Carbon and climate implications of rewetting a raised bog in Ireland.

Peatland rewetting has been proposed as a vital climate change mitigation tool to reduce greenhouse gas emissions and to generate suitable conditions for the return of carbon (C) sequestration. In this study, we present annual C balances for a 5-year period at a rewetted peatland in Ireland (rewetted at the start of the study) and compare the results with an adjacent drained area (represents business-as-usual). Hydrological modelling of the 230-hectare site was carried out to determine the likely ecotopes (vegetation communities) that will develop post-rewetting and was used to inform a radiative forcing modelling exercise to determine the climate impacts of rewetting this peatland under five high-priority scenarios (SSP1-1.9, SS1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5). The drained area (marginal ecotope) was a net C source throughout the study and emitted 157 ± 25.5 g C m-2  year-1 . In contrast, the rewetted area (sub-central ecotope) was a net C sink of 78.0 ± 37.6 g C m-2  year-1 , despite relatively large annual methane emissions post-rewetting (average 19.3 ± 5.2 g C m-2  year-1 ). Hydrological modelling predicted the development of three key ecotopes at the site, with the sub-central ecotope predicted to cover 24% of the site, the sub-marginal predicted to cover 59% and the marginal predicted to cover 16%. Using these areal estimates, our radiative forcing modelling projects that under the SSP1-1.9 scenario, the site will have a warming effect on the climate until 2085 but will then have a strong cooling impact. In contrast, our modelling exercise shows that the site will never have a cooling impact under the SSP5-8.5 scenario. Our results confirm the importance of rapid rewetting of drained peatland sites to (a) achieve strong C emissions reductions, (b) establish optimal conditions for C sequestration and (c) set the site on a climate cooling trajectory.

Cost-Effectiveness of Cemiplimab Versus Standard of Care in the United States for First-Line Treatment of Advanced Non-small Cell Lung Cancer With Programmed Death-Ligand 1 Expression ≥50.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness, from a US commercial payer perspective, of cemiplimab versus other first-line treatments for advanced non-small cell lung cancer with programmed death-ligand 1 expression ≥50%. METHODS: A 30-year "partitioned survival" model was constructed. Overall survival and progression-free survival were estimated by applying time-varying hazard ratios from a network meta-analysis of randomized clinical trials. Overall survival and progression-free survival were estimated from EMPOWER-Lung 1 (cemiplimab monotherapy vs chemotherapy) and KEYNOTE-024 and KEYNOTE-042 (pembrolizumab monotherapy vs chemotherapy). Drug acquisition costs were based on published 2020 US list prices. A 3% discount rate was applied to life-years, quality-adjusted life-years (QALYs), and costs. A deterministic analysis was performed on the base case; 1-way sensitivity and probabilistic sensitivity analyses assessed model and parameter uncertainties. RESULTS: Cemiplimab was associated with increased time in the "preprogression" (13.08 vs 7.90 and 6.08 months) and "postprogression" (47.30 vs 29.49 and 14.78 months) health states versus pembrolizumab and chemotherapy, respectively. Compared with pembrolizumab and chemotherapy, cemiplimab generated 1.00 (95% CI -0.266 to 2.440) and 1.78 (95% CI 0.607-3.20) incremental QALYs, respectively, with incremental cost-effectiveness ratios of $68 254 and $89 219 per QALY for cemiplimab versus pembrolizumab and cemiplimab versus chemotherapy, respectively. The probability of cemiplimab being cost-effective at a willingness-to-pay threshold of $100 000 to $150 000 per QALY was 62% to 76% versus pembrolizumab and 56% to 84% versus chemotherapy. CONCLUSIONS: Findings suggest that cemiplimab, versus pembrolizumab or versus chemotherapy, is a cost-effective first-line treatment option for advanced non-small cell lung cancer with programmed death-ligand 1 expression ≥50%.

Cdk-dependent phosphorylation regulates TRF1 recruitment to PML bodies and promotes C-circle production in ALT cells.

TRF1, a duplex telomeric DNA binding protein, is implicated in homologous-recombination-based alternative lengthening of telomeres, known as ALT. However, how TRF1 promotes ALT activity has yet to be fully characterized. Here we report that Cdk-dependent TRF1 phosphorylation on T371 acts as a switch to create a pool of TRF1, referred to as (pT371)TRF1, which is recruited to ALT-associated PML bodies (APBs) in S and G2 phases independently of its binding to telomeric DNA. We find that phosphorylation of T371 is essential for APB formation and C-circle production, both of which are hallmarks of ALT. We show that the interaction of (pT371)TRF1 with APBs is dependent upon ATM and homologous-recombination-promoting factors Mre11 and BRCA1. In addition, (pT371)TRF1 interaction with APBs is sensitive to transcription inhibition, which also reduces DNA damage at telomeres. Furthermore, overexpression of RNaseH1 impairs (pT371)TRF1 recruitment to APBs in the presence of campothecin, an inhibitor that prevents topoisomerase I from resolving RNA-DNA hybrids. These results suggest that transcription-associated DNA damage, perhaps arising from processing RNA-DNA hybrids at telomeres, triggers (pT371)TRF1 recruitment to APBs to facilitate ALT activity.

National scale assessment of total trihalomethanes in Irish drinking water.

Ireland reported the highest non-compliance with respect to total trihalomethanes (TTHMs) in drinking water across the 27 European Union Member States for the year 2010. We carried out a GIS-based investigation of the links between geographical parameters and catchment land-uses with TTHMs concentrations in Irish drinking water. A high risk catchment map was created using peat presence, rainfall (>1400 mm) and slope (<5%) and overlain with a map comprising the national dataset of routinely monitored TTHM concentrations. It appeared evident from the map that the presence of peat, rainfall and slope could be used to identify catchments at high risk to TTHM exceedances. Furthermore, statistical analyses highlighted that the presence of peat soil with agricultural land was a significant driver of TTHM exceedances for all treatment types. PARAFAC analysis from three case studies identified a fluorophore indicative of reprocessed humic natural organic matter as the dominant component following treatment at the three sites. Case studies also indicated that (1) chloroform contributed to the majority of the TTHMs in the drinking water supplies and (2) the supply networks contributed to about 30 µg L-1 of TTHMs.

Systematic review and network meta-analysis comparing palbociclib with chemotherapy agents for the treatment of postmenopausal women with HR-positive and HER2-negative advanced/metastatic breast cancer.

PURPOSE: To compare palbociclib + letrozole and palbociclib + fulvestrant with chemotherapy agents in postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (ABC/MBC) who had no prior systemic treatment for advanced disease (first line) or whose disease progressed after prior endocrine therapy or chemotherapy (second line). METHODS: A systematic search identified randomized controlled trials (RCTs) published from January 2000 to January 2016 that compared endocrine-based therapies, chemotherapy agents, and/or chemotherapy agents + biological therapies in the first- and second-line treatment of postmenopausal women with HR+/HER2- ABC/MBC. The main outcome of interest was progression-free survival (PFS)/time to progression (TTP). Bayesian network meta-analyses (NMAs) and pairwise meta-analyses were conducted. Heterogeneity and inconsistency were assessed. RESULTS: Sixty RCTs met eligibility criteria and were stratified by line of therapy. In the first line, palbociclib + letrozole showed statistically significant improvements in PFS/TTP versus capecitabine [intermittent: HR 0.28 (95% CrI 0.11-0.72)] and mitoxantrone [HR 0.28 (0.13-0.61)], and trended toward improvements versus paclitaxel [HR 0.59 (0.19-1.96)], docetaxel [HR 0.51 (0.14-2.03)] and other monotherapy or combination agents (HRs ranging from 0.24 to 0.99). In the second line, palbociclib + fulvestrant showed statistically significant improvements in PFS/TTP versus capecitabine [intermittent: HR 0.28 (0.13-0.65)], mitoxantrone [HR 0.26 (0.12-0.53)], and pegylated liposomal doxorubicin [HR 0.19 (0.07-0.50)], and trended toward improvements versus paclitaxel [HR 0.48 (0.16-1.44)], docetaxel [HR 0.71 (0.24-2.13)] and other monotherapy or combination agents (HRs ranging from 0.23-0.89). NMA findings aligned with direct evidence and were robust to sensitivity analyses. CONCLUSIONS: Palbociclib + letrozole and palbociclib + fulvestrant demonstrate trends in incremental efficacy compared with chemotherapy agents for the first- and second-line treatment of HR +/HER2- ABC/MBC.

Multiyear greenhouse gas balances at a rewetted temperate peatland.

Drained peat soils are a significant source of greenhouse gas (GHG) emissions to the atmosphere. Rewetting these soils is considered an important climate change mitigation tool to reduce emissions and create suitable conditions for carbon sequestration. Long-term monitoring is essential to capture interannual variations in GHG emissions and associated environmental variables and to reduce the uncertainty linked with GHG emission factor calculations. In this study, we present GHG balances: carbon dioxide (CO2 ), methane (CH4 ) and nitrous oxide (N2 O) calculated for a 5-year period at a rewetted industrial cutaway peatland in Ireland (rewetted 7 years prior to the start of the study); and compare the results with an adjacent drained area (2-year data set), and with ten long-term data sets from intact (i.e. undrained) peatlands in temperate and boreal regions. In the rewetted site, CO2 exchange (or net ecosystem exchange (NEE)) was strongly influenced by ecosystem respiration (Reco ) rather than gross primary production (GPP). CH4 emissions were related to soil temperature and either water table level or plant biomass. N2 O emissions were not detected in either drained or rewetted sites. Rewetting reduced CO2 emissions in unvegetated areas by approximately 50%. When upscaled to the ecosystem level, the emission factors (calculated as 5-year mean of annual balances) for the rewetted site were (±SD) -104 ± 80 g CO2 -C m-2  yr-1 (i.e. CO2 sink) and 9 ± 2 g CH4 -C m-2  yr-1 (i.e. CH4 source). Nearly a decade after rewetting, the GHG balance (100-year global warming potential) had reduced noticeably (i.e. less warming) in comparison with the drained site but was still higher than comparative intact sites. Our results indicate that rewetted sites may be more sensitive to interannual changes in weather conditions than their more resilient intact counterparts and may switch from an annual CO2 sink to a source if triggered by slightly drier conditions.

Phosphorylated (pT371)TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation.

TRF1, a duplex telomeric DNA-binding protein, plays an important role in telomere metabolism. We have previously reported that a fraction of endogenous TRF1 can stably exist free of telomere chromatin when it is phosphorylated at T371 by Cdk1; however, the role of this telomere-free (pT371)TRF1 has yet to be fully characterized. Here we show that phosphorylated (pT371)TRF1 is recruited to sites of DNA damage, forming damage-induced foci in response to ionizing radiation (IR), etoposide and camptothecin. We find that IR-induced (pT371)TRF1 foci formation is dependent on the ATM- and Mre11/Rad50/Nbs1-mediated DNA damage response. While loss of functional BRCA1 impairs the formation of IR-induced (pT371)TRF1 foci, depletion of either 53BP1 or Rif1 stimulates IR-induced (pT371)TRF1 foci formation. In addition, we show that TRF1 depletion or the lack of its phosphorylation at T371 impairs DNA end resection and repair of nontelomeric DNA double-strand breaks by homologous recombination. The lack of TRF1 phosphorylation at T371 also hampers the activation of the G2/M checkpoint and sensitizes cells to PARP inhibition, IR and camptothecin. Collectively, these results reveal a novel but important function of phosphorylated (pT371)TRF1 in facilitating DNA double-strand break repair and the maintenance of genome integrity.

Active afforestation of drained peatlands is not a viable option under the EU Nature Restoration Law.

The EU Nature Restoration Law (NRL) is critical for the restoration of degraded ecosystems and active afforestation of degraded peatlands has been suggested as a restoration measure under the NRL. Here, we discuss the current state of scientific evidence on the climate mitigation effects of peatlands under forestry. Afforestation of drained peatlands without restoring their hydrology does not fully restore ecosystem functions. Evidence on long-term climate benefits is lacking and it is unclear whether CO2 sequestration of forest on drained peatland can offset the carbon loss from the peat over the long-term. While afforestation may offer short-term gains in certain cases, it compromises the sustainability of peatland carbon storage. Thus, active afforestation of drained peatlands is not a viable option for climate mitigation under the EU Nature Restoration Law and might even impede future rewetting/restoration efforts. Instead, restoring hydrological conditions through rewetting is crucial for effective peatland restoration.

Indirect treatment comparison of lurbinectedin versus other second-line treatments for small-cell lung cancer.

Aim: Compare lurbinectedin versus other second-line (2L) small-cell lung cancer (SCLC) treatments. Methods: An unanchored matching-adjusted indirect comparison connected the platinum-sensitive SCLC cohort of a single-arm lurbinectedin trial to a network of three randomized controlled trials (oral and intravenous [IV] topotecan, and platinum re-challenge) identified by systematic literature review. Network meta-analysis methods estimated relative treatment effects. Results: In platinum-sensitive patients, lurbinectedin demonstrated a survival benefit and favorable safety profile versus oral and IV topotecan and platinum re-challenge (overall survival, hazard ratio [HR]: 0.43; 95% credible interval [CrI]: 0.27, 0.67; HR: 0.43; 95% CrI: 0.26, 0.70; HR: 0.42; 95% CrI: 0.30, 0.58 respectively). Conclusion: Lurbinectedin showed a robust survival benefit and favorable safety versus other SCLC treatments in 2L platinum-sensitive SCLC.

Peatland dynamics: A review of process-based models and approaches.

Despite peatlands' important feedbacks on the climate and global biogeochemical cycles, predicting their dynamics involves many uncertainties and an overwhelming variety of available models. This paper reviews the most widely used process-based models for simulating peatlands' dynamics, i.e., the exchanges of energy and mass (water, carbon, and nitrogen). 'Peatlands' here refers to mires, fens, bogs, and peat swamps both intact and degraded. Using a systematic search (involving 4900 articles), 45 models were selected that appeared at least twice in the literature. The models were classified into four categories: terrestrial ecosystem models (biogeochemical and global dynamic vegetation models, n = 21), hydrological models (n = 14), land surface models (n = 7), and eco-hydrological models (n = 3), 18 of which featured "peatland-specific" modules. By analysing their corresponding publications (n = 231), we identified their proven applicability domains (hydrology and carbon cycles dominated) for different peatland types and climate zones (northern bogs and fens dominated). The studies range in scale from small plots to global, and from single events to millennia. Following a FOSS (Free Open-Source Software) and FAIR (Findable, Accessible, Interoperable, Reusable) assessment, the number of models was reduced to 12. Then, we conducted a technical review of the approaches and associated challenges, as well as the basic aspects of each model, e.g., spatiotemporal resolution, input/output data format and modularity. Our review streamlines the process of model selection and highlights: (i) standardization and coordination are required for both data exchange and model calibration/validation to facilitate intercomparison studies; and (ii) there are overlaps in the models' scopes and approaches, making it imperative to fully optimize the strengths of existing models rather than creating redundant ones. In this regard, we provide a futuristic outlook for a 'peatland community modelling platform' and suggest an international peatland modelling intercomparison project.

An examination of the influence of drained peatlands on regional stream water chemistry.

Currently, 50% of Irish rivers do not meet water quality standards, with many declining due to numerous pressures, including peatland degradation. This study examines stream water quality in the Irish midlands, a region where raised bogs have been all historically disturbed to various extent and the majority drained for industrial or domestic peat extraction. For the first time, we provide in-depth analysis of stream water chemistry within a heavily modified bog landscape. Small streams from degraded bogs exhibited greater levels of pollutants, in particular: total dissolved nitrogen (0.48 mg/l) and sulphate (18.49 mg/l) as well as higher electrical conductivity (mean: 334 µS/cm) compared to similar bog streams in near-natural bogs. Except for site-specific nitrogen pollution in certain streams surrounding degraded peatlands, the chemical composition of the receiving streams did not significantly differ between near-natural and degraded sites, reflecting the spatio-temporal scales of disturbance in this complex peat-scape. Dissolved organic carbon concentrations in all the receiving streams were high (27.2 mg/l) compared to other Irish streams, even within other peatland catchments. The region is experiencing overall a widespread loss of fluvial nitrogen and carbon calling for (a) the development of management instruments at site-level (water treatment) and landscape-level (rewetting) to assist with meeting water quality standards in the region, and (b) the routine monitoring of water chemistry as part of current and future peatland management activities. Supplementary Information: The online version contains supplementary material available at 10.1007/s10750-023-05188-5.

