Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150?IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350?IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P?=?.02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350?IU/mL and those who started at CMV >350?IU/mL (44% versus 57%; P?=?.42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P?=?.001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P?=?.02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P?<.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150?IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350?IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.     

Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation

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Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells

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Persistent reduction in sialylation of cerebral glycoproteins following postnatal inflammatory exposure

Background

The extension of sepsis encompassing the preterm newborn’s brain is often overlooked due to technical challenges in this highly vulnerable population, yet it leads to substantial long-term neurodevelopmental disabilities. In this study, we demonstrate how neonatal neuroinflammation following postnatal E. coli lipopolysaccharide (LPS) exposure in rat pups results in persistent reduction in sialylation of cerebral glycoproteins.

Methods

Male Sprague-Dawley rat pups at postnatal day 3 (P3) were injected in the corpus callosum with saline or LPS. Twenty-four hours (P4) or 21?days (P24) following injection, brains were extracted and analyzed for neuraminidase activity and expression as well as for sialylation of cerebral glycoproteins and glycolipids.

Results

At both P4 and P24, we detected a significant increase of the acidic neuraminidase activity in LPS-exposed rats. It correlated with significantly increased neuraminidase 1 (Neu1) mRNA in LPS-treated brains at P4 and with neuraminidases 1 and 4 at P24 suggesting that these enzymes were responsible for the rise of neuraminidase activity. At both P4 and P24, sialylation of N-glycans on brain glycoproteins decreased according to both mass-spectrometry analysis and lectin blotting, but the ganglioside composition remained intact. Finally, at P24, analysis of brain tissues by immunohistochemistry showed that neurons in the upper layers (II–III) of somatosensory cortex had a reduced surface content of polysialic acid.

Conclusions

Together, our data demonstrate that neonatal LPS exposure results in specific and sustained induction of Neu1 and Neu4, causing long-lasting negative changes in sialylation of glycoproteins on brain cells. Considering the important roles played by sialoglycoproteins in CNS function, we speculate that observed re-programming of the brain sialome constitutes an important part of pathophysiological consequences in perinatal infectious exposure.

     

Defining electronic-prescribing and infusion-related medication errors in paediatric intensive care – a Delphi study

Background

The use of health information technology (HIT) to improve patient safety is widely advocated by governmental and safety agencies. Electronic-prescribing and smart-pump technology are examples of HIT medication error reduction strategies. The introduction of new errors on HIT implementation is, however, also recognised. To determine the impact of HIT interventions, clear medication error definitions are required. This study aims to achieve consensus on defining as medication errors a range of either technology-generated, or previously unaddressed infusion-related scenarios, common in the paediatric intensive care setting.

Methods

This study was conducted in a 23-bed paediatric intensive care unit (PICU) of an Irish tertiary paediatric hospital. A modified Delphi technique was employed: previously undefined medication-incidents were identified by retrospective review of voluntary incident reports and clinical pharmacist interventions; a multidisciplinary expert panel scored each incident using a 9-point Likert scale over a number of iterative rounds; levels of agreement were assessed to produce a list of medication errors. Differences in scoring between healthcare professionals were assessed.

Results

Seventeen potential errors or ‘scenarios’ requiring consensus were identified, 13 of which related to technology recently implemented into the PICU. These were presented to a panel of 37 participants, comprising of doctors, nurses and pharmacists. Consensus was reached to define as errors all reported smart-pump scenarios (n =?6) and those pertaining to the pre-electronic process of prescribing weight-based paediatric infusions (n =?4). Of 7 electronic-prescribing scenarios, 4 were defined as errors, 2 were deemed not to be and consensus could not be achieved for the last. Some differences in scoring between healthcare professionals were found, but were only significant (p <?0.05) for two and three scenarios in consensus rounds 1 and 2 respectively.

Conclusion

The list of medication errors produced using the Delphi technique highlights the diversity of previously undefined medication errors in PICU. The increased complexity of electronic-prescribing processes is evident from the difficulty in achieving consensus on those scenarios. Reducing ambiguity in defining medication errors should assist future research on the impact of HIT medication safety initiatives in critical care. The increasing use of HIT and associated new errors will necessitate further similar studies.