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1.
Use of (1→3)-β-d-glucan for diagnosis and management of invasive mycoses in HIV-infected patients.
Farhour, Z, Mehraj, V, Chen, J, Ramendra, R, Lu, H, Routy, JP
Mycoses. 2018;(10):718-722
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Abstract
People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualise and culture fungi before initiating treatment. Such techniques are less practical in resource-limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)-β-d-glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV-infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels.
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Real-Life Use of Neurohormonal Antagonists and Loop Diuretics in Chronic Heart Failure: Analysis of Serial Biomarker Measurements and Clinical Outcome.
Brankovic, M, Akkerhuis, KM, van Boven, N, Manintveld, O, Germans, T, Brugts, J, Caliskan, K, Umans, V, Constantinescu, A, Kardys, I
Clinical pharmacology and therapeutics. 2018;(2):346-355
Abstract
We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF.
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Quality of life in children participating in a non-selective INR self-monitoring VKA-education programme.
Amedro, P, Bajolle, F, Bertet, H, Cheurfi, R, Lasne, D, Nogue, E, Auquier, P, Picot, MC, Bonnet, D
Archives of cardiovascular diseases. 2018;(3):180-188
Abstract
BACKGROUND The quality of life (QoL) of children receiving vitamin K antagonist (VKA) treatment has been scarcely studied. AIM: To assess QoL of children, and its evolution, throughout our non-selective international normalized ratio (INR) self-monitoring education programme. METHODS Children and parents completed QoL questionnaires (Qualin, PedsQL) during education sessions. Scores were compared with those from controls. RESULTS A total of 111 children (mean±standard deviation age 8.7±5.4 years) were included over a 3-year period. Indications for VKA treatment were congenital heart diseases (valve replacement [42.3%], total cavopulmonary connection [29.7%]), myocardiopathy (11.7%), coronary aneurysm (7.2%), venous/intracardiac thrombosis (4.5%), pulmonary artery hypertension (1.8%), arrhythmia (0.9%) and extra-cardiac disease (1.8%). Eighty children, 105 mothers and 74 fathers completed the QoL questionnaires. QoL was good among children aged 1-4 years and moderately impaired in those aged between 5 and 18 years. There was no significant relationship between self-reported QoL and patient's sex, type of VKA, number of group sessions attended, disease duration or time of diagnosis (prenatal or postnatal). QoL scores were significantly lower among children with congenital heart diseases compared with other diseases. There were few differences in QoL between children under transient VKA treatment and those treated for life. Parental proxy QoL scoring correlated well with but was significantly lower than child self-assessments. QoL reported by mothers increased throughout the education programme, independently of any improvement of the health condition. CONCLUSIONS This QoL study provides original data from a large cohort of children and their parents participating in a formalized INR self-monitoring education programme for VKA treatment.
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Monitoring recommendations for oral azathioprine, methotrexate and cyclosporin in a paediatric dermatology clinic and literature review.
Yee, J, Orchard, D
The Australasian journal of dermatology. 2018;(1):31-40
Abstract
BACKGROUND/OBJECTIVES Systemic oral immunomodulators azathioprine, methotrexate and cyclosporin are widely used in paediatric dermatology. Routine blood tests are performed to minimise drug-related adverse events. However, the frequency of monitoring tests may lead to significant fearful experiences for patients. We reviewed haematological abnormalities and clinical side-effects in a paediatric clinic population commencing immunomodulators for dermatological conditions, where haematological profiles are monitored less frequently than in current recommendations. METHODS A retrospective chart review of children started on azathioprine, methotrexate or cyclosporin for a dermatological condition between 2001-2015 from a primarily paediatric, private dermatology practice was performed. Blood tests were done at baseline, 1 month, 2 months and then 3-monthly for children on azathioprine. Children on methotrexate and cyclosporin had tests done at baseline, after 1 month and then 3-monthly. RESULTS In total, 242 children were included in this study. Azathioprine, methotrexate and cyclosporin cohorts had 95, 97 and 50 patients treated for a mean duration of 656, 758 and 313 days, respectively. Isolated abnormal blood tests indicated the cessation of azathioprine in 3/95 (3%), methotrexate in 5/97 (5%) and cyclosporin in 2/50 (4%) of patients. Abnormal blood test results were not associated with any reported clinical side-effects in the azathioprine (P = 0.726), methotrexate (P = 0.06) or cyclosporin groups (P = 0.250). CONCLUSION In our experience, less frequent monitoring did not result in any significant adverse events over a 15-year period. We suggest that haematological monitoring during immunosuppressants use can be safely reduced from current recommendations.
