Septic Cardiomyopathy.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Studies on septic cardiomyopathy report a wide range of prevalence ranging from 10% to 70%. Myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Mitochondrial dysfunction is the leading problem in the development of septic cardiomyopathy and includes oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism, and mitophagy. Echocardiography provides several possibilities for the diagnosis of septic cardiomyopathy. Systolic and diastolic dysfunction of left ventricular is present in 50-60% of patients with sepsis. Right ventricular dysfunction is present in 50-55% of cases, while isolated right ventricular dysfunction is present in 47% of cases. Left ventricle (LV) diastolic dysfunction is very common in septic shock, and it represents an early biomarker, it has prognostic significance. Right ventricular dysfunction associated with sepsis patients with worse early prognosis. Global longitudinal stress and magnetic resonance imaging (MRI) of the heart are sufficiently sensitive methods, but at the same time MRI of the heart is difficult to access in intensive care units, especially when dealing with critically ill patients. Previous research has identified two biomarkers as a result of the integrated mitochondrial response to stress, and these are fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15). Both of the mentioned biomarkers can be easily quantified in serum or plasma, but they are difficult to be specific in patients with multiple comorbidities. Mitochondrial dysfunction is also associated with reduced levels of miRNA (microRNA), some research showed significance of miRNA in sepsis-induced myocardial dysfunction, but further research is needed to determine the clinical significance of these molecules in septic cardiomyopathy. Therapeutic options in the treatment of septic cardiomyopathy are not specific, and include the optimization of hemodynamic parameters and the use of antibiotic thera-pies with targeted action. Future research aims to find mechanisms of targeted action on the initial mechanisms of the development of septic cardiomyopathy.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

Association between Health Literacy and Prevalence of Obesity, Arterial Hypertension, and Diabetes Mellitus.

Background: Health literacy (HL) is linked to many health outcomes, including self-management of chronic diseases. The aim of this study was to assess the association of health literacy with the prevalence of obesity, arterial hypertension (AH), and type 2 diabetes mellitus (T2DM). Methods: This cross-sectional, single-center study included 500 patients (42.2% male and 57.8% females; median age, 63 years (interquartile range, 42−73)) hospitalized at General County Hospital in Pozega, Croatia, between July and October 2020. The Short Assessment of Health Literacy for Croatian Adults (SAHLCA-50) questionnaire was used. Descriptive statistics (median with interquartile range (IQR), frequency, and percentages) and binary logistic regression were utilized. Results: Patients with AH had an inadequate level of health literacy as compared to those without AH (32 vs. 40 points; Mann−Whitney U test, p < 0.001). Patients with T2DM scored 31 points versus 39 points in patients without T2DM (Mann−Whitney U test, p < 0.001). Patients suffering from both AH and T2DM scored 31 points versus 33 points in those with either AH or T2DM and 41 points in patients without AH and T2DM (Kruskal−Wallis test, p < 0.001). There were no statistically significant differences in SAHLCA-50 scores according to the patient body mass index. Conclusions: An inadequate level of health literacy is significantly associated with AH and T2DM but not with obesity. Male gender, low level of education, rural place of residence, retirement, and older age are significant predictors of inadequate health literacy.

Rapid clearance of tacrolimus blood concentration triggered by variant pharmacogenes.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (TAC) is an immunosuppressant with large interpatient pharmacokinetic variability and a narrow therapeutic index. We report a case of acute cellular rejection (ACR) type IB with insufficient TAC blood concentrations (TAC C0 ). CASE SUMMARY: ACR developed on the eighth postoperative day of kidney transplantation. During this period, TAC C0 were insufficient. This referred pharmacogenetic assessment disclosed the patient as a CYP3A5 expresser and CYP3A4*1B carrier. According to the genotype, higher doses of TAC, 15 mg twice daily, were administered and targeted TAC C0 were achieved. WHAT IS NEW AND CONCLUSION: Our case presents an association of TAC rapid clearance and two alleles modifying greater CYP3A enzyme activity.

Croatian Version of the Short Assessment of Health Literacy for Spanish Adults (SAHLSA-50): Cross-Cultural Adaptation and Psychometric Evaluation.

