Post-exposure vaccine effectiveness and contact management in the mpox outbreak, Madrid, Spain, May to August 2022.

BackgroundAppropriate vaccination strategies have been key to controlling the outbreak of mpox outside endemic areas in 2022, yet few studies have provided information on mpox vaccine effectiveness (VE).AimTo assess VE after one dose of a third-generation smallpox vaccine against mpox when given as post-exposure prophylaxis (PEP) within 14 days.MethodsA survival analysis in a prospective cohort of close contacts of laboratory-confirmed mpox cases was conducted from the beginning of the outbreak in the region of Madrid in May 2022. The study included contacts of cases in this region diagnosed between 17 May and 15 August 2022. Follow up was up to 49 days. A multivariate proportional hazard model was used to evaluate VE in the presence of confounding and interaction.ResultsInformation was obtained from 484 close contacts, of which 230 were vaccinated within 14 days of exposure. Of the close contacts, 57 became ill during follow-up, eight vaccinated and 49 unvaccinated. The adjusted effectiveness of the vaccine was 88.8% (95% CI: 76.0-94.7). Among sexual contacts, VE was 93.6% (95% CI: 72.1-98.5) for non-cohabitants and 88.6% (95% CI: 66.1-96.2) for cohabitants.ConclusionPost-exposure prophylaxis of close contacts of mpox cases is an effective measure that can contribute to reducing the number of cases and eventually the symptoms of breakthrough infections. The continued use of PEP together with pre-exposure prophylaxis by vaccination and other population-targeted prevention measures are key factors in controlling an mpox outbreak.

Epidemiologic Features and Control Measures during Monkeypox Outbreak, Spain, June 2022.

During June 2022, Spain was one of the countries most affected worldwide by a multicountry monkeypox outbreak with chains of transmission without identified links to disease-endemic countries. We provide epidemiologic features of cases reported in Spain and the coordinated measures taken to respond to this outbreak.

Monkeypox outbreak predominantly affecting men who have sex with men, Madrid, Spain, 26 April to 16 June 2022.

Up to 22 June 2022, 508 confirmed cases of monkeypox (MPX) have been reported in the Madrid region of Spain, 99% are men (n = 503) with a median age of 35 years (range: 18-67). In this ongoing outbreak, 427 cases (84.1%) reported condomless sex or sex with multiple partners within the 21 days before onset of symptoms, who were predominantly men who have sex with men (MSM) (n = 397; 93%). Both the location of the rash, mainly in the anogenital and perineal area, as well as the presence of inguinal lymphadenopathy suggest that close physical contact during sexual activity played a key role in transmission. Several cases reported being at a sauna in the city of Madrid (n = 34) or a mass event held on the Spanish island of Gran Canaria (n = 27), activities which may represent a conducive environment for MPX virus spread, with many private parties also playing an important role. Because of the rapid implementation of MPX surveillance in Madrid, one of the largest outbreaks reported outside Africa was identified. To minimise transmission, we continue to actively work with LGBTIQ+ groups and associations, with the aim of raising awareness among people at risk and encouraging them to adopt preventive measures.

Whole-genome sequencing-based phylogeny, antibiotic resistance, and invasive phenotype of Escherichia coli strains colonizing the cervix of women in preterm labor.

