Κυριακή 29 Μαΐου 2022

Prenatal exposure to phthalate and decreased body mass index of children: a systematic review and meta-analysis

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Carglumic acid in methylmalonic acidemia: Use of breast milk as an alternative vehicle to water

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Carglumic acid in methylmalonic acidemia: Use of breast milk as an alternative vehicle to water

We aim to report the use of breast milk (BM) as an alternative vehicle in a neonate with methylmalonic acidemia rejecting carglumic acid (NCG) diluted in water. The patient presented symptomatic acidemia and hyperammonemia and after refusal of oral NCG administration, the clinician consulted the Pharmacy Department for advice. Data sheet of NCG does not recommend administration in other vehicle than water. Consequently, a dissolution test was conducted in BM showing correct dissolution. The solution was well tolerated, and plasma ammonium concentrations remained within range in subsequent analytical controls.


Abstract

What Is Known and Objective

Carbaglu® or N-carbamylglutamate (NCG) is not recommended for administration in a vehicle other than water. We aim to report the use of breast milk (BM) as an alternative vehicle in a neonate rejecting NCG diluted in water.

Case Summary

A neonate diagnosed with methylmalonic acidemia presented symptomatology of acidemia and hyperammonemia. After the patient refused oral NCG administration, a dissolution test was conducted in BM showing correct dissolution. The NCG-BM solution was tolerated and plasma ammonium concentrations remained within range in subsequent analytical controls.

What Is New and Conclusion

BM as a vehicle for NCG is a safe and effective option for patients who refuse suspension in water and could lead to better treatment compliance in paediatric patients.
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Rapid, simple, and economical LC–MS/MS method for simultaneous determination of ceftazidime and avibactam in human plasma and its application in therapeutic drug monitoring

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Rapid, simple, and economical LC–MS/MS method for simultaneous determination of ceftazidime and avibactam in human plasma and its application in therapeutic drug monitoring

Pharmacokinetics/pharmacodynamics (PK/PD) targets of antibiotics are critical for optimizing their dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. Furthermore, a high heterogeneity is presented in patients that are known to exhibit variations in antimicrobial PK. Therefore, therapeutic drug monitoring of CAZ and AVI to evaluate the PK/PD targets and PK/PD-based dosage adjustment in patients are beneficial for rational use of these drugs. Herein, we developed and validated a simple method for the simultaneous determination of CAZ and AVI in human plasma using LC–MS/MS. Finally, the established and validated method was successfully applied to the determination of CAZ and AVI in plasma for patients. The results showed considerable PK variations in patients, demonstrating the great significance of TDM in the clinic.


Abstract

What is Known and Objective

Carbapenem-resistant Gram-negative bacterial pathogens continue to threaten public health. Avibactam (AVI), a novel non-β-lactam β-lactamase inhibitor, has been approved for use with ceftazidime (CAZ) mainly against carbapenem-resistant Enterobacteriaceae. Therapeutic drug monitoring (TDM) is urgently needed to optimize dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. This study aims to develop and validate a rapid, simple, and economical LC–MS/MS method for simultaneous determination of CAZ/AVI in human plasma.

Methods

Samples were processed by simple protein precipitation, and gradient elution strategy was applied to separate CAZ and AVI on a reverse-phase C18 column; with subsequent detection by the mass spectrometer in a positive and negative ion switching mode. Plasma samples from patients were analysed.

Results and Discussion

A 4-min run of LC–MS/MS was developed. The precision, trueness, matrix effect, extraction recovery, carry-over, dilution integrity, and stability were all acceptable for a bioanalytical method. The method was successfully applied to the determination of CAZ and AVI in patients, and a considerable PK variability of CAZ/AVI was observed among patients.

What is New and Conclusion

A robust, rapid, simple, and economical LC–MS/MS method for the simultaneous determination of CAZ and AVI was developed. The considerable PK variability of CAZ/AVI among patients demonstrates the clinical significance of TDM.
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Molecular basis for avirulence of spontaneous variants of Porphyromonas gingivalis: genomic analysis of strains W50, BE1 and BR1

