Effects of Ibuprofen and Diclofenac Pre-Treatment on Viability and Apoptosis Processes in Human Dental Pulp Stem Cells.

Background and Objectives: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, which is managed by using nonsteroidal anti-inflammatory drugs (NSAIDs). However, information is limited about how NSAIDs affect the therapeutic potential of stem cells. Materials and Methods: We investigated the effects of ibuprofen and diclofenac on the characteristics, morphology, and immunophenotype of human mesenchymal stromal cells isolated from the dental pulp (DPSCs) and cultured in vitro, as well as their effects on the expression of angiogenic growth factors (VEGFA and HGF) and selected genes in apoptosis signalling pathways (BAX, BAK, CASP3, CASP9, and BCL2). Results: Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of HGF, while the expression of VEGFA remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including the upregulation of CASP9 and BCL2, with decreased CASP3 expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. Conclusions: Our results suggest that concomitant use of the NSAIDs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, affecting the efficacy of stem cell therapy.

Atorvastatin Treatment Significantly Increased the Concentration of Bone Marrow-Derived Mononuclear Cells and Transcutaneous Oxygen Pressure and Lowered the Pain Scale after Bone Marrow Cells Treatment in Patients with "No-Option" Critical Limb Ischaemia.

BACKGROUND: The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with "no-option" critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy related to the therapeutic efficacy of BMCs treatment. METHODS: In the present study, we reviewed thirty-three patients (mean age 64.9 ± 10 years; 31 males) with advanced CLI after failed or impossible revascularisation, who were treated with 40 mL of autologous BMCs by local intramuscular application. Patients with limb salvage and wound healing (N = 22) were considered as responders to BMCs therapy, and patients with limb salvage and complete ischemic wound healing (N = 13) were defined as super-responders. Logistic regression models were used to screen and identify the prognostic factors, and a receiver operating characteristics (ROC) curve, a linear regression, and a survival curve were drawn to determine the predictive accuracy, the correlation between the candidate predictors, and the risk of major amputation. RESULTS: Based on the univariate regression analysis, baseline C-reactive protein (CRP) and transcutaneous oxygen pressure (TcPO2) values were identified as prognostic factors of the responders, while CRP value, ankle-brachial index (ABI), and bone marrow-derived mononuclear cells (BM-MNCs) concentration were identified as prognostic factors of the super-responders. An area under the ROC curve of 0.768 indicated good discrimination for CRP > 8.1 mg/L before transplantation as a predictive factor for negative clinical response. Linear regression analysis revealed a significant dependence between the levels of baseline CRP and the concentration of BM-MNCs in transplanted bone marrow. Patients taking atorvastatin before BMCs treatment (N = 22) had significantly improved TcPO2 and reduced pain scale after BMCs transplant, compared to the non-atorvastatin group. Statin treatment was associated with reduced risk for major amputation. However, the difference was not statistically significant. Statin use was also associated with a significantly higher concentration of BM-MNCs in the transplanted bone marrow compared to patients without statin treatment. Patients treated with RAS-acting agents (N = 20) had significantly reduced pain scale after BMCs transplant, compared to the non-RAS-acting agents group. Similar results, reduced pain scale and improved TcPO2, were achieved in patients treated with atorvastatin and RAS-acting agents (N = 17) before BMCs treatment. Results of the Spearman correlation showed a significant positive correlation between CLI regression, responders, and previous therapy before BMCs transplant with RAS-acting agents alone or with atorvastatin. CONCLUSIONS: CRP and TcPO2 were prognostic factors of the responders, while CRP value, ABI, and BM-MNCs concentration were identified as predictive factors of the super-responders. Atorvastatin treatment was associated with a significantly increased concentration of BM-MNCs in bone marrow concentrate and higher TcPO2 and lower pain scale after BMCs treatment in CLI patients. Similarly, reduced pain scales and improved TcPO2 were achieved in patients treated with atorvastatin and RAS-acting agents before BMCs treatment. Positive correlations between responders and previous treatment before BMCs transplant with RAS-acting agents alone or with atorvastatin were significant.

Multivessel Coronary Disease and Severe Atherosclerotic Aorta: Real-World Experience.

