Global potential for natural regeneration in deforested tropical regions.

Extensive forest restoration is a key strategy to meet nature-based sustainable development goals and provide multiple social and environmental benefits1. Yet achieving forest restoration at scale requires cost-effective methods2. Tree planting in degraded landscapes is a popular but costly forest restoration method that often results in less biodiverse forests when compared to natural regeneration techniques under similar conditions3. Here we assess the current spatial distribution of pantropical natural forest (from 2000 to 2016) and use this to present a model of the potential for natural regeneration across tropical forested countries and biomes at a spatial resolution of 30 m. We estimate that an area of 215 million hectares-an area greater than the entire country of Mexico-has potential for natural forest regeneration, representing an above-ground carbon sequestration potential of 23.4 Gt C (range, 21.1-25.7 Gt) over 30 years. Five countries (Brazil, Indonesia, China, Mexico and Colombia) account for 52% of this estimated potential, showcasing the need for targeting restoration initiatives that leverage natural regeneration potential. Our results facilitate broader equitable decision-making processes that capitalize on the widespread opportunity for natural regeneration to help achieve national and global environmental agendas.

Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

BACKGROUND: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. METHODS: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. RESULTS: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. CONCLUSIONS: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Global conservation of species' niches.

Environmental change is rapidly accelerating, and many species will need to adapt to survive1. Ensuring that protected areas cover populations across a broad range of environmental conditions could safeguard the processes that lead to such adaptations1-3. However, international conservation policies have largely neglected these considerations when setting targets for the expansion of protected areas4. Here we show that-of 19,937 vertebrate species globally5-8-the representation of environmental conditions across their habitats in protected areas (hereafter, niche representation) is inadequate for 4,836 (93.1%) amphibian, 8,653 (89.5%) bird and 4,608 (90.9%) terrestrial mammal species. Expanding existing protected areas to cover these gaps would encompass 33.8% of the total land surface-exceeding the current target of 17% that has been adopted by governments. Priority locations for expanding the system of protected areas to improve niche representation occur in global biodiversity hotspots9, including Colombia, Papua New Guinea, South Africa and southwest China, as well as across most of the major land masses of the Earth. Conversely, we also show that planning for the expansion of protected areas without explicitly considering environmental conditions would marginally reduce the land area required to 30.7%, but that this would lead to inadequate niche representation for 7,798 (39.1%) species. As the governments of the world prepare to renegotiate global conservation targets, policymakers have the opportunity to help to maintain the adaptive potential of species by considering niche representation within protected areas1,2.

Targeted temperature control following traumatic brain injury: ESICM/NACCS best practice consensus recommendations.

AIMS AND SCOPE: The aim of this panel was to develop consensus recommendations on targeted temperature control (TTC) in patients with severe traumatic brain injury (TBI) and in patients with moderate TBI who deteriorate and require admission to the intensive care unit for intracranial pressure (ICP) management. METHODS: A group of 18 international neuro-intensive care experts in the acute management of TBI participated in a modified Delphi process. An online anonymised survey based on a systematic literature review was completed ahead of the meeting, before the group convened to explore the level of consensus on TTC following TBI. Outputs from the meeting were combined into a further anonymous online survey round to finalise recommendations. Thresholds of ≥ 16 out of 18 panel members in agreement (≥ 88%) for strong consensus and ≥ 14 out of 18 (≥ 78%) for moderate consensus were prospectively set for all statements. RESULTS: Strong consensus was reached on TTC being essential for high-quality TBI care. It was recommended that temperature should be monitored continuously, and that fever should be promptly identified and managed in patients perceived to be at risk of secondary brain injury. Controlled normothermia (36.0-37.5 °C) was strongly recommended as a therapeutic option to be considered in tier 1 and 2 of the Seattle International Severe Traumatic Brain Injury Consensus Conference ICP management protocol. Temperature control targets should be individualised based on the perceived risk of secondary brain injury and fever aetiology. CONCLUSIONS: Based on a modified Delphi expert consensus process, this report aims to inform on best practices for TTC delivery for patients following TBI, and to highlight areas of need for further research to improve clinical guidelines in this setting.

Preoperative Echocardiographically Derived Mean dP/dTic Predicts Early Post-operative Dysfunction in Children Undergoing Mitral Valve Surgery.

