INTRODUCTION: It is hypothesized that systemically administered antibiotics penetrate wound sites more effectively during negative pressure wound therapy (NPWT). However, there is a lack of clinical data from patients who receive NPWT for deep sternal wound infection (DSWI) after open-heart surgery. Here, we evaluated vancomycin penetration into exudate in this patient group. PATIENTS AND METHODS: For this prospective observational study, we enrolled 10 consecutive patients treated with NPWT for post-sternotomy DSWI. On the first sampling day, serum and exudate samples were synchronously collected at 0 (pre-dose), 0.5, 1, 2, 3 and 6 h after vancomycin administration. On the following three consecutive days, additional samples were collected, only before vancomycin administration. RESULTS: The ratio of average vancomycin concentration in wound exudate to in serum was higher for free (unbound) (1.51 ± 0.53) than for total (bound + unbound) (0.91 ± 0.29) concentration (p = 0.049). The percentage of free vancomycin was higher in wound exudate than serum (0.79 ± 0.19 vs. 0.46 ± 0.16; p = 0.04). Good vancomycin wound penetration was maintained on the following three days (vancomycin trough exudate-to-serum concentration ratio > 1). The total hospital stay was significantly longer in patients with DSWI (46 ± 11.6 days) versus without DSWI (14 ± 11.7 days) (p < 0.001). There was no in-hospital or 90-day mortality. Two patients experienced late DSWI recurrence. All-cause mortality was 4.8% during a median follow-up of 2.5 years. CONCLUSION: Vancomycin effectively penetrates wound exudate in patients receiving NPWT for DSWI after open-heart surgery.The protocol for this study was registered at ClinicalTrials.gov on July 16, 2024 (NCT06506032).
- MeSH
- antibakteriální látky * farmakokinetika aplikace a dávkování MeSH
- exsudáty a transsudáty metabolismus mikrobiologie MeSH
- infekce chirurgické rány * MeSH
- kardiochirurgické výkony * škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- prospektivní studie MeSH
- senioři MeSH
- sternotomie * škodlivé účinky MeSH
- sternum chirurgie MeSH
- terapie ran pomocí řízeného podtlaku * metody MeSH
- vankomycin * aplikace a dávkování farmakokinetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.
- MeSH
- antigeny CD278 metabolismus MeSH
- antigeny CD279 antagonisté a inhibitory MeSH
- antigeny CD28 MeSH
- CD8-pozitivní T-lymfocyty imunologie účinky léků metabolismus MeSH
- dospělí MeSH
- inhibitory kontrolních bodů * terapeutické užití farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom * farmakoterapie imunologie krev patologie MeSH
- nádory plic * farmakoterapie imunologie krev patologie MeSH
- nemalobuněčný karcinom plic * farmakoterapie imunologie krev patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Despite efforts to improve undergraduate clinical pharmacology & therapeutics (CPT) education, prescribing errors are still made regularly. To improve CPT education and daily prescribing, it is crucial to understand how therapeutic reasoning works. Therefore, the aim of this study was to gain insight into the therapeutic reasoning process. METHODS: A narrative literature review has been performed for literature on cognitive psychology and diagnostic and therapeutic reasoning. RESULTS: Based on these insights, The European Model of Therapeutic Reasoning has been developed, building upon earlier models and insights from cognitive psychology. In this model, it can be assumed that when a diagnosis is made, a primary, automatic response as to what to prescribe arises based on pattern recognition via therapy scripts (type 1 thinking). At some point, this response may be evaluated by the reflective mind (using metacognition). If it is found to be incorrect or incomplete, an alternative response must be formulated through a slower, more analytical and deliberative process, known as type 2 thinking. Metacognition monitors the reasoning process and helps a person to form new therapy scripts after they have chosen an effective therapy. Experienced physicians have more and richer therapy scripts, mostly based on experience and enabling conditions, instead of textbook knowledge, and therefore their type 1 response is more often correct. CONCLUSION: Because of the important role of metacognition in therapeutic reasoning, more attention should be paid to metacognition in CPT education. Both trainees and teachers should be aware of the possibility to monitor and influence these cognitive processes. Further research is required to investigate the applicability of these insights and the adaptability of educational approaches to therapeutic reasoning.