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Abstract

The periodontal pathogen Porphyromonas gingivalis is genetically heterogeneous. However, the spontaneous generation of phenotypically different sub-strains has also been reported. McKee (McKee et al., 1988) cultured P. gingivalis W50 in a chemostat during investigations into the growth and properties of this bacterium. Cell viability, on blood agar plates, revealed two types of non-pigmenting variants, W50 Beige (BE1) and W50 Brown (BR1) in samples grown in a high haemin medium after day 7 and the population of these variants increased to approximately 25% of the total counts by day 21. W50, BE1 and BR1 had phenotypic alterations in pigmentation, reduced protease activity and haemagglutination, and susceptibility to complement killing. Furthermore, the variants exhibited significant attenuation in a mouse model of virulence. Other investigators showed that in BE1, the predominant extracellular Arg-gingipain was RgpB, and no reaction with an A-LPS specific MAb 1B 5 (Collinson et al., 1998; Slaney et al., 2006). In order to determine the genetic basis for these phenotypic properties we performed hybrid DNA sequence long reads using Oxford Nanopore, and the short paired-end DNA sequence reads of Illumina Hiseq platforms to generate closed circular genomes of the parent and variants. Comparative analysis indicated loss of intact kgp in the 20 kb region of the hagA-kgp locus in the two variants BE1 and BR1. Deletions in hagA led to smaller open reading frames in the variants, and BR1 had incurred a major chromosomal DNA inversion. Additional minor changes to the genomes of both variants were also observed. Given the importance of Kgp and HagA to protease activity and haemagglutination respectively in this bacterium, genomic changes at this locus may account for most of the phenotypic alterations of the variants. The homologous and repetitive nature of hagA and kgp, and the features at the inverted jun ctions are indicative of specific and stable homologous recombination events which may underlie the genetic heterogeneity of this species.

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Subjective Sleep Complaints were Associated with Painful Temporomandibular Disorders in Adolescents: the Epidor‐Adolescere Study

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Abstract

Background

Sleep disturbances in adolescents has received a lot of attention in the literature and it is recognized as a serious health concern. The association between pain and sleep disturbances in adolescents has been extensively studied. However, to the best of our knowledge, there is a lack of studies investigating the association between various subjective sleep variables and painful TMD in adolescents.

Objectives

to investigate the association between painful TMD and subjective sleep variables in adolescents' non-clinical sample. We conducted a cross-sectional study. TMD was classified according to the RDC/TMD criteria. The Revised Face Scale evaluated TMD pain intensity, and pressure pain thresholds (PPTs) were assessed in trigeminal and extra-trigeminal areas. The subjective sleep variables were assessed according to the Sleep Disturbance Scale for Children and Sleep Behavior Questionnaire.

Results

The final sample consisted of 690 adolescents (12.7±0.76 years), with 16.2% of them presenting painful TMD. Adolescents who frequently reported waking up more than twice per night and feeling tired when awake were more likely to present painful TMD symptoms [OR= 1.7 (95% CI: 1.04-2.90); p=0.034 and OR= 1.6 (95% CI: 1.01-2.48); p=0.046, respectively]. The intensity of TMD pain was negatively associated with sleep quality (p=0.015). Also, PPT values in the trigeminal and extra-trigeminal areas were negatively associated with total sleep time (p= 0.048 and p=0.042, respectively).

Conclusions

the present results point out the importance of considering sleep complaints associated with painful TMD in adolescents.
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Plasma trough concentration distribution and safety of high‐dose teicoplanin for patients with augmented renal clearance

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Plasma trough concentration distribution and safety of high-dose teicoplanin for patients with augmented renal clearance

Teicoplanin plasma trough concentration (C min) and probability rates of C min > 10 mg/L in the augmented renal clearance (ARC) and non-ARC groups on the third day of medication (day 3) and during the dose maintenance period. After the HD, plasma samples were collected before the third day of medication. The teicoplanin C min values in the ARC and non-ARC groups were 17.3 ± 9.2 mg/L and 15.5 ± 7.9 mg/L, respectively (p = 0.663) (Figure A). The probability rate of C min > 10 mg/L also did not differ significantly between the two groups (85.7% [6/7] vs. 60.0% [6/10], p = 0.338, Figure C). During the dose maintenance period (3 days after medication), the teicoplanin C min was significantly lower in ARC group than in the non-ARC group (18.3 ± 5.1 mg/L vs. 25.5 ± 11.9 mg/L, p = 0.016, Figure A), while there was no significant difference in the probability rate of C min > 10 mg/L between the two groups (90.0% [9/10] vs. 96.2% [25/26], p = 0.484, Figure C). After the LD, plasma samples were collected before the third day of medication. The teicoplanin C min values in the ARC and non-ARC groups were 6.8 ± 3.9 mg/L and 7.9 ± 3.1 mg/L, respectively (p = 0.585) (Figure B). The probability rate of C min > 10 mg/L did not differ significantly between the two groups (20.0% [1/5] vs. 11.1% [1/9], p = 1.000, Figure D). During the dose maintenance period, the teicoplanin C min values in the ARC and non-ARC groups were 12.2 ± 6.3 mg/L and 13.0 ± 4.6 mg/L, respectively (p = 0.713) (Figure B). The probability rate of C min > 10 mg/L was 61.5% (8/13) in both groups (Figure D). It should be noted that on the third day of medication, the HD group had a significantly higher teicoplanin C min than the LD group for ARC (17.3 ± 9.2 mg/L vs. 6.8 ± 3.9 mg/L, p = 0.039, Figure A and B), but there was no significant intergroup difference in the probability rates of C min > 10 mg/L (85.7% [6/7] vs. 20.0% [1/5], p = 0.072, Figures C and D). During the dose maintenance period, the teicoplanin C min was significantly higher in the HD group than in the LD group for ARC (18.3 ± 5.1 mg/L vs. 12.2 ± 6.3 mg/L, p = 0.022, Figures A and B), while there was no significant intergroup difference in their probability rates of C min > 10 mg/L (90.0% [9/10] vs. 61.5% [8/13], p = 0.179, Figures C and D). Notes: A, HD; B, LD; C, HD; D, LD; *p < 0.05.


