A modelling analysis of the effectiveness of second wave COVID-19 response strategies in Australia.

There is a significant challenge in responding to second waves of COVID-19 cases, with governments being hesitant in introducing hard lockdown measures given the resulting economic impact. In addition, rising case numbers reflect an increase in coronavirus transmission some time previously, so timing of response measures is highly important. Australia experienced a second wave from June 2020 onwards, confined to greater Melbourne, with initial social distancing measures failing to reduce rapidly increasing case numbers. We conducted a detailed analysis of this outbreak, together with an evaluation of the effectiveness of alternative response strategies, to provide guidance to countries experiencing second waves of SARS-Cov-2 transmission. An individual-based transmission model was used to (1) describe a second-wave COVID-19 epidemic in Australia; (2) evaluate the impact of lockdown strategies used; and (3) evaluate effectiveness of alternative mitigation strategies. The model was calibrated using daily diagnosed case data prior to lockdown. Specific social distancing interventions were modelled by adjusting person-to-person contacts in mixing locations. Modelling earlier activation of lockdown measures are predicted to reduce total case numbers by more than 50%. Epidemic peaks and duration of the second wave were also shown to reduce. Our results suggest that activating lockdown measures when second-wave case numbers first indicated exponential growth, would have been highly effective in reducing COVID-19 cases. The model was shown to realistically predict the epidemic growth rate under the social distancing measures applied, validating the methods applied. The timing of social distancing activation is shown to be critical to their effectiveness. Data showing exponential rise in cases, doubling every 7-10 days, can be used to trigger early lockdown measures. Such measures are shown to be necessary to reduce daily and total case numbers, and the consequential health burden, so preventing health care facilities being overwhelmed. Early control of second wave resurgence potentially permits strict lockdown measures to be eased earlier.

The hippocampal extracellular matrix regulates pain and memory after injury.

Chronic pain poses a heavy burden for the individual and society, comprising personal suffering, comorbid psychiatric symptoms, cognitive decline, and disability. Treatment options are poor due in large part to pain centralization, where an initial injury can result in lasting CNS maladaptations. Hippocampal cellular plasticity in chronic pain has become a focus of study due to its roles in cognition, memory, and the experience of pain itself. However, the extracellular alterations that parallel and facilitate changes in hippocampal function have not been addressed to date. Here we show structural and biochemical plasticity in the hippocampal extracellular matrix (ECM) that is linked to behavioral, cellular, and synaptic changes in a mouse model of chronic pain. Specifically, we report deficits in working location memory that are associated with decreased hippocampal dendritic complexity, altered ECM microarchitecture, decreased ECM rigidity, and changes in the levels of key ECM components and enzymes, including increased levels of MMP8. We also report aberrations in long-term potentiation (LTP) and a loss of inhibitory interneuron perineuronal ECM nets, potentially accounting for the aberrations in LTP. Finally, we demonstrate that MMP8 is upregulated after injury and that its genetic downregulation normalizes the behavioral, electrophysiological, and extracellular alterations. By linking specific extracellular changes to the chronic pain phenotype, we provide a novel mechanistic understanding of pain centralization that provides new targets for the treatment of chronic pain.

Intrathecal administration of AYX2 DNA-decoy produces a long-term pain treatment in rat models of chronic pain by inhibiting the KLF6, KLF9 and KLF15 transcription factors.

Background: Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia­spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo­in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing. Results: Results demonstrated that a one-time administration of decoys binding to the Kruppel-like transcription factors (KLFs) 6, 9, and 15 produces a significant and weeks­month long reduction in mechanical hypersensitivity compared to controls. In the spared nerve injury model, decoy efficacy was correlated to its capacity to bind KLF15 and KLF9 at a specific ratio, while in the chronic constriction injury model, efficacy was correlated to the combined binding capacity to KLF6 and KLF9. AYX2, an 18-bp DNA decoy binding KLF6, KLF9, and KLF15, was optimized for clinical development, and it demonstrated significant efficacy in these models. Conclusions: These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain.