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Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer
No full textBACKGROUND: Triple-negative breast cancer (TNBC), an aggressive subtype lacking oestrogen and progesterone receptors and amplification of HER2 receptors, accounts for 12% to 17% of breast cancers. Adjuvant and neoadjuvant chemotherapy improve survival; however, 30% to 40% of early-stage TNBC cases progress to metastatic disease. Recent evidence suggests that combining immune checkpoint inhibitors (PD-1/PD-L1 inhibitors) with chemotherapy may improve pathological complete response and event-free survival. OBJECTIVES: To assess the benefits and harms of immune checkpoint inhibitors (PD-1 or PD-L1 inhibitors) plus chemotherapy compared with chemotherapy for people with early TNBC. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, the WHO ICTRP, and ClinicalTrials.gov up to 6 November 2024. We also searched the reference lists of identified relevant trials or reviews for potentially eligible studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing PD-1 or PD-L1 inhibitors plus chemotherapy with chemotherapy alone in participants with early TNBC. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently identified studies for inclusion and performed data extraction and risk of bias assessment. Outcomes were pathological complete response, event-free survival (EFS), overall survival (OS), health-related quality of life (HRQoL), and overall rates of any adverse events and serious adverse events (SAEs). We calculated hazard ratios (HRs) for time-to-event data, risk ratios (RRs), odds ratios (ORs), or risk differences (RDs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes with corresponding 95% confidence intervals (CIs). We performed random-effects meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE approach. MAIN RESULTS: We included seven RCTs with a total of 4341 participants. Two trials investigated PD-1 inhibitors (i.e. pembrolizumab), and five investigated PD-L1 inhibitors (i.e. durvalumab, atezolizumab) in the intervention group. Six studies used neoadjuvant chemotherapy (NACT), and one study used adjuvant chemotherapy (ACT) in the control group. The studies cover a five-year follow-up period. Two studies were at low risk of bias for all reported outcomes. The main limitation of the other trials was lack of blinding. PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone beforebreast cancer surgery PD-1 or PD-L1 inhibitors plus chemotherapy probably increase pathological complete response rate (RR 1.47, 95% CI 1.15 to 1.86; 6 studies, 1564 participants; moderate-certainty evidence); improve EFS (HR 0.64, 95% CI 0.52 to 0.79; 4 studies, 1789 participants; high-certainty evidence); and probably improve OS (HR 0.56, 95% CI 0.34 to 0.93; 3 studies, 1681 participants; moderate-certainty evidence) compared with chemotherapy alone. There may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone in HRQoL (MD -1.49, 95% CI -3.88 to 0.91; 2 studies, 1395 participants; low-certainty evidence). PD-1 or PD-L1 inhibitors plus chemotherapy probably have little or no effect on any adverse events (OR 0.26, 95% CI 0.05 to 1.24; 3 studies, 1781 participants; moderate-certainty evidence) and treatment-related deaths (RD 0.2%, 95% CI -0.4% to 0.8%; 4 studies, 1761 participants; moderate-certainty evidence) compared with chemotherapy alone. PD-1 or PD-L1 inhibitors plus chemotherapy probably increase immune-related SAEs (OR 1.75, 95% CI 1.15 to 2.67; 5 studies, 2016 participants; moderate-certainty evidence) compared with chemotherapy alone. PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone afterbreast cancer surgery There may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone in EFS (HR 1.11, 95% CI 0.87 to 1.42; 1 study, 2199 participants; low-certainty evidence), OS (HR 1.23, 95% CI 0.87 to 1.73; 1 study, 2199 participants; low-certainty evidence), HRQoL (MD -1.02, 95% CI -2.71 to 0.67; 1 study, 2168 participants; low-certainty evidence), any adverse events (OR 3.38, 95% CI 0.93 to 12.33; 1 study, 2177 participants; low-certainty evidence), and treatment-related