Confronting the Joint Legacies of the Holocaust and Colonialism in Alex Miller''s Landscape of Farewell

The aim of this article is to apply the concept of synergy to the workings of memory in Alex Miller''s Landscape of Farewell (2007) by focusing on the relationship between its two main characters, Max Otto, a German professor of history, and Dougald Gnapun, an Aboriginal elder. It does so with a view to analysing the way in which fiction can weave connections between different histories of violence-in this case the Holocaust and the colonisation of Australia-while simultaneously pointing to the risks of downplaying the specificities of each case. Both men are burdened by traumatic memories of past atrocities: for Max it is his father''s complicity in the crimes of Nazism, while for Dougald it is the 1861 Cullin-la-Ringo massacre of white settlers, allegedly led by his great-grandfather. Max and Dougald meet through Vita McLelland, a young Aboriginal academic visiting Hamburg, who invites Max to a conference at the University of Sydney and then to visit her uncle Dougald in Queensland so that the professor can learn about the history of Australia''s indigenous people. Though far from one another in terms of geographical and cultural background, a close friendship develops between these two men whose only initial link is their being descendants of perpetrators. I argue that by confronting the joint legacies of the Holocaust and colonialism through Max and Dougald''s synergistic and transformative friendship, and by placing their stories/memories in a broader transnational and transhistorical context, Miller''s fictional recreation of these historical events engages with the complex relationship between victimisers and victims, perpetrators and descendants, history and fiction, remembrance and appropriation, which, as in the case of Max and Dougald, suggests the possibility of reconciliation with, and a letting go, of traumatic pasts

A holistic and integrated approach to implementing cognitive pharmaceutical services

La Farmacia Comunitaria forma parte del sistema de salud. Este sistema actualmente se encuentrasometido a presiones económicas y debe afrontar cambios en la demanda tanto de los consumidorescomo de los gobiernos. La respuesta de la profesión farmacéutica está dirigida a orientar su prácticahacia el paciente y a implantar servicios cognitivos farmacéuticos (CPS). En distintos países estosservicios tiene objetivos similares aunque presentan diferencias en el énfasis de los servicios, en susdefiniciones, denominaciones y en la utilización de diferentes herramientas. Sin embargo, todos ellospueden clasificarse utilizando un amplio modelo jerárquico que se basa en la toma de decisionesclínicas y en la amplitud del cambio requerido. (Box 1). Los retos que debe afrontar la profesión estánrelacionados con el desarrollo de un nuevo modelo de farmacia orientado al paciente que afecta a laspolíticas de salud, a la formación e investigación, a la evolución de los mercados, a los abordajes delcambio tanto a nivel individual como organizacional, y a la implantación de CPS. Estos temas y lainvestigación en práctica farmacéutica que se ha venido realizando con anterioridad han sidosintetizados para proporcionar una plataforma para el cambio que pueda guiar un planteamientoholístico e integrado de implantación de CPS. Conceptualmente la implantación de CPS puedeenmarcarse en seis niveles: clínico, provisión de servicios, farmacia comunitaria, organizaciónprofesional, gobierno y agentes implicados (Figura 1). La experiencia reciente relacionada con laimplantación de servicios ha mostrado la aplicación de programas de implantación que han incluidouno o dos de estos niveles en lugar de haber utilizado un abordaje holístico. Por ello se ha desarrolladoun modelo concéntrico para ilustrar la implantación de CPS dentro del planteamiento integrado yholístico necesario para apoyar el cambio En España se ha desarrollado un programa (conSIGUE) quepretende integrar los seis niveles con el objetivo de apoyar la implantación y evaluación de un CPS, elservicio de seguimiento farmacoterapéutico.Community pharmacy is part of the health care system which is currently under economic pressureand facing changes in demands from consumers and government. In response, the pharmacy profession is becoming more patient orientated and implementing cognitive pharmaceutical services(CPS). CPS in various countries has similar objectives with different emphasis, definitions, labels andusing different tools. However, they can be classified using a broad hierarchical model based onclinical decision making and the extent of change required (Box 1). The challenges faced by theprofession are related the development of a new patient orientated model of pharmacy which affectshealth care policy, education and research, the evolution of the market, the individual andorganisational approaches to change and the implementation of CPS. These issues and previousresearch conducted in pharmacy practice have been synthesised to provide a platform for change thatcan guide a holistic and integrated approach to CPS implementation. Implementation can beconceptually framed in six levels: clinical, service provision, community pharmacy, professionalorganisation, government and stakeholder (Figure 1). Past experience with service implementation hasseen the application of programs that include one or two of these levels in practice rather than aholistic approach. A concentric model was developed to illustrate the implementation of CPS and theholistic and integrated approach required to support change. A program (conSIGUE) being conductedin Spain has attempted to integrate all six levels to support the implementation and evaluation of amedication management service (Seguimiento Farmacoterapéutico