BACKGROUND: Major depressive disorder (MDD) is a mental illness with a high worldwide prevalence and suboptimal pharmacological treatment, which necessitates the development of novel, more efficacious MDD medication. Nuclear magnetic resonance (NMR) can non-invasively provide insight into the neurochemical state of the brain using proton magnetic resonance spectroscopy (1H MRS), and an assessment of regional cerebral blood flow (rCBF) by perfusion imaging. These methods may provide valuable in vivo markers of the pathological processes underlying MDD. METHODS: This study examined the effects of the chronic antidepressant medication, citalopram, in a well-validated MDD model induced by bilateral olfactory bulbectomy (OB) in rats. 1H MRS was utilized to assess key metabolite ratios in the dorsal hippocampus and sensorimotor cortex bilaterally, and arterial spin labelling was employed to estimate rCBF in several additional brain regions. RESULTS: The 1H MRS data results suggest lower hippocampal Cho/tCr and lower cortical NAA/tCr levels as a characteristic of the OB phenotype. Spectroscopy revealed lower hippocampal Tau/tCr in citalopram-treated rats, indicating a potentially deleterious effect of the drug. However, the significant OB model-citalopram treatment interaction was observed using 1H MRS in hippocampal mI/tCr, Glx/tCr and Gln/tCr, indicating differential treatment effects in the OB and control groups. The perfusion data revealed higher rCBF in the whole brain, hippocampus and thalamus in the OB rats, while citalopram appeared to normalise it without affecting the control group. CONCLUSION: Collectively, 1H MRS and rCBF approaches demonstrated their capacity to capture an OB-induced phenotype and chronic antidepressant treatment effect in multiple brain regions.
- MeSH
- bulbus olfactorius metabolismus chirurgie účinky léků MeSH
- citalopram * farmakologie MeSH
- deprese farmakoterapie metabolismus MeSH
- depresivní porucha unipolární farmakoterapie metabolismus MeSH
- hipokampus metabolismus účinky léků MeSH
- krysa rodu rattus MeSH
- magnetická rezonanční spektroskopie metody MeSH
- modely nemocí na zvířatech * MeSH
- mozek * metabolismus účinky léků MeSH
- mozkový krevní oběh * účinky léků MeSH
- potkani Sprague-Dawley MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Despite significant improvement in the survival of pediatric patients with cancer, treatment outcomes for high-risk, relapsed, and refractory cancers remain unsatisfactory. Moreover, prolonged survival is frequently associated with long-term adverse effects due to intensive multimodal treatments. Accelerating the progress of pediatric oncology requires both therapeutic advances and strategies to mitigate the long-term cytotoxic side effects, potentially through targeting specific molecular drivers of pediatric malignancies. In this report, we present the results of integrative genomic and transcriptomic profiling of 230 patients with malignant solid tumors (the "primary cohort") and 18 patients with recurrent or otherwise difficult-to-treat nonmalignant conditions (the "secondary cohort"). The integrative workflow for the primary cohort enabled the identification of clinically significant single nucleotide variants, small insertions/deletions, and fusion genes, which were found in 55% and 28% of patients, respectively. For 38% of patients, molecularly informed treatment recommendations were made. In the secondary cohort, known or potentially driving alteration was detected in 89% of cases, including a suspected novel causal gene for patients with inclusion body infantile digital fibromatosis. Furthermore, 47% of findings also brought therapeutic implications for subsequent management. Across both cohorts, changes or refinements to the original histopathological diagnoses were achieved in 4% of cases. Our study demonstrates the efficacy of integrating advanced genomic and transcriptomic analyses to identify therapeutic targets, refine diagnoses, and optimize treatment strategies for challenging pediatric and young adult malignancies and underscores the need for broad implementation of precision oncology in clinical settings.
- MeSH
- dítě MeSH
- genomika * metody MeSH
- individualizovaná medicína * metody MeSH
- kohortové studie MeSH
- kojenec MeSH
- lékařská onkologie metody MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádory * genetika terapie MeSH
- předškolní dítě MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Tartrazine belongs to the colors raising significant concerns regarding consumer safety at low doses relevant for real-life human exposure. Scientific literature continues to grow after the European Food Safety Authority (EFSA) re-evaluation in 2009 and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2016. Therefore, this review aims to collect recent knowledge on the toxicity issues of tartrazine, namely its genotoxicity, cytotoxicity, carcinogenicity, reproductive, developmental, and neurotoxicity, alterations of blood biochemical parameters, and hematotoxicity. The second part of the review covers the potential protective factors against the toxic effects of tartrazine based on the hypothesis of mitigation of oxidative stress induced by the color. The reviewed protective factors are crocin, royal jelly, fish oil, honey, acetylsalicylic acid, black caraway, blackthorn, turmeric, vitamin E, and riboflavin. This review concludes that tartrazine seems safe under the current acceptable daily intake (ADI) and the evidence on the potential protective factors is insufficient to reach any conclusion regarding their use.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A lot of hope for high-risk cancers is being pinned on immunotherapy but the evidence in children is lacking due to the rarity and limited efficacy of single-agent approaches. Here, we aim to assess the effectiveness of multimodal therapy comprising a personalized dendritic cell (DC) vaccine in children with relapsed and/or high-risk solid tumors using the N-of-1 approach in real-world scenario. A total of 160 evaluable events occurred in 48 patients during the 4-year follow-up. Overall survival of the cohort was 7.03 years. Disease control after vaccination was achieved in 53.8% patients. Comparative survival analysis showed the beneficial effect of DC vaccine beyond 2 years from initial diagnosis (HR = 0.53, P = .048) or in patients with disease control (HR = 0.16, P = .00053). A trend for synergistic effect with metronomic cyclophosphamide and/or vinblastine was indicated (HR = 0.60 P = .225). A strong synergistic effect was found for immune check-point inhibitors (ICIs) after priming with the DC vaccine (HR = 0.40, P = .0047). In conclusion, the personalized DC vaccine was an effective component in the multimodal individualized treatment. Personalized DC vaccine was effective in less burdened or more indolent diseases with a favorable safety profile and synergized with metronomic and/or immunomodulating agents.
- MeSH
- cyklofosfamid * terapeutické užití aplikace a dávkování MeSH
- dendritické buňky * imunologie MeSH
- dítě MeSH
- imunoterapie metody MeSH
- individualizovaná medicína * metody MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metronomické podávání léků MeSH
- mladiství MeSH
- nádory * mortalita imunologie terapie farmakoterapie MeSH
- následné studie MeSH
- předškolní dítě MeSH
- protinádorové vakcíny * aplikace a dávkování terapeutické užití MeSH
- vinblastin aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.
- MeSH
- antipsychotika farmakologie škodlivé účinky MeSH
- benzodiazepiny farmakologie škodlivé účinky MeSH
- glukagonu podobné peptidy * analogy a deriváty farmakologie MeSH
- hmotnostní přírůstek účinky léků MeSH
- imunoglobuliny - Fc fragmenty * farmakologie MeSH
- kalorická restrikce metody MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- olanzapin * farmakologie škodlivé účinky MeSH
- potkani Sprague-Dawley * MeSH
- přijímání potravy účinky léků MeSH
- receptor pro glukagonu podobný peptid 1 agonisté metabolismus MeSH
- rekombinantní fúzní proteiny * farmakologie MeSH
- tělesná hmotnost účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.
- MeSH
- antipsychotika farmakologie MeSH
- haloperidol farmakologie MeSH
- kognitivní dysfunkce metabolismus farmakoterapie MeSH
- krysa rodu rattus MeSH
- kyselina kynurenová * metabolismus MeSH
- methylazoxymethanolacetát * analogy a deriváty MeSH
- modely nemocí na zvířatech MeSH
- piperidiny farmakologie MeSH
- potkani Sprague-Dawley * MeSH
- prefrontální mozková kůra * metabolismus účinky léků MeSH
- pyrazoly farmakologie MeSH
- receptor kanabinoidní CB1 metabolismus MeSH
- schizofrenie * metabolismus farmakoterapie MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.
- Publikační typ
- časopisecké články MeSH
