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    "Kind of blurry": Deciphering clues to prevent, investigate and manage prescribing cascades
    (Public Library of Science, 2022-08-31) Farrell, Barbara; Galley, Emily; Jeffs, Lianne; Howell, Pam; McCarthy, Lisa M.
    Background Prescribing cascades, where a medication is used to treat the side effect of another medication, contribute to polypharmacy and related morbidity. Little is known about clinicians’ and patients’ experiences with prescribing cascades. In this study, we explored why and how prescribing cascades occur across a variety of care settings and how they are managed. Methods and findings This descriptive qualitative study employed semi-structured interviews with older adults who may have experienced a prescribing cascade(s), their caregivers, and healthcare providers. Interviewees were recruited through physician referral from a Geriatric Day Hospital, two long-term care homes in Ottawa, Ontario, and through self-referral across Ontario, Canada. An inductive approach was used to code data and determine themes. Thirty-one interviews were conducted for ten unique patient cases. Some interviewees were involved in more than one case, resulting in 22 unique interviewees. Three themes were identified. First, recognition of prescribing cascades is linked to awareness of medication side effects. Second, investigation and management of prescribing cascades is simultaneous and iterative (rather than linear and sequential). Third, prevention of prescribing cascades requires intentional strategies to help people anticipate and recognize medication side effects. Difficulty with recruitment from both long-term care homes and through self-referral was the central limitation. This exemplifies challenges associated with studying a poorly recognized and underexplored phenomenon. Conclusions In order to better recognize, investigate and manage prescribing cascades, clinicians and patients need to know more about medication side effects; they need to ask ‘can this be caused by a drug?’ when signs and symptoms arise or worsen; and they need access to information about medication experiences to have benefit-risk discussions and make decisions about deprescribing. Approaches for raising public awareness of prescribing cascades should be trialed to raise the profile of this issue and facilitate continued exploration of the phenomenon.
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    Examining social class as it relates to heuristics women use to determine the trustworthiness of information regarding the link between alcohol and breast cancer risk
    (Public Library of Science, 2022-09-12) Meyer, Samantha B.; Lunnay, Belinda; Warin, Megan; Foley, Kristen; Olver, Ian N.; Wilson, Carlene; Macdonald S., Sara; Ward, Paul R.
    Background High rates of alcohol consumption by midlife women, despite the documented risks associated with breast cancer, varies according to social class. However, we know little about how to develop equitable messaging regarding breast cancer prevention that takes into consideration class differences in the receipt and use of such information. Objective To explore the heuristics used by women with different (inequitable) life chances to determine the trustworthiness of information regarding alcohol as a modifiable risk factor for breast cancer risk. Methods and materials Interviews were conducted with 50 midlife (aged 45–64) women living in South Australia, diversified by self-reported alcohol consumption and social class. Women were asked to describe where they sought health information, how they accessed information specific to breast cancer risk as it relates to alcohol, and how they determined whether (or not) such information was trustworthy. De-identified transcripts were analysed following a three-step progressive method with the aim of identifying how women of varying life chances determine the trustworthiness of alcohol and breast cancer risk information. Three heuristics were used by women: (1) consideration of whose interests are being served; (2) engagement with ‘common sense’; and (3) evaluating the credibility of the message and messenger. Embedded within each heuristic are notable class-based distinctions. Conclusions More equitable provision of cancer prevention messaging might consider how social class shapes the reception and acceptance of risk information. Class should be considered in the development and tailoring of messages as the trustworthiness of organizations behind public health messaging cannot be assumed.
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    Constructing functional models from biophysically-detailed neurons
    (Public Library of Science, 2022-09-08) Duggins, Peter; Eliasmith, Chris
    Improving biological plausibility and functional capacity are two important goals for brain models that connect low-level neural details to high-level behavioral phenomena. We develop a method called “oracle-supervised Neural Engineering Framework” (osNEF) to train biologically-detailed spiking neural networks that realize a variety of cognitively-relevant dynamical systems. Specifically, we train networks to perform computations that are commonly found in cognitive systems (communication, multiplication, harmonic oscillation, and gated working memory) using four distinct neuron models (leaky-integrate-and-fire neurons, Izhikevich neurons, 4-dimensional nonlinear point neurons, and 4-compartment, 6-ion-channel layer-V pyramidal cell reconstructions) connected with various synaptic models (current-based synapses, conductance-based synapses, and voltage-gated synapses). We show that osNEF networks exhibit the target dynamics by accounting for nonlinearities present within the neuron models: performance is comparable across all four systems and all four neuron models, with variance proportional to task and neuron model complexity. We also apply osNEF to build a model of working memory that performs a delayed response task using a combination of pyramidal cells and inhibitory interneurons connected with NMDA and GABA synapses. The baseline performance and forgetting rate of the model are consistent with animal data from delayed match-to-sample tasks (DMTST): we observe a baseline performance of 95% and exponential forgetting with time constant τ = 8.5s, while a recent meta-analysis of DMTST performance across species observed baseline performances of 58 − 99% and exponential forgetting with time constants of τ = 2.4 − 71s. These results demonstrate that osNEF can train functional brain models using biologically-detailed components and open new avenues for investigating the relationship between biophysical mechanisms and functional capabilities.
