Simple, fast and robust LC-MS/MS method for the simultaneous quantification of canagliflozin, dapagliflozin and empagliflozin in human plasma and urine

Sodium–glucose cotransporter 2 –inhibitors (SGLT2i) are oral glucose-lowering drugs that have also demonstrated cardioprotective and renoprotective effects. SGLT2i play an increasingly important role in the treatment of type 2 diabetes. Here we report a simple and robust liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantification of three SGLT2i (canagliflozin, dapagliflozin and empagliflozin) in human plasma, serum and urine with a runtime of 1 min. Methanol was used as protein precipitating agent. Chromatographic separation was accomplished using a Waters ACQUITY UPLC HSS T3 1.8 μm; 2.1 × 50 mm column with a Waters ACQUITY UPLC HSS T3 1.8 μm VanGuard Pre-column; 2.1 × 5 mm, using gradient elution with ammonium acetate 20 mM (pH 5) and acetonitrile as mobile phase at a flow rate of 0.8 ml/min. Mass spectrometric analysis of the acetate adduct ions was carried out using electrospray with negative ionization and SRM mode. The assay was validated according to FDA and EMA guidelines, including selectivity, linearity, accuracy and precision, dilution integrity, stability and recovery. With a sample volume of 200 µl, linear ranges of 10–5000 µg/L, 1–500 µg/L and 2–1000 µg/L for canagliflozin, dapagliflozin and empagliflozin respectively, were achieved. The assay was successfully applied in two pharmacokinetic studies with dapagliflozin and empagliflozin. In conclusion, we developed and validated a simple, fast and robust LC-MS/MS method for the simultaneous quantification of canagliflozin, dapagliflozin and empagliflozin, that allows rapid analysis of large numbers of samples and can be used for both pharmacokinetic studies and biomedical analysis of canagliflozin, dapagliflozin and empagliflozin

Radiation dose reduction for CT assessment of urolithiasis using iterative reconstruction: A prospective intra-individual study

Objective: To assess the performance of hybrid (HIR) and model-based iterative reconstruction (MIR) in patients with urolithiasis at reduced-dose computed tomography (CT). Methods: Twenty patients scheduled for unenhanced abdominal CT for follow-up of urolithiasis were prospectively included. Routine dose acquisition was followed by three low-dose acquisitions at 40%, 60% and 80% reduced doses. All images were reconstructed with filtered back projection (FBP), HIR and MIR. Urolithiasis detection rates, gall bladder, appendix and rectosigmoid evaluation and overall subjective image quality were evaluated by two observers. Results: 74 stones were present in 17 patients. Half the stones were not detected on FBP at the lowest dose level, but this improved with MIR to a sensitivity of 100%. HIR resulted in a slight decrease in sensitivity at the lowest dose to 72%, but outperformed FBP. Evaluation of other structures with HIR at 40% and with MIR at 60% dose reductions was comparable to FBP at routine dose, but 80% dose reduction resulted in non-evaluable images. Conclusions: CT radiation dose for urolithiasis detection can be safely reduced by 40 (HIR)–60 (MIR) % without affecting assessment of urolithiasis, possible extra-urinary tract pathology or overall image quality. Key Points: • Iterative reconstruction can be used to substantially lower the radiation dose. • This allows for radiation reduction without affecting sensitivity of stone detection. • Possible extra-urinary tract pathology evaluation is feasible at 40–60% reduced dose

Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides

Contains fulltext : 88022.pdf (publisher's version ) (Closed access)PURPOSE: In peptide-receptor radionuclide therapy (PRRT), the maximum activity dose that can safely be administered is limited by high renal uptake and retention of radiolabelled peptides. The kidney radiation dose can be reduced by coinfusion of agents that competitively inhibit the reabsorption of radiolabelled peptides, such as positively charged amino acids, Gelofusine, or trypsinised albumin. The aim of this study was to identify more specific and potent inhibitors of the kidney reabsorption of radiolabelled peptides, based on albumin. METHODS: Albumin was fragmented using cyanogen bromide and six albumin-derived peptides with different numbers of electric charges were selected and synthesised. The effect of albumin fragments (FRALB-C) and selected albumin-derived peptides on the internalisation of (111)In-albumin, (111)In-minigastrin, (111)In-exendin and (111)In-octreotide by megalin-expressing cells was assessed. In rats, the effect of Gelofusine and albumin-derived peptides on the renal uptake and biodistribution of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide was determined. RESULTS: FRALB-C significantly reduced the uptake of all radiolabelled peptides in vitro. The albumin-derived peptides showed different potencies in reducing the uptake of (111)In-albumin, (111)In-exendin and (111)In-minigastrin in vitro. The most efficient albumin-derived peptide (peptide #6), was selected for in vivo testing. In rats, 5 mg of peptide #6 very efficiently inhibited the renal uptake of (111)In-minigastrin, by 88%. Uptake of (111)In-exendin and (111)In-octreotide was reduced by 26 and 33%, respectively. CONCLUSIONS: The albumin-derived peptide #6 efficiently inhibited the renal reabsorption of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide and is a promising candidate for kidney protection in PRRT.1 februari 201

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Annemarie Ní Churreáin speaks to the C21 Editions project about the role of social media in writing