BACKGROUND: Escherichia coli is a major neonatal pathogen and the leading cause of early-onset sepsis in preterm newborns. Maternal E. coli strains are transmitted to the newborn causing invasive neonatal disease. However, there is a lack of data regarding the phenotypic and genotypic characterization of E. coli strains colonizing pregnant women during labor. METHODS: This prospective study performed at the University of Oklahoma Medical Center (OUHSC) from March 2014 to December 2015, aimed to investigate the colonization rate, and the phylogeny, antibiotic resistance traits, and invasive properties of E. coli strains colonizing the cervix of fifty pregnant women diagnosed with preterm labor (PTL). Molecular analyses including bacterial whole-genome sequencing (WGS), were performed to examine phylogenetic relationships among the colonizing strains and compare them with WGS data of representative invasive neonatal E. coli isolates. Phenotypic and genotypic antibiotic resistance traits were investigated. The bacteria's ability to invade epithelial cells in vitro was determined. RESULTS: We recruited fifty women in PTL. Cervical samples yielded E. coli in 12 % (n=6). The mean gestational age was 32.5 (SD±3.19) weeks. None delivered an infant with E. coli disease. Phenotypic and genotypic antibiotic resistance testing did not overall demonstrate extensive drug resistance traits among the cervical E. coli isolates, however, one isolate was multi-drug resistant. The isolates belonged to five different phylogroups, and WGS analyses assigned each to individual multi-locus sequence types. Single nucleotide polymorphism-based comparisons of cervical E. coli strains with six representative neonatal E. coli bacteremia isolates demonstrated that only half of the cervical E. coli isolates were phylogenetically related to these neonatal invasive strains. Moreover, WGS comparisons showed that each cervical E. coli isolate had distinct genomic regions that were not shared with neonatal E. coli isolates. Cervical and neonatal E. coli isolates that were most closely related at the phylogenetic level had similar invasion capacity into intestinal epithelial cells. In contrast, phylogenetically dissimilar cervical E. coli strains were the least invasive among all isolates. CONCLUSIONS: This pilot study showed that a minority of women in PTL were colonized in the cervix with E. coli, and colonizing strains were not phylogenetically uniformly representative of E. coli strains that commonly cause invasive disease in newborns. Larger studies are needed to determine the molecular characteristics of E. coli strains colonizing pregnant women associated with an increased risk of neonatal septicemia.

NEC-like intestinal injury is ameliorated by Lactobacillus rhamnosus GG in parallel with SIGIRR and A20 induction in neonatal mice.

BACKGROUND: Exaggerated Toll-like receptor (TLR) signaling and intestinal dysbiosis are key contributors to necrotizing enterocolitis (NEC). Lactobacillus rhamnosus GG (LGG) decreases NEC in preterm infants, but underlying mechanisms of protection remain poorly understood. We hypothesized that LGG alleviates dysbiosis and upregulates TLR inhibitors to protect against TLR-mediated gut injury. METHODS: Effects of LGG (low- and high-dose) on intestinal pro-inflammatory TLR signaling and injury in neonatal mice subjected to formula feeding (FF) and NEC were determined. 16S sequencing of stool and expression of anti-TLR mediators SIGIRR (single immunoglobulin interleukin-1-related receptor) and A20 were analyzed. RESULTS: FF induced mild intestinal injury with increased expression of interleukin-1ß (IL-1ß) and Kupffer cell (KC) (mouse homolog of IL-8) compared to controls. LGG decreased IL-1ß and KC in association with attenuated TLR signaling and increased SIGIRR and A20 expression in a dose-dependent manner. Low- and high-dose LGG had varying effects on gut microbiome despite both doses providing gut protection. Subsequent experiments of LGG on NEC revealed that pro-inflammatory TLR signaling and intestinal injury were also decreased, and SIGIRR and A20 expression increased, in a dose-dependent manner with LGG pre-treatment. CONCLUSIONS: LGG protects against intestinal TLR-mediated injury by upregulating TLR inhibitors without major changes in gut microbiome composition.

Respiratory Syncytial Virus Genotypes, Host Immune Profiles, and Disease Severity in Young Children Hospitalized With Bronchiolitis.

Background: Data on how respiratory syncytial virus (RSV) genotypes influence disease severity and host immune responses is limited. Here, we characterized the genetic variability of RSV during 5 seasons, and evaluated the role of RSV subtypes, genotypes, and viral loads in disease severity and host transcriptional profiles. Methods: A prospective, observational study was carried out, including a convenience sample of healthy infants hospitalized with RSV bronchiolitis. Nasopharyngeal samples for viral load quantitation, typing, and genotyping, and blood samples for transcriptome analyses were obtained within 24 hours of hospitalization. Multivariate models were constructed to identify virologic and clinical variables predictive of clinical outcomes. Results: We enrolled 253 infants (median age 2.1 [25%-75% interquartile range] months). RSV A infections predominated over RSV B and showed greater genotype variability. RSV A/GA2, A/GA5, and RSV B/BA were the most common genotypes identified. Compared to GA2 or BA, infants with GA5 infections had higher viral loads. GA5 infections were associated with longer hospital stay, and with less activation of interferon and increased overexpression of neutrophil genes. Conclusions: RSV A infections were more frequent than RSV B, and displayed greater variability. GA5 infections were associated with enhanced disease severity and distinct host immune responses.

