IFNL3/4 polymorphisms as a two-edged sword: An association with COVID-19 outcome.

Coronavirus Disease 2019 (COVID-19) has been ranked among the most fatal infectious diseases worldwide, with host's immune response significantly affecting the prognosis. With an aim to timely predict the most likely outcome of SARS-CoV-2 infection, we investigated the association of IFNL3 and IFNL4 polymorphisms, as well as other potentially relevant factors, with the COVID-19 mortality. This prospective observational case-control study involved 178 COVID-19 patients, hospitalized at Corona Center or Clinic for Infectious Diseases of University Clinical Centre Kragujevac, Serbia, followed up until hospital discharge or in-hospital death. Demographic and clinical data on all participants were retrieved from the electronic medical records, and TaqMan assays were employed in genotyping for IFNL3 and IFNL4 single nucleotide polymorphisms (SNPs), namely rs12980275, rs8099917, rs12979860, and rs368234815. 21.9% and 65.0% of hospitalized and critically ill COVID-19 patients, respectively, died in-hospital. Multivariable logistic regression analysis revealed increased Charlson Comorbidity Index (CCI), N/L, and lactate dehydrogenase (LDH) level to be associated with an increased likelihood of a lethal outcome. Similarly, females and the carriers of at least one variant allele of IFNL3 rs8099917 were almost 36-fold more likely not to survive SARS-CoV-2 infection. On the other hand, the presence of at least one ancestral allele of IFNL4 rs368234815 decreased more than 15-fold the likelihood of mortality from COVID-19. Our results suggest that, in addition to LDH level, N/L ratio, and CCI, IFNL4 rs368234815 and IFNL3 rs8099917 polymorphisms, but also patients' gender, significantly affect the outcome of COVID-19.

Its all about IFN-λ4: Protective role of IFNL4 polymorphism against COVID-19-related pneumonia in females.

Despite the pivotal role of IFN-λs in the innate immune response, the data on its genetic polymorphism in relation to COVID-19 severity are scarce and contradictory. In the present study, we aimed to determine if the presence of the most frequent functional single nucleotide polymorphisms (SNPs) of the two most important IFN-λs coding genes, namely IFNL3 and IFNL4, alters the likelihood of SARS-CoV-2-infected patients to develop more severe form of the disease. This observational cohort study involved 178 COVID-19 patients hospitalized at the University Clinical Centre Kragujevac, Serbia. Patients' demographics, clinical characteristics, and laboratory parameters were collected at admission. COVID-19 signs and symptoms were assessed during the hospital stay, with the worst condition determining the disease severity. Genotyping for IFNL3 (rs12980275 and rs8099917) and IFNL4 (rs12979860 and rs368234815) SNPs was conducted using TaqMan assays. Our study revealed carriers of IFNL3 and IFNL4 minor alleles to be less likely to progress from mild to moderate COVID-19, that is, to develop COVID-19-related pneumonia. After adjustment for other factors of influence, such as age, sex, and comorbidities, the likelihood of pneumonia development remained significantly associated with IFNL4 polymorphism (odds ratios [ORs] [95% confidence interval (95% CI)]: 0.233 [0.071; 0.761]). When the patients were stratified according to sex, the protective role of IFNL4 minor alleles, controlled for the effect of comorbidities, remained significant only in females (OR [95% CI]: 0.035 [0.003; 0.408]). Our results strongly suggest that IFNL4 rs12979860 and rs368234815 polymorphisms independently predict the risk of COVID-19-related pneumonia development in females.

Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials.

ABSTRACT: An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.

ST2 and the alteration of cobalt, sodium, potassium and calcium concentration in acute inflammation.

