Citations

AbstractCancer, the unregulated proliferation of cells, can occur at any age and may arise from almost all cell types. However, the incidence and types of cancer differ with age. Some cancers are predominantly observed in children, others are mostly restricted to older ages. Treatment strategies of some cancers are very successful and cure is common in childhood, while treatment of the same cancer type is much more challenging in adults. Here, we develop a stochastic model of stem cell proliferation that considers both tissue development and homeostasis and discuss the disturbance of such a system by mutations. Due to changes in population size, mutant fitness becomes context dependent and consequently the effects of mutations on the stem cell population can vary with age. We discuss different mutant phenotypes and show the age dependency of their expected abundances. Most importantly, fitness of particular mutations can change with age and advantageous mutations can become deleterious or vice versa. This perspective can explain unique properties of childhood disorders, for example, the frequently observed phenomenon of a self-limiting leukemia in newborns with trisomy 21, but also explains other puzzling observations such as the increased risk of leukemia in patients with bone marrow failure or chemotherapy induced myelodysplasia.

AbstractAimsPatients with rheumatoid arthritis (RA) might be at an increased risk of developing atrial fibrillation (AF) as a result of deleterious effects of inflammatory cytokines on cardiomyocytes. This study aimed to comprehensively review all available evidence to further characterize this possible association.MethodsWe conducted a systematic review and meta‐analysis of cohort studies that reported relative risk, hazard ratio, incidence ratio or standardized incidence ratio with 95% confidence intervals comparing the risk of incidence of AF in patients with RA versus non‐RA participants. Pooled risk ratio and 95% confidence interval were calculated using random‐effect, generic inverse‐variance methods of DerSimonian and Laird.ResultsThree retrospective cohort studies with 39 912 cases of RA and 4 269 161 non‐RA controls were included in the data analysis. The pooled risk ratio of subsequent development of AF in patients with RA versus controls was 1.29 (95% CI, 1.05–1.59). The statistical heterogeneity was moderate with an I2 of 71%.ConclusionOur meta‐analysis demonstrated a statistically significant increased risk of subsequent development of AF among patients with RA.

ObjectiveAdolescent overweight and obesity and smoking continue to be very important health challenges because of their lasting effects on overall health. Weight gain after smoking cessation is a barrier to quitting as well as a negative consequence to health. This study reports changes in the body mass index (BMI) z‐scores of adolescent smokers participating in a dose‐ranging clinical trial of bupropion SR (150 mg/day and 300 mg/day) for smoking cessation.MethodsA total of N = 296 adolescent smokers (placebo n = 100, 150 mg/day n = 101, 300 mg/day n = 95) with a BMI z‐score of 0.5 (sd: 1.4), 0.5 (sd: 1.3), and 0.5 (sd: 1.2) in the placebo, 150 mg/day, and 300 mg/day groups, respectively, were followed for 6 months.ResultsAdolescents in the 300 mg/day group had a significant reduction in BMI z‐score 6 weeks after quitting (β = −0.16, CI = (−0.29, −0.04), P‐value = 0.01). This result was not sustained at the 6‐month follow‐up.ConclusionsA reduction in BMI z‐score during smoking cessation with bupropion has important implications for the future of adolescent smoking cessation. These results are particularly relevant for adolescents who have either overweight or obesity or who have reservations about quitting for fear of gaining weight or BMI.

Biological advances have radically expanded our insights into the underpinnings of health and disease. New knowledge has formed the substrate for translation—expedited in turn by the biotechnology and pharmaceutical industry into novel therapeutic solutions impacting the management of patients and populations. Indeed, this Bioinnovation Enterprise has become the dominant growth sector in drug development and the engine driving the translation of breakthrough therapies worldwide. This annual Therapeutic Innovations issue highlights recent exceptional advances by the Bioinnovation Enterprise in translating molecular insights in pathobiology into transformative therapies.

AbstractBackground and Aim:Liver stiffness (LS) measured by magnetic resonance elastography (MRE) is emerging as an important biomarker in chronic liver diseases. We examined the diagnostic performance of MRE, factors associated with an increased LS and the prognostic value of LS as measured by MRE among patients with primary sclerosing cholangitis (PSC).Methods:We performed a retrospective review of 266 patients with PSC to examine whether LS was associated with the primary endpoint of hepatic decompensation (ascites, variceal hemorrhage and hepatic encephalopathy). The ability of MRE to differentiate stages of fibrosis was examined in a subset of patients who underwent a liver biopsy (n = 20).Results:An LS of 4.93 kPa was the optimal point to detected F4 fibrosis (sensitivity, 1.00; 95% confidence interval (CI), 0.40–1.00; specificity, 0.94; 95%CI, 0.68–1.00). While a serum alkaline phosphatase <1.5 times the upper limit of normal excluded the presence of advanced LS, it was not associated with the primary endpoint (hazard ratio, 0.26; 95%CI, 0.01–1.33). However, LS was associated with the development of decompensated liver disease (hazard ratio, 1.55; 95%CI, 1.41–1.70). The optimal LS thresholds that stratified patients at a low, medium and high risk for hepatic decompensation were <4.5, 4.5–6.0 and >6.0 kPa (respectively).Conclusion:Magnetic resonance elastography is able to detect cirrhosis with high specificity and an alkaline phosphatase <1.5 times the upper limit of normal makes the presence of advanced LS unlikely. Moreover, LS obtained by MRE is predictive of hepatic decompensation in PSC.

Background Migraine, especially chronic migraine (CM), causes substantial disability; however, health care utilization has not been well characterized among patients receiving different migraine prophylactic treatments. Methods Using a large, US-based, health care claims database, headache-related health care utilization was evaluated among adults with CM treated with onabotulinumtoxinA or oral migraine prophylactic medications (OMPMs). Headache-related health care utilization was assessed at six, nine, and 12 months pre- and post-treatment. The primary endpoint was the difference between pre- and post-index headache-related health care utilization. A logistic regression model was created to test the difference between onabotulinumtoxinA and OMPM-treated groups for headache-related emergency department (ED) visits and hospitalizations. Results Baseline characteristics were comparable between groups. The proportion of patients with ED visits or hospitalizations for a headache-related event decreased after starting onabotulinumtoxinA, but increased after starting an OMPM, for all three cohorts. Regression analyses showed that the odds of having a headache-related ED visit were 21%, 20%, and 19% lower and hospitalization were 47%, 48%, and 56% lower for the onabotulinumtoxinA group compared to the OMPM group for the six-month, nine-month, and 12-month post-index periods, respectively. Conclusions When compared with similar patients who initiated treatment with OMPM, onabotulinumtoxinA was associated with a significantly lower likelihood of headache-related ED visits and hospitalizations.