Antisense transcripts enhanced by camptothecin at divergent CpG-island promoters associated with bursts of topoisomerase I-DNA cleavage complex and R-loop formation.

DNA Topoisomerase I (Top1) is required to relax DNA supercoils generated by RNA polymerases (RNAPs). Top1 is inhibited with high specificity by camptothecin (CPT), an effective anticancer agent, and by oxidative base damage and ribonucleotides in DNA strands, resulting into Top1-DNA cleavage complexes (Top1ccs). To understand how Top1ccs affect genome stability, we have investigated the global transcriptional response to CPT-induced Top1ccs. Top1ccs trigger an accumulation of antisense RNAPII transcripts specifically at active divergent CpG-island promoters in a replication-independent and Top1-dependent manner. As CPT increases antisense transcript levels in the presence of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, a transcription inhibitor, Top1ccs likely impair antisense RNA degradation. Time-course data showed a burst of Top1ccs increased by CPT at promoter sites and along transcribed regions, causing a transient block of RNAPII at the promoter. Moreover, cell immunofluorescence analyses showed that Top1ccs induce a transient increase of R-loops specifically at highly transcribed regions such as nucleoli in a Top1-dependent manner. Thus, a specific and highly dynamic transcriptional response to Top1ccs occurs at divergent active CpG-island promoters, which may include a transient stabilization of R-loops. The results clarify molecular features of a response pathway leading to transcription-dependent genome instability and altered transcription regulation.

Genotypic and phenotypic characterization of invasive neonatal Escherichia coli clinical isolates.

OBJECTIVES: The objective of this study was to describe the clinical characteristics of neonates with Escherichia coli bacteremia and the antibiotic resistance pattern of the bacterial isolates. We assessed the isolates' genetic relatedness and virulence phenotypic characteristics in vitro. STUDY DESIGN: A total of 24 neonates with E. coli bacteremia were identified prospectively in a tertiary-care hospital. Clinical and antibiotic resistance data were investigated. The E. coli isolates were analyzed by multilocus sequence typing (MLST); the presence of the K1 capsule and their ability to invade intestinal epithelial cells were also assessed. RESULTS: Most newborns were very low birth weight infants. Overall, 75% of the isolates were ampicillin resistant and 17% were gentamicin and tobramycin nonsusceptible. MLST determined sequence types 95 and 131 (ST95 and ST131) predominated, with ST131 becoming significantly more prevalent recently. The K1 capsule was present in 50% of the isolates. ST131 isolates and those producing bacteremia in newborns younger than 7 days showed a highly invasive phenotype. CONCLUSION: Resistance to antibiotics currently used empirically to treat newborns is present in bacteremia-producing E. coli. Clonal spread among newborns of multidrug-resistant E. coli is possible; therefore, continued surveillance is needed. Identification of additional virulence factors associated with increased invasion in neonatal E. coli strains is important and further studies are warranted.

Insight Into Severe Neonatal COVID-19 Gained Through Whole Exome Sequencing of Twin Neonates.

The genetic basis of neonatal COVID-19 infection, which exhibits a range of severity, has not been investigated. We identified both shared and unique genetic variants involved in antiviral immune responses through whole exome sequencing of an infant who developed severe COVID-19 pneumonia and multisystem inflammatory syndrome and the twin brother also positive for severe acute respiratory syndrome-coronavirus-2, but with only moderate respiratory symptoms.

The effectiveness of nirsevimab in reducing the burden of disease due to respiratory syncytial virus (RSV) infection over time in the Madrid region (Spain): a prospective population-based cohort study.