INTRODUCTION: ST2 is the receptor for interleukin (IL)-33, the last discovered member of the IL-1 cytokine family. Acute inflammation is an early response of vascularized tissue to injury, in which alteration of micro- and macro-elements occurs. This study aimed to examine the alteration of cobalt, sodium, potassium, and calcium concentration at the site of acute inflammation and the role of ST2 in these alterations. MATERIAL AND METHODS: Wild-type (WT) and ST2 knockout (ST2-/-) mice were divided into groups: WT control group (WT-C), ST2 knockout control group (KO-C), WT inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). We induced acute inflammation by intramuscular injection of turpentine oil or saline in the case of the control group. After 12 h, we anesthetized mice and collected treated tissues for histopathological analysis and determination of cobalt, sodium, potassium, and calcium concentration by atomic absorption spectrometer. RESULTS: Histopathological analysis showed the inflammatory infiltrate and cell necrosis in the treated tissue in WT-I and KO-I. The concentration of sodium was significantly lower in WT-I than in WT-C. The concentration of potassium and cobalt was significantly lower in WT-I and KO-I when compared to WT-C and KO-C, respectively. However, the concentration of potassium and cobalt in the tissue was significantly lower in WT-I than in KO-I. The concentration of calcium in the tissue did not significantly differ between groups. CONCLUSION: We reported, to our knowledge for the first time, that ST2 is involved in decreasing sodium, potassium, and cobalt concentration at the site of acute inflammation.

Effects of IL-33/ST2 pathway in acute inflammation on tissue damage, antioxidative parameters, magnesium concentration and cytokines profile.

AIM: The aim of this study was to examine the role of IL-33/ST2 pathway in a pathogenesis of acute inflammation and its effects on tissue damage, antioxidative capacity, magnesium concentration and cytokine profile in acutely inflamed tissue. MATERIAL AND METHODS: Male mice were randomly divided in four groups: wild-type control group (WT-C), ST2 knockout control group (KO-C), wild-type inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). Acute inflammation was induced in WT-I and KO-I by intramuscular injection of turpentine oil, while mice in WT-C and KO-C were treated with saline. After 12h, animals were euthanized, and blood was collected for determination of creatine kinase (CK) and aspartate transaminase (AST) activity. The treated tissue was used for histopathological analysis, determination of volume density of inflammatory infiltrate (Vdii) and necrotic fiber (Vdnf), gene expression of interleukin (IL)-33, ST2, tumor necrosis factor alpha (TNF-alpha), IL-6, IL-12p35, and transforming growth factor beta (TGF-beta), concentration of magnesium (Mg), copper (Cu), selenium (Se), manganese (Mn) and reduced glutathione (GSH), and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity. RESULTS: Presence of inflammatory infiltration and necrosis in the treated tissue was histopathologically confirmed in WT-I and KO-I. Vdii was significantly higher in WT-I when compared to KO-I, whereas Vdnf did not significantly differ between WT-I and KO-I. CK and AST significantly increased in both inflammatory groups when compared to corresponding control groups. However, the values of CK and AST were significantly higher in WT-I than in KO-I. Mg in the treated tissue was significantly lower in WT-I in comparison to WT-C and KO-I, while there was no significant difference between KO-C and KO-I. There was no significant difference in Cu, Se, and Mn in the treated tissue between WT-C, KO-C, WT-I and KO-I. Gene expression of IL-33 in the treated tissue increased in both inflammatory groups when compared to the corresponding control groups, but it was significantly higher in KO-I than in WT-I. Gene expression of ST2 in the treated tissue was significantly higher in WT-I than in WT-C. Gene expression of TNF-alpha, IL-6, and IL-12p35 in the treated tissue was significantly higher in WT-I and KO-I than in the corresponding control groups, and IL-6 was significantly higher in KO-C than in WT-C. TGF-beta gene expression in the treated tissue was significantly higher in KO-I when compared to WT-I, while there was no difference between WT-C and KO-C. SOD activity decreased at the site of acute inflammation in both inflammatory groups, while the GPx activity increased. GSH in the treated tissue was significantly higher in KO-I than in KO-C or WT-I. CONCLUSION: The results of our study have indicated, to our knowledge for the first time, that IL-33/ST2 pathway plays a role in enhancing inflammation and tissue damage at the site of acute inflammation by affecting the concentration of magnesium and GSH, important for antioxidative capacity, as well as gene expression of anti-inflammatory cytokine TGF-beta.

Risk factors for potentially inappropriate prescribing to older patients in primary care.