Abstract

What Is Known and Objective

There are few reports on the distribution of the plasma trough concentration (C min) of teicoplanin in patients with augmented renal clearance (ARC) and on the safety of a high-dose regimen (HD; 800 mg loading dose for q12h three times followed by an 800 mg qd maintenance dose). The objective of this study was to determine the C min values of teicoplanin in ARC patients using HD teicoplanin to provide a reference for individualized medication.

Methods

Data on patients treated with teicoplanin from January 2019 to January 2021 were collected retrospectively and divided into ARC (creatinine clearance rate [CCr] >130 ml/min, n = 22) and non-ARC (60 ml/min ≤ CCr ≤130 ml/min, n = 24) groups. The C min values in the two patient groups were analysed during the HD and the low-dose regimen (LD; all other regimens) on the third day of medication and during the dose maintenance period. Liver and kidney function indexes were also analysed before and after medication.

Results and Discussions

On the third day of the HD, C min did not differ significantly between the ARC and non-ARC groups (17.3 ± 9.2 mg/L [mean ± SD] vs. 15.5 ± 7.9 mg/L, p = 0.663), while C min in the ARC group was significantly lower for the LD (6.8 ± 3.9 mg/L, p = 0.039). During the dose maintenance period, C min in the ARC group when receiving the HD (18.3 ± 5.1 mg/L) was significantly lower than that in the non-ARC group (25.5 ± 11.9 mg/L, p = 0.016) and significantly higher than that for the LD (12.2 ± 6.3 mg/L, p = 0.022). Nephrotoxicity and hepatotoxicity incidence rates did not differ significantly between these groups.

What Is New and Conclusion

These results suggest that it is necessary to apply a loading dose of 800 mg (but not higher) q12h three times for patients with ARC, with 800 mg needed as a maintenance dose during severe infection, and 600 mg or 400 mg for mild infection.
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Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system for augmented renal clearance prediction in a trauma subgroup of a mixed ICU population

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Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system for augmented renal clearance prediction in a trauma subgroup of a mixed ICU population

(Left) ROC curves for ARC detection in trauma subgroup: comparison between ARCTIC score ROC curve and regression ROC curve. AUC, area under the curve; CI, confidence interval. (Right) ROC curves for ARC detection in medical/surgical subgroup: comparison between ARCTIC score ROC curve and regression ROC curve.


Abstract

What is known and Objective

Augmented renal clearance is prevalent in trauma patients and leads to subtherapeutic levels of renally eliminated medications with potentially unfavourable clinical outcomes. The Augmented Renal Clearance of Trauma in Intensive Care (ARCTIC) score has been developed to predict augmented renal clearance in critically ill trauma patients. Our primary objective was to validate this score among the trauma subgroup of a mixed intensive care patient cohort.

Methods

This single-centre, retrospective, observational cohort study assessed augmented renal clearance using a timed 24-h urine collection performed weekly. ARC was defined as a measured creatinine clearance of ≥130 ml/min/1.73 m2. ARCTIC score performance was evaluated through a receiver operator characteristic curves and analysis of sensitivities and specificities for the trauma subgroup, the medical/surgical subgroup and the pooled cohort.

Results and Discussion

Augmented renal clearance was observed in 33.9% (n = 58) of trauma patients (n = 171) and 15.7% (n = 24) of medical/surgical patients (n = 153). Examination of different cutoffs for the ARCTIC score in our trauma population confirmed that the optimal cutoff score was ≥6. Comparison between ROC curves for ARCTIC score and for regression model based upon our data in trauma patients indicated validation of the score in this subgroup. Comparison of sensitivities and specificities for ARCTIC score between trauma (93.1% and 41.6%, respectively) and medical/surgical subjects (87.5% and 49.6%, respectively) showed no clinical nor statistical difference, suggesting validation for the medical/surgical subgroup as well.

What is new and Conclusion

In our mixed ICU population, the ARCTIC score was validated in the trauma subgroup. We also found that the score performed well in the medical/surgical population. Future studies should assess the performance of the ARCTIC score prospectively.
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