Limited increases in savanna carbon stocks over decades of fire suppression.

Savannas cover a fifth of the land surface and contribute a third of terrestrial net primary production, accounting for three-quarters of global area burned and more than half of global fire-driven carbon emissions1-3. Fire suppression and afforestation have been proposed as tools to increase carbon sequestration in these ecosystems2,4. A robust quantification of whole-ecosystem carbon storage in savannas is lacking however, especially under altered fire regimes. Here we provide one of the first direct estimates of whole-ecosystem carbon response to more than 60 years of fire exclusion in a mesic African savanna. We found that fire suppression increased whole-ecosystem carbon storage by only 35.4 ± 12% (mean ± standard error), even though tree cover increased by 78.9 ± 29.3%, corresponding to total gains of 23.0 ± 6.1 Mg C ha-1 at an average of about 0.35 ± 0.09 Mg C ha-1 year-1, more than an order of magnitude lower than previously assumed4. Frequently burned savannas had substantial belowground carbon, especially in biomass and deep soils. These belowground reservoirs are not fully considered in afforestation or fire-suppression schemes but may mean that the decadal sequestration potential of savannas is negligible, especially weighed against concomitant losses of biodiversity and function.

Ibrutinib as part of risk-stratified treatment for post-transplant lymphoproliferative disorder: The phase 2 TIDaL trial.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, patients with low-risk disease following initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly-diagnosed CD20-positive B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline international prognostic index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to R-CHOP immunochemotherapy, ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11/38 patients (29%, 95% confidence interval (CI) 15% - 46%). This did not reach the pre-specified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%, 95% CI 44% - 76%), and 2-year overall survival (76%, 95% CI 63% - 91%). Adverse events were mostly haematological, gastrointestinal and infective. Whilst TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered as ISRCTN32667607.

A neuropeptide signal confers ethanol state dependency during olfactory learning in Caenorhabditis elegans.

Alcohol intoxication can impact learning and this may contribute to the development of problematic alcohol use. In alcohol (ethanol)-induced state-dependent learning (SDL), information learned while an animal is intoxicated is recalled more effectively when the subject is tested while similarly intoxicated than if tested while not intoxicated. When Caenorhabditis elegans undergoes olfactory learning (OL) while intoxicated, the learning becomes state dependent such that recall of OL is only apparent if the animals are tested while intoxicated. We found that two genes known to be required for signal integration, the secreted peptide HEN-1 and its receptor tyrosine kinase, SCD-2, are required for SDL. Expression of hen-1 in the ASER neuron and scd-2 in the AIA neurons was sufficient for their functions in SDL. Optogenetic activation of ASER in the absence of ethanol during learning could confer ethanol state dependency, indicating that ASER activation is sufficient to signal ethanol intoxication to the OL circuit. To our surprise, ASER activation during testing did not substitute for ethanol intoxication, demonstrating that the effects of ethanol on learning and recall rely on distinct signals. Additionally, intoxication-state information could be added to already established OL, but state-dependent OL did not lose state information when the intoxication signal was removed. Finally, dopamine is required for state-dependent OL, and we found that the activation of ASER cannot bypass this requirement. Our findings provide a window into the modulation of learning by ethanol and suggest that ethanol acts to modify learning using mechanisms distinct from those used during memory access.

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Genomic profiling for clinical decision making in lymphoid neoplasms.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

The challenge of estimating global termite methane emissions.

