Miracle-dz/UniFAR-FTUs huggingface dataset:
'Doubly deprived': a post-death qualitative study of primary carers of people who died in Western Australia.

This paper explores the daily experiences and occupational needs of family carers of people who were dying, with particular reference to their daily routines and ability to undertake other varied activities during the period of care. The impact of the caring experience on these occupations was then examined to determine how, and if, these occupational needs were addressed in the community using potential and available services. An exploratory approach using grounded theory was employed to examine these experiences. Participants were recruited from metropolitan (n = 10) and rural (n = 4) locations across Western Australia between February and June 2009, using a purposive sampling method. A semi-structured interview guide was developed following consultation with the literature, expert opinion and piloting. Interviews were conducted in participants' homes and questions were asked about their experiences as a carer including routines, engagement in usual activities and the impact of the caring role on their daily life during and after the period of care. Each interview was transcribed verbatim and analysed to determine potential themes. Two important themes were identified: (1) Carers experienced disengagement and deprivation from their usual occupations during and after the period of care; and (2) Participants described significant disempowerment in their role as carer. Carers are 'doubly disadvantaged' as a result of their caring role; they are unable to participate in their usual occupations and they are not recognised for their contributions as carers. Carers experienced disengagement and deprivation from their usual occupations, contributing to physical, psychological and emotional difficulties and this may result in long term consequences for health and well-being. In addition, the current services and support available for carers in the community are deemed inadequate; placing further stress on a health care system which needs to cope with increasing demands as a result of the ageing population in Australia.
The BCR‐ABL1 transcript type influences response and outcome in Philadelphia chromosome‐positive chronic myeloid leukemia patients treated frontline with imatinib

The most frequent BCR‐ABL1 fusion transcripts in chronic myeloid leukemia (CML) are the e13a2 (b2a2) and the e14a2 (b3a2) ones. In the imatinib era few studies addressing the prognostic significance of the BCR‐ABL1 transcript type in early chronic phase CML have been published. Overall, these studies suggest that in e14a2 patients the response to imatinib is faster and deeper. To evaluate if the BCR‐ABL1 transcript type (e13a2 compared to e14a2) affect the response to imatinib and the clinical outcome in newly diagnosed adult CML patients, 559 patients enrolled in 3 prospective studies (NCT00514488, NCT00510926, observational study CML/023) were analyzed. A qualitative PCR was performed at baseline: 52% patients had a e14a2 transcript, 37% a e13a2 transcript, 11% co‐expressed both transcripts and 1% had other rare transcripts. The median follow‐up was 76 months (95% of the patients had at least a 5‐year observation). The complete cytogenetic response rates were comparable in e14a2 and e13a2 patients. The median time to MR3.0 (6 and 12 months) and MR4.0 (41 and 61 months) was significantly shorter for e14a2 patients compared to e13a2 patients, with a higher cumulative probability of MR3.0 (88% and 83%, P < .001) and MR4.0 (67% and 52%, P = .001). The 7‐year overall survival (90% and 83%, P = .017), progression‐free survival (89% and 81%, P = .005) and failure‐free survival (71% and 54%, P < .001) were significantly better in patients with e14a2 transcript. In conclusion, patients with e13a2 transcript had a slower molecular response with inferior response rates to imatinib and a poorer long‐term outcome.
Glycemic Control in Cardiac Surgery

Martin Martinez Rosas1, Eduardo Wilfrido Goicoechea-Turcott2, Pastor Luna Ortiz3, Alberto Salazar4 and Benito Anton Palma4 1Physiology Department, National Institute of Cardiology “Ignacio Chavez”, Mexico, D.F 2Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico, D.F 3Pharmacology Department, National Institute of Cardiology “Ignacio Chavez”, Mexico, D.F 4Laboratory of Molecular Neurobiology, National Institute of Psychiatry “Ramon de la Fuente”, Mexico, D.F Mexico
TRESK Background K+ Channel Is Inhibited by Phosphorylation via Two Distinct Pathways*

