Helminth induced monocytosis conveys protection from respiratory syncytial virus infection in mice.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infants is a major cause of viral bronchiolitis and hospitalisation. We have previously shown in a murine model that ongoing infection with the gut helminth Heligmosomoides polygyrus protects against RSV infection through type I interferon (IFN-I) dependent reduction of viral load. Yet, the cellular basis for this protection has remained elusive. Given that recruitment of mononuclear phagocytes to the lung is critical for early RSV infection control, we assessed their role in this coinfection model. METHODS: Mice were infected by oral gavage with H. polygyrus. Myeloid immune cell populations were assessed by flow cytometry in lung, blood and bone marrow throughout infection and after secondary infection with RSV. Monocyte numbers were depleted by anti-CCR2 antibody or increased by intravenous transfer of enriched monocytes. RESULTS: H. polygyrus infection induces bone marrow monopoiesis, increasing circulatory monocytes and lung mononuclear phagocytes in a IFN-I signalling dependent manner. This expansion causes enhanced lung mononuclear phagocyte counts early in RSV infection that may contribute to the reduction of RSV load. Depletion or supplementation of circulatory monocytes prior to RSV infection confirms that these are both necessary and sufficient for helminth induced antiviral protection. CONCLUSIONS: H. polygyrus infection induces systemic monocytosis contributing to elevated mononuclear phagocyte numbers in the lung. These cells are central to an anti-viral effect that reduces the peak viral load in RSV infection. Treatments to promote or modulate these cells may provide novel paths to control RSV infection in high risk individuals.

Intravenous Cefazolin Achieves Sustained High Interstitial Concentrations in Open Lower Extremity Fractures.

BACKGROUND: Infection remains a serious clinical concern in patients with open fractures, despite timely antibiotic administration and surgical debridement. Soft tissue and periosteal stripping may alter local tissue homeostasis and antibiotic pharmacokinetics in the injured limb. The tissue (interstitial) concentration of intravenously administered antibiotics at an open fracture site has not been characterized using direct sampling techniques. QUESTION/PURPOSE: We performed this study to evaluate the concentration and pharmacokinetics of intravenously delivered cefazolin at an open fracture site after surgical debridement. METHODS: Twelve patients with an open fracture distal to the knee who presented at a regional Level I trauma center were approached for enrollment in this nonrandomized, observational study. Of the 12 patients, eight adults (one female, seven male) with a median age of 32 years (range 23 to 51 years) were enrolled and underwent successful sample collection for analysis. Three patients had incomplete datasets because of equipment malfunction and one elected not to participate. Seven patients had open tibia fractures, and one patient had an open fibula fracture associated with a closed tibia fracture. There were six Gustilo-Anderson Type II injuries and two Type IIIA injuries. Empiric antibiotics were administered in the prehospital setting or in the emergency department according to institutional protocol. When patients were taken to the operating room, a 2-g intravenous dose of cefazolin was administered. After surgical debridement, fracture stabilization, and wound closure, a microdialysis catheter was placed transdermally into the injury zone (within 5 cm of the fracture site) and a second catheter was placed in the contralateral uninjured (control) limb. Additional doses of cefazolin were administered every 8 hours postoperatively. Baseline and periodic interstitial fluid and whole blood (plasma) samples were collected in the operating room and at prespecified times for 24 hours postoperatively. Free cefazolin in the interstitial fluid and plasma samples were analyzed by ultra-high-performance liquid chromatography using C 18 column separation with quadrupole time-of-flight mass spectrometry detection. Data from the second postoperative dose of cefazolin were used to characterize pharmacokinetic parameters through a noncompartmental analysis using time-concentration curves of free cefazolin and assuming first-order elimination. For pharmacodynamic analyses, the modal cefazolin minimum inhibitory concentration (MIC) of Staphylococcus aureus (1 µg/mL) was used. RESULTS: With the samples available, no difference was observed in the median free cefazolin exposure over 24 hours ( f area under the curve [AUC] 0→24hrs ) between injured limbs (352 µg∙hr/mL [IQR 284 to 594 µg∙hr/mL]) and uninjured limbs (341 µg∙hr/mL [IQR 263 to 438 µg∙hr/mL]; p = 0.64). The median time to achieve the maximum concentration of free cefazolin ( f T max ) for injured limbs was delayed (2.7 hours [IQR 2.2 to 3.1 hours]) compared with control limbs (1.7 hours [IQR 1.2 to 2.0 hours]; p = 0.046). The time to the maximum concentration for plasma was not different from that of control limbs (p = 0.08). The time the cefazolin concentration was above the modal S. aureus MIC (T > MIC) in the injured and control limbs over 24 hours was 100% (IQR 100% to 100%) and 100% (IQR 97% to 100%), respectively. CONCLUSION: These preliminary findings suggest that current prophylactic cefazolin dosing regimens result in successful antibiotic delivery to the traumatized limb in moderately severe open fractures. Although cefazolin delivery to open-fracture wound beds was delayed compared with healthy tissues, the cefazolin concentration was sustained above the European Union Committee Antimicrobial Susceptibility Testing modal MIC for S. aureus , demonstrating a high likelihood of a prophylactic antimicrobial environment at an open fracture site with this empiric antimicrobial regimen. Importantly, patients in this analysis had Gustilo-Anderson Types II and IIIA injuries. Further research with a larger patient cohort is needed to determine whether antibiotic delivery to traumatized soft tissues in patients with higher-grade open fractures (Gustilo-Anderson Types IIIB and IIIC) demonstrates similar pharmacokinetic characteristics. LEVEL OF EVIDENCE: Level II, therapeutic study.

