Dynamic Perturbations of the T-Cell Receptor Repertoire in Chronic HIV Infection and following Antiretroviral Therapy

HIV infection profoundly affects many parameters of the immune system and ultimately leads to AIDS, yet which factors are most important for determining resistance, pathology, and response to antiretroviral treatment - and how best to monitor them - remain unclear. We develop a quantitative high-throughput sequencing pipeline to characterize the TCR repertoires of HIV-infected individuals before and after antiretroviral therapy, working from small, unfractionated samples of peripheral blood. This reveals the TCR repertoires of HIV(+) individuals to be highly perturbed, with considerably reduced diversity as a small proportion of sequences are highly overrepresented. HIV also causes specific qualitative changes to the repertoire including an altered distribution of V gene usage, depletion of public TCR sequences, and disruption of TCR networks. Short-term antiretroviral therapy has little impact on most of the global damage to repertoire structure, but is accompanied by rapid changes in the abundance of many individual TCR sequences, decreases in abundance of the most common sequences, and decreases in the majority of HIV-associated CDR3 sequences. Thus, high-throughput repertoire sequencing of small blood samples that are easy to take, store, and process can shed light on various aspects of the T-cell immune compartment and stands to offer insights into patient stratification and immune reconstitution

Assessing framing of uncertainties in water management practice

Dealing with uncertainties in water management is an important issue and is one which will only increase in light of global changes, particularly climate change. So far, uncertainties in water management have mostly been assessed from a scientific point of view, and in quantitative terms. In this paper, we focus on the perspectives from water management practice, adopting a qualitative approach. We consider it important to know how uncertainties are framed in water management practice in order to develop practice relevant strategies for dealing with uncertainties. Framing refers to how people make sense of the world. With the aim of identifying what are important parameters for the framing of uncertainties in water management practice, in this paper we analyze uncertainty situations described by decision-makers in water management. The analysis builds on a series of ¿Uncertainty Dialogues¿ carried out within the NeWater project with water managers in the Rhine, Elbe and Guadiana basins in 2006. During these dialogues, representatives of these river basins were asked what uncertainties they encountered in their professional work life and how they confronted them. Analysing these dialogues we identified several important parameters of how uncertainties get framed. Our assumption is that making framing of uncertainty explicit for water managers will allow for better dealing with the respective uncertainty situations. Keywords Framing - Uncertainty - Water management practic

Brain tumour genetic network signatures of survival

Tumour heterogeneity is increasingly recognized as a major obstacle to therapeutic success across neuro-oncology. Gliomas are characterised by distinct combinations of genetic and epigenetic alterations, resulting in complex interactions across multiple molecular pathways. Predicting disease evolution and prescribing individually optimal treatment requires statistical models complex enough to capture the intricate (epi)genetic structure underpinning oncogenesis. Here, we formalize this task as the inference of distinct patterns of connectivity within hierarchical latent representations of genetic networks. Evaluating multi-institutional clinical, genetic, and outcome data from 4023 glioma patients over 14 years, across 12 countries, we employ Bayesian generative stochastic block modelling to reveal a hierarchical network structure of tumour genetics spanning molecularly confirmed glioblastoma, IDH- wildtype; oligodendroglioma, IDH-mutant and 1p/19q codeleted; and astrocytoma, IDH- mutant. Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours, and show that generative network models reveal distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories.Comment: Main article: 52 pages, 1 table, 7 figures. Supplementary material: 13 pages, 11 supplementary figure

Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (β = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (β = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families

Deep forecasting of translational impact in medical research.

The value of biomedical research-a $1.7 trillion annual investment-is ultimately determined by its downstream, real-world impact, whose predictability from simple citation metrics remains unquantified. Here we sought to determine the comparative predictability of future real-world translation-as indexed by inclusion in patents, guidelines, or policy documents-from complex models of title/abstract-level content versus citations and metadata alone. We quantify predictive performance out of sample, ahead of time, across major domains, using the entire corpus of biomedical research captured by Microsoft Academic Graph from 1990-2019, encompassing 43.3 million papers. We show that citations are only moderately predictive of translational impact. In contrast, high-dimensional models of titles, abstracts, and metadata exhibit high fidelity (area under the receiver operating curve [AUROC] > 0.9), generalize across time and domain, and transfer to recognizing papers of Nobel laureates. We argue that content-based impact models are superior to conventional, citation-based measures and sustain a stronger evidence-based claim to the objective measurement of translational potential

Patient Priorities in Autoimmune Hepatitis: The Need for Better Treatments, More Education and Challenging Stigma

BACKGROUND: Data show that patients with autoimmune hepatitis have significantly reduced quality-of-life and that corticosteroids carry marked side effects. AIMS: This study explored patients’ experiences of autoimmune hepatitis and its treatments; key aspects for developing safe and effective new approaches to therapy. METHODS: An anonymised, internet-based survey collected data including patient demographics, treatments, side-effects, impact on day-to-day life, sources of support and attitudes towards autoimmune hepatitis between December 2019–January 2020. Semi-structured interviews were conducted with 13 patients to further explore their support networks, treatment experiences and health priorities. Descriptive and quantitative analyses were undertaken using R and free text responses were subject to thematic analysis. RESULTS: In total, 270 survey responses were received (median age 55 years and 94% female). Perceived medication side-effects were reported by 66% (169/257) and 73% responded negatively about their experience of corticosteroids. The majority (62·3% [(109/175]) would ‘definitely’ or ‘probably’ consider clinical trial participation to improve their care. Only 18·7% (31/166) reported access to a specialist liver nurse and nearly half were involved in support groups. Interview and survey data suggested that major issues were stigma, loss of control and fatigue. CONCLUSIONS: This study provides insights into the realities of living with autoimmune hepatitis with clear issues around lack of support networks, need for patient empowerment and stigma surrounding liver disease. Patient priorities are better therapies to slow disease progression, avoiding corticosteroids and minimising side-effects. Patient willingness to participate in trials suggests that they are achievable provided they have the right design and clinical endpoints

Pharmacists in Pharmacovigilance: Can Increased Diagnostic Opportunity in Community Settings Translate to Better Vigilance?

The pharmacy profession has undergone substantial change over the last two to three decades. Whilst medicine supply still remains a central function, pharmacist’s roles and responsibilities have become more clinic and patient focused. In the community (primary care), pharmacists have become important providers of healthcare as Western healthcare policy advocates patient self-care. This has resulted in pharmacists taking on greater responsibility in managing minor illness and the delivery of public health interventions. These roles require pharmacists to more fully use their clinical skills, and often involve diagnosis and therapeutic management. Community pharmacists are now, more than ever before, in a position to identify, record and report medication safety incidents. However, current research suggests that diagnostic ability of community pharmacists is questionable and they infrequently report to local or national schemes. The aim of this paper is to highlight current practice and suggest ways in which community pharmacy can more fully contribute to patient safety

A theory of mobile library service delivery

Research indicates there is widespread acceptance that nomadicity of library users is a phenomenon that will continue to increase; however, mobile learning is a resource that relatively few academic libraries appear to be taking advantage of. This paper presents a model developed during an investigation using a grounded theory approach into factors that may contribute to the delivery of library services to mobile technologies. A sample of 42 professionally qualified library staff from the Australasian vocational education and training (VET) sector was investigated to determine how confident and capable library staff believed they were to respond to technology advancement challenges and the training and support required for that response. The resulting theoretical model explains the impact of mobile technologies on library services and highlights the complex factors contributing to mobile technology acceptance at both an organisational and individual level. The presence of a series of catalysing impacts forms a central core and their management can enable an organisation to move from a position of uncertainty to one where the consequences of mobile technologies have been normalised