Antimicrobial Therapeutic Drug Monitoring in critically ill adult patients -an international perspective on access, utilisation, and barriers.

BACKGROUND: Therapeutic drug monitoring (TDM) is an effective method for individualizing antimicrobial therapy in critically ill patients. The 2021 ADMIN-ICU survey studied a wide range of intensive care unit (ICU) clinicians worldwide to gain their perspectives on antimicrobial TDM. This paper reports the responses from this survey relating to TDM access, utilisation, barriers, and clinical value. METHODS: An online survey consisted of multiple-choice questions and 5-point Likert scales. The survey examined respondent's access to minimum inhibitory concentration (MIC) results, drug assays and dosing software, as well as barriers to TDM. RESULTS: The survey included 538 clinicians from 409 hospitals in 45 countries, with 71% physicians and 29% pharmacists. Despite most respondents having access to assays, 21% and 26% of respondents lacked access to vancomycin and aminoglycosides, respectively. In lower-income countries, almost 40% reported no access. Delayed drug assay turnaround time was the most significant barrier to TDM, particularly in lower-income countries. Routine access to MIC results was unavailable for 41% of respondents, with 25% of lower-income country respondents having no access to MIC or susceptibility reports. CONCLUSIONS: This global survey indicated that consistent TDM usage is hindered by assay access in some sites, and timeliness of assay results in others. Addressing barriers to TDM, particularly in low-income countries, should be a priority to ensure equitable access to affordable TDM.

Gametocidal genes: from a discovery to the application in wheat breeding.

Some species of the genus Aegilops, a wild relative of wheat, carry chromosomes that after introducing to wheat exhibit preferential transmission to progeny. Their selective retention is a result of the abortion of gametes lacking them due to induced chromosomal aberrations. These chromosomes are termed Gametocidal (Gc) and, based on their effects, they are categorized into three types: mild, intense or severe, and very strong. Gc elements within the same homoeologous chromosome groups of Aegilops (II, III, or IV) demonstrate similar Gc action. This review explores the intriguing dynamics of Gc chromosomes and encompasses comprehensive insights into their source species, behavioral aspects, mode of action, interactions, suppressions, and practical applications of the Gc system in wheat breeding. By delving into these areas, this work aims to contribute to the development of novel plant genetic resources for wheat breeding. The insights provided herein shed light on the utilization of Gc chromosomes to produce chromosomal rearrangements in wheat and its wild relatives, thereby facilitating the generation of chromosome deletions, translocations, and telosomic lines. The Gc approach has significantly advanced various aspects of wheat genetics, including the introgression of novel genes and alleles, molecular markers and gene mapping, and the exploration of homoeologous relationships within Triticeae species. The mystery lies in why gametes possessing Gc genes maintain their normality while those lacking Gc genes suffer abnormalities, highlighting an unresolved research gap necessitating deeper investigation.

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis.

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

A chromosome arm from Thinopyrum intermedium × Thinopyrum ponticum hybrid confers increased tillering and yield potential in wheat.

Tiller number is a key component of wheat plant architecture having a direct impact on grain yield. Because of their viability, biotic resistance, and abiotic stress tolerance, wild relative species are a valuable gene source for increasing wheat genetic diversity, including yield potential. Agropyron glael, a perennial hybrid of Thinopyrum intermedium and Th. ponticum, was created in the 1930s. Recent genome analyses identified five evolutionarily distinct subgenomes (J, Jst, Jvs, Jr, and St), making A. glael an important gene source for transferring useful agronomical traits into wheat. During a bread wheat × A. glael crossing program, a genetically stable translocation line, WT153397, was developed. Sequential in situ hybridizations (McGISH) with J-, St-, and D-genomic DNA probes and pSc119.2, Afa family, pTa71, and (GAA)7 DNA repeats, as well as molecular markers specific for the wheat 6D chromosome, revealed the presence of a 6DS.6Jvs Robertsonian translocation in the genetic line. Field trials in low-input and high-input breeding nurseries over four growing seasons demonstrated the Agropyron chromosome arm's high compensating ability for the missing 6DL, as spike morphology and fertility of WT153397 did not differ significantly from those of wheat parents, Mv9kr1 and 'Mv Karizma.' Moreover, the introgressed 6Jvs chromosome arm significantly increased the number of productive tillers, resulting in a significantly higher grain yield potential compared to the parental wheat cultivars. The translocated chromosome could be highly purified by flow cytometric sorting due to the intense fluorescent labeling of (GAA)7 clusters on the Thinopyrum chromosome arm, providing an opportunity to use chromosome genomics to identify Agropyron gene variant(s) responsible for the tillering capacity. The translocation line WT153397 is an important genetic stock for functional genetic studies of tiller formation and useful breeding material for increasing wheat yield potential. The study also discusses the use of the translocation line in wheat breeding. Supplementary information: The online version contains supplementary material available at 10.1007/s11032-024-01439-y.