Evaluation of Topical Off-the-Shelf Therapies to Reduce the Need to Evacuate Battlefield-Injured Warfighters.

INTRODUCTION: Immediate evacuation of burn casualties can be challenging in austere environments, and it is predicted to be even more difficult in future multi-domain battlespaces against near-peer foes. Therefore, a need exists to treat burn wounds at the point of injury to protect the exposed injury for an extended period. In this study, we compare two commercially available FDA-approved therapies to the current gold standard of care (GSOC), excisional debridement followed by the application of split-thickness skin graft, and the standard for prolonged field care, silver sulfadiazine (SSD) cream. The shelf-stable therapies evaluated were irradiated human skin (IHS) allograft and polylactic acid (PLA). Our objective was to study whether they have the potential capability to reduce the need for evacuation to a burn center for surgical intervention so that the combat power can be preserved in the field. MATERIALS AND METHODS: Sixteen burns (50 cm2) were created on the dorsum of four anesthetized swine. All materials were sterile, but a sterile field was not utilized in order to simulate the prolonged field care setting. The wounds were then treated with PLA, IHS, and SSD cream, and the remaining wounds (designated GSOC) were also treated with SSD cream. On post-operative day (POD) 3, sterile surgical debridement and skin grafting (1:4) were performed on the GSOC wounds. Burn healing was followed for either PODs 10, 14, 21, or 28, wherein one animal was humanely euthanized at each time point; each represented a time point of the healing process. A full-thickness excisional biopsy was taken from each wound immediately after euthanasia to give a cross-section view of the wound edge to edge. Wound healing was determined by the histological analysis of wound re-epithelialization, epidermal thickness, rete ridges, and scar elevation index and macroscopically using noninvasive imaging systems. RESULTS: The PLA and IHS treatments did not need to be reapplied to the wounds during the course of the experiment, unlike SSD, which was reapplied at each assessment time point. In terms of re-epithelialization, on POD 10, IHS and SSD were similar to the GSOC; on POD 14, all treatments were similar; on POD 21, PLA and IHS were similar to SSD; finally, on POD 28, re-epithelialization was similar in all groups. On POD 28, scar elevation index and rete ridges/mm were similar to all groups, and epidermal and dermal thickness for PLA and IHS were similar to GSOC. CONCLUSIONS: This preclinical study demonstrated that the use of the PLA and the IHS dressings resulted in similar outcomes to the GSOC-treated burns in several key metrics of wound healing. These therapies represent a potentially useful tool in current and future battlespaces, where surgical intervention is not possible. The products are lightweight and, more importantly, stable at room temperature for their entire shelf lives. This would allow for easy storage and transport by medical practitioners in the field.

Rebound effects could offset more than half of avoided food loss and waste.

Reducing food loss and waste (FLW) could lessen the environmental impacts of food systems and improve food security. However, rebound effects-whereby efficiency improvements cause price decreases and consumption increases-may offset some avoided FLW. Here we model rebounds in food consumption under a scenario of costless FLW reduction. We project that consumption rebound could offset 53-71% of avoided FLW. Such rebounds would imply similar percentage reductions in environmental benefits (carbon emissions, land use, water use) and improvements in food security benefits (increased calorie availability), highlighting a tension between these two objectives. Evidence from energy systems suggests that indirect effects not included in our analysis could further increase rebounds. However, costs of reducing FLW would reduce rebounds. Rebound effects are therefore important to consider in efforts aimed at reducing FLW.

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders.

Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinic:polycytidylic acid (poly I:C) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly I:C elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF; referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly I:C-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation.

Patterns of Palliation: A Review of Casualties That Received Pain Management Before Reaching Role 2 in Afghanistan.

INTRODUCTION: Battlefield pain management changed markedly during the first 20 years of the Global War on Terror. Morphine, long the mainstay of combat analgesia, diminished in favor of fentanyl and ketamine for military pain control, but the options are not hemodynamically or psychologically equivalent. Understanding patterns of prehospital analgesia may reveal further opportunities for combat casualty care improvement. MATERIALS AND METHODS: Using Department of Defense Trauma Registry data for the Afghanistan conflict from 2005 to 2018, we examined 2,402 records of prehospital analgesia administration to assess temporal trends in medication choice and proportions receiving analgesia, including subanalysis of a cohort screened for an indication with minimal contraindication for analgesia. We further employed frequency matching to explore the presence of disparities in analgesia by casualty affiliation. RESULTS: Proportions of documented analgesia increased throughout the study period, from 0% in 2005 to 70.6% in 2018. Afghan casualties had the highest proportion of documented analgesia (53.0%), versus U.S. military (31.9%), civilian/other (23.3%), and non-U.S. military (19.3%). Fentanyl surpassed morphine in the frequency of administration in 2012. The median age of those receiving ketamine was higher (30 years) than those receiving fentanyl (26 years) or nonsteroidal anti-inflammatory drugs (23 years). Among the frequency-matched subanalysis, the odds ratio for ketamine administration with Afghan casualties was 1.84 (95% CI, 1.30-2.61). CONCLUSIONS: We observed heterogeneity of prehospital patient care across patient affiliation groups, suggesting possible opportunities for improvement toward an overall best practice system. General increase in documented prehospital pain management likely reflects efforts toward complete documentation, as well as improved options for analgesia. Current combat casualty care documentation does not include any standardized pain scale.

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Good and bad news for ocean predators.

Some tunas and billfishes are recovering, but sharks continue to decline.

The Difficult Airway Redefined.

There is no all-encompassing or universally accepted definition of the difficult airway, and it has traditionally been approached as a problem chiefly rooted in anesthesiology. However, with airway obstruction reported as the second leading cause of mortality on the battlefield and first-pass success (FPS) rates for out-of-hospital endotracheal intubation (ETI) as low as 46.4%, the need to better understand the difficult airway in the context of the prehospital setting is clear. In this review, we seek to redefine the concept of the "difficult airway" so that future research can target solutions better tailored for prehospital, and more specifically, combat casualty care. Contrasting the most common definitions, which narrow the scope of practice to physicians and a handful of interventions, we propose that the difficult airway is simply one that cannot be quickly obtained. This implies that it is a situation arrived at through a multitude of factors, namely the Patient, Operator, Setting, and Technology (POST), but also more importantly, the interplay between these elements. Using this amended definition and approach to the difficult to manage airway, we outline a target-specific approach to new research questions rooted in this system-based approach to better address the difficult airway in the prehospital and combat casualty care settings.

The Immune and Regenerative Response to Burn Injury.

Burn are diverse and complex injuries that not only have local effects but also serious systemic consequences through severe and prolonged inflammatory response. They are caused by heat, electricity, friction, chemicals, or radiation and are commonly divided into superficial, superficial partial-, deep partial- and full-thickness injuries. The severity of the burn depends mainly on the size and depth of the injury but also on location, age, and underlying systemic diseases. A prolonged and strong immune response makes major burns even worse by causing multiple systemic effects including damage to the heart, lungs, blood vessels, kidneys, and other organs. Burns that do not require surgical excision, superficial and superficial partial-thickness, follow the known progression of wound healing (inflammation, proliferation, remodeling), whilst deep partial- and full thickness injuries requiring excision and grafting do not. For these burns, intervention is required for optimal coverage, function, and cosmesis. Annually millions of people worldwide suffer from burns associated with high morbidity and mortality. Fortunately, over the past decades, burn care has significantly improved. The improvement in understanding the pathophysiology of burn injury and burn wound progression has led to developments in skin grafting, fluid resuscitation, infection control and nutrition This review article focuses on the immune and regenerative responses following burn injury. In the Introduction, we describe the epidemiology of burns and burn pathophysiology. The focus of the following chapter is on systemic responses to burn injury. Next, we define the immune response to burns introducing all the different cell types involved. Subsequently, we discuss the regenerative cell response to burns as well as some of the emerging novel treatments in the battle against burns.

Indices of complement activation and coagulation changes in trauma patients.

Objectives: Early complementopathy and coagulopathy are shown often after trauma. However, the prevalence of any interplay between complement cascade (ComC) and coagulation cascade (CoaC) after trauma remains unclear. This study intended to explore whether complement-coagulation crosstalk exists, which may provide a reliable guide to clinical implications in trauma patients. Methods: This single-center cohort study of trauma patients enrolled 100 patients along with 20 healthy volunteers. Blood samples from patients were collected at admission, 45, 90, 135 minutes, and 18 hours after admission. Demographic characteristics were recorded, blood levels of ComC and CoaC factors, and inflammatory cytokines were measured by ELISA, clot-based assays, or luminex multiplex assay, and partial thromboplastin (PT) and partial thromboplastin time (PTT) were assessed using a Behring blood coagulation system. Results: Compared with the healthy controls, plasma levels of complement factors (C5b-9 and Bb) and 11 tested inflammatory cytokines increased in moderately and severely injured patients as early as 45 minutes after admission and sustained higher levels up to 18 hours after admission. C5b-9 correlated positively to patients' hospital stay. In parallel, the consumption of coagulation factors I, II, X, and XIII was shown throughout the first 18 hours after admission in moderately and severely injured patients, whereas PT, PTT, D-dimer, factor VII, and factor VIII values significantly increased from the admission to 135 minutes in moderately and severely injured patients. Along with an inverse correlation between plasma Bb, factors I and II, a positive correlation between C5b-9, Bb, D-dimer, PT, and PTT was evident. Conclusions: This study demonstrates trauma-induced early activation of plasma cascades including ComC, CoaC, and fibrinolytic cascade, and their correlation between plasma cascades in severe trauma patients. Our study suggests that the simultaneous modulation of plasma cascades might benefit clinical outcomes for trauma patients. Level of evidence: Prospective study, level III.

Advancing bipartisan decarbonization policies: lessons from state-level successes and failures.