PURPOSE: The aim of this study is to determine modifiable risk factors contributing to potentially inappropriate prescribing in older primary care outpatients (≥65 years). METHODS: Two separate, age- and sex-matched case-control studies were carried out simultaneously at the Primary Health Care Center Kragujevac, Serbia, during the period September 2013-September 2014. The cases were defined as patients with at least one prescription for potentially inappropriate medication (PIM) according to Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) criteria (n = 122), and patients who had at least one potential prescribing omission (PPO) listed in Screening Tool to Alert doctors to the Right Treatment (START) criteria (n = 108), while the control groups consisted of patients without such outcomes (n = 244 and n = 216, respectively). RESULTS: A total of 138 PIM and 161 PPO events were identified using 26 (41.3 %) of STOPP criteria and 17 (77.3 %) of START indicators, respectively. The unhealthy behaviors including at least two of the following: sedentary lifestyle, improper nutrition, active smoking or heavy alcohol consumption (adjusted OR 2.57, 95 % CI 1.28-5.20), use of multiple drugs (five to eight drugs, adjusted OR 3.05, 95 % CI 1.59-5.85; ≥9 of drugs adjusted OR 7.17, 95 % CI 3.07-16.74) and frequent contacts between patients chosen general practitioners (GPs) and pharmaceutical sales representatives (adjusted OR 2.28, 95 % CI 1.10-4.75), were identified as major risk factors for PIM use. Patients who were handled by GPs from smaller practices (adjusted OR 0.51, 95 % CI 0.29-0.93), those with more organ systems affected by the extremely severe disorders and those who often visited the outpatient specialist services (adjusted OR 0.88, 95 % CI 0.81-0.95), had a significantly reduced risk of PPO. CONCLUSIONS: This study suggests that avoidance of major polypharmacy, use of nonpharmacological measures to improve lifestyle habits and decreasing the exposure of physicians to drug promotional material may reduce the risk of PIM use in older primary care outpatients. The only modifiable protective factors for PPOs were working environment of the patients chosen GPs and more frequent ambulatory visits to specialists.

Comparative analysis of the effects combined physical procedures and alpha-lipoic acid on the electroneurographic parameters of patients with distal sensorimotor diabetic polyneuropathy.

[Purpose] Painful diabetic polyneuropathy occurs as a complication in 16% of all patients with diabetes mellitus. [Subjects and Methods] A clinical, prospective open-label randomized intervention study was conducted of 60 adult patients, with distal sensorimotor diabetic neuropathy two groups of 30 patients, with diabetes mellitus type 2 with distal sensorimotor diabetic neuropathy. Patients in group A were treated with combined physical procedures, and patients in group B were treated with alpha lipoic acid. [Results] There where a statistically significant improvements in terminal latency and the amplitude of the action potential in group A patients, while group B patients showed a statistically significant improvements in conduction velocity and terminal latency of n. peroneus. Group A patients showed a statistically significant improvements in conduction velocity and terminal latency, while group B patients also showed a statistically significant improvements in conduction velocity and terminal latency. This was reflected in a significant improvements in electrophysiological parameters (conduction velocity, amplitude and latency) of the motor and sensory nerves (n. peroneus, n. suralis). [Conclusion] These results present further evidence justifying of the use of physical agents in the treatment of diabetic sensorimotor polyneuropathy.

Effects of Il-33/St2 pathway on alteration of iron and hematological parameters in acute inflammation.

AIM: The aim of this study was to examine the role of the IL-33/ST2 pathway in pathogenesis of acute inflammation by investigating its possible role in alteration of iron and hematological parameters in experimental model of acute inflammation. MATERIAL AND METHODS: Wild-type and ST2 knockout BALB/c mice were divided into four groups: wild-type control group, ST2-/- control group, wild-type inflammatory group, and ST2-/- inflammatory group. Acute inflammation was induced by intramuscular injection of turpentine oil, while control groups were injected with saline. After 12h animals were anesthetized, and the treated tissue, blood and spleen were collected. Iron concentration in the treated tissue, hemoglobin blood concentration, mean corpuscular hemoglobin (MCH), hematocrit, erythrocyte, neutrophil and lymphocyte blood count, and erythrocytes percentage in spleen were determined. RESULTS: Iron concentration in the treated tissue was significantly higher in wild-type inflammatory group (WT-I) when compared to both, the wild-type control group (WT-C) and ST2-/- inflammatory group (KO-I). There was no significant difference in iron concentration between ST2-/- control group (KO-C) and the KO-I. MCH had significantly decreased in WT-I when compared to WT-C, while there was no significant difference between KO-C and KO-I. Hemoglobin blood concentration significantly increased in KO-I in comparison to KO-C, while it did not significantly differ between WT-I and KO-I. Erythrocyte count and hematocrit had significantly increased, while the percentage of erythrocytes in spleen decreased in both inflammatory groups when compared to their controls. Neutrophil count significantly decreased in WT-I, when compared to WT-C. Lymphocyte count decreased in both inflammatory groups when compared to their controls. CONCLUSION: Results of this study indicate that the IL-33/ST2 axis could have a role in the alteration of iron in acute inflammation, namely in an increase of iron concentration at the site of acute inflammation and a decrease of blood mean corpuscular hemoglobin.

Clinical significance of Cyclin D1, FGF3 and p21 protein expression in laryngeal squamous cell carcinoma.

PURPOSE: Laryngeal squamous cell carcinoma (LSCC) represents one of the most common cancers of the head and neck and the search for molecular markers is required for early diagnosis, prognosis and optimal therapy. The purpose of this study was to investigate the clinical significance of Cyclin D1, FGF3, p16 and p21 protein expression in LSCC and laryngeal dysplasia (LD) and to evaluate the associations between their expression levels and clinicopathological parameters of patients with LSCC. METHODS: Immunohistochemistry was employed to detect and quantify the expression levels of Cyclin D1, FGF3, p16 and p21 in the laryngeal tissues of 48 LSCC patients, 32 patients with LD and 28 subjects with healthy laryngeal mucosa (HLM). RESULTS: Significantly higher percentage of LSCC patients had positive Cyclin D1 expression compared with LD patients and HLM subjects (both p<0.01) and positive FGF3 expression than HLM subjects (p<0.05), while no differences in p16 and p21 positive expression were found among studied groups. The levels of Cyclin D1, FGF3 and p16 expression, as evaluated by immunostaining score, were significantly higher in patients with LSCC compared with LD and HLM groups (all p<0.05). Cyclin D1 proved to be highly sensitive and specific marker in differentiating LSCC from LD (sensitivity 81.2%, specificity 83.9%), while high sensitivity (81.2%) and lower specificity (41.4%) was observed in differentiating from HLM. Cyclin D1 and p21 expression levels were associated with regional lymph node metastases (both p<0.05) and Cyclin D1 expression levels significantly correlated with LSCC lymphatic invasion (x(2)=8.862; df=3; ?=0.031). CONCLUSIONS: Cyclin D1, FGF3 and p16 are overexpressed in patients with LSCC. Cyclin D1 is a highly sensitive marker in differentiating LSCC from LD or HLM. Cyclin D1 and p21 expression levels may be useful as predictive markers of metastases in LSCC.

Outcomes of long-acting injectable antipsychotics use in pregnancy: A literature review.

BACKGROUND: Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy. Long-acting injectable (LAI) antipsychotics have been widely used to improve adherence and prevent relapse in patients with various severe psychotic disorders, but there is a lack of high-quality data from previous research on the safety of LAI antipsychotics during pregnancy. AIM: To summarize relevant data on maternal, pregnancy, neonatal, and developmental outcomes from published cases of LAI antipsychotic use in pregnancy. METHODS: A literature search was performed through November 11, 2023, using three online databases: PubMed/MEDLINE, Scopus, and Web of Science. Case reports or case series that reported information about the outcomes of pregnancy in women who used LAI antipsychotics at any point in pregnancy, with available full texts, were included. Descriptive statistics, narrative summation, and tabulation of the extracted data were performed. RESULTS: A total of 19 publications satisfied the inclusion criteria: 3 case series, 15 case reports, and 1 conference abstract. They reported the outcomes of LAI antipsychotic use in 74 women and 77 pregnancies. The use of second-generation LAI antipsychotics was reported in the majority (n = 47; 61.0%) of pregnancies. First-generation LAI antipsychotics were administered during 30 pregnancies (39.0%). Most of the women (approximately 64%) had either satisfactory control of symptoms or no information about relapse, while approximately 12% of them had developed gestational diabetes mellitus. A minority of cases reported adverse outcomes such as stillbirth, spontaneous abortion, preterm birth, low birth weight, congenital anomalies, and neurological manifestations in newborns. However, there were no reports of negative long-term developmental outcomes. CONCLUSION: Currently available data seem reassuring, but further well-designed studies are required to properly evaluate the risks and benefits of LAI antipsychotic use during pregnancy.

