.1) throughout the period. Women rates decreased -4.2% (95% CI -6.9 : -1.4) in the 1019 age range and -1.1% (95% CI -2.1 : - 0.1) in the other ranges until 2008. Elderly women had a permanent decrease in rates. The rates for 10 to 59-year-old women increased 8.7% (95% CI 5.3 : 12.3) between 2008 and 2012. In the final period, 10 to 39-year-old women rates decreased -1.1% (95% CI -2.1 : -0.1), and 40 to 59 rates decreased -9.4% (95% CI -13.2 : -5.6). There were age, period, and cohort effects for adult women, with a linear increase in suicide risk from generations born after 1970. Only age effects were detected for elderly women suicide. Conclusion - In general, suicide declined for men and women. Elderly men are the only age group with a recent increasing trend. Other populations at risk today are 20 to 39-year-old women, as well as women born after 1970. Firearm suicides had a significant reduction after legislative change in the 2000s. Further research in Brazilian suicide epidemiology is recommended, considering the typical underreporting of suicide and the increase on its national rates.

A new anesthetic protocol to medullary nerve roots access in rats.

PURPOSE: To describe a new anesthetic protocol medullary and nerve roots access and in Rattus norvegicus. METHODS: Seventy female Wistar rats (n=70) were used. The animals were randomly divided into two laminectomy groups: cervical (n=40) and thoracic (n=30). In cervical group, a right posterior hemilaminectomy was performed to access the nerve roots. In thoracic group, a laminectomy of the eighth thoracic vertebra was accomplished. Thirty-five rats (20 cervical and 15 thoracic) were submitted to old anesthetic protocol (ketamine 70 mg/kg plus xylazine 10 mg/kg); and the 35 other animals (20 cervical and 15 thoracic) were submitted to a new anesthetic protocol (ketamine 60 mg/kg,xylazine 8 mg/kg and fentanyl 0.03 mg/kg). RESULTS: The time to complete induction was 4.15 ±1.20 minin ketamine, xylazine and fentanyl group, and it was 4.09 ±1.47 min in the ketamine and xylazine group. There was no correlation in the time required to perform the cervical laminectomy in the old anesthetic protocol. In all groups, the animals submitted to the old anesthetic protocol had a higher level of pain on the first and third postoperative days than the animals submitted to the new anesthetic protocol. CONCLUSIONS: The new anesthetic protocol reduces the surgical time, allows better maintenance of the anesthetic plan, and brings more satisfactory postoperative recovery.

Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications.

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer, but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in patients with AML at diagnosis and explored the mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile, not associated with inflammation or transfusion, characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that the AML-induced loss of erythroblasts is responsible for iron redistribution and increased TSAT. We also show that AML progression is delayed in mouse models of systemic iron overload and that elevated TSAT at diagnosis is independently associated with increased overall survival in AML. We suggest that TSAT may be a relevant prognostic marker in AML.

Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection.

BACKGROUND: How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear. METHODS: We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells in vitro and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant TMPRSS6. We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency. FINDINGS: We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity. CONCLUSIONS: Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders. FUNDING: Medical Research Council, UK.

Is the efficacy of remdesivir so different from that of lopinavir-ritonavir in severe COVID-19? The answer by real time-PCR: a narrative review.

This letter discusses the efficacy of current antiviral therapy used in severe COVID-19 infection. Since the first severe cases were documented, several antiviral options have been studied as adjuncts to standard supportive care [1, 2]. Firstly, the combination of lopinavir-ritonavir resurrected from SARS and MERS outbreaks and soon abandoned after the publication of several trials like the randomized controlled trial RECOVERY, which concluded that it was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progression to invasive mechanical ventilation or death [3]. Remdesivir is currently the only antiviral agent approved for the treatment of COVID-19. It is recommended for use in hospitalized patients who require supplemental oxygen. However, it is not routinely recommended for patients who require mechanical ventilation due to the lack of data showing any benefit at this advanced stage of the disease [4-6].