Prof. Bridgette Wessels speaks to Irish poet Annemarie Ní Churreáin for the C21 Editions project, which is exploring how born-digital content like social media might be included in digital scholarly editions. Prof. Wessels and Annemarie explore what it means to be w rite in the age of social media. Bridgette Wessels is Professor of Sociology at the University of Glasgow. Her research focuses on the development and use of digital technology and services in social and cultural life. This includes digital services and communication in the public sphere, everyday life and civic life, social and digital inequalities, as well as specific areas such as telehealth, mobile communication and privacy in digital communication. Annemarie Ní Churreáin is a poet from the Donegal Gaeltacht. Her books include Bloodroot (Doire Press, 2017), Town (The Salvage Press, 2018) and The Poison Glen (The Gallery Press, 2021). She is the poetry editor at The Stinging Fly magazine. C21 Editions is an international collaboration between University College Cork, the Digital Humanities Institute at the University of Sheffield, and the University of Glasgow. The project seeks to explore and make a direct contribution to the future of digital scholarly editing and digital publishing. The project was funded under the UK-Ireland Collaboration in the Digital Humanities, a joint initiative of the Irish Research Council (IRC) and the United Kingdom's Arts and Humanities Research Council (AHRC)

Effect of exercise versus cognitive behavioural therapy or no intervention on anxiety, depression, fitness and quality of life in adults with previous methamphetamine dependency : a systematic review

CITATION: Morris, L., et al. 2018. Effect of exercise versus cognitive behavioural therapy or no intervention on anxiety, depression, fitness and quality of life in adults with previous methamphetamine dependency : a systematic review. Addiction Science and Clinical Practice, 13:4, doi:10.1186/s13722-018-0106-4.The original publication is available at https://ascpjournal.biomedcentral.comBackground: Methamphetamine (MA) is a highly addictive psychostimulant used by approximately 52 million people worldwide. Chronic MA abuse leads to detrimental physiological and neurological changes, as well as increases in anxiety and depression, and decreases in overall fitness and quality of life. Exercise has been reported to possibly reverse physiological and neurological damage caused by previous MA use, and to reduce anxiety and depression in this population. The aim of this systematic review was to identify, clinically appraise and synthesise the available evidence for the effectiveness of exercise, compared to cognitive behavioural therapy (CBT), standard care or no intervention, on decreasing anxiety and depression and improving fitness and quality of life in previous MA users. Methods: Seven computerised databases were searched from inception to May 2017, namely Scopus, Cochrane Library, PubMed/MEDLINE, PEDro, CINAHL, and ScienceDirect. Search terms included exercise, methamphetamine, fitness measures, depression, anxiety and quality of life. Randomised and non-randomised controlled- or clinical trials and pilot studies, published in English, were considered for inclusion. Methodological quality was critically appraised according to the PEDro scale. Heterogeneity across studies regarding control groups and assessment intervals rendered meta analyses inappropriate for this review and results were thus described narratively using text and tables. Results: Two hundred and fifty-one titles were identified following the initial search, and 14 potentially-relevant titles were selected and the abstracts reviewed. Three studies (two randomised controlled trials and one quasi-experimental pilot) were included, with an average PEDro score of 6.66. Exercise resulted in significantly lower depression and anxiety scores versus CBT (p = 0.001). Balance also significantly improved following exercise versus standard care (p < 0.001); as did vital capacity, hand-grip and one-leg stand with eyes closed. There were significant changes in all subdivisions of the Quality of Life Scale Questionnaire (p < 0.05), except psychology (p = 0.227). Conclusions: Level II evidence suggests that exercise is effective in reducing anxiety and depression and improving fitness in previous MA users, and Level III-2 evidence suggests that exercise is beneficial for improving quality of life in this population. Overall recovery in previous MA dependents might be significantly enhanced by including exercise in the rehabilitation process. Further research is required to strengthen these conclusions and to inform policy and health systems effectively.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-018-0106-4Publisher's versio

Radiation dose reduction for CT assessment of urolithiasis using iterative reconstruction : A prospective intra-individual study

OBJECTIVE: To assess the performance of hybrid (HIR) and model-based iterative reconstruction (MIR) in patients with urolithiasis at reduced-dose computed tomography (CT). METHODS: Twenty patients scheduled for unenhanced abdominal CT for follow-up of urolithiasis were prospectively included. Routine dose acquisition was followed by three low-dose acquisitions at 40%, 60% and 80% reduced doses. All images were reconstructed with filtered back projection (FBP), HIR and MIR. Urolithiasis detection rates, gall bladder, appendix and rectosigmoid evaluation and overall subjective image quality were evaluated by two observers. RESULTS: 74 stones were present in 17 patients. Half the stones were not detected on FBP at the lowest dose level, but this improved with MIR to a sensitivity of 100%. HIR resulted in a slight decrease in sensitivity at the lowest dose to 72%, but outperformed FBP. Evaluation of other structures with HIR at 40% and with MIR at 60% dose reductions was comparable to FBP at routine dose, but 80% dose reduction resulted in non-evaluable images. CONCLUSIONS: CT radiation dose for urolithiasis detection can be safely reduced by 40 (HIR)-60 (MIR) % without affecting assessment of urolithiasis, possible extra-urinary tract pathology or overall image quality. KEY POINTS: • Iterative reconstruction can be used to substantially lower the radiation dose. • This allows for radiation reduction without affecting sensitivity of stone detection. • Possible extra-urinary tract pathology evaluation is feasible at 40-60% reduced dose

Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial

Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma$^{1}$ and colorectal cancer$^{2}$. In NABUCCO (ClinicalTrials.gov: NCT03387761), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8$^{+}$ presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8$^{+}$ T cell activity