Exploration of the effects of an innovative mentalization-based training on patient-centered communication skills of pharmacy staff: A video-observation study.

OBJECTIVE: To explore whether a mentalization-based communication training for pharmacy staff impacts their ability to elicit and recognize patients' implicit and explicit medication related needs and concerns. METHODS: A single-arm intervention pilot study was conducted, in which pre-post video-recordings of pharmacy counter-conversations on dispensed-medication (N = 50 and N = 34, respectively; pharmacy staff: N = 22) were coded. Outcome measures included: detecting needs and concerns, and implicitly and explicitly eliciting and recognizing them. Descriptive statistics and a multi-level logistic regression were conducted. Excerpts of videos with needs or concerns were analyzed thematically on mentalizing attitude aspects. RESULTS: Indications show that patients more often express their concerns in an explicit way post-measurement, just as pharmacy staffs' explicit recognition and elicitation of needs and concerns. This was not seen for patients' needs. No statistically significant differences were found for determinants for detecting needs or concerns (i.e., measurement-, professional-type, or interaction). Differences in mentalizing attitude were observed between pre-post-measurements, e.g., more attention for patients. CONCLUSION: This mentalizing training shows the potential of mentalizing to improve pharmacy staff members' explicit elicitation and recognition of patients' medication-related needs and concerns. PRACTICE IMPLICATIONS: The training seems promising for improving patient-oriented communication skills in pharmacy staff. Future studies should confirm this result.

Physical fitness and its association with fatigue in patients with low-grade glioma.

PURPOSE: To evaluate physical fitness and its association with fatigue in patients with low grade glioma (LGG). METHODS: Cross-sectional study. Muscle strength was measured with a digital dynamometer, cardiorespiratory fitness (peak oxygen uptake (VO2peak), maximal workload (MWL)) by cardiopulmonary-exercise-testing, and fatigue by using the Multidimensional Fatigue Inventory. RESULTS: Thirty patients were included, mean age of 44.1 (SD11.2) years, and 67% were men, 31.2 (SD18) months post-diagnosis. Muscle strength (p < 0.01), and cardiorespiratory fitness (VO2peak, MWL) (p < 0.01) were significantly decreased compared to predicted values based on age and gender. Thirty percent of the patients experienced severe physical fatigue, and severe mental fatigue was reported in 57% of the patients. Cardiorespiratory fitness showed weak to moderate (r - 0.46 to r - 0.52) but significant (p < 0.01) correlations with physical fatigue, not with mental and general fatigue. Muscle strength was not associated with fatigue. A lower VO2peak was independently associated with a higher level of physical fatigue, adjusted for Karnofsky Performance Status (R2 0.40). CONCLUSIONS: Physical fitness (muscle strength, cardiorespiratory fitness) is reduced in patients with LLG, and a lower level of cardiorespiratory fitness (VO2peak) is independently associated with a higher level of experienced physical fatigue. Trials to explore the benefit of exercise programs to improve cardiorespiratory fitness and, consequently, fatigue are warranted.Implications for rehabilitationPhysical fitness (muscle strength and cardiorespiratory fitness) is reduced in patients with low-grade glioma.Patients with low-grade glioma should be screened for fatigue with the multidimensional fatigue inventory, to differentiate between mental and physical fatigue.Patients with low-grade glioma with severe physical fatigue should be screened for reduced physical fitness, especially cardiorespiratory fitness by objective cardiopulmonary-exercise-testing.Rehabilitation exercise programs to improve cardiorespiratory fitness and, consequently, (physical) fatigue could be warranted in patients with low-grade glioma.

The relationship between mental fatigue, cognitive functioning, and employment status in patients with low-grade glioma: a cross-sectional single-center study.