Mean dP/dtic is a quantitative measurement of ventricular function that can be obtained noninvasively by echocardiography. In adults with mitral regurgitation (MR), it has been shown to be a more sensitive predictor of postoperative left ventricular ejection fraction (EF). The utility of dP/dtic in pediatric congenital heart diseases with MR has been underexplored. Patients (0 to ≤ 19 years) with MR who underwent mitral valve (MV) repair or replacement from 2015 to 2021 were included. Echocardiographically derived mean dP/dtic, Tei index, and EF were used to assess and compare ventricular function prior to, shortly after, and late after MV surgery. Study cohort included 61 patients (age 4.5 [IQR 0.14, 18.7] years, 89% MV repair, 11% MV replacement). Median time intervals between surgery and preoperative, early postoperative, and late postoperative echocardiograms were 6 days, 6 days, and 350 days, respectively. Median EF was 62% (z-score - 0.40) preoperatively, 56% (z-score - 1.40) early postoperatively, and 61% (z-score - 0.60) late postoperatively. Median dP/dtic was 1393 (IQR 1029, 1775) mmHg/s preoperatively, 1178 (IQR 886, 1946) mmHg/s early postoperatively, and 1270 (IQR 791, 1765) mmHg/s late postoperatively. Preoperative median dP/dtic correlated with early and late postoperative EF. Preoperative EF was not significantly correlated with early postoperative EF, but was correlated with late postoperative EF. Mitral valve intervention in pediatric patients is associated with an initial decline but subsequent recovery of systolic function. Non-invasively derived mean dP/dtic may offer advantages over other preoperative echocardiographic indices to predict postoperative systolic function.

Diversity in invasive species management networks.

Effective management of invasive species requires collaboration across a range of stakeholders. These stakeholders exhibit diverse attributes such as organisation types, operational scale, objectives, and roles within projects. Identifying the diverse attributes of stakeholders is beneficial for increasing collaboration success while minimising potential conflicts among multiple stakeholders when managing invasive species across landscapes. Despite the increasing number of studies on connections among stakeholders, there is little understanding of the diverse attributes of stakeholders involved in invasive species management. This is a notable gap because the diversity of stakeholders is one of the significant factors that can influence collaboration success. To bridge this knowledge gap, we used a social network approach to identify the attributes of stakeholders that influence their participation in collaborations using a case study of invasive wild pig (Sus scrofa) management in Queensland, Australia. Our findings suggest that even though the overall stakeholder network was diverse, the stakeholder network at the project level exhibited a lack of diversity on average, particularly regarding the scale of operation and type of organisation. In other words, stakeholders are highly likely to form ties in projects involving other stakeholders from similar types of organisations or operational scales. We suggest that targeting a greater diversity of stakeholders across types of organisations and scales of operations might enhance the success of collaborative invasive species management.

A daily temperature rhythm in the human brain predicts survival after brain injury.

Patients undergo interventions to achieve a 'normal' brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements and without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n = 114), brain temperature ranged from 32.6 to 42.3°C and mean brain temperature (38.5 ± 0.8°C) exceeded body temperature (37.5 ± 0.5°C, P < 0.0001). Of 100 patients eligible for brain temperature rhythm analysis, 25 displayed a daily rhythm, and the brain temperature range decreased in older patients (P = 0.018). In healthy participants, brain temperature ranged from 36.1 to 40.9°C; mean brain temperature (38.5 ± 0.4°C) exceeded oral temperature (36.0 ± 0.5°C) and was 0.36°C higher in luteal females relative to follicular females and males (P = 0.0006 and P < 0.0001, respectively). Temperature increased with age, most notably in deep brain regions (0.6°C over 20 years, P = 0.0002), and varied spatially by 2.41 ± 0.46°C with highest temperatures in the thalamus. Brain temperature varied by time of day, especially in deep regions (0.86°C, P = 0.0001), and was lowest at night. From the healthy data we built HEATWAVE-a 4D map of human brain temperature. Testing the clinical relevance of HEATWAVE in patients, we found that lack of a daily brain temperature rhythm increased the odds of death in intensive care 21-fold (P = 0.016), whilst absolute temperature maxima or minima did not predict outcome. A warmer mean brain temperature was associated with survival (P = 0.035), however, and ageing by 10 years increased the odds of death 11-fold (P = 0.0002). Human brain temperature is higher and varies more than previously assumed-by age, sex, menstrual cycle, brain region, and time of day. This has major implications for temperature monitoring and management, with daily brain temperature rhythmicity emerging as one of the strongest single predictors of survival after brain injury. We conclude that daily rhythmic brain temperature variation-not absolute brain temperature-is one way in which human brain physiology may be distinguished from pathophysiology.

Targeted temperature management in patients with intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke: updated consensus guideline recommendations by the Neuroprotective Therapy Consensus Review (NTCR) group.

BACKGROUND: There is a lack of consistent, evidence-based guidelines for the management of patients with fever after brain injury. The aim was to update previously published consensus recommendations on targeted temperature management after intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and acute ischaemic stroke in patients who require admission to critical care. METHODS: A modified Delphi consensus, the Neuroprotective Therapy Consensus Review (NTCR), included 19 international neuro-intensive care experts with a subspecialty interest in the acute management of intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and acute ischaemic stroke. An online, anonymised survey was completed ahead of the meeting before the group came together to consolidate consensus and finalise recommendations on targeted temperature management. A threshold of ≥80% for consensus was set for all statements. RESULTS: Recommendations were formulated based on existing evidence, literature review, and consensus. After intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and acute ischaemic stroke in patients who require critical care admission, core temperature should ideally be monitored continuously and maintained between 36.0°C and 37.5°C using automated feedback-controlled devices, where possible. Targeted temperature management should be commenced within 1 h of first fever identification with appropriate diagnosis and treatment of infection, maintained for as long as the brain remains at risk of secondary injury, and rewarming should be controlled. Shivering should be monitored and managed to limit risk of secondary injury. Following a single protocol for targeted temperature management across intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and acute ischaemic stroke is desirable. CONCLUSIONS: Based on a modified Delphi expert consensus process, these guidelines aim to improve the quality of targeted temperature management for patients after intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and acute ischaemic stroke in critical care, highlighting the need for further research to improve clinical guidelines in this setting.

How success is evaluated in collaborative invasive species management: A systematic review.

Invasive species are one of the most pressing global challenges for biodiversity and agriculture. They can cause species extinctions, ecosystem alterations, crop damage, and spread harmful diseases across broad regions. Overcoming this challenge requires collaborative management efforts that span multiple land tenures and jurisdictions. Despite evidence on the importance and approaches to collaboration, there is little understanding of how success is evaluated in the invasive species management literature. This is a major gap, considering evaluating success is crucial for enhancing the efficacy of future management projects. To overcome this knowledge gap, we systematically reviewed the published literature to identify the stages at which success is evaluated - that is, the Process stage (collaborative management actions and Processes), Outputs stage (results of management actions to protect environmental, economic, and social values) and Outcomes stage (effects of Outputs on environmental, economic, and social values) of collaborative invasive species management projects. We also assessed what indicators were used to identify success and whether these evaluations vary across different characteristics of collaborative invasive species management. Our literature search detected 1406 papers, of which 58 met our selection criteria. Out of these, the majority of papers evaluated success across two stages (n = 25, 43.1%), whereas only ten (17.2%) papers evaluated success across all stages. Outputs were the most commonly evaluated stage (n = 40, 68.9%). The most widely used indicators of success for these stages included increased collaboration of stakeholders (Process stage), the number of captured/eradicated/controlled invasive species (Outputs stage) and change in biodiversity values, such as the number of threatened species (Outcomes stage). Most indicators of success were environmentally focused. We highlight the need to align the indicators of success and evaluation stages with the fundamental objectives of the projects to increase the effectiveness of evaluations and thereby maximise the benefits of collaborative invasive species management.

Vitamin D and COVID-19-Revisited.

Vitamin D, when activated to 1,25-dihydroxyvitamin D, is a steroid hormone that induces responses in several hundred genes, including many involved in immune responses to infection. Without supplementation, people living in temperate zones commonly become deficient in the precursor form of vitamin D, 25-hydroxyvitamin D, during winter, as do people who receive less sunlight exposure or those with darker skin pigmentation. Studies performed pre-COVID-19 have shown significant but modest reduction in upper respiratory infections in people receiving regular daily vitamin D supplementation. Vitamin D deficiency, like the risk of severe COVID-19, is linked with darker skin colour and also with obesity. Greater risk from COVID-19 has been associated with reduced ultraviolet exposure. Various studies have examined serum 25-hydroxyvitamin D levels, either historical or current, in patients with COVID-19. The results of these studies have varied but the majority have shown an association between vitamin D deficiency and increased risk of COVID-19 illness or severity. Interventional studies of vitamin D supplementation have so far been inconclusive. Trial protocols commonly allow control groups to receive low-dose supplementation that may be adequate for many. The effects of vitamin D supplementation on disease severity in patients with existing COVID-19 are further complicated by the frequent use of large bolus dose vitamin D to achieve rapid effects, even though this approach has been shown to be ineffective in other settings. As the pandemic passes into its third year, a substantial role of vitamin D deficiency in determining the risk from COVID-19 remains possible but unproven.

