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Modification of belantamab mafodotin dosing to balance efficacy and tolerability in the DREAMM-7 and DREAMM-8 trials.
No full textBelantamab mafodotin (belamaf) combined with standard therapies demonstrated significant progression-free survival (PFS) and overall survival benefits in DREAMM-7 and PFS benefit in DREAMM-8 in relapsed/refractory multiple myeloma. Belamaf dose modifications managed adverse events, including belamaf-related ocular events. Ocular events included ocular adverse reactions (eg, dry eyes, photophobia, eye irritation) and protocol-mandated ophthalmic examination findings. Protocol-recommended dose modifications for ocular events were driven by ophthalmic examination findings and included belamaf dose delays until resolution and reductions. We used descriptive analyses to evaluate the impact of dose modifications on managing ocular events and treatment efficacy. In patients with normal baseline vision who were receiving treatment, dose modifications extended belamaf dosing intervals to a median of 8 to 12 weeks by 9 months; the prevalences of reduced vision to bilateral 20/50 or worse and ocular adverse reactions were highest in the first 3 months and remained low at later time points. The median time to resolution after grade ≥2 ophthalmic examination findings was 12 weeks. Rates of belamaf discontinuations due to ocular events were low. Almost all responders (partial response or better) required dose modifications. Most patients achieved a response before an extended (>2 cycles) dose delay; most who had not, subsequently achieved or deepened their response. In DREAMM-7 and DREAMM-8, the median PFS in patients with ≥1 dose delay of ≥12 weeks was 36.6 months and not reached, respectively. Ocular events were common but effectively managed with dose modifications, allowing for patients to remain on treatment and derive robust efficacy benefit. The trials were registered at www.clinicaltrials.gov as #NCT04246047 (DREAMM-7) and #NCT04484623 (DREAMM-8)
Renal macro- and microcirculatory perturbations in acute kidney injury and chronic kidney disease associated with heart failure and cardiac surgery
No full textChronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and elevated central venous pressure. However, our understanding of renal microcirculation in heart failure and CKD remains limited. This is largely due to the lack of noninvasive techniques to assess renal microcirculation in patients. Moreover, there is a lack of clinically relevant animal models of heart failure and CKD to advance our understanding of the timing and magnitude of renal microcirculatory dysfunction. Patients with heart failure and CKD commonly require cardiac surgery with cardiopulmonary bypass (CPB) to improve their prognosis. However, acute kidney injury (AKI) is a frequent unresolved clinical complication in these patients. There is emerging evidence that renal microcirculatory dysfunction, characterized by renal medullary hypoperfusion and hypoxia, plays a critical role in the pathogenesis of cardiac surgery-associated AKI. In this review, we consolidate the preclinical and clinical evidence of renal macro- and microcirculatory perturbations in heart failure and cardiac surgery requiring CPB. We also examine emerging biomarkers and therapies that may improve health outcomes for this vulnerable patient population by targeting the renal microcirculation
Sensing place-based ecological knowledge for regenerative development and design
No full textRegenerative paradigms seek to realign the built environment with living systems by activating the capacity of communities and ecosystems to coevolve in mutually beneficial ways. Supporting regenerative outcomes, this study introduces a Community Nature (Re)Connection Workshop as a place-based approach to engaging communities through the ecology of place. Informed by experiential and social collective learning theories, and inspired by biomimicry, the pilot workshop was iteratively refined through participant feedback. Quantitative analysis of pre- and post-workshop surveys demonstrated its potential to significantly strengthen participants’ sense of connection to nature, heighten interest in continued learning, and deepen appreciation of local ecology. The workshop’s experiential approach supports ecoliteracy as a foundation for place-based community engagement, ecologically informed regenerative outcomes, and community capacity-building for stewardship
The roles of non-governmental organizations in the co-production of urban greenspaces in Beijing
No full textCo-production research primarily focused on the citizen-government dynamic, but the involving of non-governmental organizations (NGOs) as intermediaries reshaped the relationship. Little is known about how NGOs navigate their roles in co-production where state control remains strong and civil society operates informally. Understanding these dynamics is crucial because NGOs can either reinforce or challenge existing power structures, influencing the extent to which co-production leads to more inclusive urban governance. This study explores how formal and informal NGO-government relations, along with the strong and weak state embeddedness, shape the roles of NGOs in the planning, development, and management of greenspaces in Beijing, China. Data were collected from 42 in-depth interviews with NGO staffs, citizens, and governments, who actively engaged in greenspace co-production in Beijing. The findings reveal that in informal interactions, NGOs are initiators, promoters, and supervisors in co-producing greenspaces. They invite government participation, initiate joint efforts, and align their environmental missions with national policies to achieve influence and advocacy. Strongly embedded NGOs typically act as service providers, while less embedded NGOs serve as advocates, shaping policy influence and public mobilization. By unpacking the mechanisms through which NGOs operate in co-production, this study sheds light on how NGOs expand civic space, negotiate authority, and navigate structural constraints. The participation of NGOs in the co-production of greenspaces in China contributes to advancing procedural and recognitional justice
