Effectiveness of social distancing measures and lockdowns for reducing transmission of COVID-19 in non-healthcare, community-based settings

Social distancing measures (SDMs) are community-level interventions that aim to reduce person-to-person contacts in the community. SDMs were a major part of the responses first to contain, then to mitigate, the spread of SARS-CoV-2 in the community. Common SDMs included limiting the size of gatherings, closing schools and/or workplaces, implementing work-from-home arrangements, or more stringent restrictions such as lockdowns. This systematic review summarized the evidence for the effectiveness of nine SDMs. Almost all of the studies included were observational in nature, which meant that there were intrinsic risks of bias that could have been avoided were conditions randomly assigned to study participants. There were no instances where only one form of SDM had been in place in a particular setting during the study period, making it challenging to estimate the separate effect of each intervention. The more stringent SDMs such as stay-at-home orders, restrictions on mass gatherings and closures were estimated to be most effective at reducing SARS-CoV-2 transmission. Most studies included in this review suggested that combinations of SDMs successfully slowed or even stopped SARS-CoV-2 transmission in the community. However, individual effects and optimal combinations of interventions, as well as the optimal timing for particular measures, require further investigation. This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'

Climate-based modelling and forecasting of dengue fever in three endemic departments of Peru

Amid profound climate change, incidence of dengue fever continues to rise and expand in distribution across the world. Here, we analysed dengue fever in three coastal departments of Peru which have recently experienced public health emergencies during the worst dengue crises in Latin American history. We developed a climate-based spatiotemporal modelling framework to model monthly incidence of new dengue cases in Piura, Tumbes, and Lambayeque over 140 months from 2010 to 2021. The framework enabled accurate description of in-sample and out-of-sample dengue incidence trends across the departments, as well as the characterisation of the timing, structure, and intensity of climatic relationships with human dengue incidence. In terms of dengue incidence rate (DIR) risk factors, we inferred non-linear and delayed effects of greater monthly mean maximum temperatures, extreme precipitation, sustained drought conditions, and extremes of a Peruvian-specific indicator of the El Niño Southern Oscillation. Building on our model-based understanding of climatic influences, we performed climate-model-based forecasting of dengue incidence across 2018 to 2021 with a forecast horizon of one month. Our framework enabled representative, reliable forecasts of future dengue outbreaks, including correct classification of 100% of all future outbreaks with DIR ≥ 50 (or 150) per 100,000, whilst retaining relatively low probability of 0.12 (0.05) for false alarms. Therefore, our model framework and analysis may be used by public health authorities to i) understand climatic drivers of dengue incidence, and ii) alongside our forecasts, to mitigate impacts of dengue outbreaks and potential public health emergencies by informing early warning systems and deployment of vector control resources

An extensive re-evaluation of evidence and analyses of the Randomised Badger Culling Trial II: In neighbouring areas

In the second investigation in a pair of analyses which re-evaluates the Randomised Badger Culling Trial (RBCT), we estimate the effects of proactive badger culling on the incidence of tuberculosis (TB) in cattle populations in unculled neighbouring areas. Throughout peer-reviewed analyses of the RBCT, proactive culling was estimated to have detrimental effects on the incidence of herd breakdowns (i.e. TB incidents) in neighbouring areas. Using previously published, publicly available data, we appraise a variety of frequentist and Bayesian models as we estimate the effects of proactive culling on confirmed herd breakdowns in unculled neighbouring areas. For the during trial period from the initial culls until 4 September 2005, we estimate consistently high probabilities that proactive culling had adverse effects on confirmed herd breakdowns in unculled neighbouring areas, thus supporting the theory of heightened risk of TB for the neighbouring cattle populations. Negligible culling effects are estimated in the post-trial period across the statistical approaches and imply unsustained long-term effects for unculled neighbouring areas. Therefore, when considered alongside estimated beneficial effects within proactive culling areas, these conflicting adverse side effects render proactive culling complex, and thus, decision making regarding potential culling strategies should include (i) ecological, geographical and scientific considerations and (ii) cost–benefit analyses

