Manoj Mathew Lalu

This multi-interest holder consensus effort highlights the essential influence and responsibility of Research-Performing Organizations (RPOs) in shaping the quality, transparency, and trustworthiness of scientific research. Despite the use of metrics to assess transparency and openness by academic journals and funders, most RPOs do not yet have metrics/indicators or monitoring that address deep-rooted shortcomings in research practice and assessment. These shortcomings manifest as restricted access to research outputs, poor availability of underlying data and materials, infrequent reproducibility checks and direct replications, and ongoing incidents of research misconduct all contributing to erosion of public trust in research. Such issues are exacerbated by institutional incentive structures that reward the number of publications and journal prestige, while neglecting research credibility, societal relevance, and transparent communication. To respond comprehensively to these challenges, our working group reached consensus on six core practices for RPOs to monitor: data, code, and material sharing; open access publishing; prospective study registration; reporting transparency; disclosures of interest and funding; and verification efforts.Collectively, these six practices offer a pragmatic and flexible framework that RPOs can tailor to their local context. The paper provides an implementation guide for these practices and calls for renewed leadership by RPOs in realigning research(er) assessment and incentives to reward quality, transparency, and trustworthiness in research, closing persistent gaps, and reinforcing science’s credibility and utility for society.

This multi-interest holder consensus effort highlights the essential influence and responsibility of Research-Performing Organizations (RPOs) in shaping the quality, transparency, and trustworthiness of scientific research. Despite the use of metrics to assess transparency and openness by academic journals and funders, most RPOs do not yet have metrics/indicators or monitoring that address deep-rooted shortcomings in research practice and assessment. These shortcomings manifest as restricted access to research outputs, poor availability of underlying data and materials, infrequent reproducibility checks and direct replications, and ongoing incidents of research misconduct all contributing to erosion of public trust in research. Such issues are exacerbated by institutional incentive structures that reward the number of publications and journal prestige, while neglecting research credibility, societal relevance, and transparent communication. To respond comprehensively to these challenges, our working group reached consensus on six core practices for RPOs to monitor: data, code, and material sharing; open access publishing; prospective study registration; reporting transparency; disclosures of interest and funding; and verification efforts.Collectively, these six practices offer a pragmatic and flexible framework that RPOs can tailor to their local context. The paper provides an implementation guide for these practices and calls for renewed leadership by RPOs in realigning research(er) assessment and incentives to reward quality, transparency, and trustworthiness in research, closing persistent gaps, and reinforcing science’s credibility and utility for society.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Beyond anticoagulation, heparin has anti-inflammatory, anti-chemotactic, and cytoprotective properties which may provide therapeutic benefits in sepsis. In COVID-19-associated sepsis, therapeutic-dose heparin improved outcomes in moderately but not critically ill patients, highlighting the importance of treatment timing. The study objectives are: (1) To identify the therapeutic window for initiating therapeutic-dose low molecular weight heparin (LMWH) in a murine model of sepsis. (2) To determine whether the protective effects of LMWH extend beyond systemic anticoagulation by comparing LMWH with a chemically-modified LMWH with reduced anticoagulant activity (Vasoflux). Sepsis was induced in 10- to 12-week old C57BL/6J mice via intraperitoneal injection of rat-derived fecal slurry. LMWH , Vasoflux, or saline was administered at 2, 8, or 16 hours post-infection, alongside analgesia, fluids, and antibiotics. Mice were monitored for 48 hours. Survival, physiological parameters, hematology, organ histology, and plasma biomarkers of inflammation, chemotaxis, coagulation, and cell death were evaluated. Compared with saline, LMWH administered at 2, 8, or 16 hours post-infection improved survival and physiological parameters, and reduced biomarkers of inflammation, chemotaxis, and cell death. LMWH remained effective when administered after organ injury was established at 16 hours post-infection. Vasoflux produced a comparable survival benefit as LMWH. Overall, LMWH administration improved outcomes when initiated between 2 and 16 hours after infection, demonstrating a therapeutic window extending beyond the onset of organ injury. The protective effects observed with Vasoflux suggest that non-anticoagulant mechanisms contribute to the beneficial effects of LMWH in sepsis.