deaths (RD -0.1%, 95% CI -0.4% to 0.2%; 1 study, 2177 participants; low-certainty evidence). PD-1 or PD-L1 inhibitors plus chemotherapy probably increase immune-related SAEs (OR 1.81, 95% CI 1.47 to 2.24; 1 study, 2177 participants; moderate-certainty evidence) compared to chemotherapy alone. AUTHORS' CONCLUSIONS: Combining PD-1 or PD-L1 inhibitors with chemotherapy compared to chemotherapy alone before breast cancer surgery improves pathological response, EFS, and OS in early TNBC. In contrast, the combination of PD-1/PD-L1 inhibitors with chemotherapy after breast cancer surgery may have little to no effect on EFS and OS in early-stage TNBC when compared with chemotherapy alone. The addition of PD-1 or PD-L1 inhibitors probably increases immune-related SAEs
Association of Off-Hour Admission With Treatment Delay and Unfavorable Outcomes in Patients With Stroke: A Systematic Review and Meta-Analysis
No full textBackground: Despite numerous efforts to reduce the elevated mortality rate of patients with stroke admitted to the hospital during weekends or nights, it remains unclear whether the off‐hour treatment has been improved. We aim to assess the treatment delay and outcomes of patients with stroke admitted to the hospital during off‐hours. Methods: Searches were conducted of PubMed, Embase, Medline, and Web of Science from inception to July 2022. Cohort studies reporting the door‐to‐treatment time, short‐term mortality rate, and 90‐day function of adult patients with stroke admitted to the hospital on weekends or at night were included. A random‐effect meta‐analysis model was applied to pool the odds ratio (OR) and mean difference with 95% CI. Results: A total of 84 studies were included. Treatment delay on weekends or nights was significant, with extended door‐to‐needle time (mean difference, 5.93 [95% CI, 1.88–9.98] minutes) and door‐to‐groin time (mean difference, 13.54 [95% CI, 5.02–22.06] minutes). Off‐hour patients were less likely to receive intravenous thrombolysis within 60 minutes (OR, 0.65 [95% CI, 0.46–0.92]). Off‐hour admission was associated with an increased short‐term mortality rate for patients with ischemic stroke (OR, 1.07 [95% CI, 1.03–1.11]), intracerebral hemorrhage (OR, 1.10 [95% CI, 1.03–1.18]), and subarachnoid hemorrhage (OR, 1.05 [95% CI, 1.02–1.09]). Conclusions: This review indicates that off‐hour admission was associated with treatment delay and increased risk of stroke death. Patients with stroke admitted on weekends and nights may require more attention, especially those with more severe and complex conditions
Oceanic Eddy Modulation of Wintertime Air-Sea Coupling and Marine Atmospheric Boundary Layer Winds over the East China Sea
No full textThis study examined the effects of air-sea coupling and oceanic mesoscale eddies on wintertime low-level wind events within the marine atmospheric boundary layer (MABL) over the Kuroshio front zone in the East China Sea. High-resolution (eddy-resolving, 5 km) and low-resolution (50 km) simulations were conducted, using prescribed sea surface temperature (SST) forcing and air-sea coupled simulations in both resolutions. Among all simulations, the eddy-resolved air-sea coupled (EC) one exhibited the strongest atmosphere-to-SST feedback, closest to reanalysis data. In the EC simulation, complex interactions of numerous oceanic eddies enhanced oceanic front intensity. Compared with uncoupled and low-resolution simulations, it better reproduced wind event statistics from reanalysis. Highly-resolved eddy pairs with positive northwest-to-southeast SST anomalies strengthened SST gradients, altering sea surface heat fluxes and MABL stability, and thereby distinctly modulating wind event durations. Specifically, short-lived events were suppressed while long-lived ones persisted, consistent with reanalysis. These effects are attributed to the influence of numerous oceanic eddy pairs, by enhancing oceanic front intensity, air-sea temperature differences, sea surface heat fluxes, and lower atmospheric stability. Anomalous winds were restrained during initiation but prolonged as events evolved
Does algorithmic trading induce herding?