Introduction: Respiratory syncytial virus (RSV) infection is one of the main causes of morbidity and mortality from lower respiratory tract infections in children under 5 years of age worldwide. Given that, the objective of this study was estimate the effectiveness of nirsevimab (a single-dose, long-acting, human recombinant monoclonal antibody against RSV) over time for the prevention of respiratory episodes treated at different levels of care. Methods: A prospective and dynamic population-based cohort study was performed including infants born between April 1 and December 31, 2023, in the Madrid region who resided there during the follow-up period from October 1, 2023, to February 29, 2024. Infants were considered immunized from the day after receiving one dose (50 or 100 mg) of nirsevimab or nonimmunized individuals if they did not receive any dose. Results: There were 4,100 episodes of primary care, 1,954 hospital emergencies, and 509 admissions, 82 of which required intensive care in the 33,859 participants analyzed. The adjusted effectiveness of nirsevimab in preventing hospitalization due to RSV infection was 93.6% (95% CI: 89.7 to 96.1) at 30 days and 87.6% (95% CI: 67.7 to 95.3) at 150 days. The number needed to treat to prevent one hospitalization were 314.19 (95% CI: 306.22 to 327.99) at 30 days and 24.30 (95% CI: 22.31 to 31.61) at 150 days. The adjusted effectiveness of nirsevimab in avoiding admission to an intensive care unit was 94.4% (95% CI: 87.3 to 97.5) at 30 days and 92.1% (95% CI: 64.0 to 98.3) at 90 days. The adjusted effectiveness of nirsevimab for avoiding primary care consultations and hospital emergency visits was lower. Discussion: Immunization with nirsevimab is an effective measure for reducing the burden of care related to RSV at all levels of care albeit it decreases throughout follow-up. At 150 days it remained high for preventing hospital admissions. Other articles already published have also demonstrated high effectiveness although with preliminary results, short follow-up periods and wide confidence intervals. None have detected a decrease in effectiveness over time. These results can be quite useful in individual infant prevention and in the design of immunization campaigns.

Microarray gene expression profiling of neural tissues in bovine spastic paresis.

BACKGROUND: Bovine Spastic Paresis (BSP) is a neuromuscular disorder which affects both male and female cattle. BSP is characterized by spastic contraction and overextension of the gastrocnemious muscle of one or both limbs and is associated with a scarce increase in body weight. This disease seems to be caused by an autosomal and recessive gene, with incomplete penetration, although no genes clearly involved with its onset have been so far identified. We employed cDNA microarrays to identify metabolic pathways affected by BSP in Romagnola cattle breed. Investigation of those pathways at the genome level can help to understand this disease. RESULTS: Microarray analysis of control and affected individuals resulted in 268 differentially expressed genes. These genes were subjected to KEGG pathway functional clustering analysis, revealing that they are predominantly involved in Cell Communication, Signalling Molecules and Interaction and Signal Transduction, Diseases and Nervous System classes. Significantly enriched KEGG pathway's classes for the differentially expressed genes were calculated; interestingly, all those significantly under-expressed in the affected samples are included in Neurodegenerative Diseases. To identify genome locations possibly harbouring gene(s) involved in the disease, the chromosome distribution of the differentially expressed genes was also investigated. CONCLUSIONS: The cDNA microarray we used in this study contains a brain library and, even if carrying an incomplete transcriptome representation, it has proven to be a valuable tool allowing us to add useful and new information to a poorly studied disease. By using this tool, we examined nearly 15000 transcripts and analysed gene pathways affected by the disease. Particularly, our data suggest also a defective glycinergic synaptic transmission in the development of the disease and an alteration of calcium signalling proteins. We provide data to acquire knowledge of a genetic disease for which literature still presents poor results and that could be further and specifically analysed in the next future. Moreover this study, performed in livestock, may also harbour molecular information useful for understanding human diseases.

Assessment of Intestinal Transcytosis of Neonatal Escherichia coli Bacteremia Isolates.