Chromosome genomics facilitates the marker development and selection of wheat-Aegilops biuncialis addition, substitution and translocation lines.

The annual goatgrass, Aegilops biuncialis is a rich source of genes with considerable agronomic value. This genetic potential can be exploited for wheat improvement through interspecific hybridization to increase stress resistance, grain quality and adaptability. However, the low throughput of cytogenetic selection hampers the development of alien introgressions. Using the sequence of flow-sorted chromosomes of diploid progenitors, the present study enabled the development of chromosome-specific markers. In total, 482 PCR markers were validated on wheat (Mv9kr1) and Ae. biuncialis (MvGB642) crossing partners, and 126 on wheat-Aegilops additions. Thirty-two markers specific for U- or M-chromosomes were used in combination with GISH and FISH for the screening of 44 Mv9kr1 × Ae. biuncialis BC3F3 genotypes. The predominance of chromosomes 4M and 5M, as well as the presence of chromosomal aberrations, may indicate that these chromosomes have a gametocidal effect. A new wheat-Ae. biuncialis disomic 4U addition, 4M(4D) and 5M(5D) substitutions, as well as several introgression lines were selected. Spike morphology and fertility indicated that the Aegilops 4M or 5M compensated well for the loss of 4D and 5D, respectively. The new cytogenetic stocks represent valuable genetic resources for the introgression of key genes alleles into wheat.

Efficiency of dosing software using Bayesian forecasting in achieving target antibiotic exposures in critically ill patients, a prospective cohort study.

INTRODUCTION: Broad-spectrum antibiotics such as beta-lactams and vancomycin are frequently used to treat critically ill patients, however, a significant number do not achieve target exposures. Therapeutic drug monitoring (TDM) combined with Bayesian forecasting dosing software may improve target attainment in these patients. This study aims to describe the efficiency of dosing software for achieving target exposures of selected beta-lactam antibiotics and vancomycin in critically ill patients. METHODS: A prospective cohort study was undertaken in an adult intensive care unit (ICU). Patients prescribed vancomycin, piperacillin-tazobactam and meropenem were included if they exhibited a subtherapeutic or supratherapeutic exposure informed by TDM. The dosing software, ID-ODS™, was used to generate dosing recommendations which could be either accepted or rejected by the treating team. Repeat antibiotic TDM were requested to determine if target exposures were achieved. RESULTS: Between March 2020 and December 2021, 70 were included in the analysis. Software recommendations were accepted for 56 patients (80%) with 50 having repeated antibiotic measurements. Forty-three of the 50 patients (86%) achieved target exposures after one software recommendation, with 3 of the remaining 7 patients achieving target exposures after 2. Forty-seven patients out of the 50 patients (94%) achieved the secondary outcome of clinical cure. There were no antibiotic exposure-related adverse events reported. CONCLUSION: The use of TDM combined with Bayesian forecasting dosing software increases the efficiency for achieving target antibiotic exposures in the ICU. Clinical trials comparing this approach with other dosing strategies are required to further validate these findings.

International survey of antibiotic dosing and monitoring in adult intensive care units.

BACKGROUND: In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time. METHODS: A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides. RESULTS: A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%). CONCLUSIONS: We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

In silico Evaluation of a Vancomycin Dosing Guideline Among Adults with Serious Infections.

BACKGROUND: This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections. METHODS: In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets. RESULTS: Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001). CONCLUSIONS: A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.

In silico evaluation of a beta-lactam dosing guideline among adults with serious infections.

STUDY OBJECTIVE: The aim of this study was to compare the achievement of therapeutic pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for beta-lactam antibiotics using product information dosing or guideline-based dosing for the treatment of serious infections. DESIGN: In silico study. DATA SOURCE: ID-ODSTM (Individually Designed Optimum Dosing Strategies). PATIENTS AND INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: In silico product information and guideline-based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK-PD targets. A multiple linear regression model was constructed to identify the effect of guideline-based dosing covariates on achieving pre-defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline-based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline-based and product information-based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline-based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA. CONCLUSIONS: Our study demonstrated that achievement of PK-PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline-based dosing; especially at 48 h.

