Vaccine uptake in caregivers family members and patients with dementia and relationship with severity of dementia and caregiver burden: a cross-sectional study.

We cross sectionally evaluated COVID-19 and seasonal flu vaccination rates among 94 dyads consisting of informal caregiver family member and non-institutionalized patient with dementia observed in family-medicine practice in Zagreb, Croatia. COVID-19 vaccination rates in caregivers (78.7%) and patients with dementia (82.9%) were significantly higher than in general population. Caregiver and patient COVID-19 vaccination status (CVS) did not correlate. Among caregivers, seasonal flu vaccination (P = 0.004) but no other investigated factors related to caregiving or dementia severity showed significant association with CVS. Among patients with dementia, CVS was significantly associated with lower number of caregiver hours dedicated per week (P = 0.017), higher caregiver SF-36 role emotional HRQoL (P = 0.017), younger patient age (P = 0.027), higher MMSE (P = 0.030), higher Barthel index (P = 0.006), absence of neuropsychiatric symptoms of agitation and aggression (P = 0.031), lower overall caregiver burden (P = 0.034), lower burden of personal strain (P = 0.023) and lower burden of frustration (P = 0.016). Caregiving and severity of dementia-related factors significantly affect patient, but not caregiver CVS.

Unique contributions of specific neuropsychiatric symptoms to caregiver burden in informal caregivers family members of patients with dementia.

INTRODUCTION: We aimed to evaluate how the presence of individual neuropsychiatric symptoms in non-institutionalised patients with dementia is associated with caregiver burden of their informal caregivers, family members. METHODS: We performed a cross-sectional study on a total of 131 pairs of one informal caregiver family member and non-institutionalised patient with dementia in a family medicine practices in a city of Zagreb, Croatia. Caregiver measures included Zarit Burden Interview (ZBI) whereas patient measures included Mini mental state examination (MMSE), Barthel index and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Total NPI-Q score explained 21% of overall burden. In order of strength of the association, after adjustments for age, sex, MMSE and Barthel index, overall burden was significantly associated with higher NPI-Q scores for agitation/aggression, apathy/indifference, irritability/lability, disinhibition, motor disturbance, appetite/eating, depression/dysphoria, anxiety, elation/euphoria and nighttime behaviours. When evaluating mutually independent contribution of unique NPI-Q symptoms to caregiver burden, agitation/aggression and apathy/indifference remained only two mutually independently associated symptoms, each explaining 5% of overall burden in this context. CONCLUSIONS: Informal caregivers who provide for family members with dementia suffering from agitation/aggression or apathy/indifference should be recognised as under special risk for the development of caregiver burden and considered as candidates for early targeted interventions.

USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN PATIENTS WITH ADVANCED ACTIVE RHEUMATOID ARTHRITIS.

This study aimed to determine whether patients with active rheumatoid arthritis (RA) regularly take non-steroidal anti-inflammatory drugs (NSAIDs) and to clarify whether their decision to take NSAIDs depends on disease activity, intensity of pain, or functional status. The study also aimed to identify the risk factors for gastrointestinal side effects. Over 6 months, we conducted a cross-sectional single-center study of consecutively hospitalized patients with confirmed RA. Activities of daily living, pain intensity, and disease activity were evaluated by the Health Assessment Questionnaire, visual analog scale, and disease activity score, respectively, in 28 joints. Of 73 patients diagnosed with RA, 48 (66%) regularly took NSAIDs. Compared to non-users, NSAID users used glucocorticoids less frequently. The decision to use NSAIDs was independent of disease activity, pain intensity, degree of functional impairment, or presence of gastrointestinal risk factors. However, a higher degree of functional impairment was associated with a longer duration of continuous NSAID and glucocorticoid use. NSAIDs are still relevant for RA treatment. The decision to use them is not necessarily affected by disease activity or pain intensity, but their prolonged use is required in patients with a higher degree of functional disability. NSAIDs enable exclusion of glucocorticoid use, sparing patients of glucocorticoid-related side effects.

Predictors of Health-Related Quality of Life in Informal Caregivers of Dementia Patients in Zagreb, Croatia, a Cross Sectional Study.