Background and Objectives: Surgical revascularisation of patients with atherosclerosis of the ascending aorta remains a challenge. Different surgical strategies have been described in coronary surgical patients to offer alternative revascularisation strategies other than the conventional surgical revascularisation in patients unsuitable for it. The aim of this study is to compare the real-world outcomes between two groups of patients who underwent off-pump surgery (left internal mammary artery graft to the left anterior descending artery) or a hybrid with a percutaneous revascularisation procedure at a later stage. Materials and Methods: This is a single-centre retrospective observational study. Between the years 2010 and 2021, 91/6863 patients (1.33%) were diagnosed with severe atherosclerosis of the ascending aorta. All the patients were treated with off-pump revascularisation (91 patients), and the cardiologist would decide at a later stage whether the rest of the vessels would be treated with percutaneous revascularisation (25 patients). Results: There was no statistical difference in the various preoperative characteristics, except for coronary artery left main disease (30.30% vs. 64%; p = 0.0043). The two groups had no statistical differences in the perioperative characteristics and postoperative complications. The 1-, 5-, and 10-year mortality rates in the two groups were 6.1% vs. 0%, 59% vs. 80%, and 93.9% vs. 100%, respectively (off-pump vs. hybrid with percutaneous revascularisation procedure, p = 0.1958). Conclusions: Both strategies have high long-term comparable mortality. The off-pump surgery and the HCR procedure at a later stage may be solutions for these high-risk patients, but the target treatment should be complete HCR revascularisation during the index hospitalization.

Selective inhibitors of cyclooxygenase 2 - their past, present and future.

Pain is a serious subjective experience, which, although it has a protective nature, it physically and mentally exhausts the patient. The pharmacological field of development and research in the treatment and relief of pain has been dynamic and interesting ever since the isolation of salicylic acid. After discovering the molecular nature of cyclooxygenase and its inhibition, research focused on selective COX-2 inhibitors, but they were a big disappointment. Today, the possibility of contributing to safe and effective analgesic-antiphlogistic treatment for the patient with a combination of drugs is emerging again.

New trends in advanced parkinson disease stage therapy.

The aim of the study was to point out the contribution of new invasive therapeutic procedures in the treatment of advanced stages of Parkinson's disease (PD) in comparison with classical oral pharmacotherapy. Data originated from a group of 43 patients with PD, 39% (17) with classic treatment, 23% (10) with intestinal gel of methyl ester levodopa (Duodopa), 19% (8) of patients were using subcutaneous delivery of apomorphine (APO) and the same quantity of patients had undergone deep brain stimulation (DBS). Majority of patients had advanced stages of PD, stage 4, by standards of Hoehn and Yahr scale (Hoehn and Yahr, 1967). Research observed improvement in majority of patients with novel treatments. A positive effect was also noted in the reduced need for oral therapy, where there was a significant decrease in all new therapies. Benefits were observed in the amount of antiparkinsonic drugs taken per os, where we observed reduction in all new therapies. A positive effect of the new therapeutic approaches in reducing "off" periods in patients has also been noted. In the case of Duodopa and DBS, the "off" period was shortened up to 50% and in the apomorphine pump up to 40%. Patients also reported reduction of some symptoms like rigidity, tremor and bradykinesis while dyskinesis still remains suba challenge. On the basis of the obtained results, it can be concluded that new therapeutic procedures for PCh will make it possible to manage symptoms typical of advanced stages of the disease, which without these procedures would lead to disability, which is the main reason for their indication. However, in early stages, well responding patients or in slow progressing disease oral antiparkinsonics are remaining as golden standard of treatment. This is not just due to good response but also because these classic drug formulations are significantly less expensive. In Slovakia, novel treatments are accessible through healthcare insurance only after secondary revision by insurance company doctors.

Effect of Atorvastatin on Angiogenesis-Related Genes VEGF-A, HGF and IGF-1 and the Modulation of PI3K/AKT/mTOR Transcripts in Bone-Marrow-Derived Mesenchymal Stem Cells.

Stem cell transplantation represents a unique therapeutic tool in tissue engineering and regenerative medicine. However, it was shown that the post-injection survival of stem cells is poor, warranting a more comprehensive understanding of activated regenerative pathways. Numerous studies indicate that statins improve the therapeutic efficacy of stem cells in regenerative medicine. In the present study, we investigated the effect of the most widely prescribed statin, atorvastatin, on the characteristics and properties of bone-marrow-derived mesenchymal stem cells (BM-MSCs) cultured in vitro. We found that atorvastatin did not decrease the viability of BM-MSCs, nor did it change the expression of MSC cell surface markers. Atorvastatin upregulated the mRNA expression levels of VEGF-A and HGF, whereas the mRNA expression level of IGF-1 was decreased. In addition, the PI3K/AKT signaling pathway was modulated by atorvastatin as indicated by the high mRNA expression levels of PI3K and AKT. Moreover, our data revealed the upregulation of mTOR mRNA levels; however, no change was observed in the BAX and BCL-2 transcripts. We propose that atorvastatin benefits BM-MSC treatment due to its ability to upregulate angiogenesis-related genes expression and transcripts of the PI3K/AKT/mTOR pathway.

