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SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with computational models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM-Covid19: an agent-based simulation of the epidemic including detailed age-stratification and realistic social networks. By default the model is parameterised to UK demographics and calibrated to the UK epidemic, however, it can easily be re-parameterised for other countries. OpenABM-Covid19 can evaluate non-pharmaceutical interventions, including both manual and digital contact tracing, and vaccination programmes. It can simulate a population of 1 million people in seconds per day, allowing parameter sweeps and formal statistical model-based inference. The code is open-source and has been developed by teams both inside and outside academia, with an emphasis on formal testing, documentation, modularity and transparency. A key feature of OpenABM-Covid19 are its Python and R interfaces, which has allowed scientists and policymakers to simulate dynamic packages of interventions and help compare options to suppress the COVID-19 epidemic.

Rationale Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before. Objectives This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders. Methods A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text. Results Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus. Conclusions There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.

Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo.  Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using [ 11 C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution ( V T ). [ 11 C]UCB-J V T was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen’s d   =  0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drug administration on SV2A levels in Sprague-Dawley rats using western blotting, [ 3 H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them. Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis. Here, using [ 11 C]UCB-J PET, the authors show for the first time in vivo that levels of the synaptic marker protein SV2A are reduced in schizophrenia and unaffected by antipsychotic treatment in a rat model.

Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson's Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for reversal of fatigue.

Advancing interventions to tackle the huge global burden of hepatitis B virus (HBV) infection depends on improved insights into virus epidemiology, transmission, within-host diversity, drug resistance and pathogenesis, all of which can be advanced through the large-scale generation of full-length virus genome data. Here we describe advances to a protocol that exploits the circular HBV genome structure, using isothermal rolling-circle amplification to enrich HBV DNA, generating concatemeric amplicons containing multiple successive copies of the same genome. We show that this product is suitable for Nanopore sequencing as single reads, as well as for generating short-read Illumina sequences. Nanopore reads can be used to implement a straightforward method for error correction that reduces the per-read error rate, by comparing multiple genome copies combined into a single concatemer and by analysing reads generated from plus and minus strands. With this approach, we can achieve an improved consensus sequencing accuracy of 99.7% and resolve intra-sample sequence variants to form whole-genome haplotypes. Thus while Illumina sequencing may still be the most accurate way to capture within-sample diversity, Nanopore data can contribute to an understanding of linkage between polymorphisms within individual virions. The combination of isothermal amplification and Nanopore sequencing also offers appealing potential to develop point-of-care tests for HBV, and for other viruses.

Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017–20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03–9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity. The impact of other pathogens on disease outcome was studied in European infants with RSV infection. Additional viruses were commonly co-detected during infection but were weakly linked to severity. However, presence of Haemophilus bacteria strongly associated with severe cases.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups. Respiratory syncytial virus (RSV) is a common infection in children and older adults but little is known about within-host viral population diversity. Here, the authors perform deep sequencing and find that RSV subgroup B exhibited more diversity than subgroup A, with implications for development of therapeutics and vaccines.

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission. There is limited data on drug resistance in South African communities strongly affected by HIV. In this study, the authors observed low levels of resistance to newer drugs but widespread resistance to older HIV medications in a South African community. Resistance to rilpivirine was detected even in untreated individuals.