Stress granule-mediated sequestration of EGR1 mRNAs correlates with lomustine-induced cell death prevention.

Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs mechanistically contribute to pro-survival or pro-apoptotic functions must be better defined. The chemotherapy drug lomustine promotes SG formation by activating the stress-sensing eIF2α kinase HRI (encoded by the EIF2AK1 gene). Here, we applied a DNA microarray-based transcriptome analysis to determine the genes modulated by lomustine-induced stress and suggest roles for SGs in this process. We found that the expression of the pro-apoptotic EGR1 gene was specifically regulated in cells upon lomustine treatment. The appearance of EGR1-encoding mRNA in SGs correlated with a decrease in EGR1 mRNA translation. Specifically, EGR1 mRNA was sequestered to SGs upon lomustine treatment, probably preventing its ribosome translation and consequently limiting the degree of apoptosis. Our data support the model where SGs can selectively sequester specific mRNAs in a stress-specific manner, modulate their availability for translation, and thus determine the fate of a stressed cell.

Clinical characteristics of children with MIS-C fulfilling classification criteria for macrophage activation syndrome.

Background: Macrophage activation syndrome (MAS) is a potentially life-threatening complication of various inflammatory disorders, including multisystem inflammatory syndrome in children (MIS-C). MIS-C refractory to treatment should raise suspicion of MAS, which can be fatal if a definitive diagnosis is delayed. Unfortunately, there is a lack of data on MAS in children with MIS-C. Objective: Our study aims to analyze the risk factors for the development of MAS in MIS-C, its clinical course and response to treatment, and identify predictive factors for pediatric intensive care. Material and methods: We analyzed data from the Polish MIS-C registry of the MultiOrgan Inflammatory Syndromes COVID-19 Related Study. Patients were diagnosed according to the WHO MIS-C definition and treated according to national guidelines (Polish Pediatric Society) based on international consensus. MAS definition was based on 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Results: Two-hundred and seventy four children met the study inclusion criteria. Fifty-nine patients fulfilled MAS classification criteria, nine of which required admission to the pediatric intensive care unit (PICU). MIS-C patients with MAS were significantly older than patients without MAS (median 11.2 vs. 8.1 years). Multivariable analysis showed that age, symptoms characteristic of atypical Kawasaki disease, and skin erosions were significant factors associated with MAS in MIS-C patients. Analysis of laboratory parameters showed that on admission, MIS-C patients with MAS had significantly lower median lymphocyte and platelet counts, albumin and sodium levels, and higher median levels of C-reactive protein, procalcitonin, ferritin, D-dimers, triglycerides, serum creatinine, urea, and γ-glutamyl transpeptidase, and neutrophil count. Multivariate analysis showed that higher procalcitonin, ferritin, and fibrinogen levels at admission were predictive of MAS. Only elevated troponin level was a factor indicating a requirement of PICU hospitalization for children with MAS. MIS-C patients fulfilling MAS criteria were treated more often with intravenous immunoglobulins and steroids than children without MAS. Children with MAS more often required mechanical ventilation. None of the patients required biological agents. Conclusions: The clinical course of MAS in MIS-C seems milder, treatment less aggressive, and the prognosis better than expected based on the current knowledge on MAS complicating other rheumatological diseases.

To vaccinate or not to vaccinate - BNT162b2 seroconversion rate and side effects among Polish healthcare workers.

OBJECTIVES: The study aimed to analyze the effect of BNT162b2 vaccination among Polish healthcare workers in terms of serologic response and adverse events. MATERIAL AND METHODS: A questionnaire survey covered data in the period January 1-March 31, 2021 gathered in 2 hospitals in Wielkopolska, Poland. Additionally, serological analysis (SARS-CoV-2 anti-S protein IgG) was performed. RESULTS: A total of 617 medical workers were vaccinated with BNT162b2 (Comirnaty, Pfizer). Data from the questionnaires were received from all of the staff after the first and the second dose. No severe side effects were observed. The most common side effect following the first and second doses of vaccination was pain at the injection site. After the first dose, 3 (1.4 %) women aged 18-55 years, 5 women (3.9 %), and 3 men (8.3 %) aged >55 years had negative SARS-CoV-2 anti-S protein IgG result. After the second dose, all those who agreed to have antibodies tested responded to vaccination with positive SARS-CoV-2 anti-S protein IgG results. CONCLUSIONS: Vaccination tolerance was good in the studied population; no severe side effects were observed. After the second dose, all tested healthcare workers responded to vaccination with antibody production. Int J Occup Med Environ Health. 2022;35(6):761-66.

