Peak alpha frequency and electroencephalographic microstates are correlated with aggression in schizophrenia.

Large scale retrospective studies have shown an association between schizophrenia and risk of violence. Overall, this increase in risk is small and does not justify or support stigmatizing public perceptions or media depictions of people with schizophrenia. Nonetheless, in some situations, some symptoms of schizophrenia can increase the risk of violent behavior. Prediction of this behavior would allow high impact preventive interventions. However, to date the neurobiological correlates of violent behavior in schizophrenia are not well understood, precluding the development of prognostic biomarkers. We used electroencephalography to measure alpha activity and microstates from 31 patients with schizophrenia and 18 age matched controls. Participants also completed multiple assessments of current aggressive tendencies and their lifetime history of aggressive acts. We found that individual alpha peak frequency was negatively correlated with aggression scores in both patients and controls (largest Spearman's r = -0.45). Furthermore, this result could be replicated in data taken from a single frontal channel suggesting that this may be possible to obtain in routine clinical settings (largest Spearman's r = -0.40). We also found that transitions between microstates corresponding to auditory and visual networks were inversely correlated with aggression scores. Finally, we found that, within patients, aggression was correlated with the degree of randomness between microstate transitions. This suggests that aggression is related to inappropriate switching between large scale brain networks and subsequent failure to appropriately integrate complicated environmental and internal stimuli. By elucidating some of the electrophysiological correlates of aggression, these data facilitate the development of prognostic biomarkers.

"We know what we should be eating, but we don't always do that." How and why people eat the way they do: a qualitative study with rural australians.

BACKGROUND: There is evidence that most people are aware of the importance of healthy eating and have a broad understanding regarding types of food that enhance or detract from health. However, greater health literacy does not always result in healthier eating. Andreasen's Social Marketing Model and Community-Based Social Marketing both posit that, in order to change health behaviours, it is crucial to understand reasons for current behaviours and perceived barriers and benefits to improved behaviours. Limited research has been conducted, however, that explores these issues with general populations. This study aimed to help address this gap in the evidence using a qualitative methodology. METHODS: Three group discussions were conducted with a total of 23 participants: (1) young women aged 18-24 with no children; (2) women aged 35-45 with primary school aged children; and (3) men aged 35-50 living with a partner and with pre- or primary school aged children. The discussions took place in a regional centre of Victoria, Australia. Transcriptions were thematically analysed using an inductive descriptive approach and with reference to a recent integrated framework of food choice that identified five key interrelated determinants: food- internal factors; food- external factors; personal-state factors; cognitive factors; and sociocultural factors. RESULTS: We found that food choice was complex, with all five determinants evident from the discussions. However, the "Social environment" sub-category of "Food-external factors", which included family, work, and social structures, and expectations (or perceived expectations) of family members, colleagues, friends, and others, was particularly prominent. Knowledge that one should practice healthy eating, which falls under the "Cognitive factor" category, while seen as an aspiration by most participants, was often viewed as unrealistic, trumped by the need and/or desire for convenience, a combination of Food-external factor: Social environment and Personal-state factor: Psychological components. CONCLUSIONS: We found that decisions regarding what, when, and how much to eat are seen as heavily influenced by factors outside the control of the individual. It appears, therefore, that a key to improving people's eating behaviours is to make it easy to eat more healthfully, or at least not much harder than eating poorly.

Inpatient Hospital Costs, Emergency Department Visits, and Readmissions for Revision Hip and Knee Arthroplasty.

BACKGROUND: Revision total hip arthroplasty (THA) and total knee arthroplasty (TKA) tremendously burden hospital resources. This study evaluated factors influencing perioperative costs, including emergency department (ED) visits, readmissions, and total costs-of-care within 90 days following revision surgery. METHODS: A retrospective analysis of 772 revision TKAs and THAs performed on 630 subjects at a single center between January 2007 and December 2019 was conducted. Cost data was available from January 2015 to December 2019 for 277 patients. Factors examined included comorbidities, demographic information, pre-operative Anesthesia Society of Anesthesiologists score, implant selection, and operative indication using mixed-effects linear regression models. RESULTS: Among 772 revisions (425 THA and 347 TKA), 213 patients required an ED visit, and 90 required hospital readmission within 90 days. There were 22.6% of patients who underwent a second procedure after their initial revision. Liver disease was a significant predictor of ED readmission for THA patients (multivariable OR [odds ratio]: 3.473, P = 0.001), while aseptic loosening, osteolysis, or instability significantly reduced the odds of readmission for TKA patients (OR: 0.368, P = 0.014). In terms of ED visits, liver disease increased the odds for THA patients (OR: 1.845, P = 0.100), and aseptic loosening, osteolysis, or instability decreased the odds for TKA patients (OR: 0.223, P < 0.001). Increased age was associated with increased costs in both THA and TKA patients, with significant cost factors including congestive heart failure for TKA patients (OR: $7,308.17, P = 0.004) and kidney disease for THA patients. Revision surgeries took longer than primary ones, with TKA averaging 3.0 hours (1.6 times longer) and THA 2.8 hours (1.5 times longer). CONCLUSION: Liver disease increases ED readmission risk in revision THA, while aseptic loosening, osteolysis, or instability decreases it in revision TKA. Increased age and CHF are associated with increased costs. These findings inform postoperative care and resource allocation in revision arthroplasty.

AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.

Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates.

Glutathione-S-transferases are key to the cellular detoxification of xenobiotics and products of oxidative damage. GSTs catalyse the reaction of glutathione (GSH) with electrophiles to form stable thioether adducts. GSTK1-1 is the main GST isoform in the mitochondrial matrix, but the GSTA1-1 and GSTA4-4 isoforms are also thought to be in the mitochondria with their distribution altering in transformed cells, thus potentially providing a cancer specific target. A mitochondria-targeted version of the GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), MitoCDNB, has been used to manipulate the mitochondrial GSH pool. To finesse this approach to target particular GST isoforms in the context of cancer, here we have determined the kcat/Km for the human isoforms of GSTK1-1, GSTA1-1 and GSTA4-4 with respect to GSH and CDNB. We show how the rate of the GST-catalysed reaction between GSH and CDNB analogues can be modified by both the electron withdrawing substituents, and by the position of the mitochondria-targeting triphenylphosphonium on the chlorobenzene ring to tune the activity of mitochondria-targeted substrates. These findings can now be exploited to selectively disrupt the mitochondrial GSH pools of cancer cells expressing particular GST isoforms.

Accidental paradiplomats? The curious case of Ontario school board budgets and Canadian soft power projection.

From the earliest studies of soft power in International Relations, the importance of educational exchanges has been well-established. Studies of international education in the context of Canadian soft power often draw on cases from the higher education sector. This article argues that greater attention should be paid to the K-12 level, especially as budgetary pressures in Ontario's education system are leading school boards to rapidly expand their international student recruitment efforts. Although this is not an example of intentional soft power projection, it nevertheless represents an important reminder that subnational actors may accidentally become paradiplomats whose actions have consequences on the international level. Further, this case reveals the importance of paying attention to actors typically overlooked by IR scholarship. Drawing on Joseph Nye's theory of soft power and in conversation with prior research on international education as a mechanism of soft power projection, this article traces the thread between budgetary pressures in Ontario school boards and the broader context of soft power projection.

Trends in Life Expectancy in Residential Long-Term Care by Sociodemographic Position in 1999-2018: A Multistate Life Table Study of Finnish Older Adults.

OBJECTIVES: Residential long-term care (LTC) use has declined in many countries over the past years. This study quantifies how changing rates of entry, exit, and mortality have contributed to trends in life expectancy in LTC (i.e., average time spent in LTC after age 65) across sociodemographic groups. METHODS: We analyzed population-register data of all Finns aged ≥65 during 1999-2018 (n=2,016,987) with dates of LTC and death, and sociodemographic characteristics. We estimated transition rates between home, LTC and death using Poisson generalized additive models, and calculated multistate life tables across 1999-2003, 2004-2008, 2009-2013 and 2014-2018. RESULTS: Between 1999-2003 and 2004-2008, life expectancy in LTC increased from 0.75 (95% CI 0.74-0.76) to 0.89 (0.88-0.90) years among men and from 1.61 (1.59-1.62) to 1.83 (1.81-1.85) years among women, mainly due to declining exit rates from LTC. Thereafter, life expectancy in LTC decreased, reaching 0.80 (0.79-0.81) and 1.51 (1.50-1.53) years among men and women, respectively, in 2014-2018. Especially among women and non-married men, the decline was largely due to increasing death rates in LTC. Admission rates declined throughout the study period, which offset the increase in life expectancy in LTC attributable to declining mortality in the community. Marital status differences in life expectancy in LTC narrowed over time. DISCUSSION: Recent declines in LTC use were driven by postponed LTC admission closer to death. The results suggest that across sociodemographic strata older adults enter LTC in ever worse health and spent a shorter time in care than before.

ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels.

BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of Abcg2-expressing ECs to vessel development and regeneration, we developed Abcg2CreErt2;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2-expressing ECs. RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2-expressing CRECs (AbcCRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in AbcCRECs. In addition, various angiogenic genes, such as Notch2 and Hey2, are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in AbcCRECs. CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction.

Potential value of a rapid syndromic multiplex PCR for the diagnosis of native and prosthetic joint infections: a real-world evidence study.

Introduction: The BIOFIRE Joint Infection (JI) Panel is a diagnostic tool that uses multiplex-PCR testing to detect microorganisms in synovial fluid specimens from patients suspected of having septic arthritis (SA) on native joints or prosthetic joint infections (PJIs). Methods: A study was conducted across 34 clinical sites in 19 European and Middle Eastern countries from March 2021 to June 2022 to assess the effectiveness of the BIOFIRE JI Panel. Results: A total of 1527 samples were collected from patients suspected of SA or PJI, with an overall agreement of 88.4 % and 85 % respectively between the JI Panel and synovial fluid cultures (SFCs). The JI Panel detected more positive samples and microorganisms than SFC, with a notable difference on Staphylococcus aureus, Streptococcus species, Enterococcus faecalis, Kingella kingae, Neisseria gonorrhoeae, and anaerobic bacteria. The study found that the BIOFIRE JI Panel has a high utility in the real-world clinical setting for suspected SA and PJI, providing diagnostic results in approximately 1 h. The user experience was positive, implying a potential benefit of rapidity of results' turnover in optimising patient management strategies. Conclusion: The study suggests that the BIOFIRE JI Panel could potentially optimise patient management and antimicrobial therapy, thus highlighting its importance in the clinical setting.

A model of mitochondrial superoxide production during ischaemia-reperfusion injury for therapeutic development and mechanistic understanding.

Ischaemia-reperfusion (IR) injury is the paradoxical consequence of the rapid restoration of blood flow to an ischaemic organ. Although reperfusion is essential for tissue survival in conditions such as myocardial infarction and stroke, the excessive production of mitochondrial reactive oxygen species (ROS) upon reperfusion initiates the oxidative damage that underlies IR injury, by causing cell death and inflammation. This ROS production is caused by an accumulation of the mitochondrial metabolite succinate during ischaemia, followed by its rapid oxidation upon reperfusion by succinate dehydrogenase (SDH), driving superoxide production at complex I by reverse electron transport. Inhibitors of SDH, such as malonate, show therapeutic potential by decreasing succinate oxidation and superoxide production upon reperfusion. To better understand the mechanism of mitochondrial ROS production upon reperfusion and to assess potential therapies, we set up an in vitro model of IR injury. For this, isolated mitochondria were incubated anoxically with succinate to mimic ischaemia and then rapidly reoxygenated to replicate reperfusion, driving a burst of ROS formation. Using this system, we assess the factors that contribute to the magnitude of mitochondrial ROS production in heart, brain, and kidney mitochondria, as well as screening for inhibitors of succinate oxidation with therapeutic potential.

A global analysis of the use of immunoglobulin, shortages in supply, and mitigating measures: A survey of hospital providers (a BEST Collaborative study).

BACKGROUND: Immunoglobulin (IG) therapy is widely used to treat primary and secondary immune deficiencies and as immunomodulatory agent for various disorders. There is great concern that shortages of IG may rise, potentially affecting medical treatment options. STUDY DESIGN AND METHODS: An international survey was developed to study how intravenous immunoglobulins (IVIGs) are used and managed within hospitals in case of shortages. Study data were collected and managed using REDCap electronic data capture tools hosted by the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. The survey was directed to hospital pharmacists and blood bank transfusion professionals and disseminated through members of the BEST Collaborative network. RESULTS: Survey respondents from institutions in the USA, Canada, Europe, Japan, and Australia (n = 13) confirmed that the primary specialties utilizing IG are neurology, hematology, and immunology. More than 60% of respondents reported IG supply shortages, but mitigation strategies were not well developed. DISCUSSION: As IG is the leading driver in plasma demand, more studies are needed to understand current and future demand for IG from the clinical perspective. Necessity lies in establishing clinical guidance to address shortages.

At least one in a dozen stars shows evidence of planetary ingestion.

Stellar chemical compositions can be altered by ingestion of planetary material1,2 and/or planet formation, which removes refractory material from the protostellar disk3,4. These 'planet signatures' appear as correlations between elemental abundance differences and the dust condensation temperature3,5,6. Detecting these planet signatures, however, is challenging owing to unknown occurrence rates, small amplitudes and heterogeneous star samples with large differences in stellar ages7,8. Therefore, stars born together (that is, co-natal) with identical compositions can facilitate the detection of planet signatures. Although previous spectroscopic studies have been limited to a small number of binary stars9-13, the Gaia satellite14 provides opportunities for detecting stellar chemical signatures of planets among co-moving pairs of stars confirmed to be co-natal15,16. Here we report high-precision chemical abundances for a homogeneous sample of ninety-one co-natal pairs of stars with a well defined selection function and identify at least seven instances of planetary ingestion, corresponding to an occurrence rate of eight per cent. An independent Bayesian indicator is deployed, which can effectively disentangle the planet signatures from other factors, such as random abundance variation and atomic diffusion17. Our study provides evidence of planet signatures and facilitates a deeper understanding of the star-planet-chemistry connection by providing observational constraints on the mechanisms of planet engulfment, formation and evolution.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

"They start on the zero-alcohol and they wanna try the real thing": Parents' views on zero-alcohol beverages and their use by adolescents.

OBJECTIVE: Zero-alcohol beverages containing 0.0-0.5% alcohol by volume may offer public health benefits if individuals use them to substitute for alcohol-containing products, thereby reducing alcohol use. There are, however, concerns that zero-alcohol beverages may encourage adolescents' earlier interest in alcohol and increase exposure to alcohol company branding. As this poses a challenge for parents, we studied parents' views on zero-alcohol beverages and their provision to adolescents. METHODS: We interviewed n=38 parents of 12-17-year-olds and used reflexive thematic analysis to interpret interview data. RESULTS: Parents considered zero-alcohol beverages to be 'adult beverages' that potentially supported reduced adult drinking but were unnecessary for adolescents. Parents were concerned that adolescent zero-alcohol beverage use could normalise alcohol consumption and be a precursor to alcohol initiation. There was a potential conflict between moderate provision in 'appropriate' contexts, and potential benefits, which were each supported by some parents. Uncertainty on health qualities was also reported. CONCLUSIONS: Parents reported conflicting and cautious views on zero-alcohol beverage provision to adolescents. IMPLICATIONS FOR PUBLIC HEALTH: As evidence on the impacts of zero-alcohol beverage availability develops, parent-targeted messages highlighting the potential risk of normalisation of alcohol use for young people could be developed, in conjunction with broader policy responses.

What is the environmental impact of a blood transfusion? A life cycle assessment of transfusion services across England.

BACKGROUND: Healthcare activities significantly contribute to greenhouse gas (GHG) emissions. Blood transfusions require complex, interlinked processes to collect, manufacture, and supply. Their contribution to healthcare emissions and avenues for mitigation is unknown. STUDY DESIGN AND METHODS: We performed a life cycle assessment (LCA) for red blood cell (RBC) transfusions across England where 1.36 million units are transfused annually. We defined the process flow with seven categories: donation, transportation, manufacturing, testing, stockholding, hospital transfusion, and disposal. We used direct measurements, manufacturer data, bioengineering databases, and surveys to assess electrical power usage, embodied carbon in disposable materials and reagents, and direct emissions through transportation, refrigerant leakage, and disposal. RESULTS: The central estimate of carbon footprint per unit of RBC transfused was 7.56 kg CO2 equivalent (CO2eq). The largest contribution was from transportation (2.8 kg CO2eq, 36% of total). The second largest was from hospital transfusion processes (1.9 kg CO2eq, 26%), driven mostly by refrigeration. The third largest was donation (1.3 kg CO2eq, 17%) due to the plastic blood packs. Total emissions from RBC transfusion are ~10.3 million kg CO2eq/year. DISCUSSION: This is the first study to estimate GHG emissions attributable to RBC transfusion, quantifying the contributions of each stage of the process. Primary areas for mitigation may include electric vehicles for the blood service fleet, improving the energy efficiency of refrigeration, using renewable sources of electricity, changing the plastic of blood packs, and using methods of disposal other than incineration.

In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy ± daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.

Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex.

Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of Lassa virus's glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we use pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affect cell entry and antibody neutralization. Our experiments define functional constraints throughout GPC. We quantify how GPC mutations affect neutralization by a panel of monoclonal antibodies and show that all antibodies are escaped by mutations that exist among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid design of therapeutics and vaccines.