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.

Serum AMH concentration as a marker evaluating gonadal function in boys operated on for unilateral cryptorchidism between 1st and 4th year of life

The aim of this study was to measure the serum AMH (anti-Mullerian hormone) concentrations in a group of boys with or without cryptorchidism, evaluation of karyotypes, testicular position, morphology, and major length of the undescended testes. Fifty boys who were 1–4 years old (median = 2.4 years) with unilateral cryptorchidism were evaluated. All of them underwent orchidopexy in 2010. Prior to the procedure, all of the subjects had undergone karyotyping to exclude chromosomal abnormalities. Fifty healthy boys within the same age range (median = 2.1 years) admitted for planned inguinal hernia repair in 2010, served as controls. Blood samples were collected, while obtaining blood for standard laboratory tests routinely performed before the surgeries. Medians of AMH in boys with cryptorchidism were lower than in boys with inguinal hernia and differed significantly between two groups. Undescended testes were generally found in superficial inguinal pouch (n = 46), in two cases were noted to be in the external ring of the inguinal canal, and in another two instances, in the abdominal cavity. The major lengths of the undescended testes were smaller in comparison to the testes positioned normally (mean of 1 cm vs. a mean of 1.5 cm, respectively). In nine of the cases, the testes had turgor deficit, a drop shape, with epididymides that were small, dysplastic, and separated from the testis. The authors found that AMH was lower in boys with unilateral cryptorchidism (also found to have smaller testis) when compared with the control group

Patient-reported outcomes in palliative gastrointestinal stenting: a Norwegian multicenter study

Background The clinical effect of stent treatment has been evaluated by mainly physicians; only a limited number of prospective studies have used patient-reported outcomes for this purpose. The aim of this work was to study the clinical effect of self-expanding metal stents in treatment of malignant gastrointestinal obstructions, as evaluated by patient-reported outcomes, and compare the rating of the treatment effect by patients and physicians. Methods Between November 2006 and April 2008, 273 patients treated with SEMS for malignant GI and biliary obstructions were recruited from nine Norwegian hospitals. Patients and physicians assessed symptoms independently at the time of treatment and after 2 weeks using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire supplemented with specific questions related to obstruction. Results A total of 162 patients (99 males; median age = 72 years) completed both assessments and were included in the study. A significant improvement in the mean global health score was observed after 2 weeks (from 9 to 18 on a 0–100 scale, P\0.03) for all stent locations. Both patients and physicians reported a significant reduction in all obstruction-related symptoms ([20 on the 0–100 scale, P\0.006) after SEMS treatment. The physicians reported a larger mean improvement in symptoms than did the patients, mainly because they reported more severe symptoms before treatment. Conclusion SEMS treatment is effective in relieving symptoms of malignant GI and biliary obstruction, as reported by patients and physicians. The physicians, however, reported a larger reduction in obstructive symptoms than did the patients. A prospective assessment of patientreported outcomes is important in evaluating SEMS treatment

From Mendel’s discovery on pea to today’s plant genetics and breeding

In 2015, we celebrated the 150th anniversary of the presentation of the seminal work of Gregor Johann Mendel. While Darwin’s theory of evolution was based on differential survival and differential reproductive success, Mendel’s theory of heredity relies on equality and stability throughout all stages of the life cycle. Darwin’s concepts were continuous variation and “soft” heredity; Mendel espoused discontinuous variation and “hard” heredity. Thus, the combination of Mendelian genetics with Darwin’s theory of natural selection was the process that resulted in the modern synthesis of evolutionary biology. Although biology, genetics, and genomics have been revolutionized in recent years, modern genetics will forever rely on simple principles founded on pea breeding using seven single gene characters. Purposeful use of mutants to study gene function is one of the essential tools of modern genetics. Today, over 100 plant species genomes have been sequenced. Mapping populations and their use in segregation of molecular markers and marker–trait association to map and isolate genes, were developed on the basis of Mendel's work. Genome-wide or genomic selection is a recent approach for the development of improved breeding lines. The analysis of complex traits has been enhanced by high-throughput phenotyping and developments in statistical and modeling methods for the analysis of phenotypic data. Introgression of novel alleles from landraces and wild relatives widens genetic diversity and improves traits; transgenic methodologies allow for the introduction of novel genes from diverse sources, and gene editing approaches offer possibilities to manipulate gene in a precise manner

Timing of tracheostomy in acute traumatic spinal cord injury: a systematic review and meta-analysis

Abstract Background Patients with acute traumatic cervical or high thoracic level spinal cord injury (SCI) typically require mechanical ventilation (MV) during their acute admission. Placement of a tracheostomy is preferred when prolonged weaning from MV is anticipated. However, the optimal timing of tracheostomy placement in patients with acute traumatic SCI remains uncertain. We systematically reviewed the literature to determine the effects of early versus late tracheostomy or prolonged intubation in patients with acute traumatic SCI on important clinical outcomes.Methods Six databases were searched from their inception to January 2020. Conference abstracts from relevant proceedings and the gray literature were searched to identify additional studies. Data was obtained by two independent reviewers to ensure accuracy and completeness. The quality of observational studies was evaluated using the Newcastle Ottawa Scale (NOS).Results Seventeen studies (2,804 patients) met selection criteria, 14 of which were published after 2009. Meta-analysis showed that early tracheostomy was not associated with decreased short-term mortality (risk ratio [RR] 0.84; 95% confidence interval [CI] 0.39 to 1.79; p = 0.65; n = 2,072), but was associated with a reduction in MV duration (mean difference [MD] 13.1 days; 95% CI -6.70 to -21.11; p = 0.0002; n = 855), intensive care unit (ICU) length of stay (MD -10.20 days; 95% CI -4.66 to -15.74; p = 0.0003; n = 855), and hospital length of stay (MD -7.39 days; 95% CI -3.74 to -11.03; p &lt; 0.0001; n = 423). Early tracheostomy was also associated with a decreased incidence of ventilator-associated pneumonia (VAP) and tracheostomy-related complications (RR 0.86; 95% CI 0.75 to 0.98; p = 0.08; n = 2,043 and RR 0.08; 95% CI -0.01 to -0.15; p = 0.02; n = 812 respectively). The majority of studies ranked as good methodologic quality on the NOS. Conclusions Early tracheostomy in patients with acute traumatic SCI may reduce duration of mechanical ventilation, length of ICU stay, and length of hospital stay. Current studies highlight the lack of high-level evidence to guide the optimal timing of tracheostomy in acute traumatic SCI. Future research should seek to understand whether early tracheostomy improves patient comfort, decreases duration of sedation and improves long-term outcomes.PROSPERO registration number: CRD42020162488</jats:p