Physical properties and biological effects of ceramic materials emitting infrared radiation for pain, muscular activity, and musculoskeletal conditions.

BACKGROUND: Up to 33% of the general population worldwide suffer musculoskeletal conditions, with low back pain being the single leading cause of disability globally. Multimodal therapeutic options are available to relieve the pain associated with muscular disorders, including physical, complementary, and pharmacological therapies. However, existing interventions are not disease modifying and have several limitations. METHOD: Literature review. RESULTS: In this context, the use of nonthermal infrared light delivered via patches, fabrics, and garments containing infrared-emitting bioceramic minerals have been investigated. Positive effects on muscular cells, muscular recovery, and reduced inflammation and pain have been reported both in preclinical and clinical studies. There are several hypotheses on how infrared may contribute to musculoskeletal pain relief, however, the full mechanism of action remains unclear. This article provides an overview of the physical characteristics of infrared radiation and its biological effects, focusing on those that could potentially explain the mechanism of action responsible for the relief of musculoskeletal pain. CONCLUSIONS: Based on the current evidence, the following pathways have been considered: upregulation of endothelial nitric oxide synthase, increase in nitric oxide bioavailability, anti-inflammatory effects, and reduction in oxidative stress.

First report of nosocomial outbreak of vancomycin-resistant Enterococcus faecium infection among COVID-19 patients hospitalized in a non-intensive care unit ward in Slovakia.

BACKGROUND: Enterococcus species account for most of the human enterococcal HAI and multidrug-resistant infections and have become a major threat to modern public health. We examine the rise in the number of vancomycin resistant E. faecium blood stream and urinary tract infections in a COVID-19 department during an epidemiologic outbreak investigation to detect and eliminate nosocomial clusters of the bacteria. METHODS:  Strain identification was performed by classical isolation and biochemical and cultivation methods. Antibiotic testing results were interpreted according to European committee on antimicrobial susceptibility testing (EUCAST) guidelines. Six isolated samples underwent the whole genome sequencing (WGS) during the outbreak investigation. Isolate relatedness was determined using the core genome multi-locus sequence typing. RESULTS:  WGS revealed two genotypically distinct VRE clusters, one of which had genetically closely related patients and environmental isolates. The cluster was terminated by enhanced infection control strategies. CONCLUSIONS:  This study provides the first description of an outbreak caused by vanB-ST117 and vanA-ST17 E. faecium strains among COVID-19 patients in Slovakia. This study can help to raise the awareness about the need for strict adherence to infection control measures and the implementation of rational antimicrobial stewardship as a routine part of COVID-19 management (Tab. 3, Fig. 3, Ref. 27). Text in PDF www.elis.sk Keywords: vancomycin-resistant Enterococcus faecium, antibiotic resistant, COVID-19, SARS-CoV-2, bacterial outbreak, healthcare-associated infection.

Improvement of the Clinical and Psychological Profile of Patients with Autism after Methylcobalamin Syrup Administration.

(1) Background: Autism, also known as autism-spectrum disorder, is a pervasive developmental disorder affecting social skills and psychological status in particular. The complex etiopathogenesis of autism limits efficient therapy, which leads to problems with the normal social integration of the individual and causes severe family distress. Injectable methylcobalamin was shown to improve the clinical status of patients via enhanced cell oxidative status and/or methylation capacity. Here we tested the efficiency of a syrup form of methylcobalamin in treating autism. (2) Methods: Methylcobalamin was administered daily at 500 µg dose to autistic children and young adults (n = 25) during a 200-day period. Clinical and psychological status was evaluated by parents and psychologists and plasma levels of reduced and oxidized glutathione, vitamin B12, homocysteine, and cysteine were determined before the treatment, and at day 100 and day 200 of the treatment. (3) Results: Good patient compliance was reported. Methylcobalamin treatment gradually improved the overall clinical and psychological status, with the highest impact in the social domain, followed by the cognitive, behavioral and communication characteristics. Changes in the clinical and psychological status were strongly associated with the changes in the level of reduced glutathione and reduced/oxidized glutathione ratio. (4) Conclusion: A high dose of methylcobalamin administered in syrup form ameliorates the clinical and psychological status of autistic individuals, probably due to the improved oxidative status.