Risk factors for lethal outcome in patients with delirium tremens - psychiatrist's perspective: a nested case-control study.

BACKGROUND: The aim was to identify potential risk factors for lethal outcome in patients with delirium tremens (DT) treated in the psychiatric setting. METHODS: In a nested case-control study, a total of 190 medical records of patients with DT hospitalized at the Psychiatric Clinic in Serbia between 2002 and 2011 were reviewed and analyzed. The characteristics of patients who died (cases) were compared with those who survived (controls). For each case, two controls (matched for age, gender, and year of hospitalization) were randomly chosen. RESULTS: Significant differences between cases and controls were found for serum potassium levels (p < 0.001), the number of hospitalizations (p < 0.001), and duration of hospitalization (p < 0.001). A significant association with lethal outcome was found for serum potassium levels even in the normal range (adjusted odds ratio 40.52; 95% CI 1.20, >1,000.00; p = 0.004). CONCLUSIONS: Even though the number and duration of psychiatric hospitalizations were identified as factors determining survival after admission for DT, only serum potassium levels were found to be significant. Patients with an increase in potassium (or absence of hypokalemia) may require more intensive treatment. Monitoring of serum levels of potassium is important not only as an indicator for replacement but also as an indicator of maladaptation.

A model to determine factors influencing intraoperative complications in sleeve gastrectomy.

Objective: The study presents a logistic regression model describing the factors leading to intraoperative complications in laparoscopic sleeve gastrectomy (LSG) and a detailed description of the intraoperative complications that occurred in our operations. Material and methods: The study was designed as a retrospective and cohort study. It includes patients who underwent laparoscopic sleeve gastrectomy between January 2008 and December 2020. Results: The study included 257 patients. The mean (SD) age of all patients included in the study was 40.28 (9.58) years. The body mass index of our patients ranged from 31.2 to 86.6 kg/m2. The Stepwise Backward model was used (Cox and Snell R2 = 0.051, Nagelkerke R2 = 0.072, Hosmer-Lemesxow χ2 = 1.968, df = 4, p = 0.742, overall model accuracy of 70.4%). The model shows that pre-operative diabetes mellitus or hypertension Stage 3 significantly increases the probability or risk of intraoperative complications. Conclusions: The study shows which intraoperative complications occur in LSG, how they can be remedied and which factors can lead to them and influence the outcome of the operation itself. The recognition and successful treatment of intraoperative complications are very important as they reduce the number of reoperations and treatment costs.

Objetivo: El estudio presenta un modelo de regresión logística que describe los factores que conducen a las complicaciones intraoperatorias en la gastrectomía en manga laparoscópica (LSG) y una descripción detallada de las complicaciones intraoperatorias que ocurrieron en nuestras operaciones. Material y métodos: Estudio de cohorte retrospectivo. Incluye pacientes que se sometieron a LSG entre enero de 2008 y diciembre de 2020. Resultados: El estudio incluyó a 257 pacientes. La edad media (DE) de los pacientes del estudio fue de 40.28 (9.58) años. El índice de masa corporal de nuestros pacientes osciló entre 31.2 y 86.6 kg/m2. Se utilizó el modelo Stepwise Backward (Cox y Snell R2 = 0.051, Nagelkerke R2 = 0.072, Hosmer-Lemesxow χ2 = 1.968, gl = 4, p = 0.742, precisión global del modelo del 70.4%). El modelo muestra que la diabetes mellitus o hipertensión preoperatoria en estadio 3 aumenta significativamente la probabilidad de complicaciones intraoperatorias. Conclusiones: El estudio muestra qué complicaciones intraoperatorias ocurren en la LSG, cómo se pueden remediar y qué factores pueden conducir a ellas e influir en el resultado de la operación en sí. El reconocimiento y el tratamiento exitoso de las complicaciones intraoperatorias son muy importantes ya que reducen el número de reintervenciones y los costos del tratamiento.

Oligoelements in serum and intestinal tissue of pediatric IBD patients.