We aimed to estimate health-related quality of life (HRQoL) in family-member caregivers of patients with dementia in Croatia and to assess relevant predictors. A cross-sectional study in family medicine practices in Zagreb (Health Care Center Zagreb-West) was performed in period 10/2017-9/2018 and included 131 dyads consisting of a patient with dementia and one dominant informal caregiver. Patient measures included Mini-mental-state-examination (MMSE), Barthel-index and the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Caregiver measures included 36-Item Short-Form-Health-Survey (SF-36), Zarit-Burden-Interview (ZBI) and structured questionnaire regarding general information on caregiver and patient. SF-36 is a reliable instrument to estimate HRQoL (Cronbach α ≥0.79 for all domains). Caregiver HRQoL was higher than reported in Croatian population in physical functioning (PF), role physical (RP), general health (GH), social functioning (SF) and role emotional (RE) domains. More pronounced neuropsychiatric symptoms in patient with dementia were associated with caregiver's lower HRQoL in vitality (VT) and mental health (MH) domains. Caregivers with higher caregiver burden assessed by ZBI had lower HRQoL in RP, bodily pain (BP), GH, VT, SF, RE and MH domains. In multivariate analyses, higher caregiver's burden was independent predictor of lower HRQoL in RP, VT, RE and MH domains. Neuropsychiatric symptoms and use of day-care service were recognized as independent predictors of lower HRQoL (in PF, BP and GH, SF, RE domains, respectively). Neuropsychiatric symptoms and caregiver burden are associated with HRQoL in caregivers of patients with dementia. Interventions including psychological support and learning of skills necessary to tackle individual problems may help in improvement of HRQoL.

Higher AURKA and PLK1 expression are associated with inferior overall survival in patients with myelofibrosis.

Aurora-kinase-A (AURKA), BORA and Polo-like-kinase-1 (PLK1) are regulating cell-cycle control and promotion of mitosis entry. AURKA contributes to Janus-kinase-2 (JAK2) activation and increased AURKA protein levels were reported in CD34+ and CD41+ cells of myeloproliferative neoplasm patients, leading to aneuploidy and aberrant megakaryopoiesis. We aimed to investigate AURKA, BORA and PLK1 mRNA expression in unfractionated bone-marrow aspirates of 43 patients with myelofibrosis (28 primary-/PMF, 15 secondary-myelofibrosis/SMF) and 12 controls and to assess their clinical correlations. AURKA expression did not significantly differ between myelofibrosis and controls (P = 0.466). Higher AURKA expression was significantly associated with higher absolute monocyte-count (P = 0.024) and shorter overall survival (HR = 3.77; P = 0.012). Patients with both PMF and SMF had lower BORA expression than controls (P = 0.009). Higher BORA expression was significantly associated with absence of constitutional symptoms (P = 0.049), absence of circulatory blasts (P = 0.047), higher monocyte- (P = 0.040) and higher eosinophil-counts (P = 0.016) and had neutral effect on survival (P > 0.05). PLK1 expression did not significantly differ between myelofibrosis and controls (P = 0.103). Higher PLK1 expression was significantly associated with higher white-blood-cell-count (P = 0.042) and inferior overall survival (HR = 5.87; P = 0.003). In conclusion, AURKA, BORA and PLK1 are involved in pathogenesis of myelofibrosis and may affect survival. Future studies investigating these interesting associations are warranted.

Patients with atrial fibrillation and mid-range ejection fraction differ in anticoagulation pattern, thrombotic and mortality risk independently of CHA2DS2-VASC score.