Disentangling direct and indirect effects of landscape structure on urban bird richness and functional diversity.

As fragmented landscapes become increasingly common around the world, managing the spatial arrangement of landscape elements (i.e., landscape configuration) may help to promote the conservation of biodiversity. However, the relative effects of landscape configuration on different dimensions of biodiversity across species assemblages are largely unknown. Thus, a key challenge consists in understanding when it is necessary to focus on landscape configuration, in addition to landscape composition, to achieve multifunctional landscapes. We tested the effects of landscape composition (the percentage of tree cover and built infrastructure) and landscape configuration (degree of fragmentation) on landscape-level species richness and different metrics of functional diversity of urban birds. We collected data on different bird guilds (nectarivores/frugivores, insectivores) from Brisbane, Australia. Using structural equation models, we found that landscape structure (landscape composition and configuration) affected functional diversity via two main pathways: (1) through effects of landscape composition, mediated by landscape configuration (indirect effects), and (2) through direct ("independent") effects of landscape composition and configuration, filtering species with extreme trait values. Our results show that landscape-level species richness declined with the extent of built infrastructure, but patterns of trait diversity did not necessarily correlate with this variable. Landscape configuration had a stronger mediating effect on some metrics of the functional diversity of insectivores than on the functional diversity of frugivores/nectarivores. In addition, fragmentation increased the effects of built infrastructure for some traits (body size and dispersal capacity), but not for others (habitat plasticity and foraging behavior). These results suggest that differential approaches to managing landscape structure are needed depending on whether the focus is on protecting functional diversity or species richness and what the target guild is. Managing landscape fragmentation in areas with high levels of built infrastructure is important if the objective is to protect insectivore species with uncommon traits, even if it is not possible to preserve high levels of species richness. However, if the target is to enhance both functional diversity and species richness of multiple guilds, the focus should be on improving composition through the reduction of negative effects of built infrastructure, rather than promoting specific landscape configurations in growing cities.

How to prioritize species recovery after a megafire.

Due to climate change, megafires are increasingly common and have sudden, extensive impacts on many species over vast areas, leaving decision makers uncertain about how best to prioritize recovery. We devised a decision-support framework to prioritize conservation actions to improve species outcomes immediately after a megafire. Complementary locations are selected to extend recovery actions across all fire-affected species' habitats. We applied our method to areas burned in the 2019-2020 Australian megafires and assessed its conservation advantages by comparing our results with outcomes of a site-richness approach (i.e., identifying areas that cost-effectively recover the most species in any one location). We found that 290 threatened species were likely severely affected and will require immediate conservation action to prevent population declines and possible extirpation. We identified 179 subregions, mostly in southeastern Australia, that are key locations to extend actions that benefit multiple species. Cost savings were over AU$300 million to reduce 95% of threats across all species. Our complementarity-based prioritization also spread postfire management actions across a wider proportion of the study area compared with the site-richness method (43% vs. 37% of the landscape managed, respectively) and put more of each species' range under management (average 90% vs. 79% of every species' habitat managed). In addition to wildfire response, our framework can be used to prioritize conservation actions that will best mitigate threats affecting species following other extreme environmental events (e.g., floods and drought).

Debido al cambio climático, los mega incendios son cada vez más comunes y tienen un impacto repentino y extenso sobre muchas especies en inmensas superficies, lo que deja a los tomadores de decisiones con incertidumbre sobre cuál es la mejor manera de priorizar la recuperación. Diseñamos un marco de apoyo a las decisiones para priorizar las acciones de conservación para mejorar los resultados para las especies inmediatamente después de un mega incendio. Para esto, se seleccionan localidades complementarias para extender las acciones de recuperación por todos los hábitats de las especies afectadas por el incendio. Aplicamos nuestro método a las áreas afectadas por los mega incendios de 2019-2020 en Australia y analizamos las ventajas de conservación del método mediante la comparación entre nuestros resultados y aquellos de un enfoque en la riqueza de especies (es decir, la identificación de las áreas que recuperan de manera rentable la mayor cantidad de especies en cualquier localidad única). Encontramos que 290 especies amenazadas estuvieron probablemente afectadas de manera severa y requerirán acciones inmediatas de conservación para prevenir la declinación poblacional y la posible eliminación. Identificamos 179 subregiones, la mayoría en el sureste de Australia, que son localidades clave para extender las acciones que benefician a muchas especies. El ahorro en los gastos fue de más de AU$300 millones para reducir el 95% de las amenazas para todas las especies. Nuestra priorización basada en la complementariedad también extendió las acciones de manejo posterior al incendio a una mayor proporción del área de estudio en comparación con el método de riqueza de especies (43% versus 37% del paisaje gestionado, respectivamente) y colocó más de la distribución de cada especie bajo manejo (en promedio 90% versus 79% del hábitat manejado de cada especie). Además de la respuesta a los incendios, nuestro marco puede usarse para priorizar las acciones de conservación que mitiguen de mejor manera las amenazas que afectan a las especies después de otros eventos ambientales extremos (p. ej., inundaciones y sequía).

