Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Overview of diagnosis and management of paediatric headache. Part I: diagnosis

Headache is the most common somatic complaint in children and adolescents. The evaluation should include detailed history of children and adolescents completed by detailed general and neurological examinations. Moreover, the possible role of psychological factors, life events and excessively stressful lifestyle in influencing recurrent headache need to be checked. The choice of laboratory tests rests on the differential diagnosis suggested by the history, the character and temporal pattern of the headache, and the physical and neurological examinations. Subjects who have any signs or symptoms of focal/progressive neurological disturbances should be investigated by neuroimaging techniques. The electroencephalogram and other neurophysiological examinations are of limited value in the routine evaluation of headaches. In a primary headache disorder, headache itself is the illness and headache is not attributed to any other disorder (e.g. migraine, tension-type headache, cluster headache and other trigeminal autonomic cephalgias). In secondary headache disorders, headache is the symptom of identifiable structural, metabolic or other abnormality. Red flags include the first or worst headache ever in the life, recent headache onset, increasing severity or frequency, occipital location, awakening from sleep because of headache, headache occurring exclusively in the morning associated with severe vomiting and headache associated with straining. Thus, the differential diagnosis between primary and secondary headaches rests mainly on clinical criteria. A thorough evaluation of headache in children and adolescents is necessary to make the correct diagnosis and initiate treatment, bearing in mind that children with headache are more likely to experience psychosocial adversity and to grow up with an excess of both headache and other physical and psychiatric symptoms and this creates an important healthcare problem for their future life

Validation of the Single Assessment Numeric Evaluation (SANE) Score as an Outcome Measure as Compared to the revised Foot Function Index (rFFI)

Category: Other Introduction/Purpose: Patient reported outcome measures serve as an invaluable tool in both the clinical and research setting to monitor a patient’s condition and efficacy of treatments over time. We aim to validate the Single Assessment Numeric Evaluation (SANE) score for disorders of the lower extremity using the revised Foot Function Index (rFFI) as a reference. The rFFI is a validated 34-question survey tool utilized in the evaluation of patients with foot and ankle related pathology [1-4], while the SANE score consists of a patient’s single numerical rating of the status of their extremity [5]. Given its ease of use and prior validation with shoulder pathology, the SANE score has potential as a practical and effective outcome measure in foot and ankle pathology. Methods: Patient age, sex, visit diagnosis by ICD-10 code, SANE score, and FFI score were collected retrospectively from 218 initial patient encounters between January 2015 through July 2017. Patients were included if they were 18 years and older presenting for outpatient evaluation to the University of Connecticut Foot and Ankle Orthopedic Department. Patients were excluded if they had incomplete SANE or rFFI data. The rFFI is a 34-question survey with subscales including pain (7 questions), stiffness (7 questions), activity limitation (3 questions), difficulty (11 questions), and social issues (6 questions). Results of the two scores were compared using the Pearson or Spearman correlation coefficients with correlation defined as excellent (>0.7), excellent-good (0.61-0.7), good (0.4-0.6), or poor (0.2-0.39) [6]. Diagnoses were categorized into 9 subgroups that were analyzed including: forefoot, plantar fasciitis, arthritis, deformity, fracture, tendinitis, OCD, soft tissue trauma and “other”. Results: The SANE score had good correlation with the overall rFFI score (r=0.51, p<0.001). When comparing the SANE score to the rFFI subscores, there was good correlation with pain (r=0.42, p<0.001), good correlation with stiffness (r=0.44, p<0.001), poor correlation with activity (r=0.36, p<0.001), good correlation with difficulty (r=0.52, p<0.001), and poor correlation with social issues (r=0.39, p<0.001). Sub-analysis showed an excellent to good correlation between SANE and rFFI score for forefoot pathology (r=0.67, p<0.001), “other” pathologies (r=0.65, p<0.001), and plantar fasciitis (r=0.63, p<0.016), good correlation for arthritis (r=0.49, p<0.038), deformity (r=0.60, p<0.010), fracture (r=0.50, p<0.004), and tendinitis (r=0.47, p<0.017), and no significant correlation for OCD of the talus (r=0.56, p<0.145) and soft tissue trauma (r=0.19, p<0.319). Conclusion: The SANE score demonstrates good correlation with the rFFI overall. However, its correlation varies depending on the subscore of the rFFI and the presenting pathology of the patient. The SANE score correlates best with the rFFI pain, stiffness, and difficulty subscore, and poorly with activity and social issues. In addition, the SANE score correlates best with forefoot pathologies, plantar fasciitis, and “other” pathologies but does not correlate with patients presenting for OCD of the talus or soft tissue trauma

Plasma Interleukin-6 Predicts Clinical Decline After Completion of Dexamethasone Therapy in Severe COVID-19

OBJECTIVES:. To identify and characterize clinical decline after completion of dexamethasone in severe COVID-19 and determine whether interleukin (IL)-6 and other inflammatory biomarkers predict the occurrence of clinical decline. DESIGN:. Prospective observational cohort. SETTING:. ICUs in three University of Washington affiliated hospitals between July 2020 and April 2021. PATIENTS:. Patients admitted to an ICU with COVID-19 who completed a course of dexamethasone. MEASUREMENTS AND MAIN RESULTS:. We identified 65 adult patients with severe COVID-19 who completed a 10-day course of dexamethasone, of whom 60 had plasma samples collected within 3 days of dexamethasone completion. We measured IL-6 with a clinical-grade electrochemiluminescent assay and a larger panel of inflammatory biomarkers (IL-8, Monocyte Chemoattractant Protein-1, Monocyte Inflammatory Protein-1 alpha, interferon gamma, C-X-C Motif Chemokine Ligand 10, WBC, bicarbonate) with a research immunoassay. We defined clinical decline by the occurrence of incident severe kidney injury, incident or escalating shock or fever, worsening hypoxemia, or death within 5 days of completion of dexamethasone. We estimated risk for clinical decline by standardized log2 transformed biomarker concentration using multivariable logistic regression. Clinical decline post-dexamethasone was common, occurring in 49% of patients (n = 32). Among all biomarkers, IL-6 levels were most strongly associated with clinical decline. After adjustment for age, sex, and study site, the odds of post-dexamethasone clinical decline were 7.33 times higher per one sd increase in log2 transformed IL-6 concentrations (adjusted odds ratio, 7.33; CI, 2.62–20.47; p < 0.001). The discriminatory power of IL-6 for clinical decline was high (cross-validated mean area under the receiver operating characteristic curve, 0.90; 95% CI, 0.79–0.95). CONCLUSIONS:. Clinical decline after completion of dexamethasone for severe COVID-19 is common. IL-6 concentrations obtained prior to completion of dexamethasone may have utility in identifying those at highest risk for subsequent worsening. If validated, future work might test whether plasma IL-6 could be used as a tool for a personalized approach to duration of dexamethasone treatment in severe COVID-19