Atrial fibrillation (AF) patients with mid-range left ventricular ejection fraction (mrEF) of 40-49% have neither preserved (pEF > 50%) nor reduced (rEF < 40%) EF and are increasingly being recognized as a distinct group with specific clinical risks. We aimed to retrospectively investigate clinical characteristics and associated thrombotic, bleeding and mortality risks of mrEF in comparison to pEF and rEF in a cohort of 1000 non-valvular AF patients presenting in our institution during the period 2013-2018. Patients with mrEF presented with older age (P < 0.001) and a higher frequency of arterial hypertension (P = 0.001) in comparison to both pEF and rEF patients. In comparison to pEF, mrEF patients were more likely to have diabetes mellitus (P = 0.004), lower HDL-cholesterol (P < 0.001) and lower estimated glomerular filtration rate (P < 0.001), significantly higher CHA2DS2-VASC score (P < 0.001), significantly higher HAS-BLED score (P = 0.002) and had a higher likelihood of receiving anticoagulant therapy, mostly warfarin (P = 0.001). In addition, mrEF patients had a significantly higher risk of thrombotic events (HR = 2.22; P = 0.015), death (HR = 1.71; P = 0.005) and composite endpoint of thrombosis, bleeding or death (HR = 1.65; P = 0.003) in comparison to pEF patients, but did not significantly differ in comparison to rEF patients. There was no significant difference regarding major bleeding risk. Associations with clinical outcomes remained statistically significant in multivariate models independently of CHA2DS2-VASC. Our findings support defining AF patients with mrEF as a subgroup with distinct clinical characteristics and increased risk for thrombotic events and death, irrespective of predetermined CHA2DS2-VASC risk. These patients seem to require special clinical considerations and more intensive control of cardiovascular risk factors.

A validation of the Croatian version of Zarit Burden Interview and clinical predictors of caregiver burden in informal caregivers of patients with dementia: a cross-sectional study.

AIM: To validate the Croatian version of the Zarit Burden Interview (ZBI) and to investigate the predictors of perceived burden. METHODS: This cross-sectional study involved 131 dyads of one informal caregiver family member and one patient with dementia visiting primary care practices (Health Care Center Zagreb-West; 10/2017-9/2018). Patient-related data were collected with the Mini-Mental-State-Examination, Barthel-index, and Neuropsychiatric-Inventory-Questionnaire (NPI-Q); caregiver-related data with the ZBI, and general information on caregivers and patients with a structured questionnaire. Principal-axis-factoring with varimax-rotation was used for factor analysis. RESULTS: The caregivers' mean age was 62.1±13 years. They were mostly women (67.9%) and patients' children (51.1%). Four dimensions of ZBI corresponding to personal strain, frustration, embarrassment, and guilt were assessed and explained 56% variance of burden. Internal consistency of ZBI (α=0.87) and its dimensions (α1=0.88, α2=0.83, α3=0.72, α4=0.75) was good. Stronger cognitive and functional impairment of patients was associated only with personal strain, whereas more pronounced neuropsychiatric symptoms and the need for daily care were associated with more dimensions. Longer caregiver education suppressed embarrassment and promoted guilt. Guilt was higher in younger caregivers, caregivers of female patients, patients' children, and non-retired caregivers. In multivariate analysis significant predictors of higher overall burden were male sex of the patient, higher NPI-Q, the need for daily-care services, shorter duration of caregiving, non-spouse relationship, higher number of hours caring per-week, and anxious-depressive symptoms in a caregiver. CONCLUSION: The Croatian version of ZBI is reliable and valid. Our data confirm that ZBI is a multidimensional construct. Caregivers may benefit from individually tailored interventions.

CDC25c expression in patients with myelofibrosis is associated with stronger myeloproliferation and shorter overall survival.

BACKGROUND: Cell division cycle 25c (CDC25c) is a gene coding a phosphatase controlling entry into mitosis upon activation through Polo-like kinase 1 (PLK1) and serves as a key regulator of cell division. The CDC25c was reported to be dysregulated in some malignant diseases, but its role in myelofibrosis has not yet been elucidated. METHODS: We have retrospectively investigated CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary [PMF] and 15 secondary myelofibrosis [SMF]) and 12 controls. RESULTS: CDC25c mRNA expression did not significantly differ between PMF, SMF and controls (median ∆CT 3.08 vs 2.86 vs 2.29 for PMF, SMF and controls, respectively; P = 0.162). Patients presenting with higher CDC25c mRNA expression were of older age (P = 0.037), had statistically significantly higher white-blood-cells (P = 0.017), larger liver size (P = 0.022), higher absolute neutrophil (P = 0.010), monocyte (P = 0.050), basophil (P = 0.012), and eosinophil counts (P = 0.013). Patients presenting with high CDC25c mRNA expression had statistically significantly inferior overall survival compared to low CDC25c expression group (HR = 2.99; P = 0.049). Median overall survival was not reached in patients with low and was 44 months in patients with high CDC25c expression. CONCLUSION: Our data suggest that higher CDC25c expression is associated with more proliferative phenotype of myelofibrosis and is prognostic of worse survival. Future studies investigating these interesting associations are warranted.

