Age-Stratified Propofol Dosage for Pediatric Procedural Sedation and Analgesia.

BACKGROUND: Procedural sedation and analgesia (PSA) for diagnostic and minimally invasive therapeutic procedures has become common practice in children of all ages. Based on our clinical experience, we suspected an inverse relation between age and dosage. However, a schedule for age-stratified propofol induction and maintenance dosage for PSA was not available and could be helpful to many anesthesiologists as a reference. METHODS: We performed a retrospective cohort study of children who received procedural sedation at the Wilhelmina Children's Hospital (WKZ), a tertiary pediatric hospital part of the University Medical Center Utrecht (UMCU), between June 2007 and December 2020. We studied whether the induction (mg·kg -1 ) and maintenance (mg·kg -1 ·h -1 ) dosage is age-dependent using linear regression models. RESULTS: A total of 6438 pediatric procedures were retrieved from Anesthesia Information Management Systems (AIMS). A total of 5567 records were available for induction dose analysis and 5420 records for analysis of the maintenance dose. After adjustment for sex, American Society of Anesthesiologists (ASA) physical status classification, opioid administration, and diagnostic or interventional, we obtained a coefficient of -0.11 (95% confidence interval [CI], -0.12 to -0.11) for age (years) from a multivariable linear regression model for propofol induction dosage (mg·kg -1 ) and a coefficient of -0.36 (95% CI, -0.39 to -0.34) for age (years) for propofol maintenance dosage. CONCLUSIONS: We found a noteworthy inverse age-effect on propofol dosage for both induction and maintenance of pediatric procedural sedation. Furthermore, our study revealed that remarkably higher propofol sedation doses were needed for infants and toddlers than previously expected and reported.

Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial.

BACKGROUND: Intravenous saline is recommended in clinical practice guidelines as the cornerstone for preventing contrast-induced nephropathy in patients with compromised renal function. However, clinical-effectiveness and cost-effectiveness of this prophylactic hydration treatment in protecting renal function has not been adequately studied in the population targeted by the guidelines, against a group receiving no prophylaxis. This was the aim of the AMACING trial. METHODS: AMACING is a prospective, randomised, phase 3, parallel-group, open-label, non-inferiority trial of patients at risk of contrast-induced nephropathy according to current guidelines. High-risk patients (with an estimated glomerular filtration rate [eGFR] of 30-59 mL per min/1·73 m2) aged 18 years and older, undergoing an elective procedure requiring iodinated contrast material administration at Maastricht University Medical Centre, the Netherlands, were randomly assigned (1:1) to receive intravenous 0·9% NaCl or no prophylaxis. We excluded patients with eGFR lower than 30 mL per min/1·73 m2, previous dialysis, or no referral for intravenous hydration. Randomisation was stratified by predefined risk factors. The primary outcome was incidence of contrast-induced nephropathy, defined as an increase in serum creatinine from baseline of more than 25% or 44 µmol/L within 2-6 days of contrast exposure, and cost-effectiveness of no prophylaxis compared with intravenous hydration in the prevention of contrast-induced nephropathy. We measured serum creatinine immediately before, 2-6 days, and 26-35 days after contrast-material exposure. Laboratory personnel were masked to treatment allocation. Adverse events and use of resources were systematically recorded. The non-inferiority margin was set at 2·1%. Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT02106234. FINDINGS: Between June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n=332) or intravenous hydration (n=328). 2-6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2·6%) of 307 non-hydrated patients and in eight (2·7%) of 296 hydrated patients. The absolute difference (no hydration vs hydration) was -0·10% (one-sided 95% CI -2·25 to 2·06; one-tailed p=0·4710). No hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5·5%) of 328 patients had complications associated with intravenous hydration. INTERPRETATION: We found no prophylaxis to be non-inferior and cost-saving in preventing contrast-induced nephropathy compared with intravenous hydration according to current clinical practice guidelines. FUNDING: Stichting de Weijerhorst.

Rising HIV-1 viral load set point at a population level coincides with a fading impact of host genetic factors on HIV-1 control.

