Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers

Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n=57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ΔΔQTcF were observed at 6 hrs (14 ms; 95% CI [1; 27]), 12 hrs (18 ms; 95% CI [−4; 40] and 18 hrs (6 ms; 95% CI [−1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P<0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG

Cancer Survival and Excess Mortality Estimates among Adolescents and Young Adults in Western Australia, 1982-2004: A Population-Based Study

Background: Data are limited on cancer outcomes in adolescents and young adults. Methods: Based on data from the Western Australian Data Linkage System, this study modelled survival and excess mortality in all adolescents and young adults aged 15-39 years in Western Australia who had a diagnosis of cancer in the period 1982-2004. Relative survival and excess all-cause mortality for all cancers combined and for principal tumour subgroups were estimated, using the Ederer II method and generalised linear Poisson modelling, respectively. Results: A cancer diagnosis in adolescents and young adults conferred substantial survival decrement. However, overall outcomes improved over calendar period (excess mortality hazard ratio [HR], latest versus earliest diagnostic period: 0.52, trend <0.0001). Case fatality varied according to age group (HR, oldest versus youngest: 1.38, trend <0.0001), sex (HR, female versus male: 0.66, 95% confidence interval [CI] 0.62-0.71), ethnicity (HR, Aboriginal versus others: 1.47, CI 1.23-1.76), geographical area (HR, rural/remote versus urban: 1.13, CI 1.04-1.23) and residential socioeconomic status (HR, lowest versus highest quartile: 1.14, trend <0.05). Tumour subgroups differed substantially in frequency according to age group and sex, and were critical outcome determinants. Conclusions: Marked progressive calendar-time improvement in overall outcomes was evident. Further research is required to disentangle the contributions of tumour biology and health service factors to outcome disparities between ethno-demographic, geographic and socioeconomic subgroups of adolescents and young adults with cancer. © 2013 Haggar et al

Increasing incidence of childhood tumours of the central nervous system in Denmark, 1980–1996

The registered incidence rate of childhood central nervous system (CNS) tumours has increased in several countries. It is uncertain whether these increases are biologically real or owing to improved diagnostic methods. We explored the medical records of 626 CNS tumours diagnosed in Danish children between 1980 and 1996. Population-based registers were used to extract data on mortality and background population. Temporal patterns were analysed by regression techniques. Most tumours were verified by computed tomography (78%) or magnetic resonance imaging (14%). Overall, the incidence rate increased by 2.9% per year (95% confidence interval (CI): 1.3;4.5) and the mortality rate increased by 1.4% per year (95% CI: −0.4;3.3). Among children aged 0–4 years, the survival rate after diagnosis remained almost unchanged, whereas among children aged 5–14 years, the 10-year survival rate improved from 59 to 74%. These data suggest that the incidence rate of CNS tumours among Danish children has truly increased, although alternative explanations cannot be excluded

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Changes in cystic fibrosis mortality in Australia, 1979-2005

OBJECTIVE: To assess mortality trends among people with cystic fibrosis (CF) in Australia. DESIGN AND SETTING: We augmented Australian summary data for deaths from CF registered during 1979-2005 with information from Australian transplant centres on lung transplantation among CF patients for 1989-2005 to allow us to follow trends in all "mortality events" (death or lung transplantation). MAIN OUTCOME MEASURE: Age at death or lung transplantation. RESULTS: Between 1979 and 2005, the mean age at death increased from 12.2 years to 27.9 years for males and from 14.8 years to 25.3 years for females. Overall, female deaths in childhood (0-14 years) occurred at an age-standardised rate of 0.40 per 100,000 (95% CI, 0.34-0.45) during 1979-2005, which exceeded the corresponding rate for males of 0.24 (95% CI, 0.20-0.28) per 100,000. Among 0-14-year-old boys, event rates declined markedly after 1989, but they declined later and more gradually for girls, with the result that the age-standardised rate for girls was 2.38 times that of boys during 1989-2005 (95% CI, 1.69-3.36). CONCLUSIONS: The pattern of CF mortality in Australia has changed substantially. Mortality rates continue to be higher for girls than for boys, but death in childhood has become uncommon. Survival has increased since 1979, but females continue to have reduced length of life.David W Reid, C Leigh Blizzard, Dace M Shugg, Ceri Flowers, Catherine Cash, Hugh M Grevill

Intracranial tumors in adult population of the Varaždin County (Croatia) 1996-2004: a population-based retrospective incidence study

Aim: To estimate the incidence of intracranial tumors in the adult population of the Varazdin County, Croatia, for the 1996-2004 period. - - - - - Methods: Setting: Varazdin County General Hospital and four university hospitals in Zagreb, the capital of Croatia. Study period: January 1, 1996 to December 31, 2004. Incident patients: county residents admitted for newly diagnosed intracranial tumors according to the WHO diagnostic criteria. Demographic data were extracted from the 2001 Croatian census. Incidence rates (IRs) per 100,000 person-years (p-y) and annual IRs (per 100,000 persons) were determined and compared as incidence rate ratios (IRRs) with 95% CI. - - - - - Results: For primary intracranial tumors (PITs), IR was 12.1/100,000 p-y (95% CI: 10.3-14.2), comparable in men and women. The highest incidence was recorded for glioblastoma (IR 4.8, 3.7-6.2) and meningioma (IR 3.1, 2.2-4.2). The incidence of PIT was somewhat greater than that of metastatic tumors (IRR 1.58, 95% CI: 1.22-2.05, P = 40 vs. population aged <= 39 (all IRRs with 95% CI greater than 1, P < 0.05 or < 0.001), comparable in men and women. Women were somewhat older than men at the time of diagnosis of PIT: median difference -6 years (95.1% CI: -10 to -1, P < 0.05). Annual IRs for all these tumor categories showed increasing trends over the study period. - - - - - Conclusion: Overall, there was an increasing trend in the incidence of primary intracranial tumors in the Varazdin County. Data did not allow estimation for most of the specific tumor types