Accuracy of a precision dosing software program for predicting antibiotic concentrations in critically ill patients.

BACKGROUND: Critically ill patients with sepsis are predisposed to physiological changes that can reduce the probability of achieving target antibiotic exposures. Precision dosing software programs may be used to improve probability of obtaining these target exposures. OBJECTIVE: To quantify the accuracy of a precision dosing software program for predicting antibiotic concentrations as well as to assess the impact of using software predictions on actual dosing adjustments. PATIENTS AND METHODS: The software program ID-ODS was used to predict concentrations for piperacillin, meropenem and vancomycin using patient covariate data with and without the use of therapeutic drug monitoring (TDM) data. The impact of these predictions on actual dosage adjustments was determined by using software predicted concentrations versus measured concentrations. RESULTS: Software predictions for piperacillin and meropenem exhibited large bias that improved with the addition of TDM data (bias improved from -28.8 to -2.0 mg/L for piperacillin and -3.0 to -0.1 mg/L for meropenem). Dosing changes using predicted concentrations of piperacillin and meropenem with TDM data versus measured concentrations were matched on 89.2% (107/120) and 71% (9/69) occasions, respectively. Although vancomycin predictions demonstrated good accuracy with and without TDM, these findings were limited by our small sample size. CONCLUSION: These data demonstrate that precision dosing software programs may have scope to reasonably predict antibiotic concentrations in critically ill patients with sepsis. The addition of TDM data improves the predictive performance of the software for all three antibiotics and the ability to anticipate the correct dose change required.

Flow karyotyping of wheat-Aegilops additions facilitate dissecting the genomes of Ae. biuncialis and Ae. geniculata into individual chromosomes.

Breeding of wheat adapted to new climatic conditions and resistant to diseases and pests is hindered by a limited gene pool due to domestication and thousands of years of human selection. Annual goatgrasses (Aegilops spp.) with M and U genomes are potential sources of the missing genes and alleles. Development of alien introgression lines of wheat may be facilitated by the knowledge of DNA sequences of Aegilops chromosomes. As the Aegilops genomes are complex, sequencing relevant Aegilops chromosomes purified by flow cytometric sorting offers an attractive route forward. The present study extends the potential of chromosome genomics to allotetraploid Ae. biuncialis and Ae. geniculata by dissecting their M and U genomes into individual chromosomes. Hybridization of FITC-conjugated GAA oligonucleotide probe to chromosomes suspensions of the two species allowed the application of bivariate flow karyotyping and sorting some individual chromosomes. Bivariate flow karyotype FITC vs. DAPI of Ae. biuncialis consisted of nine chromosome-populations, but their chromosome content determined by microscopic analysis of flow sorted chromosomes indicated that only 7Mb and 1Ub could be sorted at high purity. In the case of Ae. geniculata, fourteen chromosome-populations were discriminated, allowing the separation of nine individual chromosomes (1Mg, 3Mg, 5Mg, 6Mg, 7Mg, 1Ug, 3Ug, 6Ug, and 7Ug) out of the 14. To sort the remaining chromosomes, a partial set of wheat-Ae. biuncialis and a whole set of wheat-Ae. geniculata chromosome addition lines were also flow karyotyped, revealing clear separation of the GAA-rich Aegilops chromosomes from the GAA-poor A- and D-genome chromosomes of wheat. All of the alien chromosomes represented by individual addition lines could be isolated at purities ranging from 74.5% to 96.6% and from 87.8% to 97.7%, respectively. Differences in flow karyotypes between Ae. biuncialis and Ae. geniculata were analyzed and discussed. Chromosome-specific genomic resources will facilitate gene cloning and the development of molecular tools to support alien introgression breeding of wheat.

Transfer of the ph1b Deletion Chromosome 5B From Chinese Spring Wheat Into a Winter Wheat Line and Induction of Chromosome Rearrangements in Wheat-Aegilops biuncialis Hybrids.