Methane is a powerful greenhouse gas, more potent than carbon dioxide, and emitted from a variety of natural sources including wetlands, permafrost, mammalian guts and termites. As increases in global temperatures continue to break records, quantifying the magnitudes of key methane sources has never been more pertinent. Over the last 40 years, the contribution of termites to the global methane budget has been subject to much debate. The most recent estimates of termite emissions range between 9 and 15 Tg CH4 year-1, approximately 4% of emissions from natural sources (excluding wetlands). However, we argue that the current approach for estimating termite contributions to the global methane budget is flawed. Key parameters, namely termite methane emissions from soil, deadwood, living tree stems, epigeal mounds and arboreal nests, are largely ignored in global estimates. This omission occurs because data are lacking and research objectives, crucially, neglect variation in termite ecology. Furthermore, inconsistencies in data collection methods prohibit the pooling of data required to compute global estimates. Here, we summarise the advances made over the last 40 years and illustrate how different aspects of termite ecology can influence the termite contribution to global methane emissions. Additionally, we highlight technological advances that may help researchers investigate termite methane emissions on a larger scale. Finally, we consider dynamic feedback mechanisms of climate warming and land-use change on termite methane emissions. We conclude that ultimately the global contribution of termites to atmospheric methane remains unknown and thus present an alternative framework for estimating their emissions. To significantly improve estimates, we outline outstanding questions to guide future research efforts.

The role of specialist palliative care in individuals "living beyond cancer": a narrative review of the literature.

PURPOSE: Many patients living beyond cancer experience significant unmet needs, although few of these patients are currently reviewed by specialist palliative care teams (SPCTs). The aim of this narrative review was to explore the current and potential role of SPCTs in this cohort of patients. METHODS: A search strategy was developed for Medline, and adapted for Embase, CINAHL, and PsycInfo. Additionally, websites of leading oncology, cancer survivorship, and specialist palliative care organisations were examined. The focus of the search was on individuals living beyond cancer rather than other groups of cancer survivors. RESULTS: 111 articles were retrieved from the search for full text review, and 101 other sources of information were identified after hand searching the reference lists of the full text articles, and the aforesaid websites. The themes of the review encompass the definition of palliative care/specialist palliative care, current models of specialist palliative care, core activities of SPCTs, relevant expertise of SPCTs, and potential barriers to change in relation to extending their support and expertise to individuals living beyond cancer. The review identified a paucity of evidence to support the role of SPCTs in the management of patients living beyond cancer. CONCLUSIONS: Individuals living beyond cancer have many unmet needs, and specific services are required to manage these problems. Currently, there is limited evidence to support the role of specialist palliative care teams in the management of this cohort of people, and several potential barriers to greater involvement, including limited resources, and lack of relevant expertise.

Clinical features of audible upper airway secretions ("death rattle") in patients with cancer in the last days of life.

PURPOSE: Audible upper airway secretions ("death rattle") is a common problem in cancer patients at the end-of-life. However, there is little information about its clinical features. METHODS: This is a secondary analysis of a cluster randomised trial of clinically-assisted hydration in cancer patients in the last days of life. Patients were assessed 4 hourly for end-of-life problems (including audible secretions), which were recorded as present or absent, excepting restlessness/agitation, which was scored using the modified Richmond Agitation and Sedation Scale. Patients were followed up until death. RESULTS: 200 patients were recruited, and 186 patients died during the study period. Overall, 54.5% patients developed audible secretions at some point during the study, but only 34.5% patients had audible secretions at the time of death. The prevalence of audible secretions increased the closer to death, with a marked increase in the last 12-16 h of life (i.e. the prevalence of audible secretions was highest at the time of death). Of those with audible secretions at the time of death, 24 had had a previous episode that had resolved. Development of audible secretions was not associated with use of clinically-assisted hydration, but there was an association between audible secretions and restlessness/agitation, and audible secretions and pain. However, most patients with audible secretions were not restless/agitated, or in pain, when assessed. CONCLUSION: Audible secretions ("death rattle") are common in cancer patients at the end-of-life, but their natural history is extremely variable, with some patients experiencing multiple episodes during the terminal phase (although not necessarily experiencing an episode at the time of death).

Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted hydration in patients with advanced cancer.