No full textAlgorithmic trading (AT) plays a major role in the trading activities of developed markets. This research breaks new ground by investigating how AT influences herding behaviour in stock markets. Utilising the implementation of the Markets in Financial Instruments Directive (MiFID II), we show that AT-induced herding is quantitatively 14 times more pronounced compared to herding triggered by non-AT elements. Algorithmic traders herd more when international volatility and market uncertainty are high, revealing a heightened sensitivity to global market signals. However, during periods of high local volatility, AT seems to disregard these fluctuations, indicating an ‘inattention effect’. AT-induced anti-herding is prominent in the volatile aggressive stocks, while no such behaviour is observed in the more stable defensive stocks. The findings carry critical implications for both regulators and market professionals, as we uncover dual behaviours of AT-induced herding and anti-herding in varying market conditions
(Un)making the Frontex PeDRA controversy: Freedom of information and the regime of opacity in EU migration management
No full textThis paper examines the controversy surrounding ‘PeDRA’—a Frontex surveillance programme for harvesting data from illegalized migrants—to explore how opaque security practices are transformed into objects of public-political contestation. By centring the EU’s freedom of information (FOI) mechanism as both a methodological and analytical vantage point for interrogating the regime of opacity in EU migration management, it contributes to debates in critical border and security studies concerned with mundane entanglements between secrecy and security. How do FOI mechanisms intervene in the politics of controversy and broader epistemic struggles surrounding Europe’s border regime, and what forms of (non-)knowledge do they engender? Drawing on a large trove of confidential records, the analysis shows, first, how FOI disclosures can be mobilised to trace the emergence of controversies by exposing the internal contestations and irregularities that underpinned the unlawful expansion of PeDRA. Second, it identifies the obfuscatory tactics that EU border bureaucracies deployed to strategically manage the political reverberations of the controversy, both in the public arena and the bureaucratic backstage. While FOI mechanisms cannot undo the irreducible opacity of datafied bordering infrastructures, the paper concludes that they remain vital tools for rendering security practices (partially) visible and, thus, politically contestable
Yeast [FeFe]-hydrogenase-like protein Nar1 binds a [2Fe-2S] cluster
Get PDFNar1 is an essential eukaryotic protein proposed to function as an iron–sulphur (Fe/S) cluster trafficking factor in the cytosolic iron–sulphur protein assembly (CIA) machinery. However, such a role has remained unclear due to difficulties in purifying adequate amounts of cofactor-bound protein. The [FeFe]-hydrogenase-like protein has two conserved binding sites for [4Fe–4S] clusters but does not show hydrogenase activity in vivo due to the lack of an active site [2Fe]H cofactor. Here, we report a new preparation procedure for Nar1 that facilitated studies by UV-vis, EPR, and Mössbauer spectroscopies, along with native mass spectrometry. Nar1 recombinantly produced in E. coli contained a [4Fe–4S] cluster, bound presumably at site 1, along with an unexpected [2Fe–2S] cluster bound at an unknown site. Fe/S reconstitution reactions installed a second [4Fe–4S] cluster at site 2, leading to protein with up to three Fe/S cofactors. It is proposed that the [2Fe–2S] cluster occupies a cavity in Nar1 that is filled by the [2Fe]H cofactor in [FeFe]-hydrogenases. Strikingly, two of the Fe/S clusters were rapidly destroyed by molecular oxygen, linking Nar1 oxygen sensitivity in vitro to phenotypes observed previously in vivo. Our biochemical results, therefore, validate a direct link between cellular oxygen concentrations and the functioning of the CIA pathway. These advances also now allow for the pursuit of in vitro Fe/S cluster transfer assays, which will shed light on Fe/S trafficking and insertion by CIA components
Scale, Depth and Duration: Examples of Transformational Change in the Energy and Public Health Sectors
Get PDFThe study analyses robust, causal evidence of transformational change. We approach this topic by systematically reviewing literature that has the potential to document causal evidence for transformational change across a broad set of interventions and outcomes. Our focus is on evidence found in developing countries to inform climate interventions. We approach this learning exercise directly by looking at the energy sector and indirectly by reviewing the evidence on behavioural change in the public health sector. Both sectors show examples of transformational change with scale, depth and duration. We identify lessons on transformational change from these two sectors relevant to policymakers
Towards a vegan standpoint: the epistemological and methodological repercussions of The Animatrix
No full textQuality of mental health care for forcibly displaced children and adolescents in the WHO European region: A scoping review of barriers and facilitators
No full textForcibly displaced children and adolescents in the World Health Organization (WHO) European Region have high mental health needs, yet few manage to access mental health services, and those who do may encounter inadequate care. This scoping review aimed to identify and synthesize the available evidence on barriers and facilitators to quality mental health care for forcibly displaced children and adolescents in the WHO European Region. We applied the PRISMA guideline extension for scoping reviews, searching five scholarly databases and grey literature published between 2004 and 2025. A total of 7,327 records were screened, with 18 articles included. We used the WHO Quality Standards for Child and Youth Mental Health Services as an analytical framework to map the evidence. The identified studies represented only 7 out of 53 countries in the WHO European Region. Most studies employed qualitative research designs, with a lack of quantitative evidence using quality indicators. Available evidence revealed multiple, intersecting barriers to quality mental health care, including restrictive health care policies, service constraints and a lack of provider competence. Facilitators included the presence of community-based support, networks of interconnected services, task shifting and evidence-based scalable interventions. Major gaps remain in both the data and in the methods used to generate evidence for improving quality of mental health care for forcibly displaced children and adolescents in the WHO European Region. Our review highlighted the discrepancy between the care provided and the recommended WHO Quality Standards for Child and Youth Mental Health Services. There is a need for more targeted efforts to assess and improve the quality of mental health care for forcibly displaced children and adolescents