Newborns ingest maternal E. coli strains that colonize their intestinal tract around the time of delivery. E. coli strains with the ability to translocate across the gut invade the newborn's bloodstream, causing life-threatening bacteremia. The methodology presented here utilizes polarized intestinal epithelial cells grown on semipermeable inserts to assess the transcytosis of neonatal E. coli bacteremia isolates in vitro. This method uses the established T84 intestinal cell line that has the ability to grow to confluence and form tight junctions and desmosomes. After reaching confluence, mature T84 monolayers develop transepithelial resistance (TEER), which can be quantified using a voltmeter. The TEER values are inversely correlated with the paracellular permeability of extracellular components, including bacteria, across the intestinal monolayer. The transcellular passage of bacteria (transcytosis), on the other hand, does not necessarily alter the TEER measurements. In this model, bacterial passage across the intestinal monolayer is quantified for up to 6 h post-infection, and repeated measurements of TEER are made to monitor the paracellular permeability. In addition, this method facilitates the use of techniques such as immunostaining to study the structural changes in tight junctions and other cell-to-cell adhesion proteins during bacterial transcytosis across the polarized epithelium. The use of this model contributes to the characterization of the mechanisms by which neonatal E. coli transcytose across the intestinal epithelium to produce bacteremia.

The Detrimental Effects of Peripartum Antibiotics on Gut Proliferation and Formula Feeding Injury in Neonatal Mice Are Alleviated with Lactobacillus rhamnosus GG.

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined mechanisms by which peripartum antibiotics increase neonatal gut injury and evaluated whether probiotics protect against gut injury potentiated by peripartum antibiotics. To accomplish this objective, we administered broad-spectrum antibiotics or sterile water to pregnant C57BL6 mice and induced neonatal gut injury to their pups with formula feeding. We found that pups exposed to antibiotics had reduced villus height, crypt depth, and intestinal olfactomedin 4 and proliferating cell nuclear antigen compared to the controls, indicating that peripartum antibiotics impaired intestinal proliferation. When formula feeding was used to induce NEC-like injury, more severe intestinal injury and apoptosis were observed in the pups exposed to antibiotics compared to the controls. Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) reduced the severity of formula-induced gut injury potentiated by antibiotics. Increased intestinal proliferating cell nuclear antigen and activation of the Gpr81-Wnt pathway were noted in the pups supplemented with LGG, suggesting partial restoration of intestinal proliferation by probiotics. We conclude that peripartum antibiotics potentiate neonatal gut injury by inhibiting intestinal proliferation. LGG supplementation decreases gut injury by activating the Gpr81-Wnt pathway and restoring intestinal proliferation impaired by peripartum antibiotics. Our results suggest that postnatal probiotics may be effective in mitigating the increased risk of NEC associated with peripartum antibiotic exposure in preterm infants.

Evolutionary and functional history of the Escherichia coli K1 capsule.

Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phylogeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1-cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage.

Effect of Various Preterm Infant Milk Formulas on NEC-Like Gut Injury in Mice.

Formula feeding is an important risk factor for the development of necrotizing enterocolitis in preterm infants. The potential harmful effects of different preterm formulas on the developing intestinal tract remain incompletely understood. Here we demonstrate that feeding newborn mouse pups with various preterm formulas resulted in differing effects on intestinal inflammation, apoptosis, and activation of the pro-inflammatory transcription factor NFκB. 16S rRNA sequencing revealed that each preterm formula resulted in significant gut microbial alterations that were different from dam-fed controls. Formula feeding with EleCare and Similac Special Care caused greater intestinal injury compared to NeoSure. Pre-treatment with Lactobacillus rhamnosus GG ameliorated severity of intestinal injury from EleCare and Similac Special Care. Our findings indicate that not all preterm formulas are the same, and different formulations can have varying effects on intestinal inflammation, apoptosis, and microbiome composition.

[Evolution of COVID-19 at nursing homes from the second wave to vaccination. Description of a coordination program between Primary Care, Geriatrics and Public Health.] / Evolución de la COVID-19 en las residencias de personas mayores desde la segunda ola hasta la vacunación. Descripción de un programa de coordinación entre Atención Primaria, Geriatría y Salud Pública.