Patients with dementia and atrial fibrillation less frequently receive direct oral anticoagulants (DOACs) and experience higher thrombotic and mortality risk.

OBJECTIVE: To investigate differences in clinical presentation, anticoagulation pattern and outcomes in patients with dementia and atrial fibrillation (AF). METHODS: A total of 1217 hospitalized patients with non-valvular AF from two institutions were retrospectively evaluated. Diagnosis of dementia was established by a psychiatrist or a neurologist prior to or during hospitalization. Adequacy of warfarin anticoagulation was assessed during follow-up using at least 10 standardized international ratio values. In addition to unmatched comparison, nested case-control study was performed to further evaluate differences in clinical outcomes between patients with and without dementia. RESULTS: A total of 162/1217 (13.3%) patients were diagnosed with dementia. Among other associations, patients with dementia were significantly older with higher number of comorbidities, had lower estimated glomerular filtration rate (eGFR) and lower left ventricular ejection fraction (LVEF), (P < 0.05 for all analyses). Patients with dementia were significantly less likely to receive direct oral anticoagulants (DOACs; 27.2% vs 40.3%; P = 0.001) and were significantly more likely to be inadequately anticoagulated with warfarin (38.9% vs 28.6%; P = 0.008) than patients without dementia. After matching based on age, eGFR, LVEF, and CHA2DS2-VASC patients with dementia were significantly more likely to experience inferior overall survival (HR = 1.8; P = 0.001) and shorter time to thrombosis (HR = 2.3; P = 0.019). CONCLUSION: Our findings speak in support of increased thrombotic and mortality risks in patients with dementia, possibly due to inadequate anticoagulation and higher number of comorbidities.

The Risk of Falling and Consequences of Falling in Patients with Atrial Fibrillation Receiving Different Types of Anticoagulant.

OBJECTIVE: Our objective was to investigate the predictors of falls requiring a visit to the emergency department in patients with nonvalvular atrial fibrillation (AF) receiving different types of anticoagulants and to investigate the clinical consequences of falling in the same population. METHODS: A total of 1217 patients with nonvalvular AF from two institutions were retrospectively evaluated. Each patient underwent a physical examination, and clinical histories and medication profiles were taken from each patient at baseline. RESULTS: The median age of our cohort was 71 years; 52.3% were males, and 86.1% of patients were receiving anticoagulation at study baseline. The 5-year freedom-from-falling rate was 81.6%. The use and type of anticoagulation was not significantly associated with the risk of falling (P = 0.222), whereas higher Morse Fall Scale (MFS), CHA2DS2-VASC (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65-74 years, sex category), and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly [> 65 years], drugs/alcohol concomitantly) scores were significantly associated with a higher hazard of the first fall in univariate analyses. In the multivariate Cox regression model, MFS, older age, osteoporosis, higher levels of high-density lipoprotein cholesterol, higher diastolic blood pressure, and use of amiodarone, diuretics, or short- and medium-acting benzodiazepines were mutually independent predictors of the first fall. Of 163 patients, 93 (57%) had a bone fracture during the fall. Type of anticoagulation significantly affected survival after the first fall (P < 0.001): patients inadequately anticoagulated with warfarin had worse survival rates, and patients receiving apixaban and dabigatran had the best survival rates after the first fall. CONCLUSION: Older patients who had comorbidities and were taking amiodarone, diuretics, or short- or medium-acting benzodiazepines had the highest risk of falls. The type and quality of anticoagulation did not seem to affect the risk of falling but did significantly affect survival after the first fall.

Prognostic implications of low transferrin saturation in patients with primary myelofibrosis.

OBJECTIVES: Transferrin saturation (TSAT) 20% or less is considered to represent functional iron deficiency in the context of malignant disease, phenomenon mediated through inflammatory changes of iron homeostasis. We aimed to investigate clinical and prognostic significance of low TSAT in patients with primary (PMF) and secondary myelofibrosis (SMF), malignant diseases characterized by strong inflammatory milieu. METHODS: We retrospectively analyzed 87 patients with myelofibrosis and compared TSAT with disease specific parameters. RESULTS: One-third of patients had TSAT ≤20%. Lower TSAT was significantly associated with Janus-kinase-2 (JAK2) mutation (P = 0.007), transfusion independency (P = 0.003), higher platelets (P = 0.004), lower mean-corpuscular-volume (P < 0.001), lower ferritin (P < 0.001), higher absolute-neutrophil-count (P = 0.027), lower absolute-lymphocyte-count (P = 0.041) and lower albumin (P = 0.018). PMF patients presenting with low TSAT (≤20%) experienced significantly shorter overall-survival (OS) (HR = 2.43; P = 0.017), whereas TSAT did not affect OS of SMF patients (HR = 1.48; P = 0.623). Low TSAT remained significantly associated with inferior OS in PMF in a series of multivariate Cox regression models comparing its properties to anemia, transfusion dependency, ferritin and Dynamic-International-Prognostic-System (DIPSS). CONCLUSIONS: Low TSAT has detrimental effect on survival of PMF patients. This effect is independent of anemia and of ferritin levels that seem to be better at representing iron overload in PMF patients.

High absolute basophil count is a powerful independent predictor of inferior overall survival in patients with primary myelofibrosis.

OBJECTIVES: To investigate the clinical and prognostic significance of absolute basophil count (ABC) in patients with primary myelofibrosis (PMF). METHODS: We retrospectively investigated 58 patients with PMF treated in our institution in the period from 2006 to 2017. ABC was obtained in addition to other hematological and clinical parameters. Patients were separated into high and low ABC groups using the Receiver operating characteristic curve analysis. RESULTS: ABC was higher in PMF patients than in healthy controls (P < 0.001). Patients with high ABC had higher white blood cells (P < 0.001), higher red cell distribution width (P = 0.035), higher lactate dehydrogenase (P < 0.001), more frequently had circulatory blasts (P < 0.001), constitutional symptoms (P = 0.030) and massive splenomegaly (P = 0.014). ABC was also positively correlated with absolute monocyte count (AMC) (P < 0.001) and other components of differential blood count. There was no difference in ABC regarding driver mutations or degree of bone marrow fibrosis. Univariately, high ABC was significantly associated with inferior overall survival (hazard ratio (HR) 4.79, P < 0.001). This effect remained statistically significant (HR 4.27, P = 0.009) in a multivariate Cox regression model adjusted for age, gender, Dynamic International Prognostic Scoring System (HR 2.6, P = 0.001) and AMC (HR 8.45, P = 0.002). DISCUSSION: High ABC reflects higher disease activity and stronger proliferative potential of disease. ABC and AMC independently predict survival and therefore seem to reflect different underlying pathophysiologic processes. Hence, both have a potential for improvement of current prognostic scores. CONCLUSION: Basophils represent a part of malignant clone in PMF and are associated with unfavorable disease features and poor prognosis which is independent of currently established prognostic scoring system and monocytosis.

Elevated Neutrophil-to-Lymphocyte-ratio and Platelet-to-Lymphocyte Ratio in Myelofibrosis: Inflammatory Biomarkers or Representatives of Myeloproliferation Itself?

BACKGROUND/AIM: We aimed to investigate clinical associations of inflammatory biomarkers neutrophil-to-lymphocyte-ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in patients with myelofibrosis, myeloproliferative neoplasm with inflammatory background. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 102 myelofibrosis patients. NLR and PLR were assessed in addition to other disease-specific parameters. RESULTS: NLR and PLR were significantly higher in myelofibrosis than in healthy controls. Higher NLR was significantly associated with Janus-kinase-2 (JAK2)-mutation, wild-type-Calreticulin (CALR), older age and parameters reflecting increased proliferative potential of disease (higher leukocytes, higher hemoglobin, larger spleen-size), whereas there was no significant association with C-reactive-protein (CRP). Higher PLR was significantly associated with absence of blast-phase-disease, absence of constitutional-symptoms, lower percentage-of-circulatory-blasts, smaller spleen-size and lower CRP. In the Cox-regression-model, higher-NLR (HR=2.76; p=0.004), lower-PLR (HR=1.99; p=0.042) and Dynamic-International-Prognostic-System (DIPSS) (HR=3.26; p<0.001) predicted inferior survival independently of each other. CONCLUSION: In the context of myelofibrosis, elevated NLR and PLR are more likely to represent myeloproliferation itself and not necessary the extent of inflammation.