PURPOSE: To evaluate fatigue and cognitive functioning in patients with low-grade glioma and to assess whether cognitive functioning and employment status differ between patients with severe and non-severe mental fatigue. METHODS: Cross-sectional study. Fatigue was measured with the multidimensional fatigue inventory, objective cognitive functioning with a neuropsychological test battery, and mood with the Center for Epidemiological Studies Depression Scale. RESULTS: Thirty-one patients, mean age 44 ± 11, mean time post-diagnosis 2.5 ± 1.4 years, participated. Severe mental fatigue was present in 55% and depression in 36% of the patients. Attention deficits were observed in 75% (Stroop's test), memory deficits in 36% (Rey Auditory Verbal Learning Test), and executive functioning deficits in 42% (Stroop's test). Severe mental fatigue patients demonstrated significantly worse scores on Stroop's test-Card-II (p = 0.043), Trail Making Test-B (p = 0.014), Trail Making Test-B/A (p = 0.014), and Digit-Span (p = 0.046), compared to non-severe mental fatigue patients. Severe mental fatigue patients worked significantly less hours per week (p = 0.013) and had more changes in their employment status (p = 0.009) after diagnosis. CONCLUSIONS: Patients with low grade glioma show high rates of fatigue, especially in the mental domain, which might be associated with deficits in cognitive functioning and changes in employment status.Implications for rehabilitationThe majority of patients with low grade glioma suffers from severe mental fatigue and has deficits in cognitive functioning, which may affect employment status.Patients with low grade glioma should be screened for fatigue with the multidimensional fatigue inventory, to differentiate between mental and physical fatigue.Patients with low grade glioma with severe mental fatigue should be screened for problems in cognitive functioning with an objective neuropsychological test battery.Cognitive and vocational rehabilitation programs should aim at coping with severe mental fatigue and attention deficits in patients with low grade glioma.

European principles of care for women and girls with inherited bleeding disorders.

INTRODUCTION: Despite increasing awareness of issues faced by women and girls with inherited BDs (WGBD), standards of care are lacking, with disparities in diagnosis and treatment for WGBD across Europe. We aimed to develop practical principles of care (PoC) to promote standardization of care for WGBD within European Haemophilia Treatment and Comprehensive Care Centres (HTC/CCCs). METHODS: The co-creation process, supported by the European Association for Haemophilia and Allied Disorders, consisted of four multidisciplinary meetings with health care providers (HCPs) experienced in WGBD care, and European Haemophilia Consortium representatives, combined with broad patient and HCP consultations in the European haemophilia community. Relevant medical societies outside Europe were contacted for confirmation. RESULTS: We developed ten PoC for WGBD, stressing the importance and benefits of a centralized, multidisciplinary, comprehensive, family-centred approach to support and manage WGBD during all life stages. These PoC emphasise the right to equitable access and quality of care for all people with BDs, irrespective of gender. Multiple medical societies outside Europe also confirmed their support for endorsement. CONCLUSIONS: Ten PoC for WGBD evolved from an iterative process among stakeholders, supported by relevant medical societies worldwide. These PoC can serve as a benchmark for diagnosis and comprehensive multidisciplinary management of WGBD, and improve awareness of their unique challenges. They offer a framework to guide HTC/CCCs in providing equitable care for all WGBD, both in their own services and in other healthcare settings. Implementation of these principles aims to positively impact the health, wellbeing and quality of life for WGBD.

Long-term employment status and the association with fatigue in patients with grade II glioma.

OBJECTIVE: To investigate employment status and return to work in relation to fatigue in patients with World Health Organization (WHO) grade II glioma. DESIGN: Exploratory cross-sectional study. SUBJECTS: Patients with grade II glioma, who underwent surgery between 2005 and 2016. METHODS: A postal survey was sent in 2019, which included the Short Form-Health and Labour Questionnaire and the Multi-dimensional Fatigue Index. Outcomes of fatigue in subgroups of (not-)return to work were compared using independent t-tests and χ2 tests. The association between fatigue and return to work was analysed using multivariable logistic regression. RESULTS: In total, 73 patients were included in the study (age at diagnosis 41.0 years (standard deviation (SD) 9.2 years), time post-diagnosis 8.0 years (interquartile range (IQR) 6-11 years). At diagnosis, 61 patients were employed and 32 returned to work during follow-up. The return to work group was significantly younger than the not-return to work group (p = 0.007). The proportion of patients who indicated that the consequences of glioma had affected return to work, in terms of demotion or reduced working hours, was 68.7%. The not-return to work group reported significantly more fatigue in all domains than the return to work group (p < 0.05). Mental fatigue (p = 0.023) and physical fatigue (p = 0.065) were independently associated with return to work, adjusted for age, sex and the use of anti-epileptic drugs. CONCLUSION: Long-term fatigue is associated with return to work in patients with grade II glioma. Patients who were able to work in the long term were less fatigued, younger, more often male, and used less anti-epileptic drugs than the patients who did not return to work.