(1) Background: Short Assessment of Health Literacy for Spanish Adults (SAHLSA-50) was originally designed for Spanish-speaking regions, and translations validated for several languages. The aim of the study was to adapt and verify the psychometric characteristics of SAHLSA-50 in the Croatian context; (2) Methods: The cross-sectional study included 590 respondents from the general population older than 18 years of age. Health literacy was measured by two scales: SAHLCA-50 and the Croatian version of the Newest Vital Sign screening test (NVS-HR), which was used as a measure of concurrent validity. Subjective Health Complaints (SHC) and Satisfaction with Life Scale (SWLS) questionnaires were also used to assess convergent validity; (3) Results: Internal consistency reliability of SAHLCA-50 was high and corresponds to the findings of the authors of the original research. The Cronbach alpha coefficient for SAHLCA-50 version was 0.91. The correlation of SAHLCA-50 with the NVS-HR test speaks in favor of concurrent validity. Correlation between health literacy and SHC speaks for convergent validity, just as was expected, while correlation with life satisfaction was not observed; (4) Conclusions: The SAHLCA-50 test can be a good and quick tool to assess health literacy of the adult population in the Croatian language. HL can affect the health and quality of life of the individual and the wider community.

Sexual function in hemodialysis and post-renal transplant women in a relationship: a cross-sectional study.

PURPOSE: Difficulties in sexual functioning are very frequent in patients with chronic kidney disease (CKD). Sexual dysfunction (SD) can significantly diminish the quality of life (QOL) of affected individuals. The aim of this study was to determine the prevalence of SD in female patients undergoing chronic hemodialysis (CHD) and after renal transplantation (RTx) and to compare these groups with each other and with healthy control. METHODS: The survey was conducted among 123 female participants in a relationship, 28 of them undergoing CHD, 39 after RTx, and 56 healthy women without CKD. For the assessment of the sexual function and comorbidities, the Female Sexual Function Index (FSFI) questionnaire and Ifudu Comorbidity Index were used, respectively. RESULTS: Median age of all female participants was 60 (50-68). The median age of female CHD patients was 66 (61.3-72.8), RTx patients 56 (48-61), and the control group 59.5 (47.5-67.75). Among all participants, CHD female patients had the lowest scores in all sexual functioning domains. Compared to their age-adjusted control group, CHD patients had lower scores in desire, orgasm, and FSFI full score, whereas RTx patients had lower total FSFI scores and scores in all domains except for desire compared to their controls. Women with lower education, in marriage, and with more comorbidities had lower scores in sexual function domains. CONCLUSION: Our study shows that SD in female patients undergoing CHD treatment or those after RTx is substantially higher than that in healthy women. We suggest that female patient treated for CKD should have proper care regarding their sexual health, and differences in demographic and medical factors should be taken into consideration during the treatment management.

Levels of Depression and Anxiety and the Body Image of Female Patients on Renal Replacement Therapy.

BACKGROUND: Chronic kidney disease is a severe condition that can affect different dimensions of the patients' wellbeing. The aim of this study was to determine the role of the treatment type on the patients' levels of depression and anxiety as well as on their body image. SUBJECTS AND METHODS: A cross-sectional study was conducted on 146 respondents divided into three groups, 53 treated by hemodialysis (HD), 53 treated by kidney transplantation (TX), and 90 controls. Body image scale, PHQ-9 and GAD-7 were used to assess the patients. RESULTS: There was no difference in BIS between the groups HD and TX, nor between the TX and their age-matched controls. The TX group had lower levels of depression when compared to the HD group, and their levels of depression were similar to those of controls. No significant differences in anxiety were observed between the groups. CONCLUSION: Since the levels of depression are higher in the HD group, special attention should be given to these patients. Higher levels of psychological well-being in the transplant group is an additional factor why transplantation is the preferred method of treatment of CKD.

Early markers of gestational diabetes mellitus: what we know and which way forward?

Women's metabolism during pregnancy undergoes numerous changes that can lead to gestational diabetes mellitus (GDM). The cause and pathogenesis of GDM, a heterogeneous disease, are not completely clear, but GDM is increasing in prevalence and is associated with the modern lifestyle. Most diagnoses of GDM are made via the guidelines from the International Association of Diabetes and Pregnancy Study Groups (IADSPG), which involve an oral glucose tolerance test (OGTT) between 24 and 28 weeks of pregnancy. Diagnosis in this stage of pregnancy can lead to short- and long-term implications for the mother and child. Therefore, there is an urgent need for earlier GDM markers in order to enable prevention and earlier treatment. Routine GDM biomarkers (plasma glucose, insulin, C-peptide, homeostatic model assessment of insulin resistance, and sex hormone-binding globulin) can differentiate between healthy pregnant women and those with GDM but are not suitable for early GDM diagnosis. In this article, we present an overview of the potential early biomarkers for GDM that have been investigated recently. We also present our view of future developments in the laboratory diagnosis of GDM.

