Current fluconazole treatment regimens result in under-dosing of critically ill adults during early therapy

European Journal of Clinical Microbiology & Infectious Diseases - To evaluate current fluconazole treatment regimens in critically ill adults over the typical treatment course. Data from...     

Disability after encephalitis: development and validation of a new outcome score

Objective

To develop a simple tool for assessing the severity of disability resulting from Japanese encephalitis and whether, as a result, a child is likely to be dependent.

Methods

A new outcome score based on a 15-item questionnaire was developed after a literature review, examination of current assessment tools, discussion with experts and a pilot study. The score was used to evaluate 100 children in Malaysia (56 Japanese encephalitis patients, 2 patients with encephalitis of unknown etiology and 42 controls) and 95 in India (36 Japanese encephalitis patients, 41 patients with encephalitis of unknown etiology and 18 controls). Inter- and intra-observer variability in the outcome score was determined and the score was compared with full clinical assessment.

Findings

There was good inter-observer agreement on using the new score to identify likely dependency (Κ = 0.942 for Malaysian children; Κ = 0.786 for Indian children) and good intra-observer agreement (Κ = 1.000 and 0.902, respectively). In addition, agreement between the new score and clinical assessment was also good (Κ = 0.906 and 0.762, respectively). The sensitivity and specificity of the new score for identifying children likely to be dependent were 100% and 98.4% in Malaysia and 100% and 93.8% in India. Positive and negative predictive values were 84.2% and 100% in Malaysia and 65.6% and 100% in India.

Conclusion

The new tool for assessing disability in children after Japanese encephalitis was simple to use and scores correlated well with clinical assessment.     

The Fetus with Ganglionic Eminence Abnormality: Head Size and Extracranial Sonographic Findings Predict Genetic Diagnoses and Postnatal Outcomes

BACKGROUND AND PURPOSE:Ganglionic eminence abnormalities on fetal MR imaging are associated with cerebral malformations. Their presumed genetic basis and associated postnatal outcomes remain largely unknown. We aimed to elucidate these through a multicenter study.MATERIALS AND METHODS:Between January 2010 and June 2020, seven hospitals in 2 countries performing fetal MR imaging examinations identified fetal MR imaging studies demonstrating ganglionic eminence enlargement, cavitation, or both. Cases with no genetic diagnosis, no whole exome sequencing, or no outcome of a liveborn child were excluded. Head size was classified as large (fronto-occipital diameter > 95th centile), small (fronto-occipital diameter <5th centile), or normal.RESULTS:Twenty-two fetuses with ganglionic eminence abnormalities were identified. Of 8 with large heads, 2 were diagnosed with MTOR mutations; 1 with PIK3CA mutation–producing megalencephaly, polymicrogyria, polydactyly, hydrocephalus (MPPH) syndrome; 3 with TSC mutations; 1 with megalencephaly capillary malformation syndrome; and 1 with hemimegalencephaly. Cardiac rhabdomyoma was present prenatally in all cases of TSC; mutation postaxial polydactyly accompanied megalencephaly capillary malformation and MPPH. Of 12 fetuses with small heads, 7 had TUBA1A mutations, 1 had a TUBB3 mutation, 2 had cobblestone lissencephaly postnatally with no genetic diagnosis, 1 had a PDHA1 mutation, and 1 had a fetal akinesia dyskinesia sequence with no pathogenic mutation on trio whole exome sequencing. One of the fetuses with a normal head size had an OPHN1 mutation with postnatal febrile seizures, and the other had peri-Sylvian polymicrogyria, seizures, and severe developmental delay but no explanatory mutation on whole exome sequencing.CONCLUSIONS:Fetal head size and extracranial prenatal sonographic findings can refine the phenotype and facilitate genetic diagnosis when ganglionic eminence abnormality is diagnosed with MR imaging.

