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Öğe Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease(Oxford University Press, 2022) Silva, Pedro H. Imenez; Unwin, Robert; Hoorn, Ewout J.; Ortiz, Alberto; Trepiccione, Francesco; Nielsen, Rikke; Pesic, Vesna; Hafez, Gaye; Fouque, Denis; Massy, Ziad A.; Zeeuw, Chris I. De; Capasso, Giovambattista; Wagner, Carsten A.Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10–30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKDÖğe Actions to improve medication adherence during the COVID-19 pandemic in Europe(2023) Aarnio, E.; Mucherino, S.; Mihajlovic, J.; Hafez, Gaye; Kamusheva, M.; Leiva-Fernandez, F.; Qvarnstrom, M.; Ekenberg, M.; Treciokiene, I.; Potocnjak, I....Öğe Albuminuria as a risk factor for mild cognitive impairment and dementia—what is the evidence?(Nephrol Dial Transplant, 2021) Bikbov, Boris; Soler, Maria Jose; Pesic, Vesna; Capasso, Giovambattista; Unwin, Robert; Endres, Matthias; Remuzzi, Giuseppe; Perico, Norberto; Gansevoort, Ron; Mattace-Raso, Francesco; Bruchfeld, Annette; Figurek, Andreja; (Cognitive Decline in Nephro-Neurology European Cooperative Target; Hafez, GayeKidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria’s effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria’s link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease.Öğe Animal models to study cognitive impairment of chronic kidney disease(2024) Silva, Pedro H. Imenez; Pepin, Marion; Figurek, Andreja; Gutierrez-Jimenez, Eugenio; Bobot, Mickael; Iervolino, Anna; Mattace-Rosso, Francesco; Hoorn, Ewout J.; Bailey, Matthew A.; Henaut, Lucie; Nielsen, Rikke; Frische, Sebastian; Trepiccione, Francesco; Hafez, Gaye; Altunkaynak, Hande O.; Endlich, Nicole; Unwin, Robert; Capasso, Giovambattista; Pesic, Vesna; Massy, Ziad; Wagner, Carsten A.; Consortium, ConnectMild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD) and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives and society. However, the underlying pathomechanisms are poorly understood and current therapies mostly aim at supporting patients in their daily life. This illustrates the urgent need to elucidate the pathogenesis, and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modelling of cognitive disorders in CKD. We discuss the use of mice, rats and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving therapy of people with CKD and MCI.Öğe Barriers and unmet educational needs regarding implementation of medication adherence management across Europe: insights from cost action enable(2024) Hafez, Gaye; Aarnio, Emma; Mucherino, Sara; Kamusheva, Maria; Qvarnström, Miriam; Potocnjak, Ines; Treciokiene, Indre; Mihajlovic, Jovan; Ekenberg, Marie; Boven, Job F. M. van; Leiva-Fernandez, Francisca; European Network to Advance Best Practices Technology on Medication AdherencE (ENABLE)Background: Medication adherence is essential for the achievement of therapeutic goals. Yet, the World Health Organization estimates that 50% of patients are nonadherent to medication and this has been associated with 125 billion euros and 200,000 deaths in Europe annually. Objective: This study aimed to unravel barriers and unmet training needs regarding medication adherence management across Europe. Design: A cross-sectional study was conducted through an online survey. The final survey contained 19 close-ended questions. Participants: The survey content was informed by 140 global medication adherence experts from clinical, academic, governmental, and patient associations. The final survey targeted healthcare professionals (HCPs) across 39 European countries. Main measures: Our measures were barriers and unmet training needs for the management of medication adherence across Europe. Key results: In total, 2875 HCPs (pharmacists, 40%; physicians, 37%; nurses, 17%) from 37 countries participated. The largest barriers to adequate medication adherence management were lack of patient awareness (66%), lack of HCP time (44%), lack of electronic solutions (e.g., access to integrated databases and uniformity of data available) (42%), and lack of collaboration and communication between HCPs (41%). Almost all HCPs pointed out the need for educational training on medication adherence management. Conclusions: These findings highlight the importance of addressing medication adherence barriers at different levels, from patient awareness to health system technology and to fostering collaboration between HCPs. To optimize patient and economic outcomes from prescribed medication, prerequisites include adequate HCP training as well as further development of digital solutions and shared health data infrastructures across Europe.