U.S. political polarization is at a high point since the Civil War, and is a significant barrier to coordinated national action addressing climate change. To examine where common ground may exist, here we comprehensively review and characterize successes and failures of recent state-level decarbonization legislation, focusing especially on bipartisanship. We analyze 418 major state-government-enacted bills and 450 failed bills from 2015 to 2020, as well as the political contexts in which they were passed or defeated. We use bivariate analyses and regressions to explore correlations and partial correlations between the policy characteristics and political contexts of bills, and their passage or failure, their bipartisanship, and vote shares they received. Key results include (i) nearly one-third of these state-level decarbonization bills were passed by Republican-controlled governments. (ii) Bipartisan or Republican co-sponsors disproportionately passed financial incentives for renewable energy, and legislation that expands consumer or business choices in context of decarbonization goals; Democrat-only co-sponsors disproportionately passed bills that restricted consumer and business choice, such as mandatory Renewable Energy and Efficiency Portfolio Standards (REEPS) and emissions standards. (iii) Bipartisan bills were disproportionately proposed in "divided" states, did not restrict consumer and business choice, had environmental justice components framed economically, and lacked environmental justice components framed either using academic social-justice jargon or non-neutrally with respect to immutable characteristics such as race. (iv) Bills that expand consumer or business choice were disproportionately enacted. Though climate change is a polarized issue, our results provide tangible insights for future bipartisan successes. Supplementary Information: The online version contains supplementary material available at 10.1007/s10584-022-03335-w.

Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Systemic Influences of Mammary Cancer on Monocytes in Mice.

There is a growing body of evidence that cancer causes systemic changes. These influences are most evident in the bone marrow and the blood, particularly in the myeloid compartment. Here, we show that there is an increase in the number of bone marrow, circulating and splenic monocytes by using mouse models of breast cancer caused by the mammary epithelial expression of the polyoma middle T antigen. Cancer does not affect ratios of classical to non-classical populations of monocytes in the circulation nor does it affect their half-lives. Single cell RNA sequencing also indicates that cancer does not induce any new monocyte populations. Cancer does not change the monocytic progenitor number in the bone marrow, but the proliferation rate of monocytes is higher, thus providing an explanation for the expansion of the circulating numbers. Deep RNA sequencing of these monocytic populations reveals that cancer causes changes in the classical monocyte compartment, with changes evident in bone marrow monocytes and even more so in the blood, suggesting influences in both compartments, with the down-regulation of interferon type 1 signaling and antigen presentation being the most prominent of these. Consistent with this analysis, down-regulated genes are enriched with STAT1/STAT2 binding sites in their promoter, which are transcription factors required for type 1 interferon signaling. However, these transcriptome changes in mice did not replicate those found in patients with breast cancer. Consequently, this mouse model of breast cancer may be insufficient to study the systemic influences of human cancer.

Prepare developed democracies for long-run economic slowdowns.

Developed democracies proliferated over the past two centuries during an unprecedented era of economic growth, which may be ending. Macroeconomic forecasts predict slowing growth throughout the twenty-first century for structural reasons such as ageing populations, shifts from goods to services, slowing innovation, and debt. Long-run effects of COVID-19 and climate change could further slow growth. Some sustainability scientists assert that slower growth, stagnation or de-growth is an environmental imperative, especially in developed countries. Whether slow growth is inevitable or planned, we argue that developed democracies should prepare for additional fiscal and social stress, some of which is already apparent. We call for a 'guided civic revival', including government and civic efforts aimed at reducing inequality, socially integrating diverse populations and building shared identities, increasing economic opportunity for youth, improving return on investment in taxation and public spending, strengthening formal democratic institutions and investing to improve non-economic drivers of subjective well-being.

Empirically classifying network mechanisms.