The synapse in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and is a risk factor for dementia later in life. Research into the pathophysiology of TBI has focused on the impact of injury on the neuron. However, recent advances have shown that TBI has a major impact on synapse structure and function through a combination of the immediate mechanical insult and the ensuing secondary injury processes, leading to synapse loss. In this review, we highlight the role of the synapse in TBI pathophysiology with a focus on the confluence of multiple secondary injury processes including excitotoxicity, inflammation and oxidative stress. The primary insult triggers a cascade of events in each of these secondary processes and we discuss the complex interplay that occurs at the synapse. We also examine how the synapse is impacted by traumatic axonal injury and the role it may play in the spread of tau after TBI. We propose that astrocytes play a crucial role by mediating both synapse loss and recovery. Finally, we highlight recent developments in the field including synapse molecular imaging, fluid biomarkers and therapeutics. In particular, we discuss advances in our understanding of synapse diversity and suggest that the new technology of synaptome mapping may prove useful in identifying synapses that are vulnerable or resistant to TBI.

Isometric Exercise Increases the Diameter of the Ascending Aorta in Youth with Bicuspid Aortic Valves.

Central arterial pressure rises to much higher levels during heavy isometric exercise compared to other forms of exercise. For this reason, patients with bicuspid aortic valves (BAV) are often restricted from heavy isometric exercise. Although this approach may be theoretically appealing, no data exist regarding the efficacy of this activity restriction.Patients between 12 and 21 years old with isolated BAV were enrolled if they had a previous echocardiogram at least 2 years prior to the current clinic visit. Patients were excluded if they had additional congenital heart disease, a diagnosed syndrome, or had undergone a procedure involving the aortic valve or ascending aorta. Patients completed a questionnaire regarding frequency and intensity of isometric exercise during the 3-month period prior to the visit. We compared aortic dimensions (Z-score), aortic stenosis, and aortic insufficiency between an echocardiogram performed as part of the current visit and one obtained 2-5 years previously using paired t tests and multivariable regression controlling for age, gender, degree of aortic stenosis, and the presence of isometric exercise. In this sample of 50 adolescents with isolated bicuspid aortic valve, 30 (60%) subjects did not participate in any isometric exercise. Over an average of 2.9 years (SD 0.9 years), we did not find a significant difference between changes in the Z-score diameters of the aortic root (0.9 vs 0.9, p = 0.913) and ascending aorta Z-score (2.9 vs 2.9, p = 0.757), between subjects engaging and not engaging in isometric exercise. Further, we did not find that changes in valve function (i.e., aortic stenosis and aortic insufficiency) differed between the two groups.In this sample of adolescents with isolated bicuspid aortic valve, there was no medium-term increase in aortic dilation or worsening valve function in those who engaged in isometric exercise versus those who refrained from isometric exercise.

Assessment of Exercise Function in Children and Young Adults with Hypertrophic Cardiomyopathy and Correlation with Transthoracic Echocardiographic Parameters.

Exercise function is well characterized in adults with hypertrophic cardiomyopathy (HCM); however, there is a paucity of data in children and young adults with HCM. Here we sought to characterize exercise function in young people with HCM, understand limitations in exercise function by correlating exercise function parameters with echocardiogram parameters and identify prognostic value of exercise parameters. We performed a retrospective, single-center cohort study characterizing exercise function in patients < 26 years old with HCM undergoing cardiopulmonary exercise testing (CPET). Patients with syndromic HCM or submaximal effort were excluded. We compared exercise function in this cohort to population normal values and measured changes in exercise function over time. We correlated exercise function parameters with echocardiographic parameters and investigated the relationship between exercise test parameters and a clinical composite outcome comprised of significant ventricular arrhythmia, death, or heart transplantation. We identified 229 CPETs performed by 117 patients (mean age at time of first CPET 15.6 ± 3.2 years). Mean %-predicted peak VO2, O2 pulse, and peak heart rate were statistically significantly depressed compared to population normal values and exercise function gradually worsened over time. Abnormal exercise testing correlated closely with echocardiographic indices of diastolic dysfunction. There was a trend toward increased incidence of poor clinical outcome in patients with abnormal exercise function. While adverse clinical outcomes were rare, normal exercise function appears to be a marker of low risk for adverse clinical outcomes in this population.

