Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging.

Microglia, the brain's resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes. RNA-sequencing of hippocampal microglia revealed more aging-associated changes in female microglia than male microglia, and more sex differences in old microglia than young microglia. Pathway analyses and subsequent validation assays revealed a stronger AKT-mTOR-HIF1α-driven shift to glycolysis among old female microglia and indicated that C3a production and detection was elevated in old microglia, especially in females. Recombinant C3a induced AKT-mTOR-HIF1α signaling and increased the glycolytic and phagocytic activity of young microglia. Single cell analyses attributed the aging-associated sex dimorphism to more abundant disease-associated microglia (DAM) in old female mice than old male mice, and evaluation of an Alzheimer's Disease mouse model revealed that the metabolic and complement changes are also apparent in the context of neurodegenerative disease and are strongest in the neuroprotective DAM2 subset. Collectively, our data implicate autocrine C3a-C3aR signaling in metabolic reprogramming of microglia to neuroprotective DAM during aging, especially in females, and also in Alzheimer's Disease.

Respiratory antibacterial prescribing in primary care and the COVID-19 pandemic in England, winter season 2020-21.

BACKGROUND: Antibacterial prescribing for respiratory tract infections (RTIs) accounts for almost half of all prescribing in primary care. Nearly a quarter of antibacterial prescribing in primary care is estimated to be inappropriate, the greatest being for RTIs. The COVID-19 pandemic has changed the provision of healthcare services and impacted the levels of antibacterials prescribed. OBJECTIVES: To describe the changes in community antibacterial prescribing for RTIs in winter 2020-21 in England. METHODS: RTI antibacterial prescribing was measured in prescription items/1000 population for primary care from January 2014 and in DDDs/1000 population/day for the totality of RTI prescribing [combined with Accident & Emergency (A&E) in secondary care], from January 2016 to February 2021. Trends were assessed using negative binomial regression and seasonally adjusted interrupted time-series analysis. RESULTS: Antibacterials prescribed for RTIs reduced by a further 12.4% per season compared with pre-COVID (P < 0.001). In winter 2020-21, RTI prescriptions almost halved compared with the previous winter in 2019-20 (P < 0.001). The trend observed for total RTI prescribing (primary care with A&E) was similar to that observed in the community alone. CONCLUSIONS: During COVID-19, RTI prescribing reduced in the community and the expected rise in winter was not seen in 2020-21. We found no evidence that RTI prescribing shifted from primary care to A&E in secondary care. The most likely explanation is a decrease in RTIs and presentations to primary care associated with national prevention measures for COVID-19.

Incidence of infant Gram-negative invasive bacterial infections in England, 2011-2019: an observational study using population-wide surveillance data.

OBJECTIVE: Invasive bacterial infections account for an estimated 15% of infant deaths worldwide. We aimed to estimate the incidence and trends in invasive bacterial infections in infants caused by Gram-negative pathogens in England during 2011-2019. METHODS: Laboratory-confirmed invasive bacterial infections in infants (<1 year old) were identified in the UK Health Security Agency national laboratory surveillance data from April 2011 to March 2019. Polymicrobial infections were defined as two or more bacterial species from the same normally sterile sample site. Early-onset infections were defined as <7 days from birth and late-onset as ≥7 days (neonates 7-28 days; infants ≥29 days). Trend analyses were carried out using Poisson (for episodes/incidence) and beta (for proportions) regression. RESULTS: The annual incidence of invasive bacterial infections increased by 35.9%, from 189.8 to 258.0 cases per 100 000 live births (p<0.001). Late-onset infections in both neonates and infants increased substantially over the study period (p<0.001), whereas early-onset infections increased slightly (p=0.002). Escherichia coli was the most common Gram-negative pathogen isolated and accounted for 27.2% of the overall rise in Gram-negative infant disease incidence. Polymicrobial infections almost doubled, increasing from 29.2 to 57.7 per 100 000 live births (p<0.001), and mostly involved two species (81.3%, 1604/1974 episodes). CONCLUSIONS: The incidence of Gram-negative invasive bacterial infections in infants increased between 2011/2012 and 2018/2019 in England, driven mainly by an increase in late-onset infections. Further work is required to elucidate the risk factors and drivers of this increased incidence so that opportunities for prevention can be identified.