The Role of Glucocorticoids in the Treatment of Multisystem Inflammatory Syndrome (MIS-C)-Data from POLISH MIS-C Registry.

BACKGROUND: Multisystem inflammatory syndrome (MIS-C) is a condition related to COVID-19. It's most significant feature is cardiac involvement. METHODS: We have analyzed data from 42 hospitals in the Polish MIS-C Registry. To compare the effect of GCS on fever, we formed two groups: the first treated with IVIG and the second treated with IVIG+GCS. RESULTS: There were 111 boys and 56 girls; the mean age was 8.57 years. All the patients were treated with IVIG: 76 patients with IVIG only, and 91 patients with IVIG+GCS. There were no statistically significant differences between the groups regarding age, gender, BMI, or inflammatory markers. Methylprednisolone was the most common drug (80%). Echocardiographic abnormalities on admission were more prevalent in the IVIG+GCS group. Mean time from IVIG infusion to subsidence of fever was 1.1 days, and 1.5 for those in the IVIG+GCS group. CONCLUSIONS: GCS are commonly used in the treatment of MIS-C patients in Poland. Various GCS regimens are used, from a single dose to a month-long therapy. Children with lower lymphocyte levels and cardiac abnormalities on an echocardiographic examination performed on admission were more likely to receive GCS+IVIG. The effect of GCS is difficult to access as patients were not randomly assigned to receive the treatment.

Immune profile of children diagnosed with multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C).

Introduction: The pathophysiology of multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C) remains poorly understood. This study aimed to define peripheral blood immune features in patients with MIS-C. Material and methods: We analyzed seven children diagnosed with MIS-C between April 1 and May 15, 2021, in St. Joseph's Children's Hospital in Poznan (Poland). Results: All patients had elevated inflammatory markers, IgG antibodies against SARS-CoV-2, and lymphopenia with a marked decrease in CD4+ and CD8+ T cells. The majority of CD4+ T cells were naive cells. Almost all (6/7) of the analyzed patients had a higher CD4+/CD8+ T cell ratio than average values. B cells were within the normal range - the majority were non-memory cells. Conclusions: Children with MIS-C do not resemble adults during COVID-19 recovery. The immune profile of the studied patients differs from that of children with Kawasaki disease (KD), but it is similar to that of adults with severe COVID-19. The proposed explanation is a profound lymphopenia caused by SARS-CoV-2 infection - which persists for weeks - as a result leading to uncontrolled inflammation. In COVID-19 patients the T cell level returns to normal after the second week of the disease. Our data suggest that in children prolonged lymphopenia after COVID-19 can be a practical marker for possible MIS-C alert. If there is a continuum from lymphopenia to MIS-C, there is room for screening and prevention. Further studies are needed to determine whether steroid treatment introduced in a child with prolonged lymphopenia could stop the inflammatory process.

Mutation in the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene in a patient with acute lymphoblastic leukemia.

Autoinflammatory syndromes are disorders characterized by recurrent or chronic inflammation caused by the dysregulation of the innate immune system. Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of overactivation of the immune system. We present a case of a 20-month-old boy who was referred to an oncology clinic because of HLH suspicion. In the preceding time, our patient suffered from a severe form of chickenpox with prolonged fever. Tests including myelogram, cerebrospinal fluid, and magnetic resonance (MR) of the brain gave a diagnosis of acute lymphoblastic leukemia from B lymphocyte precursors, without occupying the central nervous system. To exclude inherited HLH in our patient, next-generation sequencing was performed, which revealed a heterozygous missense mutation in exon 15 of the PSTPIP1 gene (c.1213C>T, R405C). No mutations of genes associated with familial HLH syndrome were found. Our patient may be evidence that autoinflammatory diseases caused by PSTPIP1 gene mutations are not limited to the classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) phenotype but may have a different clinical presentation, and the spectrum of the PSTPIP1-associated inflammatory diseases (PAID) syndrome is more extensive than previously thought.

Can AI Help Pediatricians? Diagnosing Kawasaki Disease Using DRSA.

