Electronic capturing of patient-reported outcome measures on a touchscreen computer in clinical diabetes practice (the DiaPROM trial): A feasibility study

This is the final version. Available from the publisher via the DOI in this record.The datasets generated during the current study are available from the corresponding author on reasonable request.. Background: Living with type 1 diabetes (T1D) is demanding, and emotional problems may impair ability for diabetes self-management. Thus, diabetes guidelines recommend regular assessment of such problems. Using patient-reported outcome measures (PROMs) to assess diabetes-related distress and psychological well-being is considered useful. It has been proposed that future work should examine the use of PROMs to support the care of individual patients and improve the quality of health services. To our knowledge, the use of PROMs has not been systematically evaluated in diabetes care services in Norway. Electronically captured PROMs can be directly incorporated into electronic patient records. Thus, the study fs overall aim was to examine the feasibility and acceptability of capturing PROMs electronically on a touchscreen computer in clinical diabetes practice. Methods: Adults with T1D age ≥ 40 years completed PROMs on a touchscreen computer at Haukeland University Hospital fs diabetes outpatient clinic. We included 46 items related to diabetes-related distress, self-perceived diabetes competence, awareness of hypoglycaemia, occurrence of hyperglycaemia, hypoglycaemia and fluctuating glucose levels, routines for glucose monitoring, general well-being and health-related quality of life. Participants subsequently completed a paper-based questionnaire regarding comprehension and relevance of the PROMs, acceptance of the number of items and willingness to complete electronic PROMs annually. We wrote field notes in the outpatient clinic based on observations and comments from the invited participants. Results: During spring 2017, 69 participants (50.7% men), age 40 to 74 years, were recruited. Generally, the touchscreen computer functioned well technically. Median time spent completing the PROMs was 8 min 19 s. Twenty-nine (42.0%) participants completed the PROMs without missing items, with an 81.4% average instrument completion rate. Participants reported that the PROMs were comprehensible (n = 62) and relevant (n = 46) to a large or very large degree, with an acceptable number of items (n = 51). Moreover, 54 were willing to complete PROMs annually. Participants commented that the focus on living with diabetes was valued. Conclusions: Capturing PROMs on a touchscreen computer in an outpatient clinic was technically and practically feasible. The participants found the PROMs to be relevant and acceptable with a manageable number of items, and reported willingness to complete PROMs annually

Use of patient-reported outcome measures (PROMs) in clinical diabetes consultations: Study protocol for the DiaPROM randomised controlled trial pilot study

This is the final version. Available from BMJ Publishing Group via the DOI in this record.Introduction Although diabetes distress is found to be associated with decreased glycaemic control among adults with type 1 diabetes, the psychological and emotional impact of living with the condition is often not recognised and often under-reported in diabetes care. Therefore, regular assessment of diabetes distress is recommended. Assessment of diabetes distress using patient-reported outcome measures (PROMs) in clinical practice has the potential to enhance care for people with diabetes by identifying problems and improving patient-clinician communication. In this study protocol, we describe a pilot randomised controlled trial (RCT) aiming to test the feasibility of all components of an empowerment-based intervention using PROMs as dialogue support in clinical diabetes consultations, and to address the uncertainties associated with running a fully powered evaluation study. Methods and analysis We will undertake a two-Arm pilot RCT of an intervention using the Problem Areas In Diabetes (PAID) scale in clinical diabetes consultations in order to conclude whether a fully powered trial is appropriate and/or feasible. The study will also include qualitative indepth interviews with participants and healthcare providers. Our objectives are to (1) evaluate the recruitment procedures and attrition rates; (2) evaluate the performance of the randomisation procedure; (3) evaluate the participants' mean scores on the outcome measures before and after the intervention; (4) evaluate if the intervention consultations are acceptable and feasible; and (5) explore patients' and healthcare providers' experiences with the use of PAID as dialogue support and empowerment-based communication skills in clinical diabetes consultations. The quantitative data analysis includes descriptive statistics (frequencies, percentages, means, SD and CI). For the qualitative data, we will perform thematic analysis. Ethics and dissemination Ethical approval has been obtained from the Western Norway Regional Committee for Medical and Health Research Ethics (2017/1506/REC west). We will present the findings from the study phases at national and international conferences and submit manuscripts to peer-reviewed journals and popular science journals. Trial registration number NCT03471104; Pre-results.Norwegian Nurses AssociationNorwegian Diabetes AssociationWestern Norway University of Applied Science

An ambipolar BODIPY derivative for a white exciplex OLED and cholesteric liquid crystal laser toward multifunctional devices