Normalization strategy for selection of reference genes for RT-qPCR analysis in left ventricles of failing human hearts.

BACKGROUND: Quantitative RT-PCR is a valuable tool for assessing the gene expression in different human tissues, particularly due to its exceptional sensitivity, accuracy and reliability. However, the choice of adequate control for normalization is a crucial step, greatly affecting the results of all subsequent analyses. So far, only a few studies were focused on the selection of optimal reference genes in left ventricles of failing human hearts, leading to several disparities in experimental results focused on differential gene expression in this area. Therefore, the main objective of this study was to identify a set of suitable reference genes in normal and failing left ventricle tissues, which could increase the reliability of RT-qPCR-based studies in the future. METHODS: We analyzed the expression of 15 commonly used housekeeping genes (ACTB, B2M, GAPDH, GUSB, HMBS, HPRT1, IPO8, PGK1, POLR2A, PPIA, RPLP0, TBP, TFRC, UBC and YWHAZ) in left ventricles of normal and failed hearts with two-step approach. In the first step, we excluded genes which are variantly expressed using ANOVA-based statistical method. Afterwards, the remaining genes were analyzed using geNorm, NormFinder and BestKeeper algorithms, together with delta Cq method. Finally, the geometric mean of gene rankings across all methods was calculated. RESULTS: Our analysis identified IPO8 and POLR2A as the most stably expressed genes, whereas ACTB and B2M were found to be expressed variantly, suggesting a potential role of these genes in the pathophysiological processes in failing human hearts. DISCUSSION/CONCLUSION: Using our two-step approach, we identified and validated two reference genes expressed invariantly in left ventricles of both healthy and failing human hearts, as well as provided a guideline for the selection of reference genes in studies comparing gene expression in these types of tissues.

Effect of Pillbox Organizers with Alarms on Adherence to Pharmacotherapy in Parkinson Disease Patients Taking Three and More Daily Doses of Dopaminergic Medications.

Improvement of adherence to pharmacotherapy in patients with Parkinson's disease (PD) is a challenge in routine clinical practice. Our study was aimed at the effect of pillbox organizers with alarms improving adherence to pharmacotherapy and its impact on clinical outcomes. Forty nonadherent patients with PD being treated with ≥ 3 daily doses of levodopa and/or dopamine agonists were pseudorandomized and consecutively ranked to groups A (early-start intervention) and B (delayed-start intervention). We used the following validated diagnostic instruments: MMAS-8 (adherence), PDQ-8 (quality of life, QoL), GDS (depression), NMSS (non-motor symptoms), MDS-UPDRS III (motor involvement), MDS-UPDRS IV, and WOQ-9 (motor and non-motor fluctuations and dyskinesias). We proved a significantly improved rate of adherence with the use of pillbox organizers with alarms. Moreover, after only four weeks of using the pillbox organizer, we detected an improvement in QoL scores, motor involvement, motor-, and non-motor fluctuations. Our study showed that pillbox organizers with alarms are efficient in improving adherence to pharmacotherapy in PD. It also could contribute to better motor states, less severe fluctuations, and improved QoL.

Patients with COVID-19 pneumonia with 25(OH)D levels lower than 12 ng/ml are at increased risk of death.

OBJECTIVES: There is no consensus on specific serum 25-hydroxy vitamin D (25(OH) D) levels associated with higher risk of severe outcome in patients with coronavirus disease 2019 (COVID-19). According to the literature patients with serum 25(OH) D levels <12 ng/ml are clearly deficient at all ages. Our aim was to assess COVID-19 mortality in the settings of severe 25(OH) D deficiency. A cohort study of 357 patients with COVID-19 was conducted. Subjects were monitored until discharge or in-hospital death. At admission, severity parameters (C-reactive protein (CRP), IL-6, Charlson comorbidity index, etc.) were assessed. These parameters were compared regarding 25(OH) D levels threshold 12 ng/ml, where values below 12 ng/ml were considered absolute vitamin D deficiency. RESULTS: 25(OH) D levels at the time of admission were independently associated with mortality (p <0.05). Nonsurvivors (N = 168) had lower 25(OH) D levels, SO2, higher age, CRP, viral load, and Charlson comorbidity index in comparison to survivors. Patients with serum 25(OH) D levels <12 ng/ml had higher mortality (55% vs 45 %), viral load (21.5 vs 23.1), and Charlson comorbidity index (5.3 vs 4.4) than those with serum 25(OH) D levels >12 ng/ml (p <0.05). CONCLUSIONS: Patients with COVID-19 with serum 25(OH) D levels <12 ng/ml have higher mortality. Among other factors, severe vitamin D deficiency likely leads to poor outcome.