Incidence and aetiology of infant Gram-negative bacteraemia and meningitis: systematic review and meta-analysis.

BACKGROUND: One in six infant deaths worldwide are caused by invasive bacterial infections, of which a substantial but unquantified proportion are caused by Gram-negative bacteria. METHODS: We conducted a systematic review of studies published from 31 May 2010 to 1 June 2020 indexed in MEDLINE, Embase and Global Health databases. We performed meta-analyses of the incidence of Gram-negative bacteraemia and of individual Gram-negative species as proportions of all infant bacteraemia, stratified by onset (early vs late) and country income (low/middle vs high). RESULTS: 152 studies from 54 countries were included, 60 in high-income countries (HIC) and 92 in low-income/middle-income countries (LMIC). Gram-negatives represented a higher proportion (53%, 95% CI 49% to 57%) of all infant bacteraemia in LMIC compared with HIC (28%, 95% CI 25% to 32%). Incidence of infant Gram-negative bacteraemia was 2.01 (95% CI 1.15 to 3.51) per 1000 live births; it was five times higher in LMIC (4.35, 95% CI 2.94 to 6.43) compared with HIC (0.73, 95% CI 0.39 to 7.5). In HIC, Escherichia coli was the leading Gram-negative pathogen, representing 19.2% (95% CI 15.6% to 23.4%) of early and 7.3% (95% CI 5.3% to 10.1%) of all late-onset bacteraemia; Klebsiella spp were the next most common cause (5.3%) of late-onset bacteraemia. In LMIC, Klebsiella spp caused 16.4% (95% CI 11.5% to 22.7%) of early and 15.0% (95% CI 10.1% to 21.8%) of late-onset bacteraemia, followed by E. coli (early-onset 7.50%, 95% CI 4.98% to 11.1%; late-onset 6.53%, 95% CI 4.50% to 9.39%) and Pseudomonas spp (early-onset 3.93%, 95% CI 2.04% to 7.44%; late-onset 2.81%, 95% CI 1.99% to 3.95%). CONCLUSION: E. coli, Klebsiella and Pseudomonas spp cause 20%-28% of early-onset infant bacteraemia and 14% cases of infant meningitis worldwide. Implementation of preventive measures could reduce the high incidence of Gram-negative bacteraemia in LMIC. PROSPERO REGISTRATION NUMBER: CRD42020191618.

Surveillance of Antibacterial Usage during the COVID-19 Pandemic in England, 2020.

Changes in antibacterial prescribing during the COVID-19 pandemic were anticipated given that the clinical features of severe respiratory infection syndrome caused by SARS-CoV-2 mirror bacterial respiratory tract infections. Antibacterial consumption was measured in items/1000 population for primary care and in Defined Daily Doses (DDDs)/1000 admissions for secondary care in England from 2015 to October 2020. Interrupted time-series analyses were conducted to evaluate the effects of the pandemic on antibacterial consumption. In the community, the rate of antibacterial items prescribed decreased further in 2020 (by an extra 1.4% per month, 95% CI: -2.3 to -0.5) compared to before COVID-19. In hospitals, the volume of antibacterial use decreased during COVID-19 overall (-12.1% compared to pre-COVID, 95% CI: -19.1 to -4.4), although the rate of usage in hospitals increased steeply in April 2020. Use of antibacterials prescribed for respiratory infections and broad-spectrum antibacterials (predominately 'Watch' antibacterials in hospitals) increased in both settings. Overall volumes of antibacterial use at the beginning of the COVID-19 pandemic decreased in both primary and secondary settings, although there were increases in the rate of usage in hospitals in April 2020 and in specific antibacterials. This highlights the importance of antimicrobial stewardship during pandemics to ensure appropriate prescribing and avoid negative consequences on patient outcomes and antimicrobial resistance.