Effective utilization of genetic diversity in wild relatives to improve wheat requires recombination between wheat and alien chromosomes. However, this is suppressed by the Pairing homoeologous gene, Ph1, on the long arm of wheat chromosome 5B. A deletion mutant of the Ph1 locus (ph1b) has been used widely to induce homoeologous recombination in wheat × alien hybrids. However, the original ph1b mutation, developed in Chinese Spring (CS) background has poor agronomic performance. Hence, alien introgression lines are first backcrossed with adapted wheat genotypes and after this step, alien chromosome segments are introduced into breeding lines. In this work, the ph1b mutation was transferred from two CSph1b mutants into winter wheat line Mv9kr1. Homozygous genotypes Mv9kr1 ph1b/ph1b exhibited improved plant and spike morphology compared to Chinese Spring. Flow cytometric chromosome analysis confirmed reduced DNA content of the mutant 5B chromosome in both wheat genotype relative to the wild type chromosome. The ph1b mutation in the Mv9kr1 genotype allowed wheat-alien chromosome pairing in meiosis of Mv9kr1ph1b_K × Aegilops biuncialis F1 hybrids, predominantly with the Mb-genome chromosomes of Aegilops relative to those of the Ub genome. High frequency of wheat-Aegilops chromosome interactions resulted in rearranged chromosomes identified in the new Mv9kr1ph1b × Ae. Biuncialis amphiploids, making these lines valuable sources for alien introgressions. The new Mv9kr1ph1b mutant genotype is a unique resource to support alien introgression breeding of hexaploid wheat.

Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation.

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.

Identification of New QTLs for Dietary Fiber Content in Aegilops biuncialis.

Grain dietary fiber content is an important health-promoting trait of bread wheat. A dominant dietary fiber component of wheat is the cell wall polysaccharide arabinoxylan and the goatgrass Aegilops biuncialis has high ß-glucan content, which makes it an attractive gene source to develop wheat lines with modified fiber composition. In order to support introgression breeding, this work examined genetic variability in grain ß-glucan, pentosan, and protein content in a collection of Ae. biuncialis. A large variation in grain protein and edible fiber content was revealed, reflecting the origin of Ae. biuncialis accessions from different eco-geographical habitats. Association analysis using DArTseq-derived SNPs identified 34 QTLs associated with ß-glucan, pentosan, water-extractable pentosan, and protein content. Mapping the markers to draft chromosome assemblies of diploid progenitors of Ae. biuncialis underlined the role of genes on chromosomes 1Mb, 4Mb, and 5Mb in the formation of grain ß-glucan content, while other QTLs on chromosome groups 3, 6, and 1 identified genes responsible for total- and water-extractable pentosan content. Functional annotation of the associated marker sequences identified fourteen genes, nine of which were identified in other monocots. The QTLs and genes identified in the present work are attractive targets for chromosome-mediated gene transfer to improve the health-promoting properties of wheat-derived foods.

Analysis of the factors influencing the delay times of patients with ST-elevation myocardial infarction / Az ST-elevációval járó myocardialis infarktuson átesett betegek késési idejét befolyásoló tényezok vizsgálata.

Összefoglaló. Bevezetés: Myocardialis infarktus esetén a panasz kezdetétol az ér megnyitásáig eltelt ido prognosztikus jelentoségu, a legtöbb szívizom megmentésére az elso órákban van lehetoség. A Nemzeti Szívinfarktus Regiszter alapján tudjuk, hogy hazánkban a teljes ischaemiás ido kedvezotlenül hosszú. Célkituzés: Az ST-elevációval járó myocardialis infarktusos betegek késési idejét befolyásoló tényezok azonosítása. Módszer: Prospektív klinikai vizsgálatot végeztünk, melynek során a Szegedi Tudományegyetemen a II. Belgyógyászati Klinika és Kardiológiai Központ Invazív Kardiológiai Részlegére érkezett STEMI-s betegek adatait gyujtöttük saját kérdoív alapján. Az adatgyujtés 2019. 01. 01. és 2019. 12. 20. között zajlott, 121 beteg adatait dolgoztuk fel. Eredmények: A medián bejelentési ido 83 perc, a medián prehospitális ido 252 perc, a medián teljes ischaemiás ido 304 perc volt. Az Országos Mentoszolgálat (OMSZ) értesítésekor minden késési ido szignifikánsan rövidebb volt, a Sürgosségi Betegellátó Osztály (SBO) vagy a háziorvos értesítéséhez viszonyítva (a teljes ischaemiás ido mediánja: OMSZ: 233 perc, SBO: 341 perc, háziorvos: 650 perc). A betegek lakhelye szignifikánsan befolyásolta a késési idoket és a választott betegutat: a bejelentési ido mediánja városban 60 perc, faluban 147 perc volt; az OMSZ-t értesítette a városi betegek 50%-a, a falusi betegek 25%-a. A közös segélyhívó szám ismerete szignifikánsan rövidítette a betegúthoz tartozó késési idot (a betegútkésés medián ideje, ha a segélyhívó számot ismerte: 178 perc, ha nem ismerte: 268 perc). Következtetés: A késési idok rendkívül hosszúak voltak. A legszorosabb összefüggést a késési idokkel a választott betegút mutatta. A városi emberek elobb jelezték panaszaikat, és gyakrabban választották a megfelelo betegutat, az OMSZ-t, így késési idejük is rövidebb volt. Eredményeink felhívják a figyelmet a társadalom edukációjának fontosságára, különös tekintettel a kis települések lakóira. Orv Hetil. 2022; 163(11): 438-445. INTRODUCTION: The time elapsing from myocardial infarction onset to revascularization is prognostic; the most myocardium can be saved in the first hours. According to the Hungarian Myocardial Infarction Registry, the total ischaemic time is long in Hungary. OBJECTIVE: We aimed to identify the factors influencing the delay times of patients with ST-elevation myocardial infarction (STEMI). METHOD: We performed a prospective clinical study and collected data from 121 patients presenting with STEMI at the Cardiology Center of the University of Szeged in 2019. We filled out a questionnaire by interviewing patients after primary coronary intervention. RESULTS: The medians of the patient delay, prehospital delay time and total ischaemic time were 83, 252 and 304 minutes, respectively. When the Ambulance Service (AS) was notified, every delay time was significantly shorter than those measured when the Emergency Department or the general practitioner was notified. The place of residence of the patients significantly influenced the delay times and the chosen pathway of healthcare: median patient delays were 60 and 147 minutes in cities and villages, respectively; AS was called first by 50% of urban patients vs. 25% of rural patients. Knowing the emergency number was associated with reduced delay times. CONCLUSION: Delay times were long. The chosen pathway of healthcare had the greatest impact on the delay times. Urban people reported their complaints sooner, were more likely to choose the best healthcare pathway (AS), thus their delay times were shorter. These suggest that it is important to educate the society, especially rural communities. Orv Hetil. 2022; 163(11): 438-445.

Splenogonadal fusion in an infant / Splenogonadalis fúzió egy csecsemoben.

Összefoglaló. A splenogonadalis fúzió ritka fejlodési rendellenesség, melynek lényege az ivarmirigy (leggyakrabban a here) és a lépszövet rendellenes kapcsolódása. A szerzok egy féléves csecsemo esetét kívánják bemutatni, akinél már a megszületést követoen észlelheto volt a bal oldali here megnagyobbodása. A mutét elotti képalkotó vizsgálatok (ultrahang, MRI), a fizikális vizsgálat és az intraoperatív lelet a splenogonadalis fúzió lehetoségét vetette fel. A mutét során a makroszkóposan lépszövetnek imponáló elváltozás eltávolításra került, majd rutinorchiopexia történt. A hisztológiai vizsgálat alátámasztotta a feltételezett diagnózist. Az entitást 1883-ban írták le eloször, azóta kevesebb mint 200 esetrol számoltak be az angol nyelvu irodalomban. Az utóbbi 30 évben magyar szerzoktol egy közlemény jelent meg. Az elváltozás a banális szülési trauma okozta haematomára, újszülöttkori heretorzióra, malignus heretumorra is hasonlíthat, komoly differenciáldiagnosztikai problémát okozva. A splenogonadalis fúzió jóindulatú elváltozás, a helyes diagnózis esetén elkerülheto a felesleges orchiectomia. Orv Hetil. 2022; 163(7): 288-290. Summary. Splenogonadal fusion is a rare congenital malformation specified as the presence of splenic tissue connected to the gonads (mainly testis). The authors present the case of a 6-month-old male infant, in whom left inguino-scrotal mass was noticed soon after birth. The mass, based on preoperative diagnostic setup (ultrasound, MRI), physical examination and intraoperative findings were suspicious for splenogonadal fusion. At surgery, the mass was resected from the testis, which macroscopically resembled a splenic tissue. Following the resection, orchiopexy was performed. Histology confirmed splenogonadal fusion. Since the first description of the malformation in 1883, only less than 200 cases have been reported in the English literature. Only a single article has been published in Hungary in the last 30 years. Splenogonadal fusion represents a serious differential diagnostic problem. Hematoma caused by trauma, neonatal testicular torsion, benign or malignant testicular tumors may also present similarly. In our case, proper presumptive diagnosis made it possible to avoid unnecessary orchiectomy. Orv Hetil. 2022; 163(7): 288-290.