The human ganglionic eminence (GE) is a focal thickening in the proliferative neuroepithelium lining the ventricles of the telencephalic lobes, situated inferolateral to the frontal horns of the lateral ventricles, and persists throughout nearly all of fetal life, longer than other proliferative areas.^1,2 It is thickest at 20 weeks, decreases in size by approximately 50% between 26 and 28 weeks'' gestation, and involutes by 34–36 weeks'' gestation; this period of rapid involution of the GE through fibrinolysis has been theorized as a contributing factor to the selective vulnerability of preterm neonates to hemorrhage in this region.² Most cortical GABAergic interneurons are generated in the GE, and they migrate to the cortex by first tangential and then radial migration. The GE also contributes to a population of thalamic neurons and is responsible for forming most of the basal ganglia. Furthermore, the GE represents an intermediate target for thalamocortical and corticothalamic axons and is a source of oligodendrocyte precursors.^1-3Abnormal persistence, enlargement, and cavitation of GEs on fetal MR imaging have been associated with markedly reduced fetal head size and underdevelopment of sulcation (microlissencephaly),⁴ as well as a range of other brain malformations, including mild partial callosal agenesis, vermis hypoplasia and rotation, cerebellar hypoplasia, ventriculomegaly, enlarged subarachnoid spaces, and molar tooth malformation.⁵Although the normal GE is demonstrable with sonography using an endovaginal 3D technique between 9 and 13 weeks'' gestation,⁶ the pathologic GE has been identified at or after the midtrimester only recently in isolated case reports,^7,8 without postnatal outcome or genetic diagnosis. Coexistence of GE abnormalities with other brain malformations of the corpus callosum, cerebellum, or microcephaly may be the impetus for fetal MR imaging in which the GE abnormality is first recognized.A very recent report⁹ on a large cohort of fetuses with GE alterations at MR imaging highlighted the more frequently associated brain anomalies. However, the authors themselves stressed that a scarcity of knowledge on the genetic substrate of such GE anomalies is the major drawback for the correct characterization and understanding of the pathophysiology. We have also noted an association of fetal GE abnormalities with extremely large and small head sizes.Better understanding of the intracranial and extracranial associations of this abnormality, its genetic causes, and postnatal outcomes for liveborn children is pivotal for the following reasons:

1. Genetic diagnosis requires accurate fetal phenotyping; lack thereof is one of the greatest barriers to the use of prenatal whole genome and exome sequencing.^10,11
2. Given the current lack of wide availability of fetal exome and genome sequencing during pregnancy, an understanding of the causes of GE abnormalities would facilitate prenatal counseling and decision-making within a clinically realistic timeframe.

We hypothesized that a multi-institutional study of prenatal sonographic findings, genetic analyses, and postnatal outcomes of fetuses with prenatal MR imaging showing an abnormality of the GE would enable us to do the following:

1. Establish the genetic abnormalities most often associated with GE abnormalities
2. Narrow the range of differential diagnoses for a given fetus by categorization based on cranial biometry and specific extracranial structural abnormalities
3. Develop a less biased picture of the relative likelihood of various genetic causes for the GE abnormalities by involving multiple subspecialist fetal MRI centers in case identification.

     

The cholesterol-raising effect of coffee in the Syrian hamster.

Adult male Syrian hamsters were fed on a high-fat diet with or without access to boiled coffee. Plasma total, low-density-lipoprotein- and high-density-lipoprotein-cholesterol and triacylglycerol concentrations were increased by the coffee and very-low-density-lipoprotein-cholesterol concentrations were lowered. It is concluded that the Syrian hamster is a suitable animal model in which to study the hypercholesterolaemic effect of coffee.     

Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core‐rod myopathy and in distal myopathies. In this update, we present the disease‐causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM‐related myopathies. Eighty‐eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server ( http://evs.gs.washington.edu/EVS/ ), identifying that pathogenic variants are a minor fraction of all coding variants (～7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB‐associated disease.