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Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease.
Carman, N, Mack, DR, Benchimol, EI
Current gastroenterology reports. 2018;(5):18
Abstract
PURPOSE OF REVIEW Therapeutic drug monitoring (TDM) has emerged as a useful tool to optimize the use of drug therapies in adults with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC), especially during the use of biological therapies, for which the pharmacokinetics and pharmacodynamics are highly variable among patients. Fewer data exist in children. This review examines the current literature on TDM in pediatric IBD. RECENT FINDINGS Drug clearance is affected by a number of patient and disease factors. For thiopurines, adjusting dosing by monitoring 6-thioguanine (6TGN) and 6-methylmercaptopurine ((6MMP) levels is demonstrated to maximize response and minimize toxicity, while monitoring metabolite levels when treating with anti-tumor necrosis factor (anti-TNF) remain controversial. While in adults the use of TDM in the setting of loss of response to anti-TNF therapy is established, in children, only a small number of studies exist, but these too have encouraging results. There are however, conflicting data regarding the optimal timing of TDM, comparing "reactive" monitoring and "proactive" monitoring. No such data exist in pediatrics. TDM is cost-effective, and dose reduction may represent a safety benefit. There are limited adult data for use of TDM for the newer biologics, vedolizumab and ustekinumab, but early results suggest similarly promising utility. The use of TDM in pediatric IBD is increasing in clinical practice, with similar efficacy to adults demonstrated in children with loss of response to anti-TNF therapy. More prospective studies are needed in children to examine proactive monitoring and utility of TDM with newer biologics.
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Patient-Reported Outcome Measures for Use in Clinical Trials and Clinical Practice in Inflammatory Bowel Diseases: A Systematic Review.
de Jong, MJ, Huibregtse, R, Masclee, AAM, Jonkers, DMAE, Pierik, MJ
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(5):648-663.e3
Abstract
BACKGROUND & AIMS Mucosal inflammation must be carefully monitored to improve the long-term outcomes of patients with inflammatory bowel diseases (IBD). Patient-reported outcome measures (PROMs) are used increasingly to monitor disease activity in clinical practice and as endpoints in clinical trials. We performed a systematic review to provide an overview of the available PROMs on IBD activity and to evaluate their diagnostic value. METHODS A systematic search of the PubMed, Medline, Cochrane library, and Embase databases using defined keywords, identified 973 articles. These were screened by 2 independent reviewers, and 37 articles on development or validation of PROMs to assess IBD activity were identified for further analysis. Based on the recommendations of the Food and Drug Administration (FDA), the following measurement properties were evaluated: content, construct, and criterion validity; reliability; and responsiveness to change. In addition, data on ease of use in clinical practice were collected. RESULTS Seventeen articles presenting 20 different PROMs were included the final analysis, although none met all the FDA-recommended criteria. Only 2 PROMs (patient-reported Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores) reported patient involvement during its development. Only 6 PROMs (patient-reported global assessment, patient assessment of disease activity, mobile health index for Crohn's disease, mobile health index for ulcerative colitis, patient-reported outcome derived from the Mayo score, and the 6-point Mayo score) were validated as markers of IBD activity, using findings from endoscopy as the reference standard; these PROMs identified patients with mucosal inflammation with area under the curve values of 0.63-0.82. The mobile health index for CD and UC scores had the best measurement properties for use in clinical practice and in clinical trials. CONCLUSIONS In a systematic review, we identified more than 20 PROMS that have been developed and tested for their ability to determine IBD activity. Further studies are needed to determine their accuracy and whether they can be used effectively in routine practice, clinical trials, telemedicine systems, and value-based healthcare programs.
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Peptide biosensors for anticancer drugs: Design in silico to work in denaturizing environment.
Guida, F, Battisti, A, Gladich, I, Buzzo, M, Marangon, E, Giodini, L, Toffoli, G, Laio, A, Berti, F
Biosensors & bioelectronics. 2018;:298-303
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Abstract
One of the main targets in current clinical oncology is the development of a cheap device capable of monitoring in real-time the concentration of a drug in the blood of a patient. This would allow fine-tuning the dosage according to the patient's metabolism, a key condition to reduce side effects. By using surface plasmon resonance and fluorescence spectroscopy we here show that short peptides designed in silico by a recently developed algorithm are capable of binding the anticancer drug irinotecan (CPT-11) with micromolar affinity. Importantly, the recognition takes place in the denaturating solution used in standard therapeutic drug monitoring to detach the drug from the proteins that are present in human plasma, and some of the peptides are capable of distinguishing CPT-11 from its metabolite SN-38. These results suggest that the in silico design of small artificial peptides is now a viable route for designing sensing units, opening a wide range of applications in diagnostic and clinical areas.