The DRSA method (dominance-based rough set approach) was used to create decision-making rules based on the results of physical examination and additional laboratory tests in the differential diagnosis of Kawasaki disease (KD), infectious mononucleosis and S. pyogenes pharyngitis in children. The study was conducted retrospectively. The search was based on the ICD-10 (International Classification of Diseases) codes of final diagnosis. Demographic and laboratory data from one Polish hospital (Poznan) were collected. Traditional statistical methods and the DRSA method were applied in data analysis. The algorithm formed 45 decision rules recognizing KD. The rules with the highest sensitivity (number of false negatives equals zero) were based on the presence of conjunctivitis and CRP (C-reactive Protein) ≥ 40.1 mg/L, thrombocytosis and ESR (Erythrocyte Sedimentation Rate) ≥ 77 mm/h; fair general condition and fever ≥ 5 days and rash; fair general condition and fever ≥ 5 days and conjunctivitis; fever ≥ 5 days and rash and CRP ≥ 7.05 mg/L. The DRSA analysis may be helpful in diagnosing KD at an early stage of the disease. It can be used even with a small amount of clinical or laboratory data.

Semi-Automatic Volumetric and Standard Three-Dimensional Measurements for Primary Tumor Evaluation and Response to Treatment Assessment in Pediatric Rhabdomyosarcoma.

Current prognostic classification of rhabdomyosarcoma in children requires precise measurements of the tumor. The purpose of the study was to compare the standard three-dimensional (3D) measurements with semi-automatic tumor volume measurement method concerning assessment of the primary tumor size and the degree of response to treatment for rhabdomyosarcoma in children. Magnetic Resonance Imaging data on 31 children with treated rhabdomyosarcoma based on the Cooperative Weichteilsarkom Studiengruppe (CWS) guidance was evaluated. Tumor sizes were measured by two methods: 3D standard measurements and semi-automatic tumor volume measurement (VOI) at diagnosis, and after 9 and 17/18 weeks of the induction chemotherapy. Response to treatment and prediction values were assessed. The tumor volume medians calculated using VOI were significantly higher in comparison with those calculated using the 3D method both during the diagnosis as well as after 9 weeks of the chemotherapy and during the 17-18th week of the treatment. The volume measurements based on the generalized estimating equations on the VOI method were significantly better than the 3D method (p = 0.037). The volumetric measurements alone can hardly be considered an unequivocal marker used to make decisions on modification of the therapy in patients with rhabdomyosarcoma.

Arterial constriction after resection of neuroblastic tumors in children: Two-center retrospective study.

BACKGROUND/PURPOSE: Neuroblastic tumors are the most common pediatric extracranial solid tumors in infants and very young children. Although, especially in newborns, there is an increasing number of situations in which observation alone is used, surgery remains an important step in the treatment of neuroblastoma but can be complicated by arterial vasospasm in the surgical field. The aim of this two-center retrospective study was to analyze the occurrence of arterial constriction as a complication of neuroblastic tumors resection. METHODS: Medical records of patients who were treated surgically for neuroblastic tumors in the years 2012-2019 were reviewed. RESULTS: For 8 years, 113 children were treated for neuroblastic tumors. The treatment included both primary and delayed surgery after initial chemotherapy carried out according to SIOPEN protocols. In 11 out of 113 cases (9.7%) local arterial constriction was observed. In 6 out of 11 cases an attempt was made to save the organ, however, two patients suffered from kidney atrophy, two other partial kidney infarctions, one child suffered from partial limb paresis, and another from brain ischemia and death. CONCLUSIONS: Local arterial constriction constitutes a relatively common (10% of cases) and severe complication of neuroblastic tumors resection. Efficacy of local application of papaverine based on our experience remains unproven hence further research is warranted.

Simultaneous Occurrence of Choriocarcinoma in an Infant and Mother.

Infantile choriocarcinoma is an extremely rare disease. We present a case study of a 1-month-old male with choriocarcinoma diagnosed simultaneously with his mother. On admission to hospital, the disease was very advanced and massive progression and multi-organ failure caused the death of the patient despite the implemented treatment. It was too late to save the child's life, but early enough to save his mother. The authors believe that the serum levels of hCG should be determined in every newborn with anemia and liver tumor, especially when the mother has a positive history of miscarriage.

Knowledge among the rural parents about the vaccinations and vaccination coverage of children in the first year of life in Papua New Guinea - analysis of data provided by Christian health services.

Knowledge among the rural parents about the vaccinations and vaccination coverage of children in the first year of life in Papua New Guinea - analysis of data provided by Christian Health Services. BACKGROUND: This analysis aimed to assess rural parents' knowledge about the diseases prevented by vaccinations and establish vaccination coverage in PNG. METHODS: Knowledge of vaccinations was checked through a standard questionnaire (five closed questions). We analyzed data on vaccination coverage from 2016 to 2018 from all Catholic health facilities. Analyzed vaccinations were the pentavalent vaccine (DTaP-HiB-HepB) and measles vaccine given in the first year of life. Coverage was calculated based on the number of vaccines used compared to the number of eligible children. Analyzed vaccinations were the pentavalent vaccine (DTaP-HiB-HepB) and measles vaccine given in the first year of life. RESULTS: Fifty-six parents, including 52 mothers and four fathers, participated in the interview. Many parents (46%) understood that the vaccine prevents diseases. During the analyzed period, 25,502 doses of measles vaccine were given, 31,428 children were vaccinated with the pentavalent vaccine. In 2016, the measles vaccine coverage rate was 26.6 and 33.4% for the pentavalent vaccine. In 2017, measles and pentavalent vaccines' coverage rate was 12.5 and 16.6%, respectively. There were significant differences in immunization coverage between provinces. A decreasing trend in the number of administered vaccinations was observed. CONCLUSION: The results of this analysis demonstrate that in PNG, the majority of children are not fully immunized. There are significant differences in the vaccination coverage between provinces. As protection from diseases is low, there is a very high risk of an outbreak of the vaccine-preventable disease in the community. Delivery of vaccinations in PNG encounters many barriers, from access to healthcare services to natural disasters and inter-tribial conflicts.

SARS-CoV-2 testing and infection control strategies in European paediatric emergency departments during the first wave of the pandemic.

Between February and May 2020, during the first wave of the COVID-19 pandemic, paediatric emergency departments in 12 European countries were prospectively surveyed on their implementation of SARS-CoV-2 disease (COVID-19) testing and infection control strategies. All participating departments (23) implemented standardised case definitions, testing guidelines, early triage and infection control strategies early in the outbreak. Patient testing criteria initially focused on suspect cases and later began to include screening, mainly for hospital admissions. Long turnaround times for test results likely put additional strain on healthcare resources.Conclusion: Shortening turnaround times for SARS-CoV-2 tests should be a priority. Specific paediatric testing criteria are needed. What is Known: • WHO and public health authorities issued case definitions, testing and infection control recommendations for COVID-19 in January. • SARS-CoV-2 testing was made available across Europe in February. What is New: • Paediatric emergency departments implemented COVID-19-specific procedures rapidly, including case definitions, testing guidelines and early triage. • A third of surveyed departments waited more than 24 h for SARS-CoV-2 test to be reported, resulting in additional strain on resources.

Bilateral Nephroblastoma with Dilated Cardiomyopathy as an Indication for Off-Protocol Treatment: A Case Report.

Patients with a Wilms tumor are often admitted to the hospital accidentally, with an abdominal mass causing asymmetry of the abdominal wall. Hypertension accompanying a Wilms tumor occurs in about 10-27% of children, but cardiomyopathy associated with a Wilms tumor is very rarely described. This publication presents a case of a 9-month-old girl with a bilateral Wilms tumor accompanied by dilated cardiomyopathy since her initial cancer diagnosis, as well as her off-protocol treatment. The severe condition of the child forced the application of off-protocol treatment, i.e., accelerated resection of a larger tumor, which enabled the improvement of heart performance and made subsequent therapy possible. In the course of the presented treatment, a gradual normalization of cardiac ventricular function and contractility was observed. In conclusion, a massive abdominal tumor associated with abdominal compartment syndrome compromised the functioning of the cardiovascular system in the young child. Therefore, earlier removal of Wilms tumors in patients with heart failure should be considered. This may result in the improvement of cardiovascular function and the possibility of further therapy.

The Profile of Microorganisms Responsible for Port-Related Bacteremia in Pediatric Hemato-Oncological Patients.

Patients with pediatric cancer face an increased risk of infections. In most cases, these infections are associated with the use of a long-term central venous catheter. This study describes the epidemiology of a port-associated bacteremia as well as a profile of microorganisms responsible for port-associated bloodstream infections (PABSIs) in pediatric patients with cancer treated in a single center. The retrospective analysis included patients with cancer who had implanted a port, hospitalized between 2010 and 2015 at the Department of Pediatric Oncology, Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences. The medical records of patients were reviewed for demographic characteristics, diagnosis, port-related complications, and their management. Data were collected from patients' electronic medical records containing complete information on medical examinations and supplementary tests, diagnosis, timing, and type of port-associated complications. In a study period, 277 ports were inserted to 241 patients. A total of 183 094 catheter days were analyzed. Sixteen patients had more than 1 insertion of a port. The commonest observed complication was PABSI (40.07%) and the incidence density was 0.6 per 1000 port-days. Staphylococcus was the most commonly isolated organisms from patients with PABSI. From all port-associated complications, bloodstream infections and mechanical complications were the most often observed complications. The commonest pathogens responsible for PABSI were coagulase-negative staphylococci. Pathogens resistant to standard antibiotic treatment play an important role in PABSI, with methicillin-resistant Staphylococcus epidermidis being the predominant pathogen. Port-associated bloodstream infections are a common reason for preterm removal of a port.

Genes and their single nucleotide polymorphism involved in innate immune response in central nervous system in bacterial meningitis: review of literature data.

BACKGROUND: There are many studies analysing the effect of SNPs in genes coding proteins which are involved in innate immune response on susceptibility to invasive bacterial disease. Many of them gave inconclusive results. Regarding the complexity of immune response and cooperation between particular elements, number of SNPs may have a cumulative effect on the susceptibility to bacterial meningitis. FINDINGS: In most studies cooccurrence of several SNPs was not analysed. These studies were performed on small groups of patients and usually only few SNPs were checked simultaneously. Additionally, comparison of the results across the studies is hard to conduct. We hypothesise that the number of variants of genes involved in innate immune response plays a role in susceptibility to bacterial meningitis. However, the role of toll-like receptors and other part of innate immune response in the eradication of bacteria, and initiation of the inflammatory response in CNS need further studies. CONCLUSION: Large multicentre studies assessing multiple SNPs in patients with microbiologically proven pneumococcal or meningococcal meningitis are needed to find real genetic risk factors for developing bacterial meningitis. This is necessary to design more effective treatment and prevention strategies for severe infections.

How many single-nucleotide polymorphisms (SNPs) must be tested in order to prove susceptibility to bacterial meningitis in children? Analysis of 11 SNPs in seven genes involved in the immune response and their effect on the susceptibility to bacterial meningitis in children.

The aim of this study is to describe the prevalence of single single-nucleotide polymorphisms (SNPs) as well as their combinations in genes encoding proteins involved in the immune response in children with bacterial meningitis. The prospective study group consisted of 39 children with bacterial meningitis and 49 family members surveyed between 2012 and 2016. Eleven SNPs in seven genes involved in immune response were analysed. The mean number of minor frequency alleles (MAF) of studied SNPs was lowest in the control group and highest in patients with pneumococcal meningitis. We found that carrying ≥6 MAF of studied SNPs was associated with an increased risk of pneumococcal meningitis. The prevalence of risky variants was noted to be higher in patients with pneumococcal meningitis as compared to the control group. In conclusion, genetic factors are a relevant factor in determining the susceptibility to bacterial meningitis. A statistically significant cumulative effect of mutated variants on increasing the risk of bacterial meningitis was detected. Combining all three SNPs in MBL2 improves the prediction of susceptibility to pneumococcal meningitis. Analysis of risky alleles can help indicate people prone to the disease who are 'gene-immunocompromised'.

Distribution of polymorphisms rs12979860, rs8099917 and rs12980275 IL28B in patients with chronic hepatitis C.

BACKGROUND: The prognosis concerning the treatment of patients with chronic hepatitis C (CHC) is closely related to the genotype of the virus as well as to the factors dependent on the patient. It was proved that polymorphisms of the gene encoding interleukin 28B (IL28B) are associated with sustained viral response, which in the case of profitable variants of IL28B polymorphisms may reach up to 87% of the patients. OBJECTIVES: The aim of the study is to determine the prevalence of alleles and distribution of IL28B polymorphisms genotypes in the examined group of patients with CHC in Wielkopolska Province. MATERIAL AND METHODS: A total of 710 people with diagnosed hepatitis C virus were examined in order to determine the distribution of polymorphisms of gene IL28B rs12979860, rs8099917 and rs12980275. The polymorphisms were evaluated by sequencing of PCR products. RESULTS: The most often noted profitable variant was genotype TT for polymorphism rs8099917 present in 43.5% of the patients, next was AA rs12980275 in 22.5%. The rarest was the profitable variant CC of the polymorphism rs12979860 present in 17.5% of the patients. An occurrence of at least 2 IL28B polymorphisms in the preferred variants (homozygote CC, TT, AA) was found in 239 out of 710 (34%) patients, among which 117 patients had favorable genotypes for all 3 examined polymorphisms. CONCLUSIONS: The SNP distribution of gene IL28 with fixed prognostic value in the population of patients with chronic hepatitis C is different from the general population, and shows the need to evaluate polymorphisms prior to treatment.