After the first phase of the COVID-19 pandemic in Europe, a new highly pathogenic variant of echovirus 11 (E11) was detected. The aim of this study was to analyze the genetic diversity of Polish E11 environmental and clinical strains circulating between 2017 and 2023 as well as compare them with E11 strains isolated from severe neonatal sepsis cases reported in Europe between 2022 and 2023. Additionally, the study explores the effectiveness of environmental monitoring in tracking the spread of new variants. For this purpose, the complete sequences of the VP1 capsid protein gene were determined for 266 E11 strains isolated in Poland from 2017 to 2023, and phylogenetic analysis was performed. In the years 2017-2023, a significant increase in the detection of E11 strains was observed in both environmental and clinical samples in Poland. The Polish E11 strains represented three different genotypes, C3, D5 and E, and were characterized by a high diversity. In Poland, the intensive circulation of the new variant E11, responsible for severe neonatal infections with a high mortality in Europe, was detected in the years 2022-2023. This investigation demonstrates the important role of environmental surveillance in the tracking of enteroviruses circulation, especially in settings with limited clinical surveillance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world\'s population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders.

Aminoacyl-tRNA synthetases play a pivotal role in catalyzing the precise coupling of amino acids with their corresponding tRNAs. Among them, Tyrosyl tRNA synthetase, encoded by the YARS1 gene, facilitates the aminoacylation of tyrosine to its designated tRNA. Heterozygous variants in the YARS1 gene have been linked to autosomal dominant Charcot-Marie-Tooth type C, while recent findings have unveiled biallelic YARS1 variants leading to an autosomal recessive multisystemic disorder in several cases. In this report, we present a novel case characterized by dysmorphic facies, and multisystemic symptoms, prominently encompassing neurological issues and a microarray conducted shortly after birth revealed 47, XXY. Utilizing whole exome sequencing, we uncovered a paternally inherited likely pathogenic variant (c.1099C > T, p.Arg367Trp), previously reported, coinciding with the father\'s history of hearing loss and neurological symptoms. Additionally, a maternally inherited variant of uncertain significance (c.782T > G, p.Leu261Arg), previously unreported, was identified within the YARS1 gene. The observed phenotypes and the presence of compound heterozygous results align with the diagnosis of an autosomal recessive disorder associated with YARS1. Through our cases, the boundaries of this emerging clinical entity are broadened. This instance underscores the significance of comprehensive genetic testing in patients exhibiting intricate phenotypes.

UNASSIGNED: Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer. The main objective of this study is to describe the natural history of DC through a cohort of patients diagnosed in childhood and followed up for a long period of time.
UNASSIGNED: Multicenter, retrospective, longitudinal study conducted in patients followed up to 24 years since being diagnosed in childhood (between 1998 and 2020).
UNASSIGNED: Fourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis, and nine developed mucocutaneous manifestations during the first decade of life. Seven presented severe DC variants. All developed non-hematologic manifestations during follow-up. Mutations were identified in 12 patients. Thirteen progressed to bone marrow failure at a median age of 8 years [range, 3-18 years], and eight received a hematopoietic stem cell transplant. Median follow-up time was 9 years [range, 2-24 years]. Six patients died, the median age was 13 years [range, 6-24 years]. As of November 2022, eight patients were still alive, with a median age of 18 years [range, 6-32 years]. None of them have developed myeloblastic syndrome or cancer.
UNASSIGNED: DC was associated with high morbidity and mortality in our series. Hematologic manifestations appeared early and consistently. Non-hematologic manifestations developed progressively. No patient developed cancer possibly due to their young age. Due to the complexity of the disease multidisciplinary follow-up and adequate transition to adult care are essential.

Hypokinetic and hyperkinetic movement disorders are a common phenotypic feature of mitochondrial disorders. Choreaballism has been reported particularly in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome and in maternally inherited diabetes and deafness syndrome. The pathophysiological basis of movement disorders in mitochondrial disorders is the involvement of the basal ganglia or the midbrain. Haloperidol and mitochondrial cocktails have proven beneficial in some of these cases. Here we present another patient with mitochondrial choreaballism who benefited significantly from symptomatic therapy. The patient is a 14-year-old male with a history of hypoacusis, ptosis, and focal tonic-clonic seizures of the upper/lower limbs on either side since childhood. Since this time he has also developed occasional, abnormal involuntary limb movements, choreaballism, facial grimacing, carpopedal spasms, and abnormal lip sensations. He was diagnosed with a non-syndromic mitochondrial disorder after detection of the variant m.15043G > A in MT-CYB. Seizures have been successfully treated with lamotrigine. Hypocalcemia was treated with intravenous calcium. For hypoparathyroidism calcitriol was given. Choreaballism was treated with haloperidol and tetrabenazine. In addition, he received coenzyme Q10, L-carnitine, thiamine, riboflavin, alpha-lipoic acid, biotin, vitamin-C, vitamin-E, and creatine-monohydrate. With this therapy, the choreaballism disappeared completely. This case shows that mitochondrial disorders can manifest with cognitive impairment, seizures, movement disorder, hypoacusis, endocrinopathy, cardiomyopathy, neuropathy, and myopathy, that choreaballism can be a phenotypic feature of multisystem mitochondrial disorders, and that choreaballism favorably responds to haloperidol, tetrabenazine, and possibly to a cocktail of antioxidants, cofactors, and vitamins.

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Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a genodermatosis with autosomal dominant inheritance caused by mutations in FAM111B. We report another case with a new pathogenic variant and analyze all previously published 34 cases with a focus on sequence of clinical presentation and genotype-phenotype correlation. POIKTMP is characterized by marked age-dependent clinical expressivity. FAM111B encodes a catalytic nuclear protein, expressed in many tissues, which contributes to impaired DNA repair affecting multiple systems. Specific inhibition of catalytic activity might be a future strategy to halt progression of this otherwise untreatable disease. Given the relentless progression of the disease, it would make sense to start such treatment as early as possible. In order to achieve this objective, children with suspected POIKTMP should therefore undergo early imaging of all relevant organ systems.

This study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint.
Data from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response.
Within the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement.
Bespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

Langerhans cell histiocytosis (LCH) is a myeloid neoplasm characterized by a clonal proliferation of CD1a+/CD207+ dendritic cells. Although individuals of any age can be affected, the disease is most common in infants younger than 5 years of age, especially males. A wide range of manifestations, from asymptomatic to aggressive, have been described, along with multiorgan involvement. Even though the majority of bone lesions are observed, skin, lymph nodes, brain and lungs can also be involved. The involvement of hematopoietic system, including bone marrow, liver and spleen, is less frequent yet associated with worse prognosis, due to a worse treatment response. Diagnosis of LCH is based on the integration of clinical, laboratory, and radiological data; however, only histopathological examination might confirm it. As far as the spleen involvement is concerned, according to literature, it has been reported in about 15% patients with multisystem involvement, nonetheless only a few cases show parenchymal lesions. The present study reports the case of an infant with LCH with multisystem involvement, including bone, skin, liver, and spleen, with evidence of parenchymal lesions.

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