PURPOSE: The provision of clinically assisted hydration (CAH) in patients with advanced cancer is controversial, and there is a paucity of specific guidance and so a diversity in clinical practice. Consequently, the Palliative Care Study Group of the Multinational Association of Supportive Care in Cancer (MASCC) formed a sub-group to develop evidence-based guidance on the use of CAH in patients with advanced cancer. METHODS: This guidance was developed in accordance with the MASCC Guidelines Policy. A search strategy for Medline was developed, and the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were explored for relevant reviews/trials, respectively. RESULTS: Due to the paucity of evidence, the sub-group was not able to develop a prescribed guideline, but was able to generate a number of "expert opinion statements": these statements relate to assessment of patients, indications for CAH, contraindications for CAH, procedures for initiating CAH, and reassessment of patients. CONCLUSIONS: This guidance provides a framework for the use of CAH in advanced cancer, although every patient requires individualised management.

Patient-reported outcomes following total shoulder arthroplasty and hemiarthroplasty: an analysis of data from the National Joint Registry.

BACKGROUND: Total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) are used in the management of end-stage glenohumeral arthritis. Improvement in shoulder function and resolution of symptoms are high priorities for patients. The aim of this study was to compare patient-reported outcome measures (PROMs) following TSA and HA. METHODS: Records from the National Joint Registry of England, Wales, Northern Ireland, and the Isle of Man were linked to the PROMs data set. The study included anatomic shoulder arthroplasties performed for osteoarthritis in patients with an intact rotator cuff. Patients with preoperative and postoperative Oxford Shoulder Scores (OSSs) were included. The improvement in OSS at 6 months and 5 years and the trend in scores over time were analyzed for each prosthesis. A cohort of 2002 patients were matched on 10 variables using propensity scores. OSSs at 6 months following TSA vs. HA were compared in the matched sample. RESULTS: There was a significant improvement in the OSS in both groups (P < .001). At 6 months, the OSSs were superior following TSA compared with HA (median 42 vs. 36, P < .001). The median score at 5 years was 44 following TSA and 35 following HA. Score distributions were skewed toward the maximum score. The highest possible score (48) was achieved in 28% (134 of 478) of TSAs and 9% (20 of 235) of HAs at 5 years. The improvement in the preoperative to 6-month OSS reached the minimal clinically important difference of 5.5 in 92% (1653 of 1792) of TSAs and in 80% (416 of 523) of HAs. At 5 years, this improvement was maintained in 91% (339 of 374) of TSAs and 78% (136 of 174) of HAs. CONCLUSION: TSA resulted in superior OSSs at 6 months in patients with osteoarthritis. The median OSS improved from 6 months to 5 years following TSA; however, there was a small decline in scores following HA. A ceiling effect was shown in the OSS following TSA at 5 years.

The risk of revision is higher following shoulder hemiarthroplasty compared with total shoulder arthroplasty for osteoarthritis: a matched cohort study of 11,556 patients from the National Joint Registry, UK.

BACKGROUND AND PURPOSE: Total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) are used in the management of osteoarthritis of the glenohumeral joint. We aimed to determine whether TSA or HA resulted in a lower risk of adverse outcomes in patients of all ages with osteoarthritis and an intact rotator cuff and in a subgroup of patients aged 60 years or younger. PATIENTS AND METHODS: Shoulder arthroplasties recorded in the National Joint Registry, UK, between April 1, 2012 and June 30, 2021, were linked to Hospital Episode Statistics in England. Elective TSAs and HAs were matched on propensity scores based on 11 variables. The primary outcome was all-cause revision. Secondary outcomes were combined revision/non-revision reoperations, 30-day inpatient complications, 1-year mortality, and length of stay. 95% confidence intervals (CI) were reported. RESULTS: 11,556 shoulder arthroplasties were included: 7,641 TSAs, 3,915 HAs. At 8 years 95% (CI 94-96) of TSAs and 91% (CI 90-92) of HAs remained unrevised. The hazard ratio (HR) varied across follow-up: 4-year HR 2.7 (CI 1.9-3.5), 8-year HR 2.0 (CI 0.5-3.5). Rotator cuff insufficiency was the most common revision indication. In patients aged 60 years or younger prosthesis survival at 8 years was 92% (CI 89-94) following TSA and 84% (CI 80-87) following HA. CONCLUSION: The risk of revision was higher following HA in patients with osteoarthritis and an intact rotator cuff. Patients aged 60 years and younger had a higher risk of revision following HA.