This multi-interest holder consensus effort highlights the essential influence and responsibility of Research-Performing Organizations (RPOs) in shaping the quality, transparency, and trustworthiness of scientific research. Despite the use of metrics to assess transparency and openness by academic journals and funders, most RPOs do not yet have metrics/indicators or monitoring that address deep-rooted shortcomings in research practice and assessment. These shortcomings manifest as restricted access to research outputs, poor availability of underlying data and materials, infrequent reproducibility checks and direct replications, and ongoing incidents of research misconduct all contributing to erosion of public trust in research. Such issues are exacerbated by institutional incentive structures that reward the number of publications and journal prestige, while neglecting research credibility, societal relevance, and transparent communication. To respond comprehensively to these challenges, our working group reached consensus on six core practices for RPOs to monitor: data, code, and material sharing; open access publishing; prospective study registration; reporting transparency; disclosures of interest and funding; and verification efforts. Collectively, these six practices offer a pragmatic and flexible framework that RPOs can tailor to their local context. The paper provides an implementation guide for these practices and calls for renewed leadership by RPOs in realigning research(er) assessment and incentives to reward quality, transparency, and trustworthiness in research, closing persistent gaps, and reinforcing science’s credibility and utility for society.

Objectives: To examine the effect of biological sex on mortality, inflammation, organ dysfunction, and bacterial burden in preclinical sepsis models. Data sources: MEDLINE and Embase from January 1, 2011, to May 13, 2025. Study selection: We included in vivo animal models of experimentally- induced sepsis with or without intervention that reported sex-stratified data. We excluded non-infectious models and interventions hypothesized to worsen sepsis outcomes. Data extraction: We performed full-text screening and data extraction on mortality (primary outcome), inflammation, organ dysfunction, and bacterial burden. We applied a novel three-level analytic framework to determine: (1) baseline sepsis effect (female versus male differences), (2) unadjusted treatment effect (post-treatment risk differences), and (3) adjusted treatment effect (post-treatment risk differences accounting for baseline sepsis differences). Using random-effects models, we pooled outcomes as risk differences (RDs) or difference of standardized mean differences with differences > 0 indicating worse outcomes in males. Data synthesis: We screened 7,896 citations; 94 studies met eligibility criteria, and 83 studies were analyzed quantitatively. Cecal ligation and puncture (CLP) was the most common model (46%), followed by bacteremia (37%). Across the three-level framework (baseline sepsis effect, unadjusted and adjusted treatment effects), effect estimates were generally imprecise. Direction of effect analysis more often suggested worse outcomes in males (69/99 pooled comparisons). For mortality, the pooled RDs were 0.04 [95% CI, -0.02 to 0.10] for baseline sepsis effect, 0.05 [95% CI, 0.00 to 0.09] for unadjusted treatment effect, and 0.07 [95% CI, 0.00 to 0.14] for adjusted treatment effect. We observed similar direction of effects for inflammation (22/27 pooled comparisons) and organ dysfunction (9/12 pooled comparisons). The direction of effect for bacterial burden suggested worse outcomes in females (12/22 pooled comparisons). Most studies had “unclear” risk of bias. Conclusions: Sex-stratified reporting in preclinical sepsis studies remains rare. The available evidence was uncertain but showed a recurring direction toward worse outcomes and less favourable treatment responses in males. Future studies should systematically incorporate sex as a biological variable in their design and analysis to reduce this uncertainty and better define sex-based differences in sepsis and treatment response.

Systematic reviews of preclinical data are helpful in informing experimental design and translation, yet their own reproducibility has not been evaluated. We conducted a community-led Reproducibility Challenge to address this gap. Five international teams assessed reproducibility and identified factors affecting the replication success for four published reviews involving animal models of disease. Most teams successfully reproduced the original conclusions. However, we identified important quantitative and qualitative discrepancies in replicating individual steps of the systematic reviews. Differences arose in study selection, data processing and meta-analysis, and risk of bias assessments, due largely to incomplete or ambiguous reporting in the original reviews and to restricted access to underlying data and analysis code. Our findings suggest that preclinical systematic reviews may be more robust to replication than studies assessed in initiatives from other fields, although a lack of methodological transparency remains a significant barrier to exact replication. We provide recommendations, including refinements to reporting standards, to strengthen the transparency of preclinical evidence syntheses. We demonstrate that such collaborative challenges serve as a scalable model for community-driven engagement with reproducibility and the validation of systematic review findings. Wider adoption of reporting standards and open science practices is needed to ensure that preclinical systematic reviews provide a reliable foundation for translational research.