The two-pore domain K+ channel, TRESK (TWIK-related spinal cord K+ channel, KCNK18) is directly regulated by the calcium/calmodulin-dependent phosphatase calcineurin and 14-3-3 adaptor proteins. The calcium signal robustly activates the channel via calcineurin, whereas the anchoring of 14-3-3 interferes with the return of the current to the resting state after the activation in Xenopus oocytes. In the present study, we report that the phosphorylation of TRESK at two distinct regulatory regions, the 14-3-3 binding site (Ser-264) and the cluster of three adjacent serine residues (Ser-274, Ser-276, and Ser-279), are responsible for channel inhibition. The phosphorylation of Ser-264 by protein kinase A accelerated the return of the current of S276E mutant TRESK to the resting state after the calcineurin-dependent activation. In the presence of 14-3-3, the basal current of the S276E mutant was reduced, and its calcineurin-dependent activation was augmented, suggesting that the direct binding of the adaptor protein to TRESK contributed to the basal inhibition of the channel under resting conditions. Unexpectedly, we found that 14-3-3 impeded the recovery of the current of S264E mutant TRESK to the resting state after the calcineurin-dependent activation, despite of the mutated 14-3-3 binding site. This suggests that 14-3-3 inhibited the kinase phosphorylating the regulatory cluster of Ser-274, Ser-276, and Ser-279, independently of the direct interaction between TRESK and 14-3-3. In conclusion, two distinct inhibitory kinase pathways converge on TRESK, and their effect on the calcineurin-dependent regulation is differentially modulated by the functional availability of 14-3-3.
Optimization of antipsoriatic treatments with special reference to monitoring of methotrexate-induced liver toxicity.

Background: In 2003, the Dutch guideline ‘Photo(chemo) therapy and systemic therapy for severe chronic plaque psoriasis’ was established. Objectives: To document how closely this guideline is followed in clinical practice with respect to the methotrexate (MTX) treatment and to formulate recommendations to adjust the guideline. Methods: A survey was conducted among Dutch dermatologists and residents in dermatology. The questionnaire assessed the knowledge of and the adherence to the guideline with respect to MTX treatment. Results: Fifty percent of the contacted dermatologists/residents responded. Fifty-two percent follow the guideline with respect to MTX. Liver biopsy and the frequency of blood investigations cause a discrepancy between guideline and reality. There is a lack of consensus between guidelines of the different specialisms concerning liver biopsy. Conclusion: The need for liver biopsies in combination with the frequent check-ups and the lack of consensus between rheumatologists, hepatologists and dermatologists seem to restrict the adherence to the guideline. Copyright © 2007 S. Karger AG, Basel Received: January 12, 2007 Accepted: February 9, 2007 M.J.P. Gerritsen Department of Dermatology Radboud University Medical Centre Nijmegen PO Box 9101, NL–6500 HB Nijmegen (The Netherlands) Tel. +31 24 361 0265, Fax +31 24 354 1184, E Mail m.gerritsen@derma.umcn. nl © 2007 S. Karger AG, Basel 1018–8665/07/2151–0045$23.50/0 Accessible online at: www.karger. com/drm Chapter 3 How to improve monitoring of liver toxicity in patients treated with methotrexate 48 Berends/de Jong/van de Kerkhof/ Gerritsen Dermatology 2007;215:45–52 46 sity Medical Centre Nijmegen, The Netherlands, in conjunction with the Committee Psoriasis of the Dutch Society of Dermatology and Venereology, conducted a survey among Dutch dermatologists and residents in dermatology. This publication describes the adherence of the Dutch dermatologist to the guideline ‘Photo(chemo)therapy and systemic therapy for severe chronic plaque psoriasis’, in relation to the treatment of patients with MTX. These results together with an update of the recent literature may lead to recommendations to adjust the guideline with respect to treatment with MTX. Because of the resemblance to the international guidelines, these results may, at least to some extent, be applicable to other countries. A summary of the American, British and Dutch guidelines is drawn in tables 1 , 2 and 3 .
Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain

The painful vaso‐occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady‐state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural‐mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser‐Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso‐reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso‐occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady‐state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.
Perspectives on Quality of Reference Service in an Academic Library: A Qualitative Study.

A qualitative study was conducted to explore the concept of quality as it applies to reference service in an academic library. The study explicates the dimensions of quality service and points to the interconnectedness and interdependence of these dimensions. Time and morale were found to provide the essential environmental context for quality service. These critical dimensions require highly competent management, as they have impact on the knowledge and willingness of the reference librarian, on the process of assessment and action, and on the partnership between user and librarian. Implications for management are discussed, as effective management involves a holistic understanding of the complex nature of connections among the dimensions of quality service.
Targeted next‐generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS‐R

A 27‐gene panel was used for next‐generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS‐R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2‐2.5), SETBP1 (HR 4.1, 95% CI 1.6‐10.2) and TP53 (HR 2.2, 95% CI 1.3‐3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5‐10.2), IDH2 (HR 3.7, 95% CI 1.2‐11.4), and CSF3R (HR 6.0, 95% CI 1.6‐22.6) for leukemia‐free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS‐R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS‐R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia‐free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS‐R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision‐making in lower risk MDS.
Impaired Glucose Tolerance and Predisposition to the Fasted State in Liver Glycogen Synthase Knock-out Mice*

Conversion to glycogen is a major fate of ingested glucose in the body. A rate-limiting enzyme in the synthesis of glycogen is glycogen synthase encoded by two genes, GYS1, expressed in muscle and other tissues, and GYS2, primarily expressed in liver (liver glycogen synthase). Defects in GYS2 cause the inherited monogenic disease glycogen storage disease 0. We have generated mice with a liver-specific disruption of the Gys2 gene (liver glycogen synthase knock-out (LGSKO) mice), using Lox-P/Cre technology. Conditional mice carrying floxed Gys2 were crossed with mice expressing Cre recombinase under the albumin promoter. The resulting LGSKO mice are viable, develop liver glycogen synthase deficiency, and have a 95% reduction in fed liver glycogen content. They have mild hypoglycemia but dispose glucose less well in a glucose tolerance test. Fed, LGSKO mice also have a reduced capacity for exhaustive exercise compared with mice carrying floxed alleles, but the difference disappears after an overnight fast. Upon fasting, LGSKO mice reach within 4 h decreased blood glucose levels attained by control floxed mice only after 24 h of food deprivation. The LGSKO mice maintain this low blood glucose for at least 24 h. Basal gluconeogenesis is increased in LGSKO mice, and insulin suppression of endogenous glucose production is impaired as assessed by euglycemic-hyperinsulinemic clamp. This observation correlates with an increase in the liver gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression and activity. This mouse model mimics the pathophysiology of glycogen storage disease 0 patients and highlights the importance of liver glycogen stores in whole body glucose homeostasis.
Alternate use of thrombopoietin receptor agonists in adult primary immune thrombocytopenia patients: A retrospective collaborative survey from Italian hematology centers

Sequential use of the TPO‐RAs romiplostim and eltrombopag in ITP patients failing either agent was retrospectively evaluated to assess efficacy and impact of clinical characteristics on outcome. Patients were grouped into 5 categories: efficacy issues: 1st TPO‐RA failure; loss of response; non‐efficacy issues: platelet fluctuations; patient's preference; adverse event development. Either one TPO‐RA sequence was analyzed at 3 month and at last follow‐up. 106/546 patients on TPO‐RA underwent switch and 65% achieved, regained or maintained a short‐ term response independent of switch sequence, gender or age; lower response rates were associated with lines of previous therapy; disease duration lowers probability to respond. Clinically, patients switched for efficacy issue did not differ from those switched for non‐efficacy issues. Response was achieved/regained in 57.8% of patients switched for efficacy issues, the lowest response rates were observed in non‐responders to 1st TPO‐RA; 80% of patients switched for non‐efficacy issues maintained a response. Platelet fluctuation resolved in 44.4%. Of the 49 patients evaluable for long‐term outcome, 27 were in response on therapy; 16 discontinued the TPO‐RA for reasons other than efficacy, while only 6 were non responders. We confirm the efficacy of TPO‐RA switch; once achieved, response to the 2nd TPO‐RA seems durable.
Recent advances in refractory coeliac disease: a review

Coeliac disease (CD) is an immune‐mediated disease of the small intestine caused by intolerance to gluten. Removal of gluten from the diet results in a return to normal health for the majority of patients. A significant proportion of patients do not respond to a gluten‐free diet and are considered to be suffering from refractory coeliac disease (RCD). Two types of RCD are now recognized: type 1 RCD is characterized by a polyclonal population of intraepithelial lymphocytes (IELs) with a normal immunophenotype, and type 2 RCD shows monoclonal IELs with an aberrant immunoprofile. Patients with RCD have a high risk of complications such as ulcerative jejunitis (UJ) and enteropathy‐type T‐cell lymphoma (ETTL). RCD2 may represent an early stage in the development of overt lymphoma. The diagnosis of RCD, therefore, has important implications, but remains a challenging area. In this paper we review the latest developments in RCD, including the diagnostic approach and a discussion of the key clinical, histological, immunohistochemical and molecular features of RCD and its complications.
Differences between indirect comparison studies of the oral anticoagulants for stroke prevention in atrial fibrillation: where do we go next?

Sir, Superior or equivalent efficacy and safety of the oral direct thrombin inhibitor dabigatran and the oral direct factor Xa inhibitors rivaroxaban and apixaban was shown for the prevention of ischaemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) in the RE-LY trial (dabigatran 150 and 110 mg bid), the ROCKET-AF trial (rivaroxaban 20 mg od) and the ARISTOTLE trial (apixaban 5 mg bid) vs. international normalized ratio (INR)-adjusted warfarin.1 Testa et al. 1 performed an indirect comparison of these anticoagulants in those patients by pooling the results of the control groups of the three studies treated with warfarin. In addition, they also pooled the results of new oral anticoagulants (NOAC) and compared them with the results they calculated for the pooled data of the warfarin groups of the three studies. Until mid-2012, …
Tumours and tumour‐like conditions of the thymus other than thymoma; a practical approach

Masses within the thymus and mediastinum are frequently biopsied to establish a diagnosis. The specimens sent for histopathological analysis are typically small (needle) biopsy specimens on which the pathologist is challenged to provide a classifying diagnosis. Despite the fact that the pathology of the anterior mediastinum is predominantly centred on the thymus and it thus might be expected that the range of possible diagnoses is limited, the list of disease entities is in fact extensive, encompassing hyperplastic conditions and both benign and malignant neoplasms. In addition to primary thymic epithelial tumours, a number of less common diseases typical for this location may be encountered, including extragonadal germ cell tumours, lymphomas, soft tissue tumours and a number of conditions which may simulate a tumour, such as cysts and inflammatory conditions. In this review, the disease entities that may be encountered in biopsy material from anterior mediastinal/thymic processes are discussed and an approach to tackle the differential diagnosis is provided.
Solution Conformation and Dynamics of the HIV-1 Integrase Core Domain*

The human immunodeficiency virus type 1 (HIV-1) integrase (IN) is a critical enzyme involved in infection. It catalyzes two reactions to integrate the viral cDNA into the host genome, 3′ processing and strand transfer, but the dynamic behavior of the active site during catalysis of these two processes remains poorly characterized. NMR spectroscopy can reveal important structural details about enzyme mechanisms, but to date the IN catalytic core domain has proven resistant to such an analysis. Here, we present the first NMR studies of a soluble variant of the catalytic core domain. The NMR chemical shifts are found to corroborate structures observed in crystals, and confirm prior studies suggesting that the α4 helix extends toward the active site. We also observe a dramatic improvement in NMR spectra with increasing MgCl2 concentration. This improvement suggests a structural transition not only near the active site residues but also throughout the entire molecule as IN binds Mg2+. In particular, the stability of the core domain is linked to the conformation of its C-terminal helix, which has implications for relative domain orientation in the full-length enzyme. 15N relaxation experiments further show that, although conformationally flexible, the catalytic loop of IN is not fully disordered in the absence of DNA. Indeed, automated chemical shift-based modeling of the active site loop reveals several stable clusters that show striking similarity to a recent crystal structure of prototype foamy virus IN bound to DNA.
Obesity and kidney disease in type 1 and 2 diabetes: an analysis of the National Diabetes Audit.

BACKGROUND Obesity is increasingly prevalent in many countries. Obesity is a major risk factor for the development of type 2 diabetes but its relationship with diabetic kidney disease (DKD) remains unclear. Some studies have suggested that the metabolic syndrome (including obesity) may be associated with DKD in type 1 diabetes. AIM To investigate the association between obesity and DKD. DESIGN Retrospective cross-sectional study. METHODS National Diabetes Audit data were available for the 2007-08 cycle. Type 1 and 2 diabetes patients with both a valid serum creatinine and urinary albumin:creatinine ratio were included. DKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), albuminuria or both. Logistic regression was used to analyse associations of obesity (body mass index ≥30 kg/m(2)) and other variables including year of birth, year of diagnosis, ethnicity and stage of kidney disease. RESULTS A total of 58 791 type 1 and 733 769 type 2 diabetes patients were included in the analysis. After adjustment, when compared with type 1 diabetes patients with normal renal function those with DKD were up to twice as likely to be obese. Type 2 DKD patients were also more likely to be obese. For example, type 2 diabetes patients with an eGFR <15 ml/min/1.73 m(2) and normoalbuminuria, microalbuminuria or macroalbuminuria were all more likely to be obese; odds ratios (95% CI) 1.65 (1.3-2.1), 1.56 (1.28-1.92) and 1.27 (1.05-1.54), respectively. CONCLUSION This study has highlighted a strong association between obesity and kidney disease in type 1 diabetes and confirmed their association in type 2 diabetes.