Effect of preservation of Hoffa's fat pad on patellar height in primary total knee arthroplasty procedures.

BACKGROUND: We have previously reported our experience of the effect of complete excision of Hoffa's fat pad on patella height post TKR. In this study, we compared the change of patellar height post TKR before and after the senior author changed his practice to preserving Hoffa's fat pad. METHODS: This was a retrospective analysis of a prospective series of TKRs performed or directly supervised by the senior author. In Group 1 were 72 patients performed before April 2011 who had complete excision of Hoffa's fat pad to maximise exposure during the procedure. In Group 2 were 138 patients performed after April 2011 who had the minimum excision of Hoffa's fat pad to allow adequate surgical exposure. The surgical technique and rehabilitation protocol were identical in all other respects. Patellar height was assessed using the Caton-Deschamps Index both immediately postoperative and at a minimum follow up of 1 year. RESULTS: Group 1 included 28 males, 44 females with mean age 68.36 years. The mean CDI in this group changed from 0.54 immediately post-operatively to 0.46 at minimum one year follow-up (P = 0.001) indicating progressive patella baja. Group 2 included 56 males, 82 females with mean age 65 years. The mean CDI changed from 0.67 immediately post-operative to 0.68 at minimum one year post follow-up (P = 0.32) indicating no statistically or clinically relevant post-operative change in patellar height. CONCLUSION: Total excision of Hoffa's fat pad is associated with progressive post-operative patella baja. This can be avoided by resecting the minimum amount of fat pad to allow adequate exposure during the procedure.

Feedback loops between 3D vegetation structure and ecological functions of animals.

Ecosystems function in a series of feedback loops that can change or maintain vegetation structure. Vegetation structure influences the ecological niche space available to animals, shaping many aspects of behaviour and reproduction. In turn, animals perform ecological functions that shape vegetation structure. However, most studies concerning three-dimensional vegetation structure and animal ecology consider only a single direction of this relationship. Here, we review these separate lines of research and integrate them into a unified concept that describes a feedback mechanism. We also show how remote sensing and animal tracking technologies are now available at the global scale to describe feedback loops and their consequences for ecosystem functioning. An improved understanding of how animals interact with vegetation structure in feedback loops is needed to conserve ecosystems that face major disruptions in response to climate and land-use change.

Textbook Oncological Outcome in European GASTRODATA.

OBJECTIVE: To assess the rate of textbook outcome (TO) and textbook oncological outcome (TOO) in the European population based on the GASTRODATA registry. BACKGROUND: TO is a composite parameter assessing surgical quality and strongly correlates with improved overall survival. Following the standard of treatment for locally advanced gastric cancer, TOO was proposed as a quality and optimal multimodal treatment parameter. METHODS: TO was achieved when all the following criteria were met: no intraoperative complications, radical resection according to the surgeon, pR0 resection, retrieval of at least 15 lymph nodes, no severe postoperative complications, no reintervention, no admission to the intensive care unit, no prolonged length of stay, no postoperative mortality and no hospital readmission. TOO was defined as TO with the addition of perioperative chemotherapy compliance. RESULTS: Of the 2558 patients, 1700 were included in the analysis. TO was achieved in 1164 (68.5%) patients. The use of neoadjuvant chemotherapy [odds ratio (OR) = 1.33, 95% CI: 1.04-1.70] and D2 or D2+ lymphadenectomy (OR = 1.55, 95% CI: 1.15-2.10) had a positive impact on TO achievement. Older age (OR = 0.73, 95% CI: 0.54-0.94), pT3/4 (OR = 0.79, 95% CI: 0.63-0.99), ASA 3/4 (OR = 0.68, 95% CI: 0.54-0.86) and total gastrectomy (OR = 0.56, 95% CI: 0.45-0.70), had a negative impact on TO achievement. TOO was achieved in 388 (22.8%) patients. Older age (OR = 0.37, 95% CI: 0.27-0.53), pT3 or pT4 (OR = 0.52, 95% CI: 0.39-0.69), and ASA 3 or 4 (OR = 0.58, 95% CI: 0.43-0.79) had a negative impact on TOO achievement. CONCLUSIONS: Despite successively improved surgical outcomes, stage-appropriate chemotherapy in adherence to the current guidelines for multimodal treatment of gastric cancer remains poor. Further implementation of oncologic quality metrics should include greater emphasis on perioperative chemotherapy and adequate lymphadenectomy.

