Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.

BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

The occurrence of non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma among metastatic melanoma patients: an observational cohort study in Denmark.

BACKGROUND: Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations. However, BRAF inhibitors are found to induce cutaneous squamous cell carcinoma (cuSCC). Population-based background rates of cuSCC and non-cutaneous squamous cell carcinoma (non-cuSCC) in the metastatic melanoma population may contextualize safety signals from randomized clinical trials or the clinics. However, these background rates are lacking. METHODS: We conducted a historical cohort study to evaluate the background rates of new-onset non-melanoma skin lesions and non-cuSCC among 2,814 metastatic malignant melanoma patients diagnosed in 1997-2010, identified through the Danish Cancer Registry and the National Pathology Registry. Patients were excluded if they had a history of cancer before the metastatic melanoma diagnosis, other than skin cancers. We determined the incidence of non-melanoma malignant skin lesions and non-cuSCC that occurred post metastatic melanoma diagnosis, censoring patients at death, emigration, or December 31, 2011 (end of study period), whichever came first. RESULTS: The median age at metastatic melanoma diagnosis was 64 years. Over 40% of patients died within one year of metastatic diagnosis and ~70% died within 5 years. The percentages of patients with prior history or prevalent disease at metastatic melanoma diagnosis included: 8.6% with cuSCC or basal cell carcinoma (BCC), 3.9% with actinic keratosis (AK), and 0.7% with Bowen's disease. No patients had past or current non-cuSCC per study exclusion criterion. The incidence of non-melanoma skin lesions during the 6 months post-metastatic melanoma diagnosis was as follows: BCC, 1.8% (42.5 per 1000 person-years [PY]); AK, 0.8% (18.6 per 1000 PY); cuSCC, 0.1% (1.7 per 1000 PY); Bowen's disease, 0.04% (0.8 per 1000 PY); and keratoacanthoma (KA), 0%. Non-cuSCC was observed in 3 patients (0.1%; 2.5 per 1000 PY) at 3 sites: bronchi, heart and lung. CONCLUSION: CuSCC and non-cuSCC were rare events among metastatic melanoma patients.

Hospital-Diagnosed Pertussis Infection in Children and Long-term Risk of Epilepsy.

IMPORTANCE: Pertussis is associated with encephalopathy and seizures in infants. However, the risk of childhood epilepsy following pertussis is unknown. OBJECTIVE: To examine whether pertussis is associated with the long-term risk of epilepsy. DESIGN, SETTING, AND PARTICIPANTS: We used individually linked data from population-based medical registries covering all Danish hospitals to identify a cohort of all patients with pertussis born between 1978 and 2011, followed up through 2011. We used the Civil Registration System to identify 10 individuals from the general population for each patient with pertussis, matched on sex and year of birth. EXPOSURES: Inpatient or hospital-based outpatient diagnosis of pertussis. MAIN OUTCOMES AND MEASURES: Cumulative incidence and hazard ratio of time to hospital-based epilepsy diagnosis (pertussis cohort vs general population cohort), adjusted for birth year, sex, maternal history of epilepsy, presence of congenital malformations, and gestational age. Unique personal identifiers permitted unambiguous data linkage and complete follow-up for death, emigration, and hospital contacts. RESULTS: We identified 4700 patients with pertussis (48% male), of whom 90 developed epilepsy during the follow-up. The cumulative incidence of epilepsy at age 10 years was 1.7% (95% CI, 1.4%-2.1%) for patients with pertussis and 0.9% (95% CI, 0.8%-1.0%) for the matched comparison cohort. The corresponding adjusted overall hazard ratio was 1.7 (95% CI, 1.3-2.1). CONCLUSIONS AND RELEVANCE: In Denmark, risk of epilepsy was increased in children with hospital-diagnosed pertussis infections compared with the general population; however, the absolute risk was low.

The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients.

BACKGROUND: The Charlson comorbidity index is often used to control for confounding in research based on medical databases. There are few studies of the accuracy of the codes obtained from these databases. We examined the positive predictive value (PPV) of the ICD-10 diagnostic coding in the Danish National Registry of Patients (NRP) for the 19 Charlson conditions. METHODS: Among all hospitalizations in Northern Denmark between 1 January 1998 and 31 December 2007 with a first-listed diagnosis of a Charlson condition in the NRP, we selected 50 hospital contacts for each condition. We reviewed discharge summaries and medical records to verify the NRP diagnoses, and computed the PPV as the proportion of confirmed diagnoses. RESULTS: A total of 950 records were reviewed. The overall PPV for the 19 Charlson conditions was 98.0% (95% CI; 96.9, 98.8). The PPVs ranged from 82.0% (95% CI; 68.6%, 91.4%) for diabetes with diabetic complications to 100% (one-sided 97.5% CI; 92.9%, 100%) for congestive heart failure, peripheral vascular disease, chronic pulmonary disease, mild and severe liver disease, hemiplegia, renal disease, leukaemia, lymphoma, metastatic tumour, and AIDS. CONCLUSION: The PPV of NRP coding of the Charlson conditions was consistently high.

Incidence and risk of chondrolysis in Denmark: A nationwide population-based study.

BACKGROUND: Chondrolysis is a rare disease with destruction of cartilage of joints. Incidence and risk factors have not been studied in a formal epidemiologic population-based setting. METHODS: We used the Danish National Registry of Patients (NRP) covering all Danish hospitals to identify all cases of chondrolysis from 1994 to 2008. Incidence rates were estimated using the general population as the denominator. For each chondrolysis patient, 10 age-matched population controls were sampled for a case-control analysis. For cases and controls, we ascertained in the NRP history of diabetes, rheumatoid arthritis, orthopedic surgery, including surgery of shoulder and upper arm, injury to shoulder girdle or upper arm, and treatment with pain pump. We determined the prevalence of these risk factors in cases and controls, and computed odds ratios (OR). RESULTS: We identified 43 patients with chondrolysis in the 15-year study period. The incidence rate was 5.5 per 10,000,000 person-years. Diabetes was more prevalent in chondrolysis cases, compared with the 430 controls (OR = 6.7; 95% confidence intervals [CI]: 1.1-39.9). Orthopedic surgery was also associated with an increased risk of chondrolysis (OR = 28.8, 95% CI: 11.0-75.6), while previous injury was not (OR = 0.8; 95% CI: 0.1-5.9). CONCLUSION: Chondrolysis was rarely diagnosed in Denmark. Diabetes and orthopedic surgery may be risk factors.