An electrical model-free three-phase OPF for PV-rich LV networks using smart meter and transformer data
No full textThe growing uptake of residential solar photovoltaic (PV) systems is prompting distribution companies to actively calculate PV inverters’ setpoints to manage voltage and thermal issues in low-voltage (LV) distribution networks. Although the model-driven Optimal Power Flow (OPF) has shown great potential for this purpose, the unavailability of electrical models (e.g., topology) for three-phase LV networks hinders its adoption by distribution companies. To address this, we propose an electrical model-free (independent from LV network models) three-phase OPF approach to calculate the PV inverters’ setpoints. No electrical model is used at any stage, instead a Neural Network is trained solely with historical measurement data (that calculates voltages instead of using power flows) to capture the nonlinear relationships of the LV network. The performance of the proposed approach is assessed using synthetic data considering a realistic Australian residential LV network with 146 customers, part of an integrated MV-LV network with 3,400+ customers. Time-series results demonstrate that the proposed approach has similar accuracy as the state-of-art model-driven OPF (that fully captures the physics) in calculating PV setpoints and almost same overall curtailment. Thus, the proposed approach presents an alternative for distribution companies to manage PV without any LV network models, only historical measurement data
The Gendered Flexibility Paradox and Remote-First Work: How Working Parents Reconcile Work and Care
No full textRecent technological advances and globalised distribution of work have accelerated the rise of remote-first organisations where everyone works remotely, yet the effects of this approach on working parents remain underexplored. Drawing on qualitative interviews with 25 mothers and 16 fathers from 31 remote-first organisations, this study examines the gendered impact of standardised remote-first flexibility on work–family reconciliation. Findings show that remote-first work enhances location and schedule freedom, allowing parents to sustain a dual devotion to work and family. Fathers used this flexibility to increase engagement with domestic tasks and caregiving, while mothers focused on meeting work demands (in addition to caregiving responsibilities). The use of remote-first working arrangements increased employee trust and empathy among working parents, reducing flexibility stigma concerns. While fathers resisted tendencies to overwork, the remote-first model perpetuated the gendered flexibility paradox for mothers, leading to increased labour expansion and self-exploitation in both paid and unpaid work
Mutation-Specific Cardiomyocyte Lines from Patients with Fabry Disease: A Sustainable In Vitro Model to Investigate Structure, Function, and Disease Mechanisms †
No full textBackground: Fabry disease (FD) results from pathogenic GLA variants, causing lysosomal α-galactosidase A (α-GalA) deficiency and sphingolipid ceramide trihexoside (Gb3 or THC) accumulation. Disease phenotype varies widely but cardiomyopathy is commonly life-limiting. As a multisystemic disorder, FD initiates at the cellular level; however, the mechanism/s underlying Gb3-induced cell dysfunction remains largely unknown. This study established an in vitro mutation-specific model of Fabry cardiomyopathy using human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes to explore underlying cell pathology. Methods: Skin biopsies from consenting Fabry patients and normal control subjects were reprogrammed to iPSCs then differentiated into cardiomyocytes. The GLA mutations in Fabry cell lines were corrected using CRISP-Cas9. Phenotypic characteristics, α-Gal A activity, Gb3 accumulation, functional status, and lipid analysis were assessed. Cardiomyocytes derived from two patients with severe clinical phenotype and genotypes, GLAc.851T>C, GLAc.1193_1196del, and their respective corrected lines, GLAcorr c.851T>C, GLAcorr c.1193_1196del, were selected for further studies. Results: Cardiomyocytes derived from individuals with FD iPSCs exhibited stable expression of cardiomyocyte markers and spontaneous contraction, morphological features of FD, reduced α-Gal A activity, and accumulation of Gb3. Lipidomic profiling revealed differences in the Gb3 isoform profile between the control and FD patient iPSC-derived cardiomyocytes. Contraction strength was unchanged but relaxation after contraction was delayed, mimicking the diastolic dysfunction typical of Fabry cardiomyopathy. Conclusions: iPSC-derived cardiomyocytes provide a useful model to explore aspects of Fabry cardiomyopathy, including disruptions in sphingolipid pathways, proteomics, and multigene expression that together link genotype to phenotype. The platform potentially offers broad applicability across many genetic diseases and offers the prospect of testing and implementation of individualised therapies
Cortical stability and chaos during focal seizures: insights from inference-based modeling
No full textObjective.Epilepsy affects millions globally, with a significant subset of patients suffering from drug-resistant focal seizures. Understanding the underlying neurodynamics of seizure initiation and propagation is crucial for advancing treatment and diagnostics. In this study, we present a novel, inference-based approach for analyzing the temporal evolution of cortical stability and chaos during focal epileptic seizures.Approach.Utilizing a multi-region neural mass model, we estimate time-varying synaptic connectivity from intracranial electroencephalography (iEEG) data collected from individuals with drug-resistant focal epilepsy.Main results.Our analysis reveals distinct preictal and ictal phases characterized by shifts in cortical stability, heightened chaos in the ictal phase, and highlight the critical role of inter-regional communication in driving chaotic cortical behaviour. We demonstrate that cortical dynamics are consistently destabilized prior to seizure onset, with a transient reduction in instability at seizure onset, followed by a significant increase throughout the seizure.Significance.This work provides new insights into the mechanisms of seizure generation and offers potential biomarkers for predicting seizure events. Our findings pave the way for innovative therapeutic strategies targeting cortical stability and chaos to manage epilepsy
Methods, Assumptions, Scenarios and Sensitivities
No full textThe Net Zero Australia (NZAu) Project is a partnership between The University of Melbourne, The University of Queensland and Princeton University. The NZAu Project is intended to be rigorous and granular, evidence driven, technology neutral and non-political in its approach. Our modelling:uses a scenario-based approach;uses the best available inputs and assumptions;uses a least cost optimization approach; and‘downscales’ our results to a regional and sub-regional basis.Phase 2 of the NZAu Project is focused on:tracking how the Nation is performing relative to what is needed;analysing major aspects of the decarbonisation challenge with sufficient depth and rigour for policy development and planning;making practical recommendations that can achieve deep decarbonisation while acknowledging environmental and social objectives and trade-offs; andtranslating these recommendations more strongly into policy, planning, investments and, ultimately, operational projects.Given the large, uncertain and unprecedented changes that are required to achieve deep decarbonisation, there will inevitably be different views on the plausibility of projections made by ourselves and others. Rather than seeking consensus on all aspects of our modelling, the NZAu Project therefore intends to develop and present a methodology that is transparently defined, appropriate for the task and based upon input assumptions that are stated clearly and from authoritative sources. This Methods, Assumptions, Scenarios, and Sensitivities (MASS) report therefore describes our modelling methods and its input assumptions and does not present result
Methods used to construct disability indicators in linked administrative datasets: a systematic scoping review
No full textBACKGROUND: In this scoping review, we aimed to examine evidence on methods used to construct disability indicators in linked administrative datasets and describe the approaches used to assess the validity of the indicators. METHODS: Medline (Ovid) and Embase (Ovid) were searched for studies published between January 2010 and June 2023. Original, peer-reviewed studies that aimed to construct a disability indicator using linked administrative data sources were included. Studies identifying any types of disability were included, but not those which defined the target population in terms of specific health conditions. We produced a narrative synthesis of findings related to disability indicator construction methods and validation approaches. RESULTS: Thirty-six relevant studies were included, with 30 of those identifying a cohort of people with intellectual and/or developmental disability. Health data sources were most commonly used for indicator construction, with 33 of the studies using at least one health data source. Disability and education sector data sources were also commonly used. Diagnostic codes were used for disability identification in 34 of the 36 studies; 16 used diagnostic codes alone and 18 used diagnostic codes along with other information. A subgroup of 19 studies had a primary aim to create a disability cohort or estimate disability prevalence. Thirteen of these 19 studies compared their estimated prevalence rates with previously published estimates. Only five studies conducted testing to investigate the extent to which their derived disability indicator captured the intended target population. DISCUSSION: We found a paucity of evidence on methods for identifying a target population of people with diverse disabilities. In the existing literature, diagnostic information is relied upon heavily for disability identification, likely due to a lack of other types of disability-relevant information in administrative data sources. Use of derived disability indicators within linked data holds potential to advance research regarding people with disability. It is crucial, however, to conduct and report validation testing to understand the strengths and limitations of the indicators and inform their use for specific purposes