Network meta-analysis of immune-oncology monotherapy as first-line treatment for advanced non-small-cell lung cancer in patients with PD-L1 expression ⩾50.

Background: For patients with advanced non-small-cell lung cancer (NSCLC) and high (⩾50%) programmed cell death-ligand 1 (PD-L1) expression, effective first-line immune-oncology monotherapies with significant survival benefits are approved, cemiplimab being the most recent. In a phase III trial, cemiplimab demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced NSCLC and PD-L1 ⩾50%. A systematic literature review and network meta-analysis (NMA) was conducted to identify/compare the efficacy/safety of cemiplimab versus pembrolizumab or other immune-oncology monotherapies from randomized-controlled trials (RCTs) published in November 2010-2020. Methods: Relevant RCTs were identified by searching databases and conference proceedings as per ISPOR, NICE, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR) and safety/tolerability. Fixed-effect models were used due to limited evidence. Various sensitivity analyses were conducted to validate the base case analyses. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded because an incompatible PD-L1 assay (SP142) was used for patient selection. For first-line advanced NSCLC with PD-L1 ⩾50%, cemiplimab was associated with statistically significant improvements in PFS [HR (95% credible interval [CrI]): 0.65 (0.50-0.86), 1-12 months] and ORR [odds ratio (OR) (95% CrI): 1.64 (1.04-2.62)], and comparable OS [HR (95% CrI): 0.77 (0.54-1.10), 1-12 months] versus pembrolizumab. There was no evidence of differences between cemiplimab and pembrolizumab for Grade 3-5 adverse events (AEs) [OR (95% CrI): 1.47 (0.83-2.60)], immune-mediated AEs [1.75 (0.33-7.49)], and all-cause discontinuation due to AEs [1.21 (0.58-2.61)]. Conclusions: Considering the limitations of indirect treatment comparisons, in patients with advanced NSCLC and PD-L1 ⩾50%, cemiplimab monotherapy demonstrated significant improvements in PFS and ORR, comparable OS, and no evidence of differences in safety/tolerability versus pembrolizumab.

Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer.

Objectives: In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression. Methods: Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring). Results: In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction-the most suitable method based on published guidelines and trial characteristics-produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction. Conclusions: After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.

CO2 fluxes from drained and rewetted peatlands using a new ECOSSE model water table simulation approach.

The ability of peatlands to remove and store atmospheric carbon (C) depends on the drainage characteristics, which can be challenging to accommodate in biogeochemical models. Many studies indicate that restoration (by rewetting) of damaged peatlands can re-establish their capacity as a natural C sink. The purpose of this research was to improve the biogeochemical modelling of peatlands using the ECOSSE process-based model, which will account for the effects of drainage and rewetting during simulation, and potentially contribute towards improved estimation of carbon dioxide (CO2) fluxes from peatlands, using the IPCC Tier 3 approach. In this study, we present a new drainage factor with seasonal variability Dfa (i) developed specifically for ECOSSE, using empirical data from two drained and rewetted Irish peatlands. Dfa(i) was developed from the Blackwater drained bare-peat site (BWdr), and its application was tested at the vegetated Moyarwood peatland site under drained (MOdr) and rewetted conditions (MOrw). Dfa(i) was applied to the rainfall model inputs for the periods of active drainage in conjunction with the measured water table (WT) inputs. The results indicate that Dfa(i) application can improve the model performance to predict model-estimated water level (WL) and CO2 fluxes under drained conditions [WL: r2 = 0.89 (BWdr) and 0.94 (Modr); CO2: r2 = 0.66 (BWdr) and 0.78 (MOdr)] along with model-ability to capture their seasonal trends. The prediction of WL for the rewetted period was less successful at the MOrw site, where the simulation was run for drained to rewetted, which would suggest that additional work on the water model component is still needed. Despite this, the application of Dfa(i) showed successful model simulation of CO2 fluxes at MOrw (r2 = 0.75) and model ability to capture seasonal trends. This work hopes to positively contribute towards potential future development of Tier 3 methodology for estimating emissions/sinks in peatlands.

Comparative effectiveness of nivolumab versus standard of care for third-line patients with small-cell lung cancer.

Aim: To estimate the comparative effectiveness of nivolumab versus standard of care (SOC) in terms of overall survival (OS) for small-cell lung cancer patients treated with two prior lines of chemotherapy, in other words, third line in the USA. Materials & methods: Data were from CheckMate 032, a single-arm trial of nivolumab, and real-world electronic patient records. Comparisons of OS were conducted using three different methods to adjust for differences (regression, weighting and doubly robust) between the populations. Results: Nivolumab was associated with longer survival compared with SOC (hazard ratio for OS: 0.58-0.70) across all methods for adjustment. Conclusion: Nivolumab was more efficacious in terms of OS as third-line treatment for small-cell lung cancer compared with current SOC in the USA.

Acquisition of antimicrobial-resistant bacteria in the absence of antimicrobial exposure: A systematic review and meta-analysis.

OBJECTIVE: The main risk factor for acquisition of antimicrobial-resistant bacteria (ARB) is antimicrobial exposure, although acquisition can occur in their absence. The aim of this study was to quantify the proportion of patients who acquire ARB without antimicrobial exposure. STUDY DESIGN: We searched Medline, Embase, and the Cochrane library for publications between January 1, 2000, and July 24, 2017, to identify studies of ARB acquisition in endemic settings. Studies required collection of serial surveillance cultures with acquisition defined as a negative baseline culture and a subsequent positive culture for an ARB, including either multidrug-resistant gram-negative bacteria or antimicrobial-resistant enterococci. Intervention studies were excluded. For each study, the proportion of patients who acquired an ARB but were not exposed to antimicrobials during the study period was quantified. RESULTS: A total of 4,233 citations were identified; 147 underwent full-text review. Of these, 10 studies met inclusion criteria; 7 studies were considered to be at low risk of bias; and 6 studies were conducted in the intensive care unit (ICU) setting. The overall summary estimate for the proportion of patients who were not exposed to antimicrobials among those who acquired an ARB was 16.6% (95% CI, 7.8%-31.8%; P < .001), ranging from 0% to 57.1%. We observed no heterogeneity in the ICU studies but high heterogeneity among the non-ICU studies. CONCLUSION: In most included studies, a subset of patients acquired an ARB but were not exposed to antimicrobials. Future studies need to address transmission dynamics of ARB acquisition in the absence of antimicrobials.

Treatment sequence network meta-analysis in Crohn's disease: a methodological case study.

OBJECTIVE: Several biologic therapies are available for the treatment of mild-to-moderate Crohn's disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1 year of treatment. METHODS: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards. RESULTS: Thirteen RCTs were identified. Ustekinumab 90 mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300 mg. For clinical remission, ustekinumab 90 mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300 mg q8w. Findings from sub-population analyses had similar results but were not statistically significant. CONCLUSIONS: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1 year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.

Herceptin® (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis.

BACKGROUND: Originator trastuzumab (Herceptin®; H) is an antibody-targeted therapy to treat patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). We investigated the overall survival (OS) advantage conferred by the addition of H to chemotherapy for HER2+ EBC patients and how the OS advantage changed over time. METHODS: A systematic literature review (SLR) identified randomized controlled trials (RCTs) and non-randomized studies (NRSs) published from January 1, 1990 to January 19, 2017, comparing systemic therapies used in the neoadjuvant/adjuvant settings to treat HER2+ EBC patients. Bayesian cumulative network meta-analyses (cNMAs) of OS were conducted to assess the published literature over time. Heterogeneity was assessed through sensitivity and subgroup analyses. RESULTS: The SLR identified 31 unique studies (28 RCTs, 3 NRSs) included in the OS analyses from 2008 to 2016. In the reference case cNMA (RCTs alone), initial evidence demonstrated an OS advantage for H/chemotherapy compared with chemotherapy alone in HER2+ EBC patients. As additional OS data were published, the precision around this survival benefit strengthened over time. Both H/anthracycline-containing chemotherapy and H/non-anthracycline-containing chemotherapy regimens provided similar OS advantages for HER2+ EBC patients. CONCLUSION: This analysis represents the most comprehensive SLR/cNMA to date of published OS data in HER2+ EBC studies. These findings demonstrate why H/chemotherapy is now the established standard of care in HER2+ EBC. In the case of H, the benefits of early patient access far outweighed the risk of waiting for more precise information. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055763.

The Importance of Considering Differences in Study Design in Network Meta-analysis: An Application Using Anti-Tumor Necrosis Factor Drugs for Ulcerative Colitis.

BACKGROUND AND AIMS: Adaptive trial designs present a methodological challenge when performing network meta-analysis (NMA), as data from such adaptive trial designs differ from conventional parallel design randomized controlled trials (RCTs). We aim to illustrate the importance of considering study design when conducting an NMA. METHODS: Three NMAs comparing anti-tumor necrosis factor drugs for ulcerative colitis were compared and the analyses replicated using Bayesian NMA. The NMA comprised 3 RCTs comparing 4 treatments (adalimumab 40 mg, golimumab 50 mg, golimumab 100 mg, infliximab 5 mg/kg) and placebo. We investigated the impact of incorporating differences in the study design among the 3 RCTs and presented 3 alternative methods on how to convert outcome data derived from one form of adaptive design to more conventional parallel RCTs. RESULTS: Combining RCT results without considering variations in study design resulted in effect estimates that were biased against golimumab. In contrast, using the 3 alternative methods to convert outcome data from one form of adaptive design to a format more consistent with conventional parallel RCTs facilitated more transparent consideration of differences in study design. This approach is more likely to yield appropriate estimates of comparative efficacy when conducting an NMA, which includes treatments that use an alternative study design. CONCLUSIONS: RCTs based on adaptive study designs should not be combined with traditional parallel RCT designs in NMA. We have presented potential approaches to convert data from one form of adaptive design to more conventional parallel RCTs to facilitate transparent and less-biased comparisons.

Herceptin® (trastuzumab) in HER2-positive early breast cancer: protocol for a systematic review and cumulative network meta-analysis.

BACKGROUND: Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive disease that makes up about 20% of all invasive breast cancers. HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival. Numerous clinical trials and reviews have investigated the efficacy of HER2-targeted therapies over the past few decades; however, no study has specifically investigated the vast body of evidence on trastuzumab in comparison to chemotherapy regimens, endocrine therapies, and other targeted therapies. This systematic review and cumulative network meta-analysis (NMA) will synthesize available evidence to evaluate the survival benefit conferred by the addition of originator trastuzumab to standard chemotherapy and to compare the most widely used trastuzumab regimens in patients with HER2+ early breast cancer, based on results from randomized controlled trials (RCTs) and comparative observational studies. METHODS/DESIGN: A systematic search of Embase, MEDLINE®, and the Cochrane Library has been designed by an experienced medical information specialist and peer reviewed by another senior information specialist. RCTs and comparative observational studies of patients with HER2+ early breast cancer indexed from 1990 onwards will be eligible for inclusion. Two investigators will independently assess studies for inclusion and use standardized data extraction templates to collect data on study and patient characteristics. The primary outcome of interest is overall survival. Bayesian cumulative NMA methods will be used to quantify the evolution of publicly available evidence using both fixed and random effects models. DISCUSSION: This study will evaluate survival trends associated with originator trastuzumab in patients with HER2+ early breast cancer. As originator trastuzumab has been researched in both clinical and real-world settings for close to 20 years, a cumulative NMA is likely to show improved precision around the parameter estimates for trastuzumab now compared with when the drug was initially launched in the USA in 1998. A better understanding of the evolution of publicly available comparative evidence for originator trastuzumab will further inform treatment for patients with HER2+ early breast cancer, providing benefit to patients, health professionals, and researchers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055763 https://www.crd.york.ac.uk/PROSPERO.