EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion‐Almeida type

Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion‐Almeida type (MFDGA). MFDGA‐associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss‐of‐function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss‐of‐function are self‐evident, the mechanisms by which missense variants are disease‐causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss‐of‐function. Only four of 19 assessed missense variants cause EFTUD2 loss‐of‐function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre‐messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory‐based validation of bioinformatic predictions for EFTUD2 missense variants.     

Efficacy of "high-intensity" blue-light and "standard" daylight phototherapy for non-haemolytic hyperbilirubinaemia

We report our clinical experience with phototherapy in 3802 infants; 3629 were exposed to "standard" daylight phototherapy and 173 to "high-intensity" blue-light phototherapy. High-intensity blue-light phototherapy was twice as effective as standard daylight phototherapy in decreasing bilirubin concentrations. No failures occurred with high-intensity phototherapy compared with an overall failure rate of 1.84/1000 with daylight lamps; these cases were transferred to high-intensity phototherapy with prompt response. Rebound after cessation of phototherapy was greater in those exposed to high-intensity blue light with a significantly greater number requiring a second exposure. However, the incidence was still low. No third exposure was required in any infant. Nursing of infants under high-intensity blue light was more difficult and inconvenient as was clinical monitoring. The light also caused more stress on the nursing and medical personnel. However, the infants tolerated both types of phototherapy equally well. High-intensity blue-light phototherapy would seem to be the treatment of choice for infants with rapidly increasing or very high bilirubin levels, as well as in those not responding adequately to daylight phototherapy.     

Effect of interhospital transfer on resource utilization and outcomes at a tertiary care referral center

OBJECTIVE: Mortality and length of stay are two outcome variables commonly used as benchmarks in rating the performance of medical centers. Acceptance of transfer patients has been shown to affect both outcomes and the costs of health care. Our objective was to compare observed and predicted lengths of stay, observed and predicted mortality, and resource consumption between patients directly admitted and those transferred to the intensive care unit (ICU) of a large academic medical center. DESIGN: Observational cohort study. SETTING: Mixed medical/surgical ICU of a university hospital. PATIENTS: A total of 4,569 consecutive patients admitted to a tertiary care ICU from April 1, 1997, to March 30, 2000. INTERVENTIONS: None. MEASUREMENTS: Acute Physiology and Chronic Health Evaluation (APACHE) III score, actual and predicted ICU and hospital lengths of stay, actual and predicted ICU and hospital mortality, and costs per admission. MAIN RESULTS: Crude comparison of directly admitted and transfer patients revealed that transfer patients had significantly higher APACHE III scores (mean, 60.5 vs. 49.7, p < .001), ICU mortality (14% vs. 8%, p < .001), and hospital mortality (22% vs. 14%, p < .001). Transfer patients also had longer ICU lengths of stay (mean, 6.0 vs. 3.8 days, p < .001) and hospital lengths of stay (mean, 20 vs. 15.9 days, p < .001). Stratified by disease severity using the APACHE III model, there was no difference in either ICU or hospital mortality between the two populations. However, in the transfer group with the lowest predicted mortality of 0-20%, ICU and hospital lengths of stay were significantly higher. In crude cost analysis, transfer patients' costs were $9,600 higher per ICU admission compared with nontransfer patients (95% confidence interval, $6,000-$13,400). Risk stratification revealed that the higher per-patient cost was entirely confined to the transfer patients with the lowest predicted mortality. CONCLUSIONS: Patients transferred to a tertiary care ICU are generally more severely ill and consume more resources. However, they have similar adjusted mortality outcomes when compared with directly admitted patients. The difference in resource consumption is mainly attributable to the group of patients in the lowest predicted risk bracket.     

Amygdala and insula volumes prior to illness onset in bipolar disorder: a magnetic resonance imaging study

There are now numerous reports of neuroanatomical abnormalities in people with bipolar disorder. However, it remains unclear whether those abnormalities predate the onset of the illness. In this cross-sectional magnetic resonance imaging study, we assessed 11 young people clinically at ultra-high risk of development of psychosis (UHR), who all developed bipolar I or II disorder by follow-up (median time to onset 328 days - UHR-BP), 11 matched UHR participants, who had no psychiatric diagnosis after at least 12 months of follow-up (UHR-Well) and 11 matched healthy controls (HC). Our main outcome measures were amygdala, hippocampus, insula, lateral ventricular and whole brain volumes. Amygdala and insula volume reductions were more pronounced in the UHR-BP than in the UHR-Well and HC group. Lateral ventricle, whole-brain and hippocampal volumes did not differ between groups. If these findings are confirmed, they suggest that imaging investigations could help to distinguish people who will subsequently develop bipolar disorder from those who will not, at least in symptomatically enriched samples.     

Serum insulin‐like growth factor‐I concentrations in late middle age: no association with birthweight in three UK cohorts

Background: Small body size at birth and during infancy is associated with an increased risk of adult osteoporosis and cardiovascular disease. Fetal programming of the growth hormone–insulin‐like growth factor (GH‐IGF) axis may provide a mechanism for these epidemiological findings. Aims: To determine whether measurements of GH and IGF‐I in late middle age were related to size at birth and in infancy. Methods: Overnight urinary GH excretion and fasting serum IGF‐I were measured in 309 men and 193 women from Hertfordshire (born 1920–1930) for whom birthweight and weight at 1 year were recorded. Serum IGF‐I was measured in men and women from Preston (n = 254, born 1935–1943) and Sheffield (n = 215, born 1939–1940) whose birthweight and other birth measurements were recorded. Results: Urinary GH and serum IGF‐I were not related to birthweight, other measurements at birth, or weight at 1 year. Conclusion: In contrast to previous studies in children or young adults, these data do not support the hypothesis that IGF‐I concentrations are programmed by intra‐uterine events, as assessed by birthweight, in late middle age.     

Selection of an animal model for resurfacing hip arthroplasty

This study was done to determine whether sheep provide a better model of resurfacing hip arthroplasty than dogs. Eighteen sheep were subjected to unilateral resurfacing arthroplasty. Fifty-eight percent developed femoral loosening by 10 months. This reflects the clinical situation in humans: loosening has been the leading cause of failure. By contrast, reports of experiments with dogs describe very low loosening rates. Sheep provide a more stringent test of hip arthroplasty than dogs. The critical difference appears to be activity level. Sheep allowed free activity on a farm more closely simulate the situation of active patients than do dogs housed in small enclosures in conventional research facilities. New techniques of prosthetic hip arthroplasty that lend themselves to animal models should be studied in sheep before being studied in humans.