Disfunción multiorgánica en el recién nacido con Encefalopatía hipóxico-isquémica en la era de la Hipotermia terapéutica

[spa] La aproximación al paciente asfíctico desde el punto de vista neurológico es fundamental por las implicaciones a corto y largo plazo, sin embargo el insulto hipóxico-isquémico altera la homeostasis global del recién nacido afectando a los diferentes órganos y sistemas. La evidencia científica acerca del daño extraneural en el recién nacido asfíctico hasta el momento actual es escasa y los estudios pertenecen a la era previa a la implantación de la hipotermia terapéutica que ha supuesto un cambio de paradigma clínico en este tipo de pacientes. Por otra parte, dado que la mayor parte de recién nacidos con encefalopatía hipóxico-isquémica nacen en centros que no disponen de hipotermia terapéutica, estos pacientes necesitarán ser trasladados en hipotermia pasiva a centros de referencia. El transporte de estos pacientes supone un reto, principalmente por la necesidad de mantener la temperatura en el rango de seguridad. Esta tesis, en base al estudio de una serie amplia de pacientes con el espectro completo de encefalopatía hipóxico-isquémica, ha abordado aspectos determinantes y hasta el momento desconocidos en el manejo del recién nacido asfíctico como son, en primer lugar, la correlación del daño multiorgánico y la encefalopatía hipóxico-isquémica en la era de la hipotermia terapéutica, aportando datos de gran utilidad clínica. Podemos concluir que la disfunción de otros órganos es prácticamente universal en el paciente con cualquier grado de encefalopatía hipóxico-isquémica en la era de la hipotermia terapéutica. El daño extraneural se correlaciona con la gravedad de la encefalopatía hipóxico-isquémica, sin embargo esta correlación se funda básicamente en la diferencia en el grado de afectación multiorgánica entre los pacientes con encefalopatía grave y los pacientes con encefalopatía moderada y leve. De esta manera, podemos establecer los siguientes patrones de afectación sistémica según el grado de EHI: 1) En el paciente con encefalopatía grave se debe anticipar una disfunción moderada o grave de otros órganos desde las primeras 24 horas de vida. En caso de no producirse, es preciso descartar exhaustivamente otras causas de encefalopatía neonatal. 2) Los pacientes con encefalopatía moderada con frecuencia presentan afectación orgánica de escasa relevancia clínica, pero una minoría de casos puede presentar afectación sistémica moderada o grave. 3) Los pacientes con encefalopatía leve presentan habitualmente afectación sistémica leve y resuelven con rapidez las alteraciones en la homeostasis. Respecto al perfil de afectación orgánica, el hígado y el medio interno son los órganos o sistemas que se afectan con mayor frecuencia en el recién nacido con encefalopatía hipóxico-isquémica, sin embargo los órganos afectados con mayor gravedad son el sistema respiratorio y cardiovascular. La disfunción renal y hematológica se producen con menor frecuencia que el resto de órganos o sistemas, sin embargo en el caso del daño renal, su afectación es con frecuencia clínicamente relevante. Así mismo, el daño extraneural en el paciente con encefalopatía hipóxico-isquémica es más intenso en las primeras 24 horas de vida. Los pacientes que sobreviven presentan una tendencia a mejorar a lo largo de las primeras 72 horas de vida. En segundo lugar, el estudio del curso del transporte del recién nacido con encefalopatía hipóxico isquémica nos ha permitido dilucidar como la gravedad de la encefalopatía hipóxico-isquémica se correlaciona inversamente con la temperatura durante el transporte en hipotermia pasiva. Los pacientes con encefalopatía grave presentan un mayor riesgo de sobreenfriamiento durante el transporte en hipotermia pasiva. Por otra parte, los eventos adversos más frecuentemente descritos durante el transporte interhospitalario en hipotermia pasiva son el deterioro cardiovascular, la presencia de hipoglucemia y sangrado endotraqueal, estos podrían disminuir con una mejor estabilización previa al transporte y con un mejor control de la temperatura.[eng] Perinatal asphyxia is a major cause of multiorgan dysfunction in the newborn. Only scarce data about the correlation of extracerebral damage and the severity of hypoxic-ischemic encephalopathy are available. This information might help to anticipate the evolution of multiorgan dysfunction according to the severity of hypoxic-ischemic encephalopathy and vice versa. On the other hand, hypoxic-ischemic encephalopathy has become a time- dependent emergency after clinical trials demonstrated the efficacy of cooling started within 6 hours of birth in reducing the risk of death or disability. Most asphyxiated infants are born in non-tertiary neonatal units and they must be transferred urgently to a center equipped with a hypothermia program. To start hypothermia as soon as possible, transferred infants are passively cooled. Nevertheless, studies do not outline medical complications during transport nor indicate whether the efficacy in maintaining target temperatures and complications are related to the severity of the hypoxic-ischemic encephalopathy in the first 6 h of life. This is the first study to evaluate the correlation of multiple organ dysfunction with the severity of hypoxic-ischemic encephalopathy. In the hypothermia era, multiple organ damage continues to be almost universal in newborns with hypoxic-ischemic encephalopathy. There is a high correlation between the severity of hypoxic-ischemic encephalopathy and multiple organ injury during the first 3 days of life. Therefore, a high index of suspicion of relevant multiorgan dysfunction is required in infants admitted with a diagnosis of severe hypoxic-ischemic encephalopathy. Patients with moderate hypoxic-ischemic encephalopathy present wide variability in the severity of multiorgan dysfunction. Finally, in the absence of multiorgan dysfunction a perinatal hypoxic-ischemic origin of acute severe neonatal encephalopathy should be carefully reconsidered. Secondly, this study shows that the risk of overcooling during transport is greater in newborns with severe hypoxic- ischemic encephalopathy and those with more severe acidosis at birth. The most common adverse events during transport are related to physiological deterioration and bleeding from the endotracheal tube. This observation provides useful information to identify those asphyxiated infants who require closer clinical surveillance during transport

The Effects of Alcohol and Drugs of Abuse on Maternal Nutritional Profile during Pregnancy

Abstract The consumption of alcohol and drugs of abuse among pregnant women has experienced a significant increase in the last decades. Suitable maternal nutritional status is crucial to maintain the optimal environment for fetal development but if consumption of alcohol or drugs of abuse disrupt the intake of nutrients, the potential teratogenic effects of these substances increase. Despite evidence of the importance of nutrition in addicted pregnant women, there is a lack of information on the effects of alcohol and drugs of abuse on maternal nutritional status; so, the focus of this review was to provide an overview on the nutritional status of addicted mothers and fetuses. Alcohol and drugs consumption can interfere with the absorption of nutrients, impairing the quality and quantity of proper nutrient and energy intake, resulting in malnutrition especially of micronutrients (vitamins, omega⁻3, folic acid, zinc, choline, iron, copper, selenium). When maternal nutritional status is compromised by alcohol and drugs of abuse the supply of essential nutrients are not available for the fetus; this can result in fetal abnormalities like Intrauterine Growth Restriction (IUGR) or Fetal Alcohol Spectrum Disorder (FASD). It is critical to find a strategy to reduce fetal physical and neurological impairment as a result of prenatal alcohol and drugs of abuse exposure combined with poor maternal nutrition. Prenatal nutrition interventions and target therapy are required that may reverse the development of such abnormalities. KEYWORDS: Fetal Alcohol Spectrum Disorder (FASD); Intrauterine Growth Restriction (IUGR); alcohol; drugs of abuse; fetal nutrition; maternal nutrition; pregnanc

The Effects of Vegetarian and Vegan Diet during Pregnancy on the Health of Mothers and Offspring

Vegetarian and vegan diets have increased worldwide in the last decades, according to the knowledge that they might prevent coronary heart disease, cancer, and type 2 diabetes. Althought plant-based diets are at risk of nutritional deficiencies such as proteins, iron, vitamin D, calcium, iodine, omega-3, and vitamin B12, the available evidence shows that well planned vegetarian and vegan diets may be considered safe during pregnancy and lactation, but they require a strong awareness for a balanced intake of key nutrients. A review of the scientific literature in this field was performed, focusing specifically on observational studies in humans, in order to investigate protective effects elicited by maternal diets enriched in plant-derived foods and possible unfavorable outcomes related to micronutrients deficiencies and their impact on fetal development. A design of pregestational nutrition intervention is required in order to avoid maternal undernutrition and consequent impaired fetal growth

Incidence, clinical characteristics and management of inflammatory bowel disease in Spain: large-scale epidemiological study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD—Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)—during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100, 000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31–56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362