Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study.

BACKGROUND: Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown. STUDY DESIGN AND METHODS: Sub-study of the inception cohort study 'Thrombocytopenia and Platelet Transfusions in the ICU (PLOT-ICU)', including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 109/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. RESULTS: Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1-4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180-308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 1011 platelets/transfusion) whilst some (mainly in France) used weight-based dosing (ranging from 0.5 to 0.7 × 1011 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (-1 to 8) × 109/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. CONCLUSIONS: Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts.

Real-world causal evidence for planned predictive enrichment in critical care trials: A scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness due, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Although causal evidence from rich real-world critical care can help overcome these challenges by informing predictive enrichment, no overview exists. METHODS: We conducted a scoping review, systematically searching 10 general and speciality journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We collected trial metadata on 22 variables including recruitment period, intervention type and early stopping (including reasons) as well as data on the use of causal evidence from secondary data for planned predictive enrichment. RESULTS: We screened 9020 records and included 316 unique RCTs with a total of 268,563 randomised participants. One hundred seventy-three (55%) trials tested drug interventions, 101 (32%) management strategies and 42 (13%) devices. The median duration of enrolment was 2.2 (IQR: 1.3-3.4) years, and 83% of trials randomised less than 1000 participants. Thirty-six trials (11%) were restricted to COVID-19 patients. Of the 55 (17%) trials that stopped early, 23 (42%) used predefined rules; futility, slow enrolment and safety concerns were the commonest stopping reasons. None of the included RCTs had used causal evidence from secondary data for planned predictive enrichment. CONCLUSION: Work is needed to harness the rich multiverse of critical care data and establish its utility in critical care RCTs. Such work will likely need to leverage methodology from interventional and analytical epidemiology as well as data science.

Platelet transfusions in adult thrombocytopenic ICU patients: Protocol for a sub-study of the PLOT-ICU cohort.

INTRODUCTION: Platelet transfusions are frequently used in intensive care unit (ICU) patients, but contemporary epidemiological data are sparse. We aim to present contemporary international data on the use of platelet transfusions in adult ICU patients with thrombocytopenia. METHODS: This is a protocol and statistical analysis plan for a post hoc sub-study of 504 thrombocytopenic patients from the 'Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)'. The primary outcome will be the number of patients receiving platelet transfusion in the ICU reported according to the type of product received (apheresis-derived versus pooled whole-blood-derived transfusions). Secondary platelet transfusion outcomes will include platelet transfusion volumes; timing of platelet transfusion; approach to platelet transfusion dosing (fixed dosing versus weight-based dosing) and platelet count increments for prophylactic transfusions. Secondary clinical outcomes will include the number of patients receiving red blood cell- and plasma transfusions during ICU stay; the number of patients who bled in the ICU, the number of patients who had a new thrombosis in the ICU, and the number of patients who died. The duration of follow-up was 90 days. Baseline characteristics and secondary clinical outcomes will be stratified according to platelet transfusion status in the ICU and severity of thrombocytopenia. Data will be presented descriptively. CONCLUSIONS: The outlined study will provide detailed epidemiological data on the use of platelet transfusions in adult ICU patients with thrombocytopenia using data from the large international PLOT-ICU cohort study. The findings will inform the design of future randomised trials evaluating platelet transfusions in ICU patients.

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU).

PURPOSE: Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. METHODS: We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. RESULTS: We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4-46.1) had thrombocytopenia; 23.4% (20-26) had thrombocytopenia at ICU admission, and 19.8% (17.6-22.2) developed thrombocytopenia during their ICU stay. Absence of acquired immune deficiency syndrome (AIDS), non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19-2.42). CONCLUSION: Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.

Patient and public involvement in contemporary large intensive care trials: A meta-epidemiological study.

BACKGROUND: Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials. METHODS: We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary. RESULTS: We included 100 trials, with 18 using patient and public involvement; these were larger and conducted in more centres than trials without patient and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1-6894) were involved. CONCLUSIONS: We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted.

Strategies to Improve the Impact of Artificial Intelligence on Health Equity: Scoping Review.