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Successful treatment of Aspergillus ventriculitis through voriconazole adaptive pharmacotherapy, immunomodulation, and therapeutic monitoring of cerebrospinal fluid (1→3)-β-D-glucan.
Chen, TK, Groncy, PK, Javahery, R, Chai, RY, Nagpala, P, Finkelman, M, Petraitiene, R, Walsh, TJ
Medical mycology. 2017;(1):109-117
Abstract
Aspergillus ventriculitis is an uncommon but often fatal form of invasive aspergillosis of the central nervous system (CNS). As little is known about the diagnosis, treatment, and outcome of this potentially lethal infection, we report the strategies used to successfully treat Aspergillus ventriculitis complicating a pineal and pituitary germinoma with emphasis on the critical role of adaptive pharmacotherapy of voriconazole and serial monitoring of (1→3)-β-D-glucan in cerebrospinal fluid. We describe several rationally based therapeutic modalities, including adaptive pharmacotherapy, combination therapy, sargramostim-based immunomodulation, and biomarker-based therapeutic monitoring of the CNS compartment. Through these strategies, our patient remains in remission from both his germinoma and Aspergillus ventriculitis making him one of the few survivors of Aspergillus ventriculitis.
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[Treatment and Secondary Prevention of Venous Thromboembolism - Change in Oral Anticoagulation].
Helms, TM, Gulba, D, Ahrens, I, Schäfer, A, Hankowitz, J, Kuhlencordt, P, Lipp, HP, Nikol, S, Riess, H, Stargardt, T, et al
Deutsche medizinische Wochenschrift (1946). 2017;(13):986-993
Abstract
With the recent approval of the fourth direct non vitamin K dependent oral anticoagulant (NOAC) edoxaban the range of available NOACs for the treatment of venous thromboembolism (VTE) has expanded. Shortly thereafter, two updated guidelines for the prevention and treatment of VTE have been published. In these NOACs are listed as equal anticoagulants to low-molecular weight heparin (LMWH), or fondaparinux (FDX), and VKA for the initial or maintenance treatment of VTE. All NOACs are approved for the maintenance therapy after VTE and two NOACs (rivaroxaban and apixaban) for the initial treatment in addition in an increased dose.NOACs differ in their pharmacodynamic and pharmacokinetic properties. In patients with renal insufficiency the dose of all NOACs should be reduced similarly to NMH/FDX. In contrast to VKAs, bridging with NOACs in case of surgical interventions is generally dispensable. Similar to NMHs or FPX renal function and individual bleeding risk dependent dose intermission is generally sufficient. Conventional coagulation parameters like aPTT and INR are not suitable for the monitoring of NOACs. Only in seldom cases, laboratory monitoring with use of adjusted anti-Xa testing or diluted thrombin time (dabigatran) may be helpful.
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In vivo monitoring of topical therapy for acne with reflectance confocal microscopy.
Manfredini, M, Greco, M, Farnetani, F, Mazzaglia, G, Ciardo, S, Bettoli, V, Virgili, A, Pellacani, G
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). 2017;(1):36-40
Abstract
BACKGROUND Acne vulgaris is a common disease of the pilosebaceous unit. The aim of the study was to evaluate compartment-specific treatment action through the microscopic non-invasive imaging of skin changes. METHODS Mild-moderate acne patients, that were prescribed a topical anti-acne product, were followed by clinical and reflectance confocal microscopy (RCM) imaging every 14 days to 6 weeks. Mean and standard deviation of the scores were analyzed for each time point. RESULTS After 2 weeks, the RCM count of papules/pustules and the RCM scores of exocytosis and dermal inflammation, decreased substantially. After 4 weeks, the RCM number of comedos was reduced. After 6 weeks, the number of regular follicles increased, while the infundibula with thickened bright border decreased significantly. CONCLUSION The progressive reduction in the clinical scores was correlated with the improvement of the RCM parameters. RCM study of acne skin showed a different timing for inflammatory and hyperkeratotic components to achieve a significant reduction during topical therapy with the association of retinoid and antibacterial molecules. The microscopic changes observed showed the regularization of the skin and the improvement of acne related features. RCM may represent a useful tool for the objective assessment of treatment efficacy and individual response evaluation.