Characterization of technical skill progress in a standardized rabbit model for training in laparoscopic duodenal atresia repair.

BACKGROUND: Laboratory skills training is an essential step before conducting minimally invasive surgery in clinical practice. Our main aim was to develop an animal model for training in clinically highly challenging laparoscopic duodenal atresia repair that could be useful in establishing a minimum number of repetitions to indicate safe performance of similar interventions on humans. MATERIALS AND METHODS: A rabbit model of laparoscopic duodenum atresia surgery involving a diamond-shaped duodeno-duodenostomy was designed. This approach was tested in two groups of surgeons: in a beginner group without any previous clinical laparoscopic experience (but having undergone previous standardized dry-lab training, n = 8) and in an advanced group comprising pediatric surgery fellows with previous clinical experience of laparoscopy (n = 7). Each participant performed eight interventions. Surgical time, expert assessment using the Global Operative Assessment of Laparoscopic Skills (GOALS) score, anastomosis quality (leakage) and results from participant feedback questionnaires were analyzed. RESULTS: Participants in both groups successfully completed all eight surgeries. The surgical time gradually improved in both groups, but it was typically shorter in the advanced group than in the beginner group. The leakage rate was significantly lower in the advanced group in the first two interventions, and it reached its optimal level after five operations in both groups. The GOALS and participant feedback scores showed gradual increases, evident even after the fifth surgery. CONCLUSIONS: Our data confirm the feasibility of this advanced pediatric laparoscopic model. Surgical time, anastomosis quality, GOALS score and self-assessment parameters adequately quantify technical improvement among the participants. Anastomosis quality reaches its optimal value after the fifth operation even in novice, but uniformly trained surgeons. A minimum number of wet-lab operations can be determined before surgery can be safely conducted in a clinical setting, where the development of further non-technical skills is also required.

Population Pharmacokinetics of Intraperitoneal Gentamicin and the Impact of Varying Dwell Times on Pharmacodynamic Target Attainment in Patients with Acute Peritonitis Undergoing Peritoneal Dialysis.

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data were obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio > 10) and toxicity (plasma area under the concentration-time curve [AUC] < 120 mg·h/L) was determined for 0.3- to 1.2-mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 h and for the duration of a 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility breakpoint of 4 mg/L, only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. The probability of achieving exposure below the threshold of 120 mg·h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2-mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical breakpoint of 4 mg/L is likely to produce early toxic levels of exposure that are expected to be detrimental to the renal system.

Sorting Out the Risks and Benefits of the #797 Recommended Intrapartum Vancomycin Dosing Approach.

ACOG Committee Opinion #797 proposed intrapartum vancomycin dosing guidelines in the absence of thorough evaluation of its risk versus benefit profile on the maternal and neonatal systems. The previously published serum and cord-blood concentration-time data of vancomycin given to mothers in the intrapartum period was analyzed in this work with a two-compartment pharmacokinetic (PK) model. Monte Carlo simulation was used to establish exposure for the studied population for doses of 1000 mg to 2000 mg every 8 h for gestational ages (GA) of 33 to 40 weeks and for birth times up to 4-h intervals. Probabilities of target attainment (PTA) were calculated for efficacy and toxicity indices unique to the peripartum maternal and neonatal population. Neonatal evaluations indicate uniformly high PTAs for the evaluated dosing regimens when the efficacy target is considered. On the other hand, the PTAs for potentially nephrotoxic exposure is expected to reach undesirable levels when three or more doses were to be administered. The risk is profoundly high in GA below 36 weeks and birth times beyond 20 h after the initiation of intrapartum prophylaxis and with doses greater than 1250 mg. Maternal vancomycin exposures seem reasonable up to two intrapartum doses given at 8 h intervals when the dose is kept to 1250 mg or less. Most mothers (up to 83%) who receive three or more doses of the commonly administered regimens are subjected to nephrotoxic exposures. Thus, it appears that the current recommendations by #797 for dosing of vancomycin pose considerable risk to mother and newborn alike, especially in cases with lengthy duration of preterm labor. Capping of doses at 1250 mg may be considered to minimize the need for therapeutic drug monitoring (TDM) interventions. Alternatively, and irrespective of the baseline maternal renal function, TDM for all cases requiring more than two doses of 1500 mg or higher must be assured.