Network data are often explained by assuming a generating mechanism and estimating related parameters. Without a way to test the relevance of assumed mechanisms, conclusions from such models may be misleading. Here we introduce a simple empirical approach to mechanistically classify arbitrary network data as originating from any of a set of candidate mechanisms or none of them. We tested our approach on simulated data from five of the most widely studied network mechanisms, and found it to be highly accurate. We then tested 1284 empirical networks spanning 17 different kinds of systems against these five widely studied mechanisms. We found that 387 (30%) of these empirical networks were classified as unlike any of the mechanisms, and only 1% or fewer of the networks classified as each of the mechanisms for which our approach was most sensitive. Based on this, we use Bayes' theorem to show that most of the 70% of empirical networks our approach classified as a mechanism could be false positives, because of the high sensitivity required of a test to detect rarely occurring mechanisms. Thus, it is possible that very few of our empirical networks are described by any of these five widely studied mechanisms. Additionally, 93 networks (7%) were classified as plausibly being governed by each of multiple mechanisms. This raises the possibility that some systems are governed by mixtures of mechanisms. We show that mixtures are often unidentifiable because different mixtures can produce structurally equivalent networks, but that we can still accurately predict out-of-sample functional properties.

Aerobic exercise improves memory and prevents cognitive deficits of relevance to schizophrenia in an animal model.

INTRODUCTION AND OBJECTIVES: Cognitive impairment associated with schizophrenia (CIAS) greatly reduces patients' functionality, and remains an unmet clinical need. The sub-chronic phencyclidine (scPCP) rat model is commonly employed in studying CIAS. We have previously shown that voluntary exercise reverses impairments in novel object recognition (NOR) induced by scPCP. However, there has not been a longitudinal study investigating the potential protective effects of exercise in a model of CIAS. This study aimed to investigate the pro-cognitive and protective effects of exercise on CIAS using the translational NOR and attentional set-shifting tasks (ASST). METHODS: Female Lister Hooded rats were either exercised (wheel running for one hour per day, five days per week, for six weeks; n=20) or not (n=20) and then tested in a natural-forgetting NOR test. Rats in each group were then administered either PCP (2 mg/kg intraperitoneally (i.p.)) or saline solution (1 mL/kg i.p.) for seven days, followed by seven days washout. Three NOR tests were conducted immediately and two and nine weeks after washout, and a natural-forgetting NOR test was carried out again eight weeks post washout. Rats were trained and tested in ASST from week 6 to week 10 post washout. RESULTS: Non-exercised rats displayed a deficit in both of the natural-forgetting NOR tests, whereas exercised rats did not. The scPCP exercise group did not show the expected deficit in NOR at any time point, and had a significantly ameliorated deficit in the ASST compared to the scPCP control group. CONCLUSION: Voluntary exercise has long-lasting pro-cognitive and protective effects in two cognitive domains. Exercise improves cognition and could provide protection against CIAS.

Orbital-use fees could more than quadruple the value of the space industry.

The space industry's rapid recent growth represents the latest tragedy of the commons. Satellites launched into orbit contribute to-and risk damage from-a growing buildup of space debris and other satellites. Collision risk from this orbital congestion is costly to satellite operators. Technological and managerial solutions-such as active debris removal or end-of-life satellite deorbit guidelines-are currently being explored by regulatory authorities. However, none of these approaches address the underlying incentive problem: satellite operators do not account for costs they impose on each other via collision risk. Here, we show that an internationally harmonized orbital-use fee can correct these incentives and substantially increase the value of the space industry. We construct and analyze a coupled physical-economic model of commercial launches and debris accumulation in low-Earth orbit. Similar to carbon taxes, our model projects an optimal fee that rises at a rate of 14% per year, equal to roughly $235,000 per satellite-year in 2040. The long-run value of the satellite industry would more than quadruple by 2040-increasing from around $600 billion under business as usual to around $3 trillion. In contrast, we project that purely technological solutions are unlikely to fully address the problem of orbital congestion. Indeed, we find debris removal sometimes worsens economic damages from congestion by increasing launch incentives. In other sectors, addressing the tragedy of the commons has often been a game of catch-up with substantial social costs. The infant space industry can avert these costs before they escalate.

Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial.

PURPOSE: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS: This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/AKT1/PTEN alterations, tumor response, and safety. RESULTS: Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION: Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.