FGF23 impairs peripheral microvascular function in renal failure.

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

Fatigue in patients with low grade glioma: systematic evaluation of assessment and prevalence.

Fatigue is the most prevalent and disabling symptom in cancer patients. Yet, scientific literature on this topic is scarce and reports disparate results. This study systematically reviews how fatigue is assessed in patients with low-grade glioma and evaluates its prevalence in LGG patients. A systematic literature search was performed in PubMed, Embase and PsychINFO for articles reporting on fatigue in patients with LGG. Two reviewers independently extracted data from selected articles. Inclusion criteria were: (1) patients with suspected or confirmed LGG; (2) fatigue was assessed as primary or secondary outcome measure; (3) age≥ 18 years; (4) full-length article written in English or Dutch. In total, 19 articles were selected, including 971 patients. Seven self-assessment instruments were identified. Prevalence rates ranged from 39 to 77%. Fatigue was found to be a common side effect of treatment. The prevalence rates ranged from 20 to 76% when fatigue was reported as a mild or moderate side effect and fatigue was prevalent in 4% when reported as a severe side effect. Fatigue is a common problem in LGG patients that warrants more therapeutic and scientific attention. Gaining deeper insight in the underlying mechanisms of fatigue is essential in targeting therapy to individual patients.

Calcium Extrusion Pump PMCA4: A New Player in Renal Calcium Handling?

Calcium (Ca2+) is vital for multiple processes in the body, and maintenance of the electrolyte concentration is required for everyday physiological function. In the kidney, and more specifically, in the late distal convoluted tubule and connecting tubule, the fine-tuning of Ca2+ reabsorption from the pro-urine takes place. Here, Ca2+ enters the epithelial cell via the transient receptor potential vanilloid receptor type 5 (TRPV5) channel, diffuses to the basolateral side bound to calbindin-D28k and is extruded to the blood compartment via the Na+/Ca2+ exchanger 1 (NCX1) and the plasma membrane Ca2+ ATPase (PMCA). Traditionally, PMCA1 was considered to be the primary Ca2+ pump in this process. However, in recent studies TRPV5-expressing tubules were shown to highly express PMCA4. Therefore, PMCA4 may have a predominant role in renal Ca2+ handling. This study aimed to elucidate the role of PMCA4 in Ca2+ homeostasis by characterizing the Ca2+ balance, and renal and duodenal Ca2+-related gene expression in PMCA4 knockout mice. The daily water intake of PMCA4 knockout mice was significantly lower compared to wild type littermates. There was no significant difference in serum Ca2+ level or urinary Ca2+ excretion between groups. In addition, renal and duodenal mRNA expression levels of Ca2+-related genes, including TRPV5, TRPV6, calbindin-D28k, calbindin-D9k, NCX1 and PMCA1 were similar in wild type and knockout mice. Serum FGF23 levels were significantly increased in PMCA4 knockout mice. In conclusion, PMCA4 has no discernible role in normal renal Ca2+ handling as no urinary Ca2+ wasting was observed. Further investigation of the exact role of PMCA4 in the distal convoluted tubule and connecting tubule is required.

Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

The Na+/Ca2+ Exchanger 1 (NCX1) Variant 3 as the Major Extrusion System in Renal Distal Tubular Transcellular Ca2+-Transport.