A new interface engineering method is demonstrated for the preparation of an efficient white organic light-emitting diode (WOLED) by embedding an ultrathin layer of the novel ambipolar red emissive compound 4,4-difluoro-2,6-di(4-hexylthiopen-2-yl)-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (bThBODIPY) in the exciplex formation region. The compound shows a hole and electron mobility of 3.3 × 10–4 and 2 × 10–4 cm2 V–1 s–1, respectively, at electric fields higher than 5.3 × 105 V cm–1. The resulting WOLED exhibited a maximum luminance of 6579 cd m–2 with CIE 1931 color coordinates (0.39; 0.35). The bThBODIPY dye is also demonstrated to be an effective laser dye for a cholesteric liquid crystal (ChLC) laser. New construction of the ChLC laser, by which a flat capillary with an optically isotropic dye solution is sandwiched between two dye-free ChLC cells, provides photonic lasing at a wavelength well matched with that of a dye-doped planar ChLC cell

Enzymatically active apurinic/apyrimidinic endodeoxyribonuclease 1 is released by mammalian cells through exosomes

The apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), the main AP-endonuclease of the DNA base excision repair pathway, is a key molecule of interest to researchers due to its unsuspected roles in different nonrepair activities, such as: I) adaptive cell response to genotoxic stress, ii) regulation of gene expression, and iii) processing of microRNAs, which make it an excellent drug target for cancer treatment. We and others recently demonstrated that APE1 can be secreted in the extracellular environment and that serum APE1 may represent a novel prognostic biomarker in hepatocellular and non-smallcell lung cancers. However, the mechanism by which APE1 is released extracellularly was not described before. Here, using three different approaches for exosomes isolation: Commercial kit, nickel-based isolation, and ultracentrifugation methods and various mammalian cell lines, we elucidated the mechanisms responsible for APE1 secretion. We demonstrated that APE1 p37 and p33 forms are actively secreted through extracellular vesicles (EVs), including exosomes from different mammalian cell lines. We then observed that APE1 p33 form is generated by proteasomal-mediated degradation and is enzymatically active in EVs. Finally, we revealed that the p33 form of APE1 accumulates in EVs upon genotoxic treatment by cisplatin and doxorubicin, compounds commonly found in chemotherapy pharmacological treatments. Taken together, these findings provide for the first time evidence that a functional Base Excision Repair protein is delivered through exosomes in response to genotoxic stresses, shedding new light into the complex noncanonical biological functions of APE1 and opening new intriguing perspectives on its role in cancer biology

A new APE1/Ref-1-dependent pathway leading to reduction of NF-κB and AP-1, and activation of their DNA-binding activity

APE1/Ref-1 is thought to be a multifunctional protein involved in reduction–oxidation (redox) regulation and base excision DNA repair, and is required for early embryonic development in mice. APE1/Ref-1 has redox activity and AP endonuclease activity, and is able to enhance DNA-binding activity of several transcription factors, including NF-κB, AP-1 and p53, through reduction of their critical cysteine residues. However, it remains elusive exactly how APE1/Ref-1 carries out its essential functions in vivo. Here, we show that APE1/Ref-1 not only reduces target transcription factors directly but also facilitates their reduction by other reducing molecules such as glutathione or thioredoxin. The new activity of APE1/Ref-1, termed redox chaperone activity, is exerted at concentration significantly lower than that required for its redox activity and is neither dependent on its redox activity nor on its AP endonuclease activity. We also show evidence that redox chaperone activity of APE1/Ref-1 is critical to NF-κB-mediated gene expression in human cells and is mediated through its physical association with target transcription factors. Thus, APE1/Ref-1 may play multiple roles in an antioxidative stress response pathway through its different biochemical activities. These findings also provide new insight into the mechanism of intracellular redox regulation

Inherited MC1R variants in patients with melanoma are associated with better survival in women

Background: Women have a better melanoma prognosis, and fairer skin/hair colour. The presence of inherited MC1R variants has been associated with a better melanoma prognosis, but its interaction with sex is unknown. Objectives: To evaluate the relationship between germline MC1R status and survival, and determine any association with sex. Methods: This was a cohort study including 1341 patients with melanoma from the Melanoma Unit of the Hospital Clinic of Barcelona, between January 1996 and April 2018. We examined known sex‐related prognosis factors as they relate to features of melanoma and evaluated the sex‐specific role of MC1R in overall and melanoma‐specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox logistic regression. Results: Men showed lower overall survival than women (P < 0·001) and the presence of inherited MC1R variants was not associated with better survival in our cohort. However, in women the presence of MC1R variants was associated with better overall survival in the multivariate analysis [HR 0·57, 95% confidence interval (CI) 0·38-0·85; P = 0·006] but not in men [HR 1·26, 95% CI 0·89-1·79; P = 0·185 (P‐value for interaction 0·004)]. Analysis performed for melanoma‐specific survival showed the same level of significance. Conclusions: Inherited MC1R variants are associated with improved overall survival in women with melanoma but not in men. Intrinsic sex‐dependent features can modify the role of specific genes in melanoma prognosis. We believe that survival studies of patients with melanoma should include analysis by sex and MC1R genotype

Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice

Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrP(sc)) of the natural cellular prion protein (PrP(c)) encoded by the Prnp gene. Although several roles have been attributed to PrP(c), its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrP(c) studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Principal Findings: Here we explore the role of PrP(c) expression in neurotransmission and neural excitability using wild-type, Prnp -/- and PrP(c)-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp -/- mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp -/- and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABA(A) and AMPA-kainate receptors are co-regulated in both Prnp -/- and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrP(c) is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABA(A) and AMPA-Kainate neurotransmission. New PrP(c) functions have recently been described, which point to PrP(c) as a target for putative therapies in Alzheimer's disease. However, our results indicate that a "gain of function" strategy in Alzheimer's disease, or a "loss of function" in prionopathies, may impair PrP(c) function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies

Time and tumor type (primary or metastatic) do not influence the detection of BRAF/NRAS mutations in formalin fixed paraffin embedded samples from melanomas.

BACKGROUND: BRAF and NRAS mutation detection is crucial for advanced melanoma treatment. Our aim was to evaluate how different characteristics from formalin-fixed paraffin-embedded (FFPE) samples, age of the block or DNA concentration could influence the success of BRAF and NRAS mutational screening. METHODS: DNA was obtained from 144 FFPE samples (62 primary melanoma, 43 sentinel lymph nodes [SLN] and 39 metastasis). BRAF and NRAS were sequenced by Sanger sequencing. RESULTS: Complete sequencing results were obtained from 75% (108/144) of the samples, and at least one gene was sequenced in 89% (128/144) of them. BRAF was mutated in 55% (29/53) and NRAS in 11% (5/45) of the primary melanomas sequenced. DNA concentration correlated with the tumor area used for DNA extraction (mm2) (adj p-value<0.01, r=0.73). The age of the block did not affect sequencing success. In 60% of samples kept for more than 10 years, both BRAF and NRAS were successfully sequenced. CONCLUSIONS: Preserving sufficient tumor area in FFPE blocks is important. It is necessary to keep the FFPE blocks, no matter their age, as they are necessary to decide the best treatment for the melanoma patient

Prevalence of MITF p.E318K in patients with melanoma independent of the presence of CDKN2A causative mutations

Importance The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers.Objectives To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features.Design, Setting, and Participants A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age- and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls. Patients were recruited between January 1, 1992, and June 30, 2014; data analysis was conducted from September 1 to November 30, 2014.Main Outcomes and Measures The genetic results of the MITF p.E318K variant were correlated with clinical and phenotypic features.Results Among the 531 patients, the prevalence of the MITF p.E318K variant was calculated among the different subsets of patients included and was 1.9% (9 of 462) in all melanoma patients with wild-type p16INK4A, 2.6% (7 of 271) in those with MPM, and 2.9% (2 of 69) in the probands of families with p16INK4A mutations. With results reported as odds ratio (95% CI), the MITF p.E318K was associated with an increased melanoma risk (3.3 [1.43-7.43]; P 200 nevi) (8.4 [2.14-33.19]; P < .01). Two fast-growing melanomas were detected among 2 MITF p.E318K carriers during dermatologic digital follow-up.Conclusions and Relevance In addition to melanoma risk, MITF p.E318K is associated with a high nevi count and could play a role in fast-growing melanomas. Testing for MITF p.E318K should not exclude patients with known mutations in p16INK4A. Strict dermatologic surveillance, periodic self-examination, and renal cell carcinoma surveillance should be encouraged in this context

Childbearing intentions in a low fertility context: the case of Romania

This paper applies the Theory of Planned Behaviour (TPB) to find out the predictors of fertility intentions in Romania, a low-fertility country. We analyse how attitudes, subjective norms and perceived behavioural control relate to the intention to have a child among childless individuals and one-child parents. Principal axis factor analysis confirms which items proposed by the Generation and Gender Survey (GGS 2005) act as valid and reliable measures of the suggested theoretical socio-psychological factors. Four parity-specific logistic regression models are applied to evaluate the relationship between the socio-psychological factors and childbearing intentions. Social pressure emerges as the most important aspect in fertility decision-making among childless individuals and one-child parents, and positive attitudes towards childbearing are a strong component in planning for a child. This paper also underlines the importance of the region-specific factors when studying childbearing intentions: planning for the second child significantly differs among the development regions, representing the cultural and socio-economic divisions of the Romanian territory