In June and July 2016, we identified 8 adults and 17 children with respiratory enterovirus D68 infections. Thirteen children required intensive care unit admission because of respiratory ...insufficiency, and 1 had concomitant acute flaccid myelitis. Phylogenetic analysis showed that all of 20 sequences obtained belong to the recently described clade B3.
Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which ...often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps.
For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened.
The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window.
Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted.
Enterovirus D68 - The New Polio? Cassidy, Hayley; Poelman, Randy; Knoester, Marjolein ...
Frontiers in microbiology,
11/2018, Letnik:
9
Journal Article
Recenzirano
Odprti dostop
Enterovirus D68 (EV-D68) has emerged over the recent years, with large outbreaks worldwide. Increased occurrence has coincided with improved clinical awareness and surveillance of non-polio ...enteroviruses. Studies showing its neurotropic nature and the change in pathogenicity have established EV-D68 as a probable cause of Acute Flaccid Myelitis (AFM). The EV-D68 storyline shows many similarities with poliovirus a century ago, stimulating discussion whether EV-D68 could be ascertaining itself as the "new polio." Increasing awareness amongst clinicians, incorporating proper diagnostics and integrating EV-D68 into accessible surveillance systems in a way that promotes data sharing, will be essential to reveal the burden of disease. This will be a necessary step in preventing EV-D68 from becoming a threat to public health.
Obesity is a risk factor for SARS-CoV-2 infected patients to develop respiratory failure. Leptin produced in visceral fat might play a role in the deterioration to mechanical ventilation. A cross ...sectional study was performed. The mean BMI was 31 kg/m2 (range 24.8–48.4) for the 31 SARS-CoV-2 ventilated patients and 26 kg/m2 (range 22.4–33.5) for 8 critically ill non-infected control patients. SARS-CoV-2 infected patients with a similar BMI as control patients appear to have significantly higher levels of serum leptin. The mean leptin level was 21.2 (6.0–85.2) vs 5.6 (2.4–8.2) ug/L for SARS-CoV-2 and controls respectively (p = 0.0007). With these findings we describe a clinical and biological framework that may explain these clinical observations. The ACE2 utilization by the virus leads to local pulmonary inflammation due to ACE2-ATII disbalance. This might be enhanced by an increase in leptin production induced by SARS-CoV-2 infection of visceral fat. Leptin receptors in the lungs are now more activated to enhance local pulmonary inflammation. This adds to the pre-existent chronic inflammation in obese patients. Visceral fat, lung tissue and leptin production play an interconnecting role. This insight can lead the way to further research and treatment.
Microbiology; Virology; Critical Care; Intensive Care Medicine; Respiratory System; SARS-CoV-2; COVID-19; fat; Leptin; ARDS; ACE2.
Abstract
Background
The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death ...in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury.
Methods
This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (
n
= 6) and bacterial sepsis (
n
= 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (
n
= 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3–4 days for bacterial sepsis patients.
Results
We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42,
p
= 0.0002) and bacterial sepsis patients (fold change 0.24,
p
< 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3,
p
= 0.0006, PV-1 fold change 1.5,
p
= 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27,
p
< 0.0001) and bacterial sepsis patients (fold change 0.67,
p
< 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33,
p
= 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09,
p
< 0.0001) suggest decreased microvascular flow in COVID-19.
Conclusions
In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.
Background Guidelines on COVID-19 management are developed as we learn from this pandemic. However, most research has been done on hospitalised patients and the impact of the disease on ...non-hospitalised and their role in transmission are not yet well understood. The COVID HOME study conducts research among COVID-19 patients and their family members who were not hospitalised during acute disease, to guide patient care and inform public health guidelines for infection prevention and control in the community and household. Methods An ongoing prospective longitudinal observational study of COVID-19 outpatients was established in March 2020 at the beginning of the COVID-19 pandemic in the Netherlands. Laboratory confirmed SARS-CoV-2 infected individuals of all ages that did not merit hospitalisation, and their household (HH) members, were enrolled after written informed consent. Enrolled participants were visited at home within 48 hours after initial diagnosis, and then weekly on days 7, 14 and 21 to obtain clinical data, a blood sample for biochemical parameters/cytokines and serological determination; and a nasopharyngeal/throat swab plus urine, stool and sperm or vaginal secretion (if consenting) to test for SARS-CoV-2 by RT-PCR (viral shedding) and for viral culturing. Weekly nasopharyngeal/throat swabs and stool samples, plus a blood sample on days 0 and 21 were also taken from HH members to determine whether and when they became infected. All participants were invited to continue follow-up at 3-, 6-, 12- and 18-months post-infection to assess long-term sequelae and immunological status.
Background: Acyclovir and valacyclovir are used for the treatment and prophylaxis of infections with herpes simplex virus (HSV) and varicella zoster virus (VZV). The aim of this study is to provide ...insight into the pharmacodynamics (PD) of (val)acyclovir. Methods: Patients were retrospectively selected, based on therapeutic drug monitoring for acyclovir, to create a population pharmacokinetic (PK) model in Pmetrics. This PK model was used to develop a PK/PD model to study the effect of acyclovir levels on VZV viral load in plasma in immunocompromised patients. Results: Immunocompromised patients with known VZV viral loads in plasma were included for PK/PD modelling (N = 4, with 23 measure points); they were part of the population of 43 patients used for PK model building. The PK/PD model described the data well (r2 = 0.83). This is a hopeful first step in clarifying the pharmacodynamics of acyclovir; however, the data in this study are limited. Conclusions: Our preliminary PK/PD model can be used in further research to determine the effect of acyclovir levels on VZV viral load.
To investigate cognitive development of singletons conceived by intracytoplasmic sperm injection (ICSI) at 5-8 years of age.
Follow-up study.
University medical center, assessments between March 2004 ...and May 2005.
Singletons born between June 1996 and December 1999 after ICSI at the Leiden University Medical Center were compared with matched singletons born after IVF and natural conception (NC).
Mode of conception.
Intelligence quotient (IQ) was measured with the Revised Amsterdam Child Intelligence Test (short form). The investigators were blinded to conception mode.
Singletons conceived by ICSI (n = 83) achieved lower IQ scores than IVF singletons (n = 83) (adjusted mean difference IQ: 3.6 95% confidence interval (CI) -0.8, 8.0). After categorizing IQ outcomes (<85, 85-115, >115), no significant difference in the distribution of IQ was found. Singletons conceived by ICSI (n = 86) achieved lower IQ scores than NC singletons (n = 85); the adjusted mean difference varied between 5 and 7 points (5.6 95% CI 0.9, 10.3; 7.1 95% CI 1.7, 12.5) depending on the covariates included in the model. Adjustment for prematurity did not change the results. Percentages in IQ categories <85, 85-115, and >115 were 12%, 64%, and 24% for ICSI and 6%, 54%, and 40% for NC, respectively.
In the relatively limited sample investigated, cognitive development among ICSI singletons was lower than among IVF and NC singletons. Infertility factors or unmeasured confounders may play a role.
To evaluate short- and long-term health in intracytoplasmic sperm injection (ICSI) singletons.
Follow-up study.
University medical center, assessments between March 2004 and May 2005.
Singletons born ...between June 1996 and December 1999 after ICSI in the Leiden University Medical Center laboratory were compared with matched singletons born after IVF and natural conception.
Mode of conception.
An examiner blinded to the conception mode of the child assessed congenital malformations and growth. Information on pregnancy, perinatal period, birth defects, general health, and medical consumption was obtained through questionnaires.
Outcomes of children conceived by ICSI and IVF (n = 81/81, preterm infants excluded) were comparable or even more positive for ICSI. Perinatal outcomes were poorer after ICSI than natural conception: prematurity: P=.014; low birth weight: odds ratio = 7.4, 95% confidence interval (CI) 0.9; 62.5; mean birth weight: Delta = 186 g, 95% CI 21; 351. The ICSI mothers had more pregnancy complications (n = 33 vs. 18) and in-hospital deliveries (prevalence ratio 1.36, 95% CI 1.17; 1.48). No further differences were found between ICSI and natural conception children on congenital malformations, health, growth, and medical consumption (n = 87/85, preterm infants included).
No adverse health outcomes were identified in ICSI singletons up to age 5-8 years compared to IVF and natural conception singletons, besides poorer perinatal outcomes after ICSI versus natural conception.
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