Advanced glycation end products predict long-term outcome of catheter ablation in paroxysmal atrial fibrillation.

PURPOSE: Oxidative stress is an important contributor to the etiology of atrial fibrillation (AF). Our aim was to study oxidative stress biomarkers in patients undergoing pulmonary vein isolation (PVI) for paroxysmal AF with radiofrequency catheter ablation and to assess its prognostic value in predicting long-term PVI outcome. METHODS: In this prospective cohort study, we included 62 patients (mean age 55±8 years, 12 females and 50 males) with paroxysmal AF and implanted ECG loop recorders who underwent PVI. Plasmatic concentrations of advanced glycation end-products (AGEs), fructosamine, advanced oxidation protein products, and thiobarbituric-acid reacting substances were measured before PVI. AF burden (percentage of time spent in AF) was continually assessed during the follow-up period (1063±271 days). RESULTS: Nineteen patients (31%) were defined as optimal responders (oR) with AF burden < 0.5% after PVI. Remaining 43 patients (69%) were defined as sub-optimal responders. Concentration of AGEs was significantly lower in oR by 3.7 g/g (CI: -6.5 to -1.7; P=0.0003). After adjustment for age, sex, BMI, left atrial size, arterial hypertension, and AF burden before PVI, only low concentration of AGEs remained significantly associated with oR (odds ratio: 1.3; P=0.04). AGEs concentration achieved area under the curve of 0.78 for predicting optimal long-term PVI response. CONCLUSIONS: AGEs concentration before PVI was associated with long-term PVI outcome in patients with paroxysmal AF. Further research will show if this biomarker could contribute to optimal patient selection for catheter ablation.

Association Between Apelin and Atrial Fibrillation in Patients With High Risk of Ischemic Stroke.

Background: Atrial fibrillation (AF) is associated with high risk of stroke preventable by timely initiation of anticoagulation. Currently available screening tools based on ECG are not optimal due to inconvenience and high costs. Aim of this study was to study the diagnostic value of apelin for AF in patients with high risk of stroke. Methods: We designed a multicenter, matched-cohort study. The population consisted of three study groups: a healthy control group (34 patients) and two matched groups of 60 patients with high risk of stroke (AF and non-AF group). Apelin levels were examined from peripheral blood. Results: Apelin was significantly lower in AF group compared to non-AF group (0.694 ± 0.148 vs. 0.975 ± 0.458 ng/ml, p = 0.001) and control group (0.982 ± 0.060 ng/ml, p < 0.001), respectively. Receiver operating characteristic (ROC) analysis of apelin as a predictor of AF scored area under the curve (AUC) of 0.658. Apelin's concentration of 0.969 [ng/ml] had sensitivity = 0.966 and specificity = 0.467. Logistic regression based on manual feature selection showed that only apelin and NT-proBNP were independent predictors of AF. Logistic regression based on selection from bivariate analysis showed that only apelin was an independent predictor of AF. A logistic regression model using repeated stratified K-Fold cross-validation strategy scored an AUC of 0.725 ± 0.131. Conclusions: Our results suggest that apelin might be used to rule out AF in patients with high risk of stroke.

Evaluation of efficacy and safety of systemic and topical intra-articular administration of tranexamic acid in primary unilateral total hip arthroplasty.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent used to reduce bleeding in major surgical procedures. This study evaluates the efficacy and safety of the systemic and topical intra-articular administration of TXA in total hip arthroplasty (THA). METHODS: Patients (N = 123) scheduled for primary unilateral THA were divided into 3 treatment groups: control group; TXA, systemic, repeated 1 g bolus; TXA, topically intra-articularly, 2 g in 50 mL saline. Primary readouts used were intra- and postoperative bleeding, transfusion requirement, postoperative hemoglobin levels and complications. RESULTS: Both systemic and topical intra-articular TXA administrations decreased bleeding and transfusion requirements. Topical intra-articular use of TXA led to the reduction in intraoperative and postoperative bleeding and affected hemoglobin levels compared with control. Systemic administration of TXA led to a significant reduction of postoperative bleeding and transfusion rate compared with control and was not different in efficacy and complication incidence when compared to topical administration of TXA. CONCLUSIONS: The use of TXA to reduce blood loss and transfusion requirements in THA is an effective and safe concept in practice. The dose of 2 g TXA topically intra-articularly and a repeated bolus of 1 g TXA systematic led to lower intra- and postoperative bleeding and a significantly lower transfusion rate than the control group. Topical intra-articular TXA administration could be a reasonable alternative in high-risk patients.

Intercalated disc protein Xinß is required for Hippo-YAP signaling in the heart.

Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinß, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinß in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinß mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinß knock-out mice-indicating a functional and genetic interaction between Xinß and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinß modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.

Ibrutinib treatment of mantle cell lymphoma complicated by progressive multifocal leukoencephalopathy
.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system, caused by reactivation of John Cunningham polyomavirus, affecting mainly patients in an immunocompromised state. Recently, drug-associated PML is gaining attention as more cases of PML in connection with the use of various immunomodulatory drugs emerge. Over the last couple of years, sporadic reports have occurred about a possible association between PML and the use of a new immunomodulatory drug, ibrutinib (Imbruvica), primarily indicated for the treatment of various B-cell malignancies. CASE REPORT: Herein, we report a case of a 62-year-old female patient with bilateral mantle cell lymphoma of conjunctiva diagnosed at IVA clinical stage (according to the Ann Arbor staging of lymphomas) of the disease. As a first line of treatment, the patient was given 6 cycles of rituximab-based chemotherapy followed by a complete remission. Seven years later, the patient relapsed, at which point the treatment with ibrutinib was initiated. Three weeks after the initial dosage, the patient started to show signs of progressive neurological symptomatology and died 4 months thereafter due to bilateral bronchopneumonia. Due to unspecific MRI signs and negative PCR results, the diagnosis of PML was confirmed only postmortem. CONCLUSION: This case report demonstrates a possible severe adverse effect of the immunomodulatory drug ibrutinib and the importance of a multidisciplinary approach in its diagnosis. Since PML is a rare but highly fatal disease, it is of utmost importance to be aware of the possible connection with the use of this drug to prevent missed or delayed diagnosis, considering that timely therapeutic intervention is crucial for improved prognosis.

A Randomized, Double-Blind, Placebo-Controlled Trial of Ibuprofen Lysinate in Comparison to Ibuprofen Acid for Acute Postoperative Dental Pain.

INTRODUCTION: Ibuprofen acid is poorly soluble in the stomach, thus reaching maximum plasma levels at approximately 90 min post-dose. Ibuprofen lysinate has been developed to accelerate absorption of ibuprofen to shorten the time to analgesic efficacy. This study compared analgesic efficacy and onset of effect of a single dose of ibuprofen lysinate or ibuprofen acid in patients undergoing third molar extraction. METHODS: Randomized, double-blind, placebo-controlled, multi-center, parallel-group single-dose study. Adults (18-60 years) undergoing extraction of ≥ 1 third molar were randomized 2:2:1 to ibuprofen lysinate, ibuprofen acid, or placebo postoperatively. Pain relief (PAR, 5-point scale, 0 = none to 4 = complete pain relief) and pain intensity (PI, 100 mm visual analog scale) were assessed between 15 and 360 min post-dose. The primary endpoint was the weighted sum of PAR scores at 6 h (TOTPAR). Time to onset of effect, global assessment of efficacy, and adverse events were also assessed. RESULTS: Overall, 351 patients received ibuprofen lysinate (N = 141), ibuprofen acid (N = 139), or placebo (N = 71). Both active treatments significantly reduced pain compared with placebo, from 15 min post-dose to 6 h (TOTPAR: ibuprofen lysinate: 19.57; ibuprofen acid: 19.96; placebo: 8.27). Ibuprofen lysinate was significantly more effective than placebo, but non-inferior to ibuprofen acid, at providing pain relief over 6 h. There was no significant difference between ibuprofen lysinate and ibuprofen acid for onset of analgesia. Both ibuprofen formulations were well tolerated; all adverse events were mild to moderate and considered unrelated to treatment. CONCLUSIONS: A single dose of ibuprofen lysinate is non-inferior to ibuprofen acid in terms of analgesic efficacy, onset of action, and tolerability in patients who have recently undergone dental surgery. TRIAL REGISTRATION: EudraCT No. 2006-006942-33. Plain language summary available for this article.

Predictive value of CHA2DS2-VASc scores regarding the risk of stroke and all-cause mortality in patients with atrial fibrillation (CONSORT compliant).

BACKGROUND: Patients with atrial fibrillation (AF) have a higher risk of fatal complications (e.g., stroke). This investigation was performed as an observational retrospective cohort study includes 137 patients (age 61 ±â€Š15; 34.3% women) with a primary diagnosis of AF (paroxysmal, persistent, and permanent). METHODS: We collected information about the drug therapy, comorbidities and survival of AF patients and determined their congestive heart failure, hypertension, age, diabetes mellitus, prior stroke or TIA or thromboembolism, vascular disease, age, sex category (CHA2DS2-VASc) scores. Statistical analysis identified patients with high CHA2DS2-VASc scores and defined the predictive value of individual parameters, or their combination, with regards to the outcomes of stroke and mortality. RESULTS: CHA2DS2-VASc scores identified 43.8% of the patients as low to intermediate risk (score 0-1) and 56.2% of the patients as high risk (score ≥2). Increasing CHA2DS2-VASc scores were not only accompanied by an increase in the incidence of stroke (Ptrend < .001) but also by an increase in the 3 to 5 years mortality (P = .005). Comparison of anticoagulation and anti-aggregation treatment between the 3 groups of AF did not show any significant statistical difference. Highly significant predictors of death were the CHA2DS2-VASc score (OR 1.71, 95% CI 1.10-2.67, P < .017) as well as other risk factors not included in the CHA2DS2-VASc score such as valvular heart disease (OR 5.04, 95% CI 1.10-23.10, P = .037), hyperlipidemia (OR 4.82, 95% CI 1.03-22.63, P = .046) and chronic renal failure (OR 14.21, 95% CI 2.41-83.91, P = .003). The type of AF type did not affect survival (P = .158) nor the incidence of stroke (P = .466). Patients with paroxysmal AF were linked to significantly lower frequencies of ischemic heart disease (P < .0001), vascular disease (P = .002), diabetes mellitus (P = .047), valvular heart disease (P = .03) and heart failure/left ventricular dysfunction (P = .015). CONCLUSION: The CHA2DS2-VASc score correctly predicted the patients at high-risk for 3 to 5 years mortality and confirmed its significant predictive value in the patients with AF.

Adherence to Pharmacotherapy in Patients With Parkinson's Disease Taking Three and More Daily Doses of Medication.

Background: Once-daily treatment formulation is associated with better adherence in comparison to more complex medication regimens. The study aimed to detect the extent of adherence to pharmacotherapy in Parkinson disease (PD) patients who take a minimum of three daily doses of drugs, and to identify factors associated with lower levels of adherence. Methods: The cohort was selected from non-demented PD patients. The 8-Item Morisky Medication Adherence Scale (MMAS-8), 8-Item Parkinson's Disease Questionnaire (PDQ-8), Geriatric Depression Scale (GDS), Non-Motor Symptom Assessment Scale (NMSS), 9-Item Wearing-off Questionnaire (WOQ-9), MDS-UPDRS III (motor examination), and IV (motor complications) scales were used in this study. Results: From a total of 124 subjects, 33.9% reported a high level of adherence, 29.8% reported a medium level of adherence, and 36.3% reported a low level of adherence to their pharmacotherapy. The level of non-adherence correlated with gender, longer disease duration, higher scores of PDQ-8, NMSS, WOQ-9, and MDS-UPDRS IV. Detailed analysis of NMSS demonstrated a correlation between the level of adherence and domains sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary symptoms. Independent risk factors for non-adherence were excessive daytime sleepiness, anhedonia, and forgetfulness. Conclusion: Non-adherence to more complicated medication regimens is frequent in PD patients and is associated with gender, longer PD duration, poorer quality of life, frequency and severity of non-motor symptoms, and more severe motor and non-motor fluctuations. Non-adherence was predicted by non-motor symptoms including fatigue, mood disturbances, and subjective cognitive complaints.