BACKGROUND/AIMS: Fine-tuning of renal calcium (Ca(2+)) reabsorption takes place in the late distal convoluted and connecting tubules (DCT2/CNT) of the kidney via transcellular Ca(2+) transport. Here, Ca(2+) enters the cell at the apical side via the epithelial Ca(2+) channel transient receptor potential vanilloid 5 and is subsequently extruded at the basolateral side by the concerted actions of the plasma membrane Ca(2+) ATPases and the Na(+)/Ca(2+) exchanger 1 (NCX1). NCX1 is responsible for ∼ 70% of basolateral Ca(2+) extrusion. The aim of this study was to determine the predominant NCX1 variant in the kidney and its role in Ca(2+) transport. METHODS: DCT2/CNT specific tubules were used to show the abundance of NCX1 specific isoforms. Renal NCX1 variants were cloned from mouse kidney tissue. Human Embryonic Kidney 293(T) cells were transiently transfected with NCX1.3, and Fura-2 measurements and 45Ca(2+) uptake assays were performed to determine several characteristics of NCX1.3 in the reverse mode. RESULTS: NCX1.3 was demonstrated to be the predominant NCX1 variant in the DCT2/CNT, next to NCX1.2 and NCX1.7. NCX1.3 could be inhibited by SN-6, an NCX-specific inhibitor, whereas stimulation of the cAMP/PKA or PKC-mediated pathway did not affect Ca(2+) influx as measured in the reverse mode. Lowering intracellular Ca(2+) concentrations resulted in a decreased Ca(2+) uptake. CONCLUSION: NCX1.3 is the predominant NCX variant in the DCT2/CNT tubules. Its function is dependent on intracellular Ca(2+) concentrations.

Shedding of klotho by ADAMs in the kidney.

The anti-aging gene klotho plays an important role in Ca(2+) and phosphate homeostasis. Membrane-bound klotho is an essential coreceptor for fibroblast growth factor-23 and can be cleaved by proteases, including a disintegrin and metalloproteinase (ADAM)10 and ADAM17. Cleavage of klotho occurs at a site directly above the plasma membrane (α-cut) or between the KL1 and KL2 domain (ß-cut), resulting in soluble full-length klotho or KL1 and KL2 fragments, respectively. The aim of the present study was to gain insights into the mechanisms behind klotho cleavage processes in the kidney. Klotho shedding was demonstrated using a Madin-Darby canine kidney cell line stably expressing klotho and human embryonic kidney-293 cells transiently transfected with klotho. Here, we report klotho expression on both the basolateral and apical membrane, with a higher abundance of klotho at the apical membrane and in the apical media. mRNA expression of ADAM17 and klotho were enriched in mouse distal convoluted and connecting tubules. In vitro ADAM/matrix metalloproteinase inhibition by TNF484 resulted in a concentration-dependent inhibition of the α-cut, with a less specific effect on ß-cut shedding. In vivo TNF484 treatment in wild-type mice did not change urinary klotho levels. However, ADAM/matrix metalloproteinase inhibition did increase renal and duodenal mRNA expression of phosphate transporters, whereas serum phosphate levels were significantly decreased. In conclusion, our data show that renal cells preferentially secrete klotho to the apical side and suggest that ADAMs are responsible for α-cut cleavage.

Membrane-bound Klotho is not expressed endogenously in healthy or uraemic human vascular tissue.

AIMS: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD), a disease state that is strongly associated with loss of renal and systemic (alpha-)Klotho. Reversely, murine Klotho deficiency causes marked medial calcification. It is therefore thought that Klotho conveys a vasculoprotective effect. Klotho expression in the vessel wall, however, is disputed. METHODS AND RESULTS: We assessed Klotho expression in healthy human renal donor arteries (n = 9), CKD (renal graft recipient) arteries (n = 10), carotid endarterectomy specimens (n = 8), other elastic arteries (three groups of n = 3), and cultured human aortic smooth muscle cells (HASMCs) (three primary cell lines), using immunohistochemistry (IHC), immunofluorescence, quantitative reverse transcriptase-polymerase chain reaction, and western blotting (WB). We have extensively validated anti-Klotho antibody KM2076 by comparing staining patterns with other anti-Klotho antibodies (SC-22220, SC-22218, and AF1819), competition assays with recombinant Klotho, IHC on Klotho-deficient kl/kl mouse kidney, and WB with recombinant Klotho. Using KM2076, we could not detect full-length Klotho in vascular tissues or HASMCs. On the mRNA level, using primers against all four exon junctions, klotho expression could not be detected either. Fibroblast growth factor 23 (FGF23) injections in mice induced FGF23 signalling in kidneys but not in the aorta, indicating the absence of Klotho-dependent FGF23 signalling in the aorta. CONCLUSION: Using several independent and validated methods, we conclude that full-length, membrane-bound Klotho is not expressed in healthy or uraemic human vascular tissue.

Assessment methods and prevalence of cognitive dysfunction in patients with low-grade glioma: A systematic review.