OBJECTIVE: Nursing homes have suffered in a particularly pronounced way from the effects of COVID-19 so it is very convenient to know the evolution in them of the disease and the impact of SARS-CoV2 vaccination The objective of this study was to analyze COVID-19 pandemic evolution from the start of the second wave to the end of the vaccination campaign at the nursing homes. A coordination program between Primary Care and Geriatrics and Public Health services was activated. METHODS: 2,668 seniors were followed at 39 nursing homes. Data from new cases, active cases, mortality and place of treatment of COVID-19 were collected. A descriptive analysis was performed with the measurement of the absolute number of positive SARS-CoV-2 cases and the frequency distribution. RESULTS: Between August 7th 2020 and February 26th 2021, 30 outbreaks occurred at 21 nursing homes. 300 people tested positive for SARS-CoV-2 (11% of total residents). The daily average of active cases was 27,166 were hospitalized (55%). 66 patients died (22% of those infected), 54 of them (78%) at the hospital. 1,984 PCR tests were performed. The temporary profile of new cases did not follow a distribution "in waves" as in the community. Thirty-seven days after the start of the second dose of vaccination, there were no active cases until March 1st, when new cases were under study for possible vaccine leakage. CONCLUSIONS: The incidence of COVID-19 at nursing homes after the first wave of the pandemic has apparently been lower. The transmission in these centers has followed a different distribution than at community. Mass vaccination has achieved the practical disappearance of the disease.

OBJETIVO: Los centros residenciales han sufrido de una manera especialmente acusada los efectos de la COVID-19 por lo que es muy conveniente conocer la evolución en ellos de la enfermedad y el impacto de la vacunación frente al SARS-CoV2. El objetivo de este estudio fue conocer la evolución de la pandemia de COVID-19 desde el comienzo de la segunda ola hasta el final del proceso de vacunación en las residencias de personas mayores de un área sanitaria, en la cual se activó un programa de coordinación entre Atención Primaria y los servicios de Geriatría y Salud Publica. METODOS: Se siguió a 2.668 personas mayores en 39 residencias. Se recogieron datos de casos nuevos, activos, fallecidos y lugar de tratamiento de la COVID-19. Se realizó un análisis descriptivo con la medición del número absoluto de casos positivo de SARS-CoV-2 y la distribución de frecuencias. RESULTADOS: Entre el 7 de agosto de 2020 y el 26 de febrero de 2021 se produjeron 30 brotes en 21 residencias. Se detectaron 300 casos positivos de SARS-CoV-2 (11% de los residentes totales). La media diaria de casos activos fue 27. Fueron hospitalizados 166 (55%). Fallecieron 66 pacientes (22% de los infectados), 54 de ellos (78%) en el hospital. Se realizaron 1.984 test PCR. El perfil temporal de aparición de casos nuevos no siguió una distribución "en olas" como en la comunidad. Treinta y siete días después del inicio de la segunda dosis de vacunación, no existieron casos activos hasta el 1 de marzo en que aparecieron nuevos casos en estudio por posible escape vacunal. CONCLUSIONES: La incidencia de la COVID-19 en las residencias de personas mayores tras la primera ola de la pandemia es aparentemente inferior. La transmisión en estos centros sigue una distribución diferente a la de la comunidad. El efecto de la vacunación masiva consigue la práctica desaparición de la enfermedad.

Hif1α down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist.

BACKGROUND: Congenital heart defect (CHD) account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453) we previously developed a mouse model of congenital heart defects (81%), thymic abnormalities (98%) and neural tube defects (20%). D-TGA (D-transposition of great arteries) was the most prevalent cardiac defect observed (61%). Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05), by oral administration of folic acid (FA). Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. RESULTS: We analysed mouse embryos (8.5 dpc) treated with BMS189453 alone and with BMS189453 plus folic acid (FA) by microarray and qRT-PCR. By selecting a fold change (FC) ≥ ± 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1α gene. In fact Hif1α is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005) and its expression level is increased in BMS+FA-treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005). Immunofluorescence experiments confirmed the under-expression of Hif1α protein in BMS-treated embryos compared to untreated and BMS+FA-treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1α is mainly expressed in the embryo heart region. CONCLUSIONS: We propose that Hif1α down-regulation in response to blocking retinoic acid binding may contribute to the development of cardiac defects in mouse newborns. In line with our hypothesis, when Hif1α expression level is restored (by supplementation of folic acid), a decrement of CHD is found. To the best of our knowledge, this is the first report that links retinoic acid metabolism to Hif1α regulation and the development of D-TGA.

[Tuberculosis trend in Madrid region in native and foreign population (2009-2018).] / Tendencia de la tuberculosis en la Comunidad de Madrid en población autóctona y extranjera (2009-2018).

OBJECTIVE: Tuberculosis is a major public health problem and most cases are concentrated in vulnerable populations. The objective was to describe the incidence rates trend in native and foreign population (2009-2018) in Madrid Region. METHODS: Retrospective analysis of cases from the Tuberculosis Regional Registry of cases of Madrid Region 2009-2018. Annual incidence rates were calculated by country of birth (Spain, other), sex and age group (<15, 15-34, 35-44, 45-64, >64), using the annual January 1st continuous register population. The infection rate trend and the annual percentage change (APC) were calculated, along with the best jointpoint adjustment using Jointpoint regression. RESULTS: 7,696 cases were analyzed, 48.2% were foreign-born individuals. Average age in native population was 50 years old (SD: 23.96) and 35 (DS: 36.64) in foreign-born individuals (p<0.001). The overall incidence rate decreased from 17.30 in 2009 to 9.00 per 100,000 in 2018 and was higher in men. Pulmonary tuberculosis reduced from 11.90 to 6.55. Among native population, the incidence of TB fell from 10.29 to 5.24 with an APC of -7.3% (95%IC: -8.9; -5.7) (p<0.05), no jointpoint was identified. Among foreign-born individuals the incidence of tuberculosis declined from 46.54 to 25.49, a joint point was identified in 2013, observing an incidence decrease for the period 2009-2013 and APC of -13.8% (IC95%: -17.5; -10.0). CONCLUSIONS: The global incidence rate in this period has decreased by approximately 7% per year. However, this reduction occurred mainly in native population. In foreign-born individuals the incidence decreased by approximately 14% during the 2009-2013 period, after this period there have been no significant incidence changes.

OBJETIVO: La tuberculosis (TB) continúa siendo un problema importante de salud pública, debido a que la mayoría de los casos se concentran en población vulnerable. El objetivo de este trabajo fue describir la tendencia de las tasas de incidencia en población autóctona y extranjera (2009-2018) en la Comunidad de Madrid (CM). METODOS: Se realizó un análisis retrospectivo de casos del Registro Regional de casos de Tuberculosis de la CM en el período 2009-2018. Se calcularon tasas de incidencia anual por cada 100.000 habitantes, por país de nacimiento (España, fuera de España), sexo y grupo de edad (<15, 15-34, 35-44, 45-64, >64), utilizando las poblaciones de padrón continuo a 1 de enero de cada año. Se calculó la tendencia de las tasas de incidencia y el porcentaje anual de cambio (APC), así como el mejor ajuste del punto de inflexión utilizando la regresión de Jointpoint. RESULTADOS: Se analizaron 7.696 casos, siendo el 48,2% en personas nacidas fuera de España. La edad media en población autóctona fue de 50 años (DS: 23,96) y 35 (DS: 36,64) en inmigrante (p<0,001). La tasa de incidencia global pasó de 17,30 por cada 100.000 habitantes en 2009 a 9 en 2018, siendo superior en hombres. La incidencia de tuberculosis pulmonar pasó de 11,90 a 6,55. En población autóctona, la incidencia de TB pasó de 10,29 a 5,24, con un APC de -7,3% (IC95%: -8,9; -5,7; p<0,05), y no se identificó ningún punto de inflexión. En población extranjera la incidencia de tuberculosis pasó de 46,54 a 25,49, identificándose un punto de inflexión en 2013, con una disminución más acusada de la incidencia para el periodo 2009-2013 debido a un APC de -13,8% (IC95%: -17,5; -10,0). CONCLUSIONES: La tasa de incidencia global en este periodo disminuye cerca de un 7% anual; sin embargo, esta disminución de la incidencia se produce fundamentalmente en población autóctona. En población extranjera la incidencia desciende cerca de un 14% durante el periodo 2009-2013. Tras este periodo no hay cambios significativos en la incidencia.