Enhanced Zika virus-like particle development using Baculovirus spp. constructs.

Zika virus (ZIKV) is one of several examples of an unprecedented pandemic spread and against which there is currently no suitable vaccine or treatment. Here, we constructed and characterized recombinant baculovirus-derived ZIKV-like particles (Zika VLPs) to study ZIKV-antibody interactions. These VLPs, uniquely consisted of the full-length ZIKV capsid (C), pre-membrane (prM), and envelope (E) proteins with either: a) the viral nonstructural NS2B and NS3 protease unit under one or two different promoters or b) an alternative host-cell furin protease encoding cleavage sequence inserted between the C and prM genes, together with lobster tropomyosin leader and honeybee signal sequences with one promoter for increased extracellular secretion. All these Zika VLPs displayed typical virion morphology in transmission electron microscopic analysis when expressed in both insect (Sf9) and mammalian (HEK293T) cells and no uncleaved prM glycoprotein was detected, as are present on immature virions. The importance of glycosylation of the E glycoprotein was shown by the effects on both polyclonal and monoclonal antibody reactions after these N-linked carbohydrate residues were disrupted by oxidation or enzymatic cleavage. Importantly, the construct which contained the host-cell furin protease cleavage sequence together with a lobster tropomyosin leader and honeybee signal sequences under one promoter produced higher Zika VLP titers and protein concentrations and which can now be tested as a superior construct in multifunctional diagnostic (ELISA and neutralization/antibody-dependent enhancement) assays and immunogenic assessments possibly leading to vaccine trials.

Oxygen treatment reduces neurological deficits and demyelination in two animal models of multiple sclerosis.

AIMS: The objective of the study is to explore the importance of tissue hypoxia in causing neurological deficits and demyelination in the inflamed CNS, and the value of inspiratory oxygen treatment, using both active and passive experimental autoimmune encephalomyelitis (EAE). METHODS: Normobaric oxygen treatment was administered to Dark Agouti rats with either active or passive EAE, compared with room air-treated, and naïve, controls. RESULTS: Severe neurological deficits in active EAE were significantly improved after just 1 h of breathing approximately 95% oxygen. The improvement was greater and more persistent when oxygen was applied either prophylactically (from immunisation for 23 days), or therapeutically from the onset of neurological deficits for 24, 48, or 72 h. Therapeutic oxygen for 72 h significantly reduced demyelination and the integrated stress response in oligodendrocytes at the peak of disease, and protected from oligodendrocyte loss, without evidence of increased oxidative damage. T-cell infiltration and cytokine expression in the spinal cord remained similar to that in untreated animals. The severe neurological deficit of animals with passive EAE occurred in conjunction with spinal hypoxia and was significantly reduced by oxygen treatment initiated before their onset. CONCLUSIONS: Severe neurological deficits in both active and passive EAE can be caused by hypoxia and reduced by oxygen treatment. Oxygen treatment also reduces demyelination in active EAE, despite the autoimmune origin of the disease.

Applying landscape metrics to species distribution model predictions to characterize internal range structure and associated changes.