Perindopril/amlodipine-induced thrombotic microangiopathy.

This is the first report on a case of perindopril/amlodipine-induced thrombotic microangiopathy (TMA) syndrome. A 48-year-old female was admitted complaining of nettle rash all over the body, bloody urine, and weakness shortly after starting antihypertensive therapy with perindopril/amlodipine. Shortly thereafter, she developed pronounced hemiparesis, somnolence, and sensorimotor aphasia. Laboratory findings were compatible with microangiopathic hemolytic anemia and thrombocytopenia. She was diagnosed with TMA. Cessation of perindopril/amlodipine therapy and treatment with plasma exchange and systemic corticosteroids resulted in full recovery. Very seldom perindopril/amlodipine may cause hematologic abnormalities, probably through an immunological mechanism, but there were no reports of causing TMA so far. In our case, the symptoms began shortly after the start of perindopril/amlodipine use. The clinical course of TMA in the case was compatible with TMA related to an acute, immune-mediated drug reaction. The most important thing is to promptly recognize TMA and its induction by a drug because distinctive treatment and cessation of the suspected drug can prevent severe outcome, as it was avoided in our patient.

The Croatian version of the Body Image Scale: translation and validation.

AIM: To validate the Croatian translation of the Body Image Scale in breast cancer and chronic kidney disease patients. METHODS: The scale was administered to 172 breast cancer patients and to 89 chronic kidney disease patients. Measures of depression and anxiety were used to assess the convergent validity. Both groups were divided based on their treatment types. RESULTS: In both samples, the scale showed high internal consistency (Cronbach's Alpha 0.958 for breast cancer patients, 0.855 for chronic kidney disease patients) item-total correlations (0.72-0.88 for breast cancer patients, 0.46-0.65 for chronic kidney disease patients), and convergent validity. In the breast cancer group, the factor analysis showed a single-factor solution, while in the chronic kidney disease group it showed a two-factor solution. Good discriminant validity was obtained among breast cancer patients, with patients who underwent complete mastectomy scoring higher than patients who underwent partial mastectomy. The scale showed no discriminant validity among chronic kidney disease patients. CONCLUSION: The Croatian BIS shows good psychometric properties.

THE IMPACT OF POSITIVE ANTI-HBC MARKER ON PERMANENT DEFERRAL OF VOLUNTARY BLOOD DONORS IN EASTERN CROATIA AND ESTIMATION OF OCCULT HEPATITIS B VIRUS INFECTION RATE.

Recently an increase has been reported in the number of HBV transmissions from anti-HBc positive blood donors that were repeatedly negative in HBsAg and nucleic acid testing using the most sensitive tests available. The aim of the study was to show the effect of anti-HBc antibody testing performed in 2006 on permanent deferral of voluntary blood donors (VBDs), and to estimate occult hepatitis B infection (OBI) rate in this population after the introduction of mandatory molecular testing in the 2013-2016 period. More than 30,000 blood donations collected during the 2005-2007 period and more than 14,000 VBDs having donated blood during the 2013-2016 period after the introduction of molecular testing from eastern Croatia were included in the study. Serologic testing was performed with HBsAg assay throughout the study period, and anti-HBc assay was only performed in 2006. As part of the confirmatory algorithm testing, all HBsAg positive and unclear results were tested with molecular tests. Anti-HBc prevalence among VBDs in 2006 was 1.5%, with a rate of 1:197, whereas HBsAg prevalence was stable from 2005 to 2007 (0.04%, 0.1% and 0.1%, respectively). The calculated OBI rate from 2013 to 2016 was 1:30,250. Ten of 161 (12.4%) VBDs had serologic anti-HBc-only pattern. Anti-HBc testing in 2006 resulted in statistically more deferrals of VBDs compared to 2005 and 2007, and to the rest of Republic of Croatia. The strategy of universal anti-HBc testing of VBDs in addition to the existing HBsAg and molecular screening could be an additional measure to prevent HBV transmission by blood and blood components.

Seroepidemiology of hepatitis E in patients on haemodialysis in Croatia.

PURPOSE: Data on the seroprevalence of hepatitis E virus (HEV) in heamodialysis (HD) patients are conflicting, ranging from 0 to 44%. The aim of this study was to determine the HEV seroprevalence and risk factors among HD patients in Croatia. METHODS: A total of 394 HD patients from six medical facilities in five Croatian cities (three sites in the continental and three sites in the coastal region) were tested for HEV IgM/IgG antibodies using an enzyme-linked immunosorbent assay. Additionally, all samples were tested for HEV RNA by RT-PCR. Sociodemographic data and risk factors were collected using a questionnaire. RESULTS: HEV IgG antibodies were detected in 110 (27.9%) patients. The seroprevalence varied significantly between dialysis centres, ranging from 5.2 to 43.4% (p = 0.001). HEV IgM antibodies were found in 0.04% of IgG positive patients. All patients tested negative for HEV RNA. Factors associated with HEV IgG seropositivity were age > 60 years (OR 8.17; 95% CI 1.08-62.14), living in the continental parts of the country (OR 2.58; 95% CI 1.55-4.30), and transfusion of blood products (OR 1.66; 95% CI 1.01-2.73). After adjusting for age and gender, patients from continental regions had higher odds of HEV seropositivity compared to patients from coastal regions (OR 2.88; 95% CI 1.71-4.85) and those who had RBC transfusions (OR 1.70, 95% CI 1.02-2.69) compared to those who did not. CONCLUSION: The study showed a high HEV seropositivity among HD patients in Croatia, with significant variations between geographical regions. Continental area of residence and RBC transfusion were the most significant risk factors for HEV seropositivity. Due to the high seroprevalence, routine HEV screening among HD patients, especially in transplant candidates should be considered.

Screening for Carpal Tunnel Syndrome in Patients on Chronic Hemodialysis.

OBJECTIVES: To determine the prevalence of carpal tunnel syndrome risk in patients on chronic hemodialysis (HD) using Levine questionnaire for assessment of carpal tunnel syndrome - related symptoms severity and patients' functional status and to examine the relation of the determined risk with the participants' demographic, anthropometric and laboratory data. PARTICIPANTS AND METHODS: This crosssectional study included 78 chronic HD patients at Department for Nephrology in University Hospital Osijek. All participants filled out the Levine questionnaire to examine the severity of carpal tunnel syndrome - related symptoms and their functional state. The participants' demographic, anthropometric and laboratory data were taken from the medical records and statistically analyzed by SPSS for Windows (version 16.0, SPSS Inc., Chicago, IL, SAD). RESULTS: Risk for carpal tunnel syndrome was found in 38.5% of the participants. No significant differences between patients with and without the risk were found in sex distribution, underlying kidney disease or vascular access. Patients at risk were older (P=0.044) and had higher body mass index (BMI), (t-test, P=0.019). Participants' age, BMI and predialytic serum urea concentration were independent predictors for carpal tunnel syndrome risk (P=0.033). CONCLUSION: The prevalence of risk for carpal tunnel syndrome among patients on chronic HD was found in more than one third of patients. Older age, higher BMI and higher predialytic serum urea concentration bear a higher risk. Electromyoneurography is thus often indicated in this population to confirm the diagnosis for consecutive surgical treatment.

FEMALE SEXUAL FUNCTION OF HEALTHY WOMEN IN EASTERN CROATIA.

The aim was to evaluate sexual function of healthy women in Croatia and the possible impact of depression, anxiety, and sociodemographic factors. A total of 204 healthy women filled in a basic sociodemographic questionnaire, the Patient Health Questionnaire-9, Anxiety Disorder-7, and Female Sexual Function Index (FSFI). Almost half of study subjects (47.1%) reported at least some degree of sexual dysfunction defined as an FSFI score lower than 26.55. Study results suggest sexual dysfunction of women in Croatia as a still unrecognized problem. More room in research and in the public must be given to this issue.

Impedance cardiography as tool for continuous hemodynamic monitoring during cesarean section: randomized, prospective double blind study.