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    New strategies for characterizing genetic structure in wide-ranging, continuously distributed species: A Greater Sage-grouse case study
    (Public Library of Science, 2022-09-13) Oyler-McCance, Sara J.; Cross, Todd B.; Row, Jeffery R.; Schwartz, Michael K.; Naugle, Dave E.; Fike, Jennifer A.; Winiarski, Kristopher; Fedy, Brad C.
    Characterizing genetic structure across a species’ range is relevant for management and conservation as it can be used to define population boundaries and quantify connectivity. Wide-ranging species residing in continuously distributed habitat pose substantial challenges for the characterization of genetic structure as many analytical methods used are less effective when isolation by distance is an underlying biological pattern. Here, we illustrate strategies for overcoming these challenges using a species of significant conservation concern, the Greater Sage-grouse (Centrocercus urophasianus), providing a new method to identify centers of genetic differentiation and combining multiple methods to help inform management and conservation strategies for this and other such species. Our objectives were to (1) describe large-scale patterns of population genetic structure and gene flow and (2) to characterize genetic subpopulation centers across the range of Greater Sage-grouse. Samples from 2,134 individuals were genotyped at 15 microsatellite loci. Using standard STRUCTURE and spatial principal components analyses, we found evidence for four or six areas of large-scale genetic differentiation and, following our novel method, 12 subpopulation centers of differentiation. Gene flow was greater, and differentiation reduced in areas of contiguous habitat (eastern Montana, most of Wyoming, much of Oregon, Nevada, and parts of Idaho). As expected, areas of fragmented habitat such as in Utah (with 6 subpopulation centers) exhibited the greatest genetic differentiation and lowest effective migration. The subpopulation centers defined here could be monitored to maintain genetic diversity and connectivity with other subpopulation centers. Many areas outside subpopulation centers are contact zones where different genetic groups converge and could be priorities for maintaining overall connectivity. Our novel method and process of leveraging multiple different analyses to find common genetic patterns provides a path forward to characterizing genetic structure in wide-ranging, continuously distributed species.
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    An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia
    (Public Library of Science, 2022-09-13) Przedborski, Michelle; Sharon, David; Cathelin, Severine; Chan, Steven; Kohandel, Mohammad
    The over-expression of the Bcl-2 protein is a common feature of many solid cancers and hematological malignancies, and it is typically associated with poor prognosis and resistance to chemotherapy. Bcl-2-specific inhibitors, such as venetoclax, have recently been approved for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and they are showing promise in clinical trials as a targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML). However, successful treatment of AML with Bcl-2-specific inhibitors is often followed by the rapid development of drug resistance. An emerging paradigm for overcoming drug resistance in cancer treatment is through the targeting of mitochondrial energetics and metabolism. In AML in particular, it was recently observed that inhibition of mitochondrial translation via administration of the antibiotic tedizolid significantly affects mitochondrial bioenergetics, activating the integrated stress response (ISR) and subsequently sensitizing drug-resistant AML cells to venetoclax. Here we develop an integrative systems biology approach to acquire a deeper understanding of the molecular mechanisms behind this process, and in particular, of the specific role of the ISR in the commitment of cells to apoptosis. Our multi-scale mathematical model couples the ISR to the intrinsic apoptosis pathway in venetoclax-resistant AML cells, includes the metabolic effects of treatment, and integrates RNA, protein level, and cellular viability data. Using the mathematical model, we identify the dominant mechanisms by which ISR activation helps to overcome venetoclax resistance, and we study the temporal sequencing of combination treatment to determine the most efficient and robust combination treatment protocol.