OBJECTIVE: Heterozygosity for a 32 base pair deletion in the CCR5 gene (CCR5wt/Δ32) and the minor alleles of a single-nucleotide polymorphism in the HCP5 gene (rs2395029) and in the HLA-C gene region (-35HLA-C; rs9264942) has been associated with a lower viral load set point. Recent studies have shown that over calendar time, viral load set point has significantly increased at a population level. Here we studied whether this increase coincides with a fading impact of above-mentioned host genetic markers on HIV-1 control. METHODS: We compared the association between viral load set point and HCP5 rs2395029, -35HLA-C rs9264942, and the CCR5wt/Δ32 genotype in HIV-1-infected individuals in the Netherlands who had seroconverted between 1982 and 2002 (pre-2003 seroconverters, n = 459) or between 2003 and 2009 (post-2003 seroconverters, n = 231). RESULTS: Viral load set point in post-2003 seroconverters was significantly higher than in pre-2003 seroconverters (P = 4.5 × 10(-5)). The minor alleles for HCP5 rs2395029, -35HLA-C rs9264942 and CCR5wt/Δ32 had a similar prevalence in both groups and were all individually associated with a significantly lower viral load set point in pre-2003 seroconverters. In post-2003 seroconverters, this association was no longer observed for HCP5 rs2395029 and CCR5wt/Δ32. The association between viral load set point and HCP5 rs2395029 had significantly changed over time, whereas the change in impact of the CCR5wt/Δ32 genotype over calendar time was not independent from the other markers under study. CONCLUSION: The increased viral load set point at a population level coincides with a lost impact of certain host genetic factors on HIV-1 control.

Intrauterine manipulation does not adversely influence the direction and frequency of endometrial waves.

OBJECTIVE: To investigate whether intrauterine manipulation affects the direction or alters the frequency of endometrial wavelike activity. DESIGN: Prospective observational study. SETTING: University hospital-based fertility clinic. PATIENT(S): Thirty-six patients undergoing intrauterine insemination (IUI). INTERVENTION(S): Ultrasound observation before and after IUI. MAIN OUTCOME MEASURE(S): Endometrial wave type and endometrial wave frequency before and after IUI. RESULT(S): There was no difference in the direction and frequency of endometrial waves before and after IUI in 36 patients. CONCLUSION(S): Although the induction of uterine contractions by intrauterine manipulation has been suggested in the literature, the present study shows no contractions or induction of unfavorable (fundus to cervix) endometrial wavelike activity in 36 patients undergoing IUI.

Complex endometrial wave-patterns in IVF.

OBJECTIVE: To reanalyze ultrasound images from IVF cycles with the aim of developing a refined endometrial wave classification system, which will allow description as well of the more complex endometrial wave patterns. DESIGN: Descriptive study. SETTING: University hospital-based fertility clinic. PATIENT(S): Twenty-four patients undergoing IVF. INTERVENTION(S): Ultrasound examination was performed on the day of hCG administration. MAIN OUTCOME MEASURE(S): Endometrial wave type and intraobserver and interobserver agreement. RESULT(S): Two new wave types were added to the endometrial wave types that were described in the existing wave classification system: recoiling CF waves and a standing wave. Furthermore, an alternation between CF waves and FC waves in the same fragment was described. Calculation of interobserver and intraobserver agreement resulted in a kappa value reflecting strong agreement. CONCLUSION(S): The refined endometrial wave classification system makes it possible to describe the more complex wave types that can be detected in IVF cycles on the day of hCG administration.

Midline intravaginal slingplasty for treatment of urinary stress incontinence: results of an independent audit up to 2 years after surgery.

Recently, the midline intravaginal slingplasty (anterior IVS) directed at reinforcing the pubourethral ligament was introduced for treatment of urinary stress incontinence. An independent telephone interview to evaluate urinary symptoms and surgery-related changes in quality of life was performed between 12 and 32 months after surgery. Of 52 women initially enrolled, 3 were lost during follow-up. None of the patients experienced infection, rejection or erosion of the tape. The procedure failed in 7 patients whereas in 42 patients cure of stress incontinence was achieved. This was not only verified by clinical examination at initial follow-up but also confirmed by the patients at the time of the interview. Although about two-thirds of the patients reported urge incontinence and/or voiding difficulties during their interview, the validation of the surgery was rather high and only in a minority did urinary complaints translate into reduced quality of life.

Endometrial waves in in vitro fertilization cycles: a validation study.

In a prospective validation study we could not confirm that the persistence of endometrial waves from fundus to cervix on the day of hCG administration is associated with a favorable pregnancy prognosis in patients undergoing IVF.

Alternative splicing controls myotonic dystrophy protein kinase structure, enzymatic activity, and subcellular localization.