BACKGROUND: Emerging artificial intelligence (AI) applications have the potential to improve health, but they may also perpetuate or exacerbate inequities. OBJECTIVE: This review aims to provide a comprehensive overview of the health equity issues related to the use of AI applications and identify strategies proposed to address them. METHODS: We searched PubMed, Web of Science, the IEEE (Institute of Electrical and Electronics Engineers) Xplore Digital Library, ProQuest U.S. Newsstream, Academic Search Complete, the Food and Drug Administration (FDA) website, and ClinicalTrials.gov to identify academic and gray literature related to AI and health equity that were published between 2014 and 2021 and additional literature related to AI and health equity during the COVID-19 pandemic from 2020 and 2021. Literature was eligible for inclusion in our review if it identified at least one equity issue and a corresponding strategy to address it. To organize and synthesize equity issues, we adopted a 4-step AI application framework: Background Context, Data Characteristics, Model Design, and Deployment. We then created a many-to-many mapping of the links between issues and strategies. RESULTS: In 660 documents, we identified 18 equity issues and 15 strategies to address them. Equity issues related to Data Characteristics and Model Design were the most common. The most common strategies recommended to improve equity were improving the quantity and quality of data, evaluating the disparities introduced by an application, increasing model reporting and transparency, involving the broader community in AI application development, and improving governance. CONCLUSIONS: Stakeholders should review our many-to-many mapping of equity issues and strategies when planning, developing, and implementing AI applications in health care so that they can make appropriate plans to ensure equity for populations affected by their products. AI application developers should consider adopting equity-focused checklists, and regulators such as the FDA should consider requiring them. Given that our review was limited to documents published online, developers may have unpublished knowledge of additional issues and strategies that we were unable to identify.

Operational Insights into Analysing Team and Player Performance in Elite Rugby League: A Narrative Review with Case Examples.

In professional team sports, like Rugby League, performance analysis has become an integral part of operational practices. This has helped practitioners gain deeper insight into phenomena like team and athlete behaviour and understanding how such behaviour may be influenced by various contextual factors. This information can then be used by coaches to design representative practice tasks, inform game principles and opposition strategies, and even support team recruitment practices. At the elite level, the constant evolution of sports technology (both hardware and software) has enabled greater access to information, making the role of the performance analyst even more valuable. However, this increase in information can create challenges regarding which variables to use to help guide decision-making, and how to present it in ways that can be utilised by coaches and other support staff. While there are published works exploring aspects of performance analysis in team sports like Rugby League, there is yet to be a perspective that explores the various operational uses of performance analysis in Rugby League, the addition of which could help guide the practices of emerging performance analysts in elite organisations like the Australian National Rugby League and the European Super League. Thus, this narrative review-with accompanying case examples-explores the various ways performance analysis can help address pertinent operational questions commonly encountered when working in high-performance sport.

Platelet transfusions and thrombocytopenia in intensive care units: Protocol for an international inception cohort study (PLOT-ICU).

INTRODUCTION: Thrombocytopenia is frequent in intensive care unit (ICU) patients and has been associated with worse outcome. Platelet transfusions are often used in the management of ICU patients with severe thrombocytopenia. However, the reported frequencies of thrombocytopenia and platelet transfusion practices in the ICU vary considerably. Therefore, we aim to provide contemporary epidemiological data on thrombocytopenia and platelet transfusion practices in the ICU. METHODS: We will conduct an international inception cohort, including at least 1000 acutely admitted adult ICU patients. Routinely available data will be collected at baseline (ICU admission), and daily during ICU stay up to a maximum of 90 days. The primary outcome will be the number of patients with thrombocytopenia (a recorded platelet count < 150 × 109 /L) at baseline and/or during ICU stay. Secondary outcomes include mortality, days alive and out of hospital, days alive without life-support, the number of patients with at least one bleeding episode, at least one thromboembolic event and at least one platelet transfusion in the ICU, the number of platelet transfusions and the indications for transfusion. The primary and secondary outcomes will be presented descriptively. In addition, we will assess risk factors for developing thrombocytopenia during ICU stay and the association between thrombocytopenia at baseline and 90-day mortality using logistic regression analyses. CONCLUSION: The outlined international PLOT-ICU cohort study will provide contemporary epidemiological data on the burden and clinical significance of thrombocytopenia in adult ICU patients and describe the current platelet transfusion practice.

Causal inference for planning randomised critical care trials: Protocol for a scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness owing, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Planned predictive enrichment based on secondary critical care data (often very rich with respect to both data types and temporal granularity) and causal inference methods may help overcome these challenges, but no overview exists about their use to this end. METHODS: We will conduct a scoping review to assess the extent and nature of the use of causal inference from secondary data for planned predictive enrichment of randomised clinical trials in critical care. We will systematically search 10 general and specialty journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We will collect trial metadata (e.g., recruitment period and phase) and, when available, information pertaining to the focus of the review (predictive enrichment based on causal inference estimates from secondary data): causal inference methods, estimation techniques and software used; types of patient populations; data provenance, types and models; and the availability of the data (public or not). The results will be reported in a descriptive manner. DISCUSSION: The outlined scoping review aims to assess the use of causal inference methods and secondary data for planned predictive enrichment in randomised critical care trials. This will help guide methodological improvements to increase the utility, and facilitate the use, of causal inference estimates when planning such trials in the future.

Chemo- and regio-divergent access to fluorinated 1-alkyl and 1-acyl triazenes from alkynyl triazenes.

The 1,1,2,2-tetrafluoroethylene unit is prevalent in bioactive molecules and functional materials. Despite being in principle a straightforward strategy to access this motif, the direct tetrafluorination of alkynes involves very hazardous or inconvenient reagents. Therefore, safer and convenient alternatives are sought after. We developed a mild and operationally simple perfluorination method converting 1-alkynyl triazenes into 1,1,2,2-tetrafluoro alkyl triazenes, employing cheap and readily accessible reagents. Moreover, a judicious tuning of the reaction conditions enables access to α-difluoro triazenyl ketones. Complementary, electrophilic fluorination of alkynyl triazenes gives rise to the regioisomeric α-difluoro acyl triazenes. These three chemo- and regio-divergent protocols enable access to elusive fluorinated 1-alkyl and 1-acyl triazenes, thus expanding the chemical space for these unusual entities. Furthermore, several reaction intermediates and side products revealed insights on the reaction pathways that may be useful for further fluorination chemistry of alkynes.

Synthesis of bicyclic vinyl triazenes by Ficini-type reactions.

Cyclic olefins with triazene functions can display interesting reactivity, but synthetic access to these compounds is limited thus far. Herein, we describe the synthesis of cyclobutenyl triazenes fused to cyclopentanone or cyclohexanone rings. The bicyclic compounds are obtained by Lewis acid-catalyzed [2 + 2] cycloaddition reactions of 1-alkynyl triazenes and enones. In the presence of Me2AlCl, bicyclic [4.2.0] triazenes rearrange into [3.2.1] ring systems. The triazene function in the latter can be used for further functionalizations. Notably, we show that vinyl triazenes can serve as substrates for Pd-catalyzed cross-coupling reactions with arylboronic acids.

Alkynyl triazenes enable divergent syntheses of 2-pyrones.

The 2-pyrone motif occurs frequently in bioactive natural products and is appreciated as synthetic intermediates. However, only few methods allow for diversifying functional group modifications on this relevant heterocycle. The distinct properties of 1-alkynyl triazenes promote a smooth addition of propiolic acids across the triple bond. Addition of catalytic amounts of silver salt induces cyclization to 2-pyrones. Depending on the reaction temperature, either 6-triazenyl or 5-triazenyl 2-pyrones are selectively formed. The triazenyl unit is subsequently replaced by a variety of valuable groups in a one-pot process yielding for instance 2-fluoro pyrones. The substitution occurs with an intriguing 1,5-carbonyl transposition. Moreover, the triazenyl group serves as traceless activating group for subsequent Diels-Alder cycloadditions and as a constituting unit for rare fused aminopyrazole pyrone heterocycles.

Patient and public involvement in contemporary large intensive care trials: Protocol for a meta-epidemiological study.

BACKGROUND: Patient and public involvement (PPI) in randomized clinical trials (RCTs) has increased in recent years but remains the exception rather than the rule. We aim to assess the frequency and extent of PPI in large, contemporary RCTs conducted in an intensive care setting. METHODS AND DESIGN: We will conduct a meta-epidemiological study of RCTs conducted in intensive care settings published since 2019 and assess their use of PPI. We will extract trial characteristics and verify the use of PPI with trial authors unless specifically stated in the published paper. The primary outcome will be the proportion of trials that use PPI. Secondary outcomes will explore which groups are consulted, at which stage of the trial process this occurs, and by what means these opinions are collected and implemented. DISCUSSION: This meta-epidemiological study will provide an important insight into the use of PPI in large, contemporary intensive care trials. We wish to reveal ways in which patient involvement could be incorporated more broadly and purposefully here and help to empower clinicians, researchers and patients to collaborate further on future research processes and goals.

Patient-important outcomes other than mortality in recent ICU trials: Protocol for a scoping review.

BACKGROUND: Randomised clinical trials (RCTs) conducted in intensive care units (ICUs) frequently focus on all-cause mortality, but other patient-important outcomes are increasingly used and recommended. Their use, however, is not straightforward: choices and definitions, operationalisation of death, handling of missing data, choice of effect measures, and statistical analyses for these outcomes vary greatly. METHODS: We will conduct a scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. We will search 10 selected general and speciality journals for RCTs conducted in adult ICU patients from 2018 and onwards reporting at least 1 patient-important outcome other than mortality (including days alive without life support/days alive and out of hospital-type outcomes, health-related quality of life, functional/cognitive/neurological outcomes, and other general patient-important outcomes). We will summarise data on outcome measures and definitions, assessment time points, proportions and handling of death, proportions and handling of missing data, and effect measures and statistical methods used for analysis. DISCUSSION: The outlined scoping review will provide an overview of choices, definitions and handling of patient-important outcomes other than mortality in contemporary RCTs conducted in adult ICU patients. This may guide discussions with patients and relatives, the design of future RCTs, and research on optimal outcome choices and handling.

Zinc Protoporphyrin Is a Reliable Marker of Functional Iron Deficiency in Patients with Inflammatory Bowel Disease.

Iron deficiency (ID) is a common manifestation of inflammatory bowel disease (IBD), arising primarily due to chronic inflammation and/or blood loss. There is no gold standard for ID diagnosis, which is often complicated by concomitant inflammation. Zinc protoporphyrin (ZnPP) correlates with parameters of iron homeostasis and has been identified as a promising marker for ID, irrespective of inflammation. We investigated the diagnostic performance of ZnPP in ID, iron deficiency anemia, anemia of chronic disease and mixed anemia in a cross-sectional study in 130 patients with IBD. Different parameters were compared by receiver operator characteristic (ROC) analysis as detectors of iron-restricted erythropoiesis (IRE). IRE was detected in 91 patients (70.0%); fifty-nine (64.8%) had absolute ID and 23 (25.4%) functional ID. When inflammation was present, ZnPP was a more reliable sole biomarker of IRE than MCV, transferrin saturation (TSAT) or ferritin (AUC; 0.855 vs. 0.763, 0.834% and 0.772, respectively). The specificity of TSAT was significantly lower than ZnPP when inflammation was present (38% vs. 71%, respectively). We conclude that ZnPP is a reliable biomarker of functional ID in patients with IBD and more dependable than ferritin or TSAT, which are influenced by chronic inflammation. We propose that ZnPP may also have utility in patients with other chronic diseases.

Time to onset of gastrointestinal bleeding in the SUP-ICU trial: A pre-planned substudy.

BACKGROUND: The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to the onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP). METHODS: We assessed the time to CIB in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. We assessed if associations between baseline characteristics including allocation to SUP and CIB changed during time in the ICU, specifically in the later (after day 2) compared to the earlier (first 2 days) period, using Cox models adjusted for SAPS II and allocation to SUP. Additionally, we described baseline characteristics and CIB episodes stratified by earlier/later/no CIB and 90-day mortality status. RESULTS: Clinically important gastrointestinal bleeding occurred in 110/3291 (3.3%) patients after a median of 6 (interquartile range 2-13) days; 25.5% of the episodes occurred early. Higher SAPS II was consistently associated with increased risk of CIB (hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05 in the earlier period vs HR 1.02, 95% CI 1.01-1.03 in the later period; P = .37); university hospital admission was associated with decreased risk of earlier CIB (HR 0.30, 95% CI 0.14-0.63); this significantly increased in the later period (to HR 0.85, 95% CI 0.53-1.37; P = .02). Patients with later compared to earlier CIB received more transfusions and had more diagnostic/therapeutic procedures for CIB. CONCLUSIONS: Clinically important gastrointestinal bleeding mostly occurred more than 2 days after randomization. University hospital admission was associated with significantly decreased risk of CIB in the earlier period only.

Overall bias and sample sizes were unchanged in ICU trials over time: a meta-epidemiological study.

OBJECTIVE: To assess time trends in risk of bias (RoB) and sample sizes in randomized clinical trials (RCTs) of adult intensive care unit (ICU) patients. STUDY DESIGN AND SETTING: A meta-epidemiological study of RCTs from Cochrane systematic reviews assessing interventions in adult ICU patients. Using run charts, we assessed time trends in the annual proportion of RCTs with overall low RoB, the annual median sample sizes, and the annual proportion of RCTs with low, unclear, and high RoB in individual bias domains. RESULTS: We included 604 RCTs published between 1977 and 2018 from 53 Cochrane systematic reviews. Only 6.8% of the RCTs had overall low RoB. We observed only random variation in the annual proportions of RCTs with overall low RoB, in the annual median sample sizes and in most individual bias domains. For "allocation concealment," we observed an increase in the proportion of low RoB RCTs and a decrease in the unclear RoB RCTs. CONCLUSIONS: Few RCTs in adult ICU patients had overall low RoB. We found no evidence of an increase in RCTs with overall low RoB or in the median sample sizes over time. The only individual RoB domain with better ratings over time was "allocation concealment."