INTRODUCTION: Inflammatory bowel disease (IBD) develops through complex interplay of genetic, microbial, immune, and environmental factors. Trace elements alterations are commonly present in IBD and may have influence on IBD development. Heavy metal pollution is one of the major environmental issues nowadays and IBD incidence is rising in countries where industry starts to develop. Metals are implicated in processes that are connected to IBD pathogenesis. AIM: The aim of this study was to investigate toxic and trace element levels in pediatric population of IBD patients both in serum and intestinal mucosa. MATERIALS AND METHODS: This prospective study enrolled children newly diagnosed with IBD in University children's hospital in Belgrade. Concentrations of thirteen elements: Al, As, Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Se and Zn in serum and intestinal mucosa of 17 newly diagnosed children with IBD (10 Crohn's disease (CD) and 7ulcerative colitis (UC)) and 10 controls were assessed using inductively coupled plasma mass spectrometry (ICP-MS). Intestinal mucosa samples were taken from terminal ileum and six different colon segments (cecum, ascending colon, colon transversum, descending and sigmoid colon and rectum). RESULTS: The results demonstrated significant alterations in serum and intestinal mucosa concentrations of investigated elements. Serum iron was significantly decreased in IBD and CD group, compared to controls while serum Cu significantly differed between three investigated groups with highest concentration observed in CD children. Serum manganese was the highest in the UC subgroup. Terminal ileums of IBD patients contained significantly lower amount of Cu, Mg, Mn and Zn with Mn being significantly decreased also in CD patients compared to control. IBD patients' caecum contained significantly less Mg and Cu while colon transversum tissue samples from IBD and Crohn's patients contained significantly more chromium than controls. Moreover, sigmoid colon of IBD patients were poorer in Mg than controls (p < 0.05). Colon Al, As and Cd were significantly reduced in IBD, and UC children compared to control. Correlations of investigated elements in CD and UC groups were different from controls. Biochemical and clinical parameters showed correlation with element concentrations in intestines. CONCLUSION: Sera of CD, UC and control children significantly differ in Fe, Cu and Mn levels. Serum manganese was the highest in the UC subgroup creating the most prominent and only significant difference between UC and CD subgroups. Terminal ileum of IBD patients contained significantly lower amount of majority of investigated essential trace elements and toxic elements were significantly reduced in colon of IBD and UC patients. Investigation of macro- and microelement alterations in children and adults has potential to further elucidate IBD pathogenesis.

Hematological parameters' changes in mice subchronically exposed to static magnetic fields of different orientations.

Static magnetic fields (SMFs) are time independent fields whose intensity can be spatially dependent. This study investigates influence of subchronic continuous exposure to upward and downward directed SMF on hematological parameters and spleen cellularity in mice. The experiment is performed on the Northern hemisphere; consequently, the vertical component of geomagnetic field is directed downward. Male, Swiss-Webster, 6 weeks old mice were exposed to the vertically declining SMF. Mice were divided in three groups and continuously exposed or not exposed for 28 days to the SMF characterized by the averaged field of 16 mT and averaged field gradient of 10 mT/cm. Differently oriented SMF did not alter hemoglobin and hematocrit content among the groups. However, the groups exposed to the upward and downward fields had statistically significant higher levels of serum transferrin compared to the control. Moreover, spleen cellularity in animals in the downward group was significantly higher compared to the upward and control group. In addition, spleen lymphocytes in both of the exposed groups were significantly higher than in the control group. In contrast, spleen granulocytes in the exposed groups were significantly lower than in the control group. Significant decrease was also observed in brain and liver iron content with concomitant increase of iron in serum and spleen in exposed animals. Subchronic continuous exposure to 16 mT SMF caused lymphocyte and granulocyte redistribution between spleen and blood. This distribution is typical for stress induced hematological changes. These results suggest that observed changes were not due to an unspecific stress response, but that they were rather caused by specific adaptation to subchronic SMF exposure.

Knowledge of the pharmacological profile of a patient improves the quality of prescribing, the outcomes of treatment, and the utilization of health services in primary health care.

PURPOSE: To evaluate the influence of the pharmacological profile of a patient (PPP) on quality of drug prescribing, treatment effectiveness, safety, and health services utilization in a group of outpatients. METHODS: The study was designed as an open, nonrandomized trial of an intervention in health care. The outpatient intervention group (n = 39) received the PPP, and the control group (n = 36) did not. In all cases, the outcomes were observed for a 2-year period in total; in the intervention group 1 year of observation was allocated before and another year after the introduction of the PPP. RESULTS: The PPPs reduced multiple prescriptions by 1.08 ± 1.13 drugs per patient, whereas in those who did not receive the PPP, an increase of 1.44 ± 1.48 drugs per patient occurred (P < 0.001, 95% CI 1.91-3.13). A decrease in the medication appropriateness index score of 0.81 ± 0.51 per drug per patient in the intervention group was observed (P = 0.001, 95% CI 0.63-0.93), and in the control group an increase was noted (0.13 ± 0.40; P = 0.063). The majority of patients with PPP experienced fewer adverse drug reactions (0.96 ± 0.58 fewer, P < 0.001 vs. controls, 95% CI 1.39-2.13), and they were more likely to have an improvement in health status (OR 22.0, 95% CI 5.87-82.41). Finally, the PPPs decreased both the number of examinations and the number of diagnostic investigations, on average by 2.15 and 2.26 services per patient, respectively. CONCLUSIONS: Use of a pharmacological profile of a patient in primary care practice could improve not only prescribing behavior of general practitioners, but also effectiveness and safety of therapy, while reducing utilization of health services.

Antimicrobial treatment of Erysipelatoclostridium ramosum invasive infections: a systematic review.

The aim of this systematic review was to determine the causal role of Erysipelatoclostridium ramosum in specific invasive infections in humans, and to assess the clinical outcome of antibiotic therapy used to treat them. Several electronic databases were systematically searched for clinical trials, observational studies or individual cases on patients of any age and gender with a systemic inflammatory response syndrome (SIRS) due to E. ramosum isolated from body fluids or tissues in which it is not normally present. Only reports identifying E. ramosum as the only microorganism isolated from a patient with SIRS were included. This systematic review included 15 studies reporting 19 individual cases in which E. ramosum caused invasive infections in various tissues, mainly in immunocompromised patients. E. ramosum was most often isolated by blood cultures and identified by specific biochemical tests. Severe infections caused by E. ramosum were in most cases effectively treated with antibiotics, except in two patients, one of whom died. More than one isolate of E. ramosum exhibited 100% susceptibility to metronidazole, amoxicillin/clavulanate and piperacillin/tazobactam. On the other hand, individual resistance of this bacterium to penicillin, ciprofloxacin, clindamycin, imipenem and ertapenem was reported. This systematic review confirmed the clinical relevance of E. ramosum as a cause of a number of severe infections mainly in immunocompromised inpatients. Metronidazole and meropenem appear to be the antibiotics of choice that should be used in combination or as monotherapy to treat E. ramosum infections, depending on the type and severity of the infection.

Antimicrobial treatment of Corynebacterium striatum invasive infections: a systematic review.

The aim of this study was to establish an evidence-based guideline for the antibiotic treatment of Corynebacterium striatum infections. Several electronic databases were systematically searched for clinical trials, observational studies or individual cases on patients of any age and gender with systemic inflammatory response syndrome, harboring C. striatum isolated from body fluids or tissues in which it is not normally present. C. striatum had to be identified as the only causative agent of the invasive infection, and its isolation from blood, body fluids or tissues had to be confirmed by one of the more advanced diagnostic methods (biochemical methods, mass spectrometry and/or gene sequencing). This systematic review included 42 studies that analyzed 85 individual cases with various invasive infections caused by C. striatum. More than one isolate of C. striatum exhibited 100% susceptibility to vancomycin, linezolid, teicoplanin, piperacillin-tazobactam, amoxicillin-clavulanate and cefuroxime. On the other hand, some strains of this bacterium showed a high degree of resistance to fluoroquinolones, to the majority majority of ß-lactams, aminoglycosides, macrolides, lincosamides and cotrimoxazole. Despite the antibiotic treatment, fatal outcomes were reported in almost 20% of the patients included in this study. Gene sequencing methods should be the gold standard for the identification of C. striatum, while MALDI-TOF and the Vitek system can be used as alternative methods. Vancomycin should be used as the antibiotic of choice for the treatment of C. striatum infections, in monotherapy or in combination with piperacillin-tazobactam. Alternatively, linezolid, teicoplanin or daptomycin may be used in severe infections, while amoxicillin-clavulanate may be used to treat mild infections caused by C. striatum.

Incivility among nursing faculty: A multi-country study.

BACKGROUND: In nursing programs, incivility can be a main issue affecting future registered nurses, and this may threaten patient safety. Nursing faculty play an important role in this scenario to reduce incivility. PURPOSE: The aim of this study was to assess incivility among nursing faculty in different countries. METHOD: This descriptive (cross-sectional) study was conducted to assess the extent of incivility among nursing faculty by using Incivility in Nursing Education-Revised tool and a non-probability (convenience) sampling method was used. Three hundred ninety-five nursing faculty in 10 countries distributed in four continents participated in this study. RESULTS: The results indicated that levels of incivility among participants in different countries were significantly different. Also, there was a significant difference (F = 9.313, P value = 0.000) among the nursing faculty concerning the behaviours that have been rated as disruptive. Furthermore, there was a significant difference (F = 6.392, P value = 0.000) among participants regarding uncivil behaviours that have occurred during the past 12 months. CONCLUSION: Regular assessments are needed to highlight uncivil behaviours and reduce them by making policies and rules in order to enhance academic achievement in nursing education.

Potential Drug-drug Interactions in Acute Ischemic Stroke Patients at the Neurological Intensive Care Unit.

BACKGROUND: Clinically relevant potential drug-drug interactions are considered preventable adverse drug reactions. OBJECTIVE: The aim of this study was to ascertain the frequency of potential drug-drug interactions in acute ischemic stroke patients and to explore factors associated with occurrence of potentially contraindicated drug-drug interactions. METHODS: This observational retrospective cohort and nested case-control study was carried out among patients treated for acute ischemic stroke at the Neurological Intensive Care Unit in the Clinical Centre Kragujevac, Serbia. The potentially drug-drug interactions for each day of hospitalization were identifi ed using Micromedex® soft ware. Based on the existence or absence of potentially contraindicated drug-drug interactions, the participants were divided into a group of cases (n=111) and the control group (n=444). RESULTS: A total of 696 patients were analysed. All patients had a minimum of one potential drug-drug interaction during hospitalization. The most common drugs involved in potential drug-drug interactions were aspirin (8.02%), diclofenac (7.49%) and warfarin (7.14%). The number of medications prescribed for simultaneous use during hospitalisation and the use of antipsychotics in therapy signifi cantly increased the likelihood of potentially contraindicated drug-drug interactions aft er adjustment by means of logistic regression for 1.2 and 3 times, respectively. CONCLUSIONS: This study suggests that patients with acute ischemic stroke are frequently exposed to potential drug-drug interactions. It is essential to identify potentially drug-drug interactions in these patients as early as possible in order to prevent adverse drug reactions and ensure safe recovery. Besides, full attention should be paid when adding each new medication in therapy, particularly when a neurologist decides to prescribe antipsychotics, such as risperidone.

The influence of ageing on the extrapineal melatonin synthetic pathway.

Ageing affects various physiological and metabolic processes in a body and a progressive accumulation of oxidative damage stands out as often used explanation. One of the most powerful scavenger of reactive oxygen species (ROS) in all organs is melatonin. A majority of melatonin supplied to the body via blood originates from the pineal gland. However, we have been interested in a locally produced melatonin. We have used 2.5- and 36-months-old Wistar rats. Tissues were collected and gene expression of AA-NAT and ASMT, the two key enzymes in a synthesis of melatonin, was determined in brain, liver, kidney, heart, skin, and intestine. Since melatonin can influence antioxidant enzymes, the activity of superoxide dismutase (SOD) and catalase (CAT), and the level of GSH were measured in liver. In addition, Copper (Cu), Zinc (Zn), and Manganese (Mn) were also determined in liver since these microelements might affect the activity of antioxidant enzymes. The expression of AA-NAT and ASMT was increased in liver and skin of old animals. A positive correlation in AA-NAT and ASMT expression was observed in liver, intestine and kidney. Moreover, the activity of CAT enzyme in liver was increased while SOD activity was decreased. SOD and CAT were probably affected by the observed decreased amount of Cu, Zn, and Mn in liver of old animals. In our model, extrapineal melatonin pathway in ageing consisted of complex interplay of locally produced melatonin, activities of SOD and CAT, and adequate presence of Cu, Zn and Mn microelements in order to defend organs against oxidative damage.