Öğe Cholinergic system in patients with chronic kidney disease: cognitive and renal implications(2025) Xu, Hong; Eriksdotter, Maria; Hafez, Gaye; Sumonto, Mitra; Bruchfeld, Annette; Pesic, Vesna; Unwin, Robert; Wagner, Carden A.; Massy, Carsten; Massy, Ziad A.; Zoccali, Carmine; Pepin, Marion; Capasso, Giovambattista; Liabeuf, Sophie; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target)Cholinergic synapses are widespread throughout the human central nervous system. Their high density in the thalamus, neocortex, limbic system, and striatum suggests that cholinergic transmission plays a vital role in memory, attention, learning and other higher cognitive functions. As a result, the brain's cholinergic system occupies a central position in research on normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. In addition to its role in the brain, neuronal cholinergic pathways are essential for the physiological regulation of bodily organs, including the kidneys, through the parasympathetic branch of the peripheral nervous system. Chronic kidney disease (CKD) is a non-communicable disease with a global prevalence of approximately 10%. Cognitive impairment is common among patients with CKD, with reported prevalence rates ranging from 30% to 60%, depending on definitions and assessment methods used. Given the importance of the cholinergic system in cognitive processes, it may be a key area of focus for evaluating cognitive function in this population. In this current narrative review, we will first examine evidence linking the cholinergic system to cognitive functions; with a specific focus on drugs that affect this system. we will then discuss the potential implications of cholinergic function in patients with CKD.Öğe Cognitive decline related to chronic kidney disease as an exclusion factor from kidney transplantation: results from an international survey(2024) Farisco, Michele; Blumblyte, Inga, A.; Franssen, Casper; Nitsch, Dorothea; Zecchino, Irene; Capasso, Giovambattista; Hafez, GayeBackground and hypothesis: There seems to be a lack of consensus on the necessity and the modality of psychological and specifically cognitive assessment of candidates for kidney transplantation. Both points are often delegated to individual hospitals/centres, whereas international guidelines are inconsistent. We think it is essential to investigate professionals' opinions to advance towards a consistent clinical practice. Methods: This paper presents the results of an international survey among clinical professionals, mainly nephrologists from the CONNECT (Cognitive decline in Nephro-Neurology: European Cooperative Target) network and beyond (i.e. from personal contacts of CONNECT members). The survey investigated their opinions about the question of whether cognitive decline in patients with chronic kidney disease may affect their eligibility for kidney transplantation. Results: Our results show that most clinicians working with patients affected by chronic kidney disease think that cognitive decline may challenge their eligibility for transplantation despite data that suggest that, in some patients, cognitive problems improve after kidney transplantation. Conclusion: We conclude that three needs emerge as particularly pressing: defining agreed-on standards for a multifaceted and multifactorial assessment (i.e. including both clinical/medical and psychosocial factors) of candidates with chronic kidney disease to kidney transplantation; further investigating empirically the causal connection between chronic kidney disease and cognition; and further investigating empirically the possible partial reversibility of cognitive decline after kidney transplantation.Öğe Öğe Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor(2023) Liabeuf, Sophie; Pesic, Vesna; Spasovski, Goce; Maciulaitis, Romaldas; Bobot, Mickael; Farinha, Ana; Wagner, Carsten A.; Unwin, Robert J.; Capasso, Giovambattista; Bumblyte, Inga Arune; Hafez, GayePeople living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.Öğe Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients(2023) Hafez, Gaye; Malyszko, Jolanta; Golenia, Aleksandra; Klimkowicz-Mrowiec, Aleksandra; Ferreira, Ana Carina; Arıcı, Mustafa; Bruchfeld, Annette; Nitsch, Dorothea; Massy, Ziad A.; Pepin, Marion; Capasso, Giovambattista; Mani, Laila-Yasmin; Liabeuf, SophieThere is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood-brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects.Öğe Drugs with a negative impact on cognitive functions (part 3): antibacterial agents in patients with chronic kidney disease(2024) Liabeuf, Sophie; Hafez, Gaye; Pesic, Vesna; Spasovski, Goce; Bobot, Mickael; Maciulaitis, Romaldas; Bumblyte, Inga Arune; Ferreira, Ana Carina; Farinha, Ana; Malyszko, Jolanta; Pepin, Marion; Massy, Ziad A.; Unwin, Robert; Capasso, Giovambattista; Mani, Laila-Yasmin; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target)The relationship between chronic kidney disease (CKD) and cognitive function has received increased attention in recent years. Antibacterial agents (ABs) represent a critical component of therapy regimens in patients with CKD due to increased susceptibility to infections. Following our reviewing work on the neurocognitive impact of long-term medications in patients with CKD, we propose to focus on AB-induced direct and indirect consequences on cognitive function. Patients with CKD are predisposed to adverse drug reactions (ADRs) due to altered drug pharmacokinetics, glomerular filtration decline, and the potential disruption of the blood-brain barrier. ABs have been identified as a major cause of ADRs in vulnerable patient populations. This review examines the direct neurotoxic effects of AB classes (e.g. beta-lactams, fluoroquinolones, aminoglycosides, and metronidazole) on the central nervous system (CNS) in patients with CKD. We will mainly focus on the acute effects on the CNS associated with AB since they are the most extensively studied effects in CKD patients. Moreover, the review describes the modulation of the gut microbiota by ABs, potentially influencing CNS symptoms. The intricate brain-gut-kidney axis emerges as a pivotal focus, revealing the interplay between microbiota alterations induced by ABs and CNS manifestations in patients with CKD. The prevalence of antibiotic-associated encephalopathy in patients with CKD undergoing intravenous AB therapy supports the use of therapeutic drug monitoring for ABs to reduce the number and seriousness of ADRs in this patient population. In conclusion, elucidating AB-induced cognitive effects in patients with CKD demands a comprehensive understanding and tailored therapeutic strategies that account for altered pharmacokinetics and the brain-gut-kidney axis.Öğe Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review(2024) Barbieri, Michelangela; Chiodini, Paolo; Di Gennaro, Piergiacomo; Hafez, Gaye; Liabeuf, Sophie; Malyszko, Jolanta; Mani, Laila-Yasmin; Raso, Francesco Mattace; Pepin, Marion; Perico, Norberto; Simeoni, Mariadelina; Zoccali, Carmine; Tortorella, Giovanni; Capuano, Annalisa; Remuzzi, Giuseppe; Capasso, Giovambattista; Paolisso, Giuseppe; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) collaboratorsPatients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.Öğe Management of medication adherence across ENABLE COST countries: a pilot study(Springer, 2022) Mucherino, Sara; Aarnio, Emma; Hafez, Gaye; Kamusheva, Maria; Leiva-Fernandez, Francisca; Mihajlovic, Jovan; Qvarnstrom, Miriam[No abstract available]Öğe Methodological challenges and biases in the field of cognitive function among patients with chronic kidney disease(Frontiers Media SA, 2023) Giannakou, Konstantinos; Golenia, Aleksandra; Liabeuf, Sophie; Malyszko, Jolanta; Mattace-Raso, Francesco; Farinha, Ana; Spasovski, Goce; Hafez, Gaye; Wiecek, Andrzej; Capolongo, Giovanna; Capasso, Giovambattista; Massy, Ziad A.Chronic kidney disease (CKD) affects approximately 850 million people globally and is associated with an increased risk of cognitive impairment. The prevalence of cognitive impairment among CKD patients ranges from 30 to 60%, and the link between CKD and cognitive impairment is partially understood. Methodological challenges and biases in studying cognitive function in CKD patients need to be addressed to improve diagnosis, treatment, and management of cognitive impairment in this population. Here, we review the methodological challenges and study design issues, including observational studies’ limitations, internal validity, and different types of bias that can impact the validity of research findings. Understanding the unique challenges and biases associated with studying cognitive function in CKD patients can help to identify potential sources of error and improve the quality of future research, leading to more accurate diagnoses and better treatment plans for CKD patients.Öğe Pan-European survey on medication adherence management by healthcare professionals(2024) Kamusheva, Maria; Aarnio, Emma; Qvarnström, Miriam; Hafez, Gaye; Mucherino, Sara; Potocnjak, Ines; Treciokiene, Indre; Mihajlovic, Jovan; Ekenberg, Marie; Boven, Job F. M. van; Leiva-Fernandez, Francisca; European Network to Advance Best Practices and Technology on Medication AdherencE (ENABLE)Aims: While medication adherence (MA) is a key prerequisite for achieving optimal clinical and economic outcomes, nonadherence is highly prevalent. Assessing how healthcare professionals (HCPs) in Europe manage MA, focusing on measurement, reporting and interventions, is the subject of this study. Methods: A cross-sectional study was conducted among 40 European countries and quantitative analysis was conducted via an online survey. The multi-language online survey was created using Webropol 3.0 survey and reporting tool. Descriptive statistics and chi-squared tests were applied. Results: In total, 2875 HCPs (pharmacists: 