Health data processes. A framework for analysing and discussing efficient use and reuse of health data with focus on Patient Reported Outcome (PRO) measures

This is is the final version. Available from Journal of Medical Internet Research via the DOI in this record.The collection and use of patient health data is central to any kind of activity in the healthcare system. This data may be produced during routine clinical processes or obtained directly from the patient using patient-reported outcome (PRO) measures. Although efficiency and other reasons justify data availability for a range of potential relevant uses, these data are nearly always collected for a single specific purpose. The healthcare data literature reflects this narrow scope, and there is limited literature on the joint use of health data for daily clinical use, clinical research, surveillance and administrative purposes. The aim of this paper is to provide a framework for a discussion of the efficient use of health data with specific focus on the role of PRO measures. PRO data may be used: i) at an individual patient level to inform patient care or shared-decision making and tailor care to individual needs or ii) at group level as a complement to health record data e.g. on mortality and readmission to inform service delivery and measure real-world effectiveness of treatment. PRO may be used either for their own sake, to provide valuable information from the patient perspective, or as proxy for clinical data that would be otherwise not feasible to collect. We introduce a framework to analyse any health care activity that involves health data. The framework consists of four data processes (patient identification, data collection, data aggregation and data use), further structured into two dichotomous dimensions in each data process (level: group vs patient; and timeframe: ad hoc vs systematic). This framework is used to analyse various health activities with respect to joint use of data considering the technical, legal, organisational and logistical challenges that characterize each data process. Finally, we propose a model for joint use of health data with data collected during follow-up as basis. Demands for health data will continue to increase which will further add to the need for the concerted use and reuse of PRO data for parallel purposes. Repeated and uncoordinated PRO data collection for the same patient for different purposes results in misuse of resources for the healthcare system as well as reduced response rates owing to questionnaire fatigue. PRO data can be routinely collected both at the hospital (in- as well as outpatients) and outside of hospital settings, in primary or social care settings, or in the patient’s home provided the health informatics infrastructure is in place. In the future, clinical settings are likely to be a prominent source of PRO data; however we are also likely to see increased remote collection of PRO data by patients in their own home (telePRO). Data collection for research and quality surveillance will have to adapt to this circumstance and adopt complementary data capture methods which take advantage of the utility of PRO data collected during daily clinical practice. The European Union’s regulation with respect to the protection of personal data, General Data Protection Regulation, imposes severe restrictions on use of health data for parallel purposes and steps should be taken to alleviate the consequences while still protecting personal data against misuse.National Institute for Health Research (NIHR

Pragmatic treatment of patients with Systemic Lupus Erythematosus with rituximab: Long-term effects on serum immunoglobulins

OBJECTIVE: B cell depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with Systemic Lupus Erythematosus (SLE). The aim of this observational study was to document long-term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice. METHODS: We included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti-dsDNA antibodies over a median of 48 months most recent follow-up. Flow cytometry was used prospectively to assess B-cell phenotypes in 17/57 patients. RESULTS: Twelve patients (21%) had persistent IgM hypogammaglobulinemia (1000IU/ml; normal<50IU/ml). Factors predictive of low serum IgM included: baseline serum IgM ≤0.8g/L (receiver-operated-curve analysis) and subsequent therapy with mycophenolate mofetil (MMF) (odds ratio=6.8 compared with other immunosuppressants). In patients maintaining normal IgM levels (9/17), the frequency of circulating IgD+CD27+ B cells was significantly higher (p=0.05). At 12 months after rituximab, 7/30 SLE patients with baseline anti-dsDNA≤1000 IU/ml had lost seropositivity. CONCLUSIONS: Lower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti-dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE. This article is protected by copyright. All rights reserved

MRI based preterm white matter injury classification: the importance of sequential imaging in determining severity of injury

The evolution of non-hemorrhagic white matter injury (WMI) based on sequential magnetic resonance imaging (MRI) has not been well studied. Our aim was to describe sequential MRI findings in preterm infants with non-hemorrhagic WMI and to develop an MRI classification system for preterm WMI based on these findings.Eighty-two preterm infants (gestation ≤35 weeks) were retrospectively included. WMI was diagnosed and classified based on sequential cranial ultrasound (cUS) and confirmed on MRI.138 MRIs were obtained at three time-points: early (<2 weeks; n = 32), mid (2-6 weeks; n = 30) and term equivalent age (TEA; n = 76). 63 infants (77%) had 2 MRIs during the neonatal period. WMI was non-cystic in 35 and cystic in 47 infants. In infants with cystic-WMI early MRI showed extensive restricted diffusion abnormalities, cysts were already present in 3 infants; mid MRI showed focal or extensive cysts, without acute diffusion changes. A significant reduction in the size and/or extent of the cysts was observed in 32% of the infants between early/mid and TEA MRI. In 4/9 infants previously seen focal cysts were no longer identified at TEA. All infants with cystic WMI showed ≥2 additional findings at TEA: significant reduction in WM volume, mild-moderate irregular ventriculomegaly, several areas of increased signal intensity on T1-weighted-images, abnormal myelination of the PLIC, small thalami.In infants with extensive WM cysts at 2-6 weeks, cysts may be reduced in number or may even no longer be seen at TEA. A single MRI at TEA, without taking sequential cUS data and pre-TEA MRI findings into account, may underestimate the extent of WMI; based on these results we propose a new MRI classification for preterm non-hemorrhagic WMI

p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor–positive breast cancer

Biomarker; Hormone receptor-positive; Breast cancerBiomarcador; Cáncer de mama; Receptor hormonal positivoBiomarcador; Càncer de mama; Receptor hormonal positiuCDK4/6 inhibitors benefit a minority of patients who receive them in the breast cancer adjuvant setting. p27Kip1 is a protein that inhibits CDK/Cyclin complexes. We hypothesized that single-nucleotide polymorphisms that impaired p27Kip1 function could render patients refractory to endocrine therapy but responsive to CDK4/6 inhibitors, narrowing the patient subpopulation that requires CDK4/6 inhibitors. We found that the p27Kip1 V109G single-nucleotide polymorphism is homozygous in approximately 15% of hormone-positive breast cancer patients. Polymorphic patients experience rapid failure in response to endocrine monotherapy compared with wild-type or heterozygous patients in the first-line metastatic setting (progression-free survival: 92 vs 485 days, P < .001); when CDK4/6 inhibitors are added, the differences disappear (progression-free survival: 658 vs 761 days, P = .92). As opposed to wild-type p27Kip1, p27Kip1 V109G is unable to suppress the kinase activity of CDK4 in the presence of endocrine inhibitors; however, palbociclib blocks CDK4 kinase activity regardless of the p27Kip1 status. p27Kip1 genotyping could constitute a tool for treatment selection.MM is supported by the Spanish Ministry of Science and Innovation (RTI2018-095582-B-100; PLEC2021-007892 and RED2018-102723-T), AES (DTS21/00132) and Comunidad de Madrid (B2017/BMD-3884 and Y2020/BIO-6519). MQF is a recipient of the following grants: AES—PI 19/00454 funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF), and B2017/BMD3733 (Immunothercan-CM) – Call for Coordinated Research Groups from the Madrid Region—Madrid Regional Government—ERDF funds. This study was also funded by a donation from CRIS Contra El Cancer Foundation

Quantitative proteomic analysis of Parkin substrates in Drosophila neurons.

Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson's Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings.Here we utilized the recently introduced BioUb strategy to isolate ubiquitinated proteins in flies. Following Parkin Wild-Type (WT) and Parkin Ligase dead (LD) expression we analysed by mass spectrometry and stringent bioinformatics analysis those proteins differentially ubiquitinated to provide the first survey of steady state Parkin substrates using an in vivo model. We further used an in vivo ubiquitination assay to validate one of those substrates in SH-SY5Y cells.We identified 35 proteins that are more prominently ubiquitinated following Parkin over-expression. These include several mitochondrial proteins and a number of endosomal trafficking regulators such as v-ATPase sub-units, Syx5/STX5, ALiX/PDCD6IP and Vps4. We also identified the retromer component, Vps35, another PD-associated gene that has recently been shown to interact genetically with parkin. Importantly, we validated Parkin-dependent ubiquitination of VPS35 in human neuroblastoma cells.Collectively our results provide new leads to the possible physiological functions of Parkin activity that are not overtly biased by acute mitochondrial depolarisation