Appearance of peanut agglutinin in the blood circulation after peanut ingestion promotes endothelial secretion of metastasis-promoting cytokines.

Peanut agglutinin (PNA) is a carbohydrate-binding protein in peanuts that accounts for ~0.15% peanut weight. PNA is highly resistant to cooking and digestion and is rapidly detectable in the blood after peanut consumption. Our previous studies have shown that circulating PNA mimics the actions of endogenous galactoside-binding protein galectin-3 by interaction with tumour cell-associated MUC1 and promotes circulating tumour cell metastatic spreading. The present study shows that circulating PNA interacts with micro- as well as macro-vascular endothelial cells and induces endothelial secretion of cytokines MCP-1 (CCL2) and IL-6 in vitro and in vivo. The increased secretion of these cytokines autocrinely/paracrinely enhances the expression of endothelial cell surface adhesion molecules including integrins, VCAM and selectin, leading to increased tumour cell-endothelial adhesion and endothelial tubule formation. Binding of PNA to endothelial surface MCAM (CD146), via N-linked glycans, and subsequent activation of PI3K-AKT-PREAS40 signalling is here shown responsible for PNA-induced secretion of MCP-1 and IL-6 by vascular endothelium. Thus, in addition to its influence on promoting tumour cell spreading by interaction with tumour cell-associated MUC1, circulating PNA might also influence metastasis by enhancing the secretion of metastasis-promoting MCP-1 and IL-6 from the vascular endothelium.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn's Disease.

BACKGROUND: Increased mucosa-associated E. coli are present in Crohn's disease, but their role in pathogenesis is uncertain. AIMS: To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. METHODS: Adults with moderately active disease (CDAI > 220-450 plus C reactive protein ≥ 5 mg/l and/or fecal calprotectin > 250 µg/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI ≤ 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. RESULTS: Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. CONCLUSION: Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

Exercise Capacity and Predictors of Performance After Fontan: Results from the Pediatric Heart Network Fontan 3 Study.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network's Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO2) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO2 declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO2 tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO2 at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO2 at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO2 at VAT was better preserved than peak VO2 across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.

Better preoperative exercise function is associated with shorter hospital stay after paediatric pulmonary valve replacement or conduit revision.

Exercise capacity is a modifiable factor in patients with CHD that has been related to surgical outcomes in adults. We hypothesised that this was true for children undergoing surgical pulmonary valve replacement; therefore, the relationship of preoperative percent predicted peak oxygen consumption to surgical outcomes as measured by total hospital length of stay was explored. METHODS: Single centre retrospective cohort study of patients aged 8-18 years who underwent surgical pulmonary valve replacement. The primary predictor was preoperative percent predicted peak oxygen consumption, and primary outcome was total hospital length of stay. Clinical, imaging, and cardiopulmonary exercise test data were reviewed and compared to total hospital length of stay. Cox proportional hazards regression was used to examine the association between total hospital length of stay and percent predicted peak oxygen consumption. RESULTS: Three-hundred and seventy patients undergoing pulmonary valve replacement/conduit change between 2003 and 2017 at Boston Children's Hospital were identified. Ninety had preoperative cardiopulmonary exercise tests within 6 months of surgery. Exclusion for inadequate exercise data (n = 3) and imaging data (n = 1) left 86 patients for review. Patients with percent predicted peak oxygen consumption ≥ 70% (n = 46, 53%) had shorter total hospital length of stay (4.4 days) than the 40 with percent predicted peak oxygen consumption <70% (5.4 days, p = 0.007). Median percent predicted peak oxygen consumption increased over sequential surgical eras (p < 0.001), but total hospital length of stay did not correlate with surgical era, preoperative left ventricular function, or preoperative right ventricular dilation. CONCLUSION: Children undergoing surgical pulmonary valve replacement with better preoperative exercise capacity had shorter total hospital length of stay. Exercise capacity is a potentially modifiable factor prior to and after pulmonary valve replacement. Until more patients systematically undergo cardiopulmonary exercise tests, the full impact of optimisation of exercise capacity will not be known.