The utility of wastewater surveillance for monitoring SARS-CoV-2 prevalence

Public health authorities have increasingly used wastewater-based epidemiology (WBE) to monitor community transmission of SARS-CoV-2 and other agents. Here, we evaluate the utility of WBE during the COVID-19 pandemic in England for estimating SARS-CoV-2 prevalence. We use wastewater data from the Environmental Monitoring for Health Protection (EMHP) programme and prevalence data from the REal-time Assessment of Community Transmission-1 (REACT-1) study. Across the pandemic, we describe how wastewater-based modelling can achieve representative SARS-CoV-2 prevalence estimates in fine and coarse spatial resolutions for relatively short time horizons (of up to one month), and thus assist in filling temporal gaps in surveillance. We infer a temporally evolving relationship between wastewater and prevalence which may limit the utility of WBE for estimating SARS-CoV-2 prevalence over longer time horizons without a concurrent prevalence survey. Exploring further our finding of time-varying, population-level faecal shedding, we characterise WBE for SARS-CoV-2 prevalence as i) vaccination-coverage-dependent and ii) variant-specific. Our research suggests that these factors are important considerations in future uses of WBE by public health authorities in infectious disease outbreaks. We further demonstrate that WBE can improve both the cost efficiency and accuracy of community prevalence surveys which on their own may have incomplete geographic coverage and/or small sample sizes. Therefore, in England, for the objective of high spatial resolution prevalence monitoring, strategic use of SARS-CoV-2 wastewater concentration data nationally could have enhanced, but not replaced, community prevalence survey programmes

Novel host biomarkers could help tailor antibiotic use in children admitted to PICU with pneumonia

Backgrounds: Much research has been carried out to identify novel host biomarkers that can accurately discriminate between bacterial and viral pneumonia in children. However, pneumonia biomarker discovery has not been carried out in a paediatric intensive care unit (PICU) setting, where children have high rates of co-morbidities and relatively indiscriminate administration of antibiotics. This study aims to identify robust novel biomarkers of bacterial pneumonia in this population.Methods: Children with clinician-diagnosed pneumonia, confirmed on chest radiograph, were recruited from the PICU at the Royal Belfast Hospital for Sick Children between April 2020 and December 2022. Blood plasma was collected and analysed using two O-Link proteomic multiplex proximity extension assays. An independent paediatric intensivist provided a final diagnosis of bacterial, viral or mixed viral and bacterial pneumonia based on clinical data and results from blood culture, bronchoalveolar lavage and sputum.Results: A total of 27 children were included in the study. The median age was 1.7 (IQR: 0.5-6.8) years and 48% were male. There were 15/27 (56%) cases of viral pneumonia, 9/27 (33%) cases of bacterial ormixed pneumonia and 3/27 (11%) with an unclear aetiology. Bacterial (n=5) and viral (n=13) samples were analysed by O-Link. 126 proteins were found to be differentially expressed between the two groups. Statistical analysis and correlation with published literature identified three promising biomarkers: Resistin, Tissue inhibitor matrix metalloproteinase 1 and Chitinase-3-like protein 1, AUCs are shown below.Conclusions/Learning Points: Additional biomarkers could help clinicians tailor antibiotic prescribing for pneumonia in the PICU. Technical verification of biomarkers is ongoing in our remaining samples and larger validation studies will be needed to assess the use of biomarkers in this group of patients.<br/

Oncostatin M: a novel biomarker for bacterial pneumonia in children

Backgrounds: Oncostatin M (OSM), a cytokine belonging to the interleukin 6 cytokine family, is a potential biomarker of pneumonia in adults. There have been no studies investigating the role of OSM in paediatric pneumonia. The aim of this study was to assess the diagnostic accuracy of OSM in diagnosing bacterial pneumonia in children admitted to the paediatric intensive care unit (PICU).Methods: Children with clinician diagnosed pneumonia confirmed on chest radiograph were recruited from the Royal Belfast Hospital for Sick Children between April 2020 and December 2022. Detailed clinical data was recorded including the paediatric sequential organ failure assessment (pSOFA), treatments given, levels of care, length of stay and survival. Blood plasma was collected and OSM tested by ELISA. A final diagnosis of bacterial, viral or mixed viral and bacterial pneumonia was provided by an independent paediatric intensivist based on clinical data and results from blood culture, broncheoalveolar lavage and sputum.Results: A total of 27 children were included in the study. The median age was 1.7 (IQR: 0.5-6.8) years and 48% were male. 22/27 (81%) received invasive ventilation, and 3/27 (11%) died. There were 15/27 (56%) cases of viral pneumonia, 9/27 (33%) cases of bacterial or mixed pneumonia and 3/27 (11%) with an unclear aetiology. OSM demonstrated excellent diagnostic test accuracy for identifying bacterial pneumonia with an area under the curve (AUC) of 0.89 (95% CI 0.72-1.1). The optimum cut-off for OSM was 5.3pg/ml with a sensitivity of 0.93 (95% CI 0.68 to 0.99) and specificity of 0.78 (95% CI 0.45 to 0.96).Conclusions/Learning Points: This small cohort study provides the first evidence that OSM could be used as a blood biomarker of bacterial pneumonia in children.<br/

The role of intestinal epithelial permeability in multisystem inflammatory syndrome in children: a case–control study

Background: Multisystem inflammatory syndrome in children (MIS-C) occurs after SARS-CoV-2 infection, with gastrointestinal symptoms a prominent feature. This syndrome has been proposed to be triggered by persistent SARS-CoV-2 antigenemia due to increased intestinal epithelial permeability. We obtained evidence for this in this study. Methods: In a single-centre study, we recruited 83 children and analysed blood samples to quantify the circulating markers of increased intestinal permeability following SARS-CoV-2 infection. Publicly available proteomics MIS-C datasets were also accessed to assess the evidence for increased intestinal permeability. We further quantified SARS-CoV-2 antigenemia and the humoral response to SARS-CoV-2 spike protein. Results: Following SARS-CoV-2 infection, healthy children demonstrated no dysregulation of the intestinal epithelial barrier. In MIS-C, considerable increases in markers of epithelial dysfunction were observed, with similar increases noted in febrile controls. Furthermore, we found little evidence of persistent SARS-CoV-2 antigenemia in MIS-C. Conclusions: Our results suggest that although increased intestinal epithelial permeability is a feature of MIS-C, it is not unique to the condition, and persistent SARS-CoV-2 antigenemia does not occur.<br/

Defining age-specific reference intervals for biomarkers distinguishing bacterial from viral infection in paediatrics

Differentiating bacterial from viral infections in children is a common clinical challenge. Novel host immune biomarkers have the potential to aid the diagnosis of infection aetiology and identify children who require antibiotics. Data on novel infection biomarkers gender and age-specific correlations, and reference intervals in healthy paediatrics is lacking. This study reports the plasma levels of three novel biomarkers that can aid in the differentiation of bacterial and viral infection in a healthy group of paediatrics. The levels of (Interferon-Gamma Inducible Protein 10 kDa (IP-10), Lipocalin-2 (LCN2) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) were quantified in 199 plasma samples from healthy paediatrics aged 2 to 16 years old from across the UK. Reference intervals (2.5th and 97.5th) were determined, and biomarker levels were examined for sex and age associations. Reference intervals for IP-10, LCN2 and TRAIL for ages 2–16 years were 36.7–168.1 pg/ml, 14.2–123.3 ng/ml, 57.4–71.4 pg/ml respectively. No biomarker showed an association with sex and IP-10 did not show any association with age. TRAIL levels had a weak continuous negative correlation with age and LCN2 levels had a continuous positive correlation with age. Specific cut-offs for LCN2 in two age categories were identified, while TRAIL did not require age partitions. This study provides age-appropriate reference intervals for three biomarkers of infection in healthy children. These findings have the potential to improve the impact of future research on these biomarkers, the accuracy of clinical decision-making in children with infection, paediatric patient care and outcomes, and antimicrobial stewardship

Dataset for the article: Effectiveness of social distancing measures and lockdowns for reducing transmission of COVID-19 in non-healthcare, community-based settings

This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'

Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.

Uncoupling protein 1 (UCP1) is a major regulator of brown and beige adipocyte energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss-of-function model has recently been shown to have a severe deficiency in the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as a regulatory site on UCP1 that elevates protein activity upon covalent modification. Here, we examine the physiological importance of this site through the generation of a UCP1 cysteine-253-null (UCP1 C253A) mouse, a precise genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses in both males and females but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, we find that a lack of C253 results in adipose tissue redox stress, which drives substantial immune cell infiltration and systemic inflammatory pathology in adipose tissues and liver of male, but not female, mice. Elevation of systemic estrogen reverses this male-specific pathology, providing a basis for protection from inflammation due to loss of UCP1 C253 in females. Together, our results establish the UCP1 C253 activation site as a regulator of acute thermogenesis and sex-dependent tissue inflammation.This work was supported by the Claudia Adams Barr Program (E.T.C), the Lavine Family Fund (E.T.C), the Pew Charitable Trust (E.T.C), NIH DK123095 (E.T.C) , NIH DK123321 (E.M.), the National Cancer Center (H.X.), R01DK078081 (N.N.D.). We thank the Nikon Imaging Center at Harvard Medical School for assistance with microscopy, Dana-Farber/Harvard Cancer Center Rodent Histopathology Core (NIH-5-P30-CA06516) for preparing histology slides and the Harvard Digestive Disease Center, Core D for assistance with thermal imaging. Cartoon illustrations were created with BioRender.com