Transcripts of the myotonic dystrophy protein kinase (DMPK) gene, a member of the Rho kinase family, are subject to cell-type specific alternative splicing. An imbalance in the splice isoform profile of DMPK may play a role in the pathogenesis of DM1, a severe multisystemic disorder. Here, we report how structural subdomains determine biochemical properties and subcellular distribution of DMPK isoforms. A newly developed kinase assay revealed that DMPK is a Lys/Arg-directed kinase. Individual DMPK isoforms displayed comparable transphosphorylation activity and sequence preference for peptide substrates. However, DMPK autophosphorylation and phosphorylation of MYPT1 (as putative in vivo target of DMPK), were dependent on presence of an alternatively spliced VSGGG motif and the nature of the C terminus. In-gel effects of the VSGGG motif on the migration behavior of full-length kinase provide evidence for a model in which this motif mediates 3-D-conformational changes in DMPK isoforms. Finally, different C termini endow DMPK with the ability to bind to either endoplasmic reticulum or mitochondria or to adopt a cytosolic location. Our results suggest that DMPK isoforms have cell-type and location dependent substrate specificities with a role in organellar and cytoarchitectural dynamics.

Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins.

The mechanism of expansion of the (CTG)n repeat in myotonic dystrophy (DM1) patients and the cause of its pathobiological effects are still largely unknown. Most likely, long repeats exert toxicity at the level of nuclear RNA transport or splicing. Here, we analyse cis- and trans-acting parameters that determine repeat behaviour in novel mouse models for DM1. Our mice carry 'humanized' myotonic dystrophy protein kinase (Dmpk) allele(s) with either a (CTG)84 or a (CTG)11 repeat, inserted at the correct position into the endogenous DM locus. Unlike in the human situation, the (CTG)84 repeat in the syntenic mouse environment was relatively stable during intergenerational segregation. However, somatic tissues showed substantial repeat expansions which were progressive upon aging and prominent in kidney, and in stomach and small intestine, where it was cell-type restricted. Other tissues examined showed only marginal size changes. The (CTG)11 allele was completely stable, as anticipated. Introducing the (CTG)84 allele into an Msh3-deficient background completely blocked the somatic repeat instability. In contrast, Msh6 deficiency resulted in a significant increase in the frequency of somatic expansions. Competition of Msh3 and Msh6 for binding to Msh2 in functional complexes with different DNA mismatch-recognition specificity may explain why the somatic (CTG)n expansion rate is differentially affected by ablation of Msh3 and Msh6.

Two HLA DRB 1 alleles confer independent genetic susceptibility to Graves disease: relevance of cross-population studies.

Recent studies of Graves disease (GD) employing genome scanning techniques excluded the major histocompatibility complex as a contributor to disease liability. These findings contradict earlier population association studies. Our own earlier studies have also emphasized that genetic variation in human populations may give novel clues to disease liability and manifestations. To this end, we studied HLA class II alleles in 47 Latvian GD patients and 111 matched healthy controls. As expected, we found that DRB1*03 and DQA1*0501 (OR = 3.6, P = 0.029 and OR 2.35, P = 0.0373, respectively) were associated with GD. Unforeseen, DRB1*04 was found to be significantly increased in the patients compared to controls (OR 3.267, corrected P = 0.0319). The two DRB1 alleles conferred two non-overlapping and independent susceptibilities to GD, in that only three patients were positive for both alleles, and the removal of each allele in turn resulted in only the other DRB1 allele showing significant association with the disease. There was no heterogeneity between the two patient groups (DRB1*03 positive and DRB1*04 positive) in clinical characteristics or disease manifestations. The phenotype DRB1*03 and/or DRB1*04 was found in 34/47 patients compared to 27/111 controls yielding an OR of 7.395 (P corrected = 0.000019). We examined the structural basis of DRB1 susceptibility to GD in light of this and previous studies, showing that DRB1*03, 04, and 08 were positively associated with the disease, whereas DRB1*07 was negatively associated. Differences in protein sequences were noted at residues 54, 57, 59, and 66; positions 54, 57, and 66 are on the same face of the alpha helix. The canonical arginine 54 is replaced by glutamine in DRB1*07. At position 66, asparagine in DRB1*03 and tyrosine in DRB1*04 are replaced by phenylalanine in DRB1*07. Residue 59, likely involved in pocket formation in the antigen binding groove, is modified by replacement of tyrosine in DRB1*03, 08, and 04 and by leucine in DRB1*07. The predicted differences in the shape and charges of the proximal reaches of the antigen binding groove between DRB1*07, and 03, 04, and 08, could determine whether or not a peptide from an auto-antigen would be bound or not. Genetic variation among human populations may yield important clues to specific disease liability.