39.9%; physicians: 36.7%; nurses: 16.4%) from 37 European countries participated. The most used methods for MA assessment were direct communication with patients (86.4%) and referring to personal patient records (56.7%) (P < 0.0001). Physicians (74.9%) and nurses (58.8%) were more aware of problems related to MA in contrast to pharmacists (48.6%) (P < 0.001). Almost all HCPs (92.6%) indicated that MA-enhancing interventions involved mainly direct communication with nonadherent patients (93.3%) and their caregivers (55.7%). Medication review and related optimization of therapy were mainly performed in Western European countries (46.8%). Technological solutions were ranked as one of the less applied approaches (10-15%) (P < 0.001). Conclusions: HCPs in all European regions recognize MA management as an integral element of overall patient-centred care. More efforts are needed to ensure timely, adequate and relevant MA assessment, reporting and improvement and involvement of all HCPs, especially among pharmacists who were generally less aware of MA issues. Promotion and use of digital technological solutions should be the focus of current and future clinical practice to optimize MA management processes.Öğe The importance of communication and dissemination in a European project on medication adherence(2023) Hafez, Gaye; Goetzinger, C.; Ghiciuc, C.; Menditto, E.; Fernandez, Leiva F.; Dimitrova, M.; Herdeiro, M. T.; Leiva, V. A.; Wettermark, B....Öğe The interface of depression and diabetes: treatment considerations(2025) Fanelli, Giuseppe; Raschi, Emanuel; Hafez, Gaye; Matura, Silke; Schiweck, Carmen; Poluzzi, Elisabetta; Lunghi, CarlottaThis state-of-the-art review explores the relationship between depression and diabetes, highlighting the two-way influences that make treatment challenging and worsen the outcomes of both conditions. Depression and diabetes often co-occur and share genetic, lifestyle, and psychosocial risk factors. Lifestyle elements such as diet, physical activity, and sleep patterns play a role on the development and management of both conditions, highlighting the need for integrated treatment strategies. The evidence suggests that traditional management strategies focusing on either condition in isolation fall short of addressing the intertwined nature of diabetes and depression. Instead, integrated care models encompassing psychological support and medical management are recommended to improve treatment efficacy and patient adherence. Such models require collaboration across multiple healthcare disciplines, including endocrinology, psychiatry, and primary care, to offer a holistic approach to patient care. This review also identifies significant patient-related barriers to effective management, such as stigma, psychological resistance, and health literacy, which need to be addressed through patient-centered education and support systems. Future directions for research include longitudinal studies in diverse populations to further elucidate causal relationships and the exploration of novel therapeutic targets, as well as the effectiveness of healthcare models aimed at preventing the onset of one condition in individuals diagnosed with the other.Öğe The wear-off phenomenon of repeated botulinum toxin injection for chronic migraine treatment: A retrospective study(Turkish Neurosurgical Society, 2024) Ruşen, Emir; Hafez, Gaye; Tunç, YeşimObjectives: This study aimed to evaluate the efficacy, predictors of response, clinical considerations, and analysis of patient-reported wear-off events during injection periods of onabotulinumtoxinA (Onabot-A). Patients and methods: This retrospective study was conducted with 30 adult chronic migraine patients (26 females, 4 males; mean age: 37.9±9.3 years; range, 24 to 72 years) followed between January 2017 and December 2022. All patients received Onabot-A injections at different frequencies throughout their treatment and responded to Onabot-A. The duration between cycles was 3 months in 26 patients, and this period varied in four patients. The Visual Analog Scale scores were measured before and after the injection, all patients responded to Onabot-A. Results: Nine patients stated that they experienced wear-off at least once during their treatment cycles. In some patients, the duration of action lasted less than 12 weeks, resulting in a wear-off phenomenon. Although sex and age were not significant variables in terms of the presence or absence of wear-off phenomenon, the number of Onabot-A injections (Onabot-A treatment cycles) among patients was found to be a statistically significant variable in terms of the presence of wear-off (p<0.011). Conclusion: Repeated treatments using Onabot-A appear to be safe and well-tolerated, but the effectiveness of the drug appears to be affected by wear-off phases that may occur during long-term treatment with Onabot-A.