Distributional shifts in species ranges provide critical evidence of ecological responses to climate change. Assessments of climate-driven changes typically focus on broad-scale range shifts (e.g. poleward or upward), with ecological consequences at regional and local scales commonly overlooked. While these changes are informative for species presenting continuous geographic ranges, many species have discontinuous distributions-both natural (e.g. mountain or coastal species) or human-induced (e.g. species inhabiting fragmented landscapes)-where within-range changes can be significant. Here, we use an ecosystem engineer species (Sabellaria alveolata) with a naturally fragmented distribution as a case study to assess climate-driven changes in within-range occupancy across its entire global distribution. To this end, we applied landscape ecology metrics to outputs from species distribution modelling (SDM) in a novel unified framework. SDM predicted a 27.5% overall increase in the area of potentially suitable habitat under RCP 4.5 by 2050, which taken in isolation would have led to the classification of the species as a climate change winner. SDM further revealed that the latitudinal range is predicted to shrink because of decreased habitat suitability in the equatorward part of the range, not compensated by a poleward expansion. The use of landscape ecology metrics provided additional insights by identifying regions that are predicted to become increasingly fragmented in the future, potentially increasing extirpation risk by jeopardising metapopulation dynamics. This increased range fragmentation could have dramatic consequences for ecosystem structure and functioning. Importantly, the proposed framework-which brings together SDM and landscape metrics-can be widely used to study currently overlooked climate-driven changes in species internal range structure, without requiring detailed empirical knowledge of the modelled species. This approach represents an important advancement beyond predictive envelope approaches and could reveal itself as paramount for managers whose spatial scale of action usually ranges from local to regional.

Metabolic tumour and nodal response to neoadjuvant chemotherapy on FDG PET-CT as a predictor of pathological response and survival in patients with oesophageal adenocarcinoma.

OBJECTIVES: 2-deoxy-2[18F]Fluoro-D-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting pathological tumour response (pTR), pathological nodal response (pNR) and survival. METHODS: Cohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy's and St Thomas' NHS Foundation Trust, London (2017-2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUVmax thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUVmax reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression. RESULTS: Optimum tumour SUVmax decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve [AUC] 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUVmax threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%, p = 0.010). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio [HR] 0.10 95% confidence interval [CI] 0.03-0.34; mTR HR 0.17 95% CI 0.06-0.48; pNR HR 0.17 95% CI 0.06-0.54; mNR HR 0.13 95% CI 0.02-0.66). CONCLUSIONS: Metabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival. KEY POINTS: • FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer. • Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection. • Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence.

Resistance of termite mounds to variation in long-term fire regimes across semi-arid African savannas.

Fire regimes are expected to change with climate change, resulting in a crucial need to understand the specific ways in which variable fire regimes impact important contributors to ecosystem functioning, such as mound-building termites. Termite mounds and fire are both important agents of savanna ecosystem heterogeneity and functioning, but there is little understanding of how they interact across savanna types. We used very high-resolution LiDAR remote sensing to measure the size and distribution of termite mounds across approximately 1300 ha of experimental burn plots in four South African savanna landscapes representing a wide range of fire treatments differing in seasonality and frequency of burning. In nutrient-poor granitic savannas, fire had no impact on termite mound size, densities and spatial distributions. In nutrient-rich basaltic savannas with high mammalian herbivore abundance and intermediate rainfall, very frequent fires caused a decrease in termite mound size, whereas in arid nutrient-rich basaltic savannas, fires that occurred at intermediate frequencies and in transitional seasons (i.e. late dry season and late wet season) decreased the degree of spatial overdispersal exhibited by mounds. Overall, our results suggest that termite mounds are resistant to variation in fire seasonality and frequency, likely indicating that ecosystem services provided by mound-building termites will be unaffected by changing fire regimes. However, consideration of changes to termite mound size and distribution could be necessary for land managers in specific savanna types, such as nutrient-rich soils with high mammalian herbivore abundance.

Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep.

PURPOSE: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization. METHODS: We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups. RESULTS: Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide. CONCLUSIONS: Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose.