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.

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.

Insufficiency fractures of the knee, ankle, and foot in rheumatoid arthritis: A case series and case-control study.

OBJECTIVE: To evaluate cases of insufficiency fractures verified by magnetic resonance imaging (MRI) of the knee, ankle, and foot in patients with rheumatoid arthritis (RA) cared for in our clinic over an 8-year period, to identify possible risk factors, and to test these in a case-control study. METHODS: All patients in the rheumatology clinic with RA were registered prospectively in the database, DANBIO. All MRIs ordered from the clinic were registered and coded according to the anatomical region. We were thus able to retrieve all patients with RA and performed an MRI of the knee or ankle/foot. The patients with fractures constituted the case series, and the patients without fractures constituted the control group. RESULTS: The RA clinic population comprised 1,624 patients who underwent a total of 70 MRIs. CASE SERIES: 39 insufficiency fractures were identified in 32 patients; 93% were women, and the median age was 68 years (range 33-89 years). Half of the patients had a T score >-2.5. The case control group without fractures comprised 38 patients; 74% were women, and the median age was 62 years (range 32-84 years). In the case series, 20 patients experienced later additional episodes of insufficiency fractures in the knee, ankle, or foot. CONCLUSION: Insufficiency fractures of the knee, ankle, and foot are a significant cause of pain and long-lasting disability in RA. Recurrent fractures are common. Diagnosis is often delayed and confused with arthritic activity. Conventional radiography and DEXA scan are often normal. Older age, female gender, radiological erosions in hand/wrist, and treatment with methotrexate were all significantly associated with fractures.

[Primary septic arthritis is a rare, atypical manifestation of invasive meningococcal disease].

We present a case report of a 50-year-old man diagnosed with a primary septic arthritis with invasive Neisseria meningitidis serogroup W (MenW) clonal complex 11 identified with culture in blood and synovial fluid. The patient recovered from rapidly instituted relevant antibiotics and synovectomy, but there may be a risk of fatal delayed diagnosis and treatment by an atypical manifestation of invasive meningococcal disease. Invasive MenW disease has been increasing in recent years and has been described with atypical presentations.