OBJECTIVE: To systematically review the literature for studies on cognitive functioning in patients with low-grade glioma to evaluate assessment methods and prevalence of cognitive dysfunction. DATA SOURCES: A search was made in PubMed, Embase, and PsycINFO for articles published between January 2002 and June 2012 using cognition, memory, attention, executive functioning, and low-grade glioma as search terms. STUDY SELECTION: Two reviewers independently performed the study selection and data extraction. Inclusion criteria were: studies including at least 10 adult patients, with suspected or confirmed low-grade glioma and cognitive functioning as outcome measure. DATA EXTRACTION: A standard data extraction form was used, with items regarding study quality, patient characteristics, type of measurement instruments, cognitive domain, definition of cognitive dysfunction, and reported prevalence. DATA SYNTHESIS: Of the 312 articles screened on title/abstract, 69 were screened on full-text and, finally, 17 were included. A total of 46 different measurement instruments were found for the assessment of cognitive functioning; 5 of these were used 5 or more times. There was variability in the definition of cognitive dysfunction. The reported prevalence of cognitive dysfunction ranged from 19% to 83%. CONCLUSION: Many patients with low-grade glioma experience cognitive dysfunction. However, there is no consensus on how to assess cognitive functioning in these patients.

Training memory self-efficacy in the chronic stage after stroke: a randomized controlled trial.

BACKGROUND: Stroke patients with a low memory self-efficacy (MSE) report more memory complaints than patients with a high MSE. OBJECTIVE: The aim of this study was to examine the effect of a memory-training program on MSE in the chronic phase after stroke and to identify which patients benefit most from the MSE training program. METHODS: In a randomized controlled trial, the effectiveness of the MSE training program (experimental group) was compared with a peer support program (control group) in chronic stroke patients. The primary outcome was MSE, measured using the Metamemory-In-Adulthood Questionnaire. Secondary outcomes included depression, quality of life, and objective verbal memory capacity. Changes in outcomes over the intervention period were compared between both groups. Demographic and clinical variables were studied as potential predictors of MSE outcome in the experimental group. RESULTS: In total, 153 patients were included: mean age = 58 years (standard deviation [SD] = 9.7), 54.9% male, and mean of 54 months (SD = 37) after stroke. Of these, 77 were assigned to the training and 76 to the control group. Improvement of MSE (B = 0.40; P = .019) was significantly greater in the training than in the control group. No significant differences were found for the secondary outcomes. An increase in MSE after training was predicted by a younger age (B = -0.033; P = .006) and a better memory capacity (B = 0.043; P = .009), adjusted for baseline MSE. CONCLUSIONS: MSE can be improved by the MSE training program for stroke patients. Younger patients and patients with a better memory capacity benefit most from the MSE training program (Dutch Trial Register: NTR-TC 1656).

The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule.

Acquiring a mechanistic understanding of the processes underlying the renal clearance of drug molecules in man has been hampered by a lack of robust in vitro models of human proximal tubules. Several human renal epithelial cell lines derived from the renal cortex are available, but few have been characterised in detail in terms of transporter expression. This includes the HK-2 proximal tubule cell line, which has been used extensively as a model of nephrotoxicity. The aim of this study was to investigate the expression and function of drug transporters in HK-2 cells and their suitability as an in vitro model of the human proximal tubule. qPCR showed no mRNA expression of the SLC22 transporter family (OAT1, OAT3, OCT2) in HK-2 cells compared to renal cortex samples. In contrast, SLC16A1 (MCT1), which is important in the uptake of monocarboxylates, and SLCO4C1 (OATP4C1) were expressed in HK-2 cells. The functional expression of these transporters was confirmed by uptake studies using radiolabelled prototypic substrates DL-lactate and digoxin, respectively. The mRNA expression of apical membrane efflux transporters ABCB1 (MDR1) and several members of the ABCC family (multidrug resistance proteins, MRPs) was shown by qPCR. ABCG1 (BCRP) was not detected. The efflux of Hoechst 33342, a substrate for MDR1, was blocked by MDR1 inhibitor cyclosporin A, suggesting the functional expression of this transporter. Similarly, the efflux of the MRP-specific fluorescent dye glutathione methylfluorescein was inhibited by the MRP inhibitor MK571. Taken together, the results of this study suggest that HK-2 cells are of limited value as an in vitro model of drug transporter expression in the human proximal tubule.