Background: Although selective COX‑2 inhibitors are commonly used in perioperative pain management, it is uncertain whether these anti-inflammatory agents meaningfully improve postoperative recovery, including the impact of pain on daily functioning. Methods: We systematically searched MEDLINE, Embase, and Cochrane CENTRAL for randomized controlled trials (RCTs) comparing systemic perioperative selective COX‑2 inhibitors with placebo, opioids, or usual care in adults. The primary outcome was postoperative acute pain, assessed using any validated multidimensional instrument evaluating pain‑related interference with daily living (e.g., Brief Pain Inventory [BPI]; 0-10 scale, minimal clinically important difference=1.0) within 1 month after surgery. Secondary outcomes included chronic pain, quality of recovery, and adverse events. Two reviewers independently performed study selection, data abstraction, risk of bias and certainty of evidence assessments. Clinical significance was assessed by estimating the difference between groups in the proportion of participants achieving the minimal important difference. Results: We screened 9,071 citations and 38 RCTs (5,424 participants) met eligibility criteria. Selective COX-2 inhibitors were associated with a reduction in acute pain‑related interference (BPI mean difference [MD], −1.1; 95% confidence interval [CI], −1.4 to −0.84; n=7; moderate certainty) and in chronic pain incidence (odds ratio, 0.44; 95% CI, 0.21 to 0.93; n=5; low certainty) but no significant effect was found on chronic pain intensity (MD, −1.0; 95% CI, −2.7 to 0.67; n=1; very low certainty). The modelled risk difference for achieving a clinically important analgesic effect showed a substantial benefit of COX-2 inhibitors for acute pain. Quality of recovery improved with the intervention (Quality of Recovery-9 [0-18 scale] MD, 0.84; 95% CI, 0.33 to 1.35; n=7; low certainty). Intraoperative blood loss was lower (MD, −22 mL; 95% CI, −40 to −4; n=3; low certainty), and no differences were observed in other adverse events (i.e., acute renal failure, gastrointestinal bleeding, impaired bone healing, myocardial infarction, stroke and death). Conclusions: Perioperative selective COX‑2 inhibitors likely provide a clinically meaningful reduction in acute pain‑related interference with daily function and may improve chronic pain and quality of recovery.

Background: Frailty is prevalent among older adults and associated with increased postoperative morbidity and death. Guidelines recommend consideration of frailty to inform preoperative cardiac risk stratification. However, its incremental prognostic value beyond established tools including clinical indices, functional capacity, and biomarkers is uncertain. Methods: We conducted a secondary analysis of a multicenter prospective cohort study involving older adults (aged ≥65 years) undergoing major elective noncardiac surgery. Frailty was assessed using the Clinical Frailty Scale. The primary outcome was 30‐day major adverse cardiac events, defined as myocardial infarction, nonfatal cardiac arrest, or death. Multivariable logistic regression evaluated the association between frailty (Clinical Frailty Scale ≥4) and major adverse cardiac events, adjusting for age, sex, Revised Cardiac Risk Index, Duke Activity Status Index, and natriuretic peptide concentration. Incremental prognostic value was assessed using the likelihood ratio test, concordance index, fraction of new predictive information, and decision curves. Results: Among 1939 participants (median age, 72 years; 42% women), 43% had frailty, and 4.9% experienced 30‐day major adverse cardiac events. The Duke Activity Status Index and the Clinical Frailty Scale were strongly correlated ( R =−0.64). Frailty was associated with major adverse cardiac events after adjustment for age, sex, and Revised Cardiac Risk Index (odds ratio, 1.62 [95% CI, 1.05–2.51]) but not after further adjustment for Duke Activity Status Index or natriuretic peptide concentrations. Frailty improved prediction beyond clinical factors alone but not when functional capacity or biomarkers were included. Conclusions: Frailty was associated with increased cardiac risk and improved prediction beyond clinical factors, but its incremental prognostic value diminished when functional capacity or biomarkers were available, supporting its selective use when these measures are unavailable.