BACKGROUND: Impedance Cardiography (ICG) is a non-invasive tool for continuous hemodynamic monitoring. Aims of our study were to assess the utility of ICG to evaluate the hemodynamic impact of 6 mg (GL6) vs 8 mg (GL8) levobupivacaine combined with fentanyl in healthy patients undergoing elective cesarean section; secondary, to compare the duration and quality of analgesia and anesthesia. METHODS: Sixty-two women receiving combined spinal-epidural (CSE) for elective cesarean delivery were randomly allocated to GL6 or GL8 groups. Mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance index (SVRI), heart rate (HR), stroke volume index (SVI) were recorded from Tbaseline to 31 min after CSE by ICG. Sensory and motor blocks, patients and surgeons satisfaction, neonatal data were also recorded. RESULTS: Fifteen of 32 patients in GL6 and 15 of 30 patients in GL8 experienced hypotension at T2 vs Tbaseline (P < .001) and SVRI reduction (P = .035 and P < .001 respectively). MAP, CI and SVRI were always slightly higher in GL6 vs GL8. HR and SVI remained stable until the end of surgery in all patients. Total ephedrine requirements was higher in GL8 (P = .010). The onset and offset time of sensory and motor block were similar in both groups, but the number of patients with motor block was lower in GL6 vs GL8 (P = .001). Patients and surgeon satisfaction scores, the number of patients needed systemic rescue doses, neonatal data were similar in both groups. CONCLUSIONS: ICG is a useful noninvasive tool to monitor continuously hemodynamics during cesarean section. The hemodynamic stability, the satisfying sensory block and rapid mobilization provided by low levobupivacaine dose may be particularly advantageous in obstetric patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03170427 . Retrospectively Registered (Date of registration: May 2017).

Hemodialysis-refractory metformin-associated lactate acidosis with hypoglycemia, hypothermia, and bradycardia in a diabetic patient with belated diagnosis and chronic kidney disease
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Metformin is a first-line oral antidiabetic therapy for patients with type 2 diabetes mellitus. Metformin-associated lactate acidosis (MALA) is a well-known, life-threatening, but rare side effect of metformin therapy. Chronic kidney disease (CKD) patients have a much greater risk of MALA. We report the case of a severe refractory MALA despite hemodialysis (HD) treatment, associated with hypoglycemia, hypothermia, and bradycardia in a neglected and thus untimely-recognized CKD patient with type 2 diabetes mellitus. Despite the recent rehabilitation of metformin as a treatment of choice for type 2 diabetes mellitus, the drug should be prescribed with caution as it can be associated with life-threatening refractory acidosis, particularly in CKD patients. Moreover, HD treatment could occasionally be ineffective, resulting in a fatal outcome.
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Prognostic nutritional index as a predictor of prognosis in patients with diffuse large B cell lymphoma.

BACKGROUND: The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with short-term and long-term outcomes of various malignancies. The prognostic value of PNI in diffuse large B cell lymphoma (DLBCL) remains unknown. The aim of the present study was to determine the prognostic value of baseline PNI in DLBCL patients. METHODS: We retrospectively analyzed data from 103 DLBCL patients treated with R­CHOP or R­CHOP-like regimens. We evaluated the significance of PNI as a predictor of response to treatment, overall survival (OS) and event-free survival (EFS). RESULTS: Patients with a PNI ≤ 44.55, where the cut-off was calculated by receiver operating characteristics (Youden index) and the same was obtained for response to treatment with 76.2 % sensitivity and a specificity of 85.4 %, for OS with 72.4 % sensitivity and a specificity of 90.5 % and for EFS with 65.6 % sensitivity and a specificity of 90.1 %, had significantly worse 5­year OS (18.3 % vs 86.4 %, P < 0.001, log rank test) and 5­year EFS (15.1 % vs 82.3 %, P < 0.001, log rank test). Regression analysis showed that PNI ≤ 44.55 was an independent prognostic factor for response to treatment with an odds ratio (OR) of 4.88 for treatment failure, 95 % confidence interval (CI) 1.077-22.105, OS hazard ratio (HR) 4.24, 95 % CI 1.451-12.392 and EFS HR 4.007, 95 % CI 1.48-10.852. Lower PNI levels were found in patients with advanced Ann Arbor clinical stage (46.6 ± 7.77 vs. 52.7 ± 5.43) and in those with poor response to therapy (40.58 ± 7.26 vs. 50.67 ± 6.26). CONCLUSIONS: The PNI is a simple and useful marker to predict long-term survival outcome in DLBCL patients. Low PNI predicted poor outcome. A limitation of the study is its retrospective design in which the prognostic value was tested in the derivation cohort only. Notwithstanding, this is the first study suggesting that PNI is an important prognostic factor in DLBCL.