Observers are a key source of detection heterogeneity and biased occupancy estimates in species monitoring

Reliable assessments of population status and trends underpin conservation management efforts but are complicated by the fact that imperfect detection is ubiquitous in monitoring data. We explore the most commonly considered variables believed to influence detection probabilities, quantifying how they influence detectability and assessing how occupancy rates are impacted when a variable is ignored. To do so, we used data from two multi-species amphibian monitoring programmes, collected by volunteers and professional surveyors. Our results suggest that although detection rates varied substantially in relation to commonly considered factors such as seasonal and annual effects, ignoring these factors in the analysis of monitoring data had negligible effect on estimated occupancy rates. Variation among surveyors in detection probabilities turned out to be most important. It was high and failing to account for it led to occupancy being underestimated. Importantly, we identified that heterogeneity among observers was as high for professional surveyors as for volunteers, highlighting that this issue is not restricted to citizen-science monitoring. Occupancy modelling has greatly improved the reliability of inference from species monitoring data, yet capturing the relevant sources of variation remains a challenge. Our results highlight that variation among surveyors is a key source of heterogeneity, and that this issue is just as pertinent to data collected by experts as by volunteers. Detection heterogeneity should be accounted for when analysing monitoring data. Furthermore, efforts to increase training of field crews and collecting data to quantify differences between observer abilities are important to avoid biased inference resulting from unmodelled observer differences

Boost in Visitor Numbers Post COVID-19 Shutdown: Consequences for an Alpine National Park

The coronavirus disease 2019 (COVID-19) pandemic changed recreation patterns worldwide. Increases in protected areas' visitor numbers were reported along with associated challenges. Changes in visitor numbers, composition, and motivation remain mostly unrecorded due to a lack of baseline records for comparison. We aimed to fill this gap with a study in the Swiss National Park (SNP), an International Union for Conservation of Nature (IUCN) strict nature reserve in the European Alps, where visitor numbers strongly increased in 2020 and 2021 compared to previous years. In summer 2020, we repeated a visitor survey previously conducted in 2006 and 2012, complemented by assessments of COVID-19-related motivations. To deepen our understanding of the COVID-19 context, we conducted semistructured interviews with SNP visitors. In general, COVID-19-related factors were a strong driver of increased visitor numbers. A fifth of survey respondents indicated that they would not have visited the SNP but for the pandemic, with most of them being first-time or infrequent visitors. Furthermore, our data showed that more young, domestic, and less experienced visitors came to the park. We discuss impacts and implications for practitioners and researchers (ie the need to better sensitize newcomers to environmental issues) and argue that our study holds insights for park managers worldwide

Quantitative Evidence for the Effects of Multiple Drivers on Continental-Scale Amphibian Declines

Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early search for a “smoking gun” was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed

Quantitative Evidence for the Effects of Multiple Drivers on Continental-Scale Amphibian Declines

Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early search for a “smoking gun” was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed

Quantitative evidence for the effects of multiple drivers on continental-scale amphibian declines.

Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early search for a "smoking gun" was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse