Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease.

TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel mutations in TLR7, F507S and L528I. While the L528I substitution arose de novo, the F507S mutation was present in three individuals from the same family, including a severely affected male, notably given that the TLR7 gene is situated on the X chromosome and that all other cases so far described have been female. The observation of mutations at residues 507 and 528 of TLR7 indicates the importance of the TLR7 dimerization interface in maintaining immune homeostasis, where we predict that altered homo-dimerization enhances TLR7 signaling. Finally, while mutations in TLR7 can result in SLE-like disease, our data suggest a broader phenotypic spectrum associated with TLR7 gain-of-function, including significant neurological involvement.

Monogenic systemic lupus erythematosus onset in a 13-year-old boy with Noonan like-syndrome: a case report and literature review.

BACKGROUND: Childhood systemic lupus erythematosus (cSLE) has been considered as a polygenic autoimmune disease; however, a monogenic lupus-like phenotype is emerging with the recent recognition of several related novel high-penetrance genetic variants. RASopathies, a group of disorders caused by mutations in the RAS/MAPK pathway, have been recently described as a cause of monogenic lupus. CASE PRESENTATION: We present a 13-year-old boy with Noonan-like syndrome with loose anagen hair who developed a monogenic lupus. The renal biopsy confirmed a class III lupus nephritis and identified the presence of zebra bodies. CONCLUSIONS: RASopathies represent a cause of monogenic lupus. We report a new case of monogenic lupus in a child with Noonan-like syndrome with loose anagen hair. Lupus nephritis which has never been described in this context, may be part of the presentation. The presence of zebra bodies in SLE or RASopathies in unclear, but no other known conditions (Fabry disease or drugs) were identified as the cause of zebra bodies in our patient.

Serological short-chain fatty acid and trimethylamine N-oxide microbial metabolite imbalances in young adults with acute myocardial infarction.

Acute myocardial infarction (AMI) is associated with systemic inflammatory processes and metabolic alterations. Microbial-derived metabolites, such as short-chain fatty acids and trimethylamine N-oxide (TMAO), have emerged in recent years as key players in the modulation of inflammation, with potential implications for cardiovascular diseases. We performed a prospective observational study that monitored the serological concentration of bacterial metabolites in 45 young patients (<55 years) without cardiovascular risk factors but with AMI, at hospital admission and at 3 months of follow-up, and compared them with a control group. TMAO and acetate levels were significantly higher in AMI, whereas butyrate and propionate were significantly lower. The acetate/propionate ratio showed the most discrimination between AMI and controls by receiver operating characteristic analysis (area under the curve 0.769, P < 0.0001). A multivariate logistic regression model revealed that this ratio was independently associated with AMI. Short-chain fatty acid concentrations, but not TMAO, exhibited significant correlations with inflammatory and coagulation parameters. Three months after the acute AMI event, all metabolite levels returned to those observed in healthy controls except butyrate. In conclusion, our study reveals disturbances of the serological concentration of microbiota-derived metabolites in AMI that are also related to inflammatory and coagulation parameters. These findings highlight an interesting field of study in the potential role of microbial metabolites from gut in cardiovascular disease.

Haematological and other manifestations in the presence of antiphospholipid antibodies in a multicentric paediatric cohort.

OBJECTIVES: To identify the variables associated with the development of haematological manifestations in the presence of antiphospholipid antibodies (aPLs) in a paediatric cohort. METHODS: We conducted a multicentric retrospective cohort study of children under the age of 18 years. RESULTS: One hundred and thirty-four children were included; 12.2% had at least one thrombotic event (TE) and 67% at least one non-criterion manifestation. Of them, 90% did not develop any TE. Haematological manifestations were the most frequent (42%), followed by neurological (19.8%), cutaneous (17.6%), cardiac (16.8%) and renal (1.5%) manifestations. In those children with haematological disorders, the aPLs positivity rate was: 67.3% LA, 65.6% aß2GPI, 60% aCL, 45.5% single, 23.6% double and 30.9% triple. A univariate analysis showed that children with IgM aCL+, IgM aß2GPI+, triple positivity and with a SLE diagnosis had a significantly higher frequency of haematological manifestations (p<0.05). Finally, a stepwise regression analysis identified IgG aß2GPI positivity [OR 2.91, 95% CI (1.26-6.74), p=0.013], SLE [OR 2.67, 95% CI (1.13-6.3), p=0.026] and LA positivity [OR 2.53, 95% CI (1.08-5.94), p=0.033] as independent risk factors for the development of haematological manifestations. CONCLUSIONS: Non-criteria manifestations and among them haematological disorders, are the most frequent events in the presence of aPLs and/or LA in our paediatric cohort. Children with SLE, LA and/or IgG aß2GPI positivity showed a higher risk of haematological manifestations.

Non-criteria manifestations in the presence of antiphospholipid antibodies in a paediatric cohort.

OBJECTIVE: To identify the variables associated with the development of non-criteria manifestations in the presence of antiphospholipid antibodies (aPLs) in a paediatric cohort. METHODS: Multicentric historical cohort study of children under the age of 18 years to determine thrombotic events (TEs) and non-criteria manifestations in the presence of aPL. RESULTS: Eighty-two children were included; 8.5% had at least one TE and 69.5% at least one non-criteria manifestation. Of them, 96.5% did not associate TEs. Haematological manifestations were the most frequent (43.65%), followed by cutaneous (22%), neurological (15.9%) and cardiac (4.9%) events. The most frequent aPLs were: 77.8% LA; 42.7% aCL and 41.5% aß2GP. The positivity rate was: 64.6% simple, 18.3% double and 17.1% triple. ANA positivity was 68.1%. A bivariate analysis revealed that children with IgM aCL+, IgM aß2GP+, ANA+, an SLE diagnosis or the absence of TEs had a significantly higher percentage of non-criteria manifestations (P <0.05). The logistic regression showed family history of autoimmune diseases [odds ratio (OR) 4.26, 95% CI: 0.8, 22.2, P =0.086] and the absence of TEs (OR 17.18, 95% CI: 1.2, 244.6, P =0.03) as independent risk factors of developing non-criteria manifestations. An SLE diagnosis, aPL profile and ANA+ were not identified. CONCLUSION: Non-criteria manifestations were more frequent than TEs. A positive family history of autoimmune diseases and the absence of TEs were associated with a higher risk of developing non-criteria manifestations. Therefore, their inclusion as APS classification criteria should be considered in order to get an improved prognosis in the paediatric population.

Fibroelastosis pleuroparenquimatosa: un nuevo tipo de neumonía instersticial asociada a conectivopatías / Pleuroparenchymal fibroelastosis: a new entity of interstitial pneumonia related to connective tissue diseases

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[Outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit: Risk factors and key preventive measures for eradication in record time]. / Brote de Klebsiella pneumoniae productora de betalactamasas de espectro extendido en una unidad de cuidados intensivos neonatales: factores de riesgo y medidas de prevención clave para su erradicación en tiempo récord.

INTRODUCTION: In November 2014, an extended-spectrum beta-lactamase producing Klebsiella pneumoniae outbreak was detected in the neonatal intensive care unit of a tertiary care hospital. OBJECTIVE: Our aim was to determine the clinical, epidemiological and microbiological characteristics of the outbreak, to analyse the identified risk factors and to describe the preventive and control measures implemented for its eradication. METHODS: We conducted a case-control study. We performed Univariate and bivariate analyses, defining statistical significance as a p-value of less than 0.05. The implemented preventive and control measures were aimed at establishing the magnitude of the outbreak, effective communication, the evaluation of health care processes and education on patient safety. Clinical samples were collected for molecular and phenotypic characterization. FINDINGS: The sample consisted of 51 newborns, of who 17 were cases and the remaining 34 controls. The distribution of cases by birth weight was: 2 cases (11.8%) greater than 2500g, 4 cases (23.5%) between 1500 and 2500g, 5 cases (29.4%) between 1000 and 1500g, and 5 cases (29.4%) less than 1000g. In one case, the birth weight was not documented in the health record. The following risk factors for colonization or infection were statistically significant in our study: presence of a central venous catheter (OR, 5.0 [95% CI, 1.4-17.8]; P=.016); parenteral nutrition (OR, 6.8 [95% CI, 1.8-25.7]; P=.006); urinary catheterization (OR, 5.9 [95% CI, 1.2-30.0]; P=.028) and birth weight (P=.035). We found statistically significant differences in the mean total length of stay in hospital (P=.004) and length of stay in the NICU (P=.002). All 17 cases presented antimicrobial resistance with presence of extended-spectrum beta-lactamase type CTX-M-14. CONCLUSION: Workplace interventions focused on patient safety need to be reinforced, especially those concerning practices with the potential to increase the extrinsic risk of colonization or infection by extended-spectrum beta-lactamase -producing K. pneumoniae in the NICU, such as the insertion, care and maintenance of central venous catheter, parenteral nutrition and urinary catheterization.

Brote de Klebsiella pneumoniae productora de betalactamasas de espectro extendido en una unidad de cuidados intensivos neonatales: factores de riesgo y medidas de prevención clave para su erradicación en tiempo récord / Outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit: Risk factors and key preventive measures for eradication in record time

Introducción: En noviembre de 2014, se detectó un brote de Klebsiella pneumoniae productora de betalactamasas de espectro extendido en la unidad de cuidados intensivos neonatales de un hospital terciario. Objetivo: El objetivo fue describir las características clínicas, epidemiológicas y microbiológicas del brote, analizar los factores de riesgo asociados y presentar las medidas preventivas y de control implementadas para su erradicación. Métodos: Estudio de casos y controles. Se realizaron análisis univariantes y bivariantes, considerándose estadísticamente significativo un valor de p < 0,05. Las medidas preventivas y de control se centraron en la necesidad de determinar la magnitud del problema, en la comunicación efectiva, la evaluación de los procedimientos sanitarios y la educación sobre la seguridad del paciente. Se realizó caracterización molecular y fenotípica de muestras clínicas. Resultados: La muestra de estudio consistió en 51 neonatos, de los que 17 fueron casos y los 34 restantes controles. La distribución de casos por peso al nacer fue: 2 con peso > 2.500 g (11,8%), 4 con peso de 1.500-2.500g (23,5%), 5 con peso de 1.000-1.500g (29,4%) y 5 con peso < 1.000g (29,4%). En un caso no se había registrado el peso al nacer en la historia clínica. Los factores de riesgo estadísticamente significativos para la colonización/infección fueron: presencia de catéter venoso (OR = 5,0 [IC 95% 1,4-17,8]; p = 0,016); nutrición parenteral (OR = 6,8 [IC 95%: 1,8-25,7]; p = 0,006); sondaje vesical (OR = 5,9 [IC 95% 1,2-30,0]; p = 0,028) y peso al nacer (p = 0,035). Encontramos diferencias estadísticamente significativas en la estancia hospitalaria media (p = 0,004) y los días de estancia en la unidad de cuidados intensivos neonatales (p=0,002). Se encontró resistencia a antimicrobianos tipo betalactamasas de espectro extendido CTX-M-14 en los 17 casos. Conclusión: Han de reforzarse las iniciativas de trabajo sobre la seguridad de los pacientes, especialmente aquellas aplicables a intervenciones con el potencial de aumentar el riesgo de colonización/infección por K. pneumoniae productora de betalactamasas de espectro extendido en la unidad de cuidados intensivos neonatales, como las asociadas a la inserción, cuidado y mantenimiento de catéter venoso, la nutrición parenteral y el sondaje vesical

Introduction: In November 2014, an extended-spectrum beta-lactamase producing Klebsiella pneumoniae outbreak was detected in the neonatal intensive care unit of a tertiary care hospital. Objective: Our aim was to determine the clinical, epidemiological and microbiological characteristics of the outbreak, to analyse the identified risk factors and to describe the preventive and control measures implemented for its eradication. Methods: We conducted a case-control study. We performed Univariate and bivariate analyses, defining statistical significance as a p-value of less than 0.05. The implemented preventive and control measures were aimed at establishing the magnitude of the outbreak, effective communication, the evaluation of health care processes and education on patient safety. Clinical samples were collected for molecular and phenotypic characterization. Findings: The sample consisted of 51 newborns, of who 17 were cases and the remaining 34 controls. The distribution of cases by birth weight was: 2 cases (11.8%) greater than 2500 g, 4 cases (23.5%) between 1500 and 2500g, 5 cases (29.4%) between 1000 and 1500 g, and 5 cases (29.4%) less than 1000g. In one case, the birth weight was not documented in the health record. The following risk factors for colonization or infection were statistically significant in our study: presence of a central venous catheter (OR, 5.0 [95% CI, 1.4-17.8]; P = .016); parenteral nutrition (OR, 6.8 [95% CI, 1.8-25.7]; P = .006); urinary catheterization (OR, 5.9 [95% CI, 1.2-30.0]; P = .028) and birth weight (P = .035). We found statistically significant differences in the mean total length of stay in hospital (P = .004) and length of stay in the NICU (P = .002). All 17 cases presented antimicrobial resistance with presence of extended-spectrum beta-lactamase type CTX-M-14. Conclusion: Workplace interventions focused on patient safety need to be reinforced, especially those concerning practices with the potential to increase the extrinsic risk of colonization or infection by extended-spectrum beta-lactamase -producing K. pneumoniae in the NICU, such as the insertion, care and maintenance of central venous catheter, parenteral nutrition and urinary catheterization