OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES: Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
METHODS: Consented, full-time prison employees were interviewed using a structured questionnaire that included sociodemographic data, history of working in the correctional system and TB-related risk. TST was placed intradermally and read after 48-72 h. Induration size of ≥10 mm was considered positive. Logistic regression analyses were conducted to explore associations with TST positivity.
RESULTS: Of the 445 recruited prison employees, 420 (94.4%) had complete data. Most were young (median=30.0 years) men (88.8%) who had only worked at this prison (76.4%) for a median total employment period of 60 months (IQR 34.5-132.0). The majority were correctional officers, while civilian employees represented only 7.6% of the sample. Only 26 (6.2%) reported having ever been screened for TB since employment. Prevalence of TST positivity was 81% and was independently associated with longer (≥12 months) prison employment (AOR 4.9; 95% CI 1.5 to 15.9) and current tobacco smoking (AOR=1.9, 95% CI 1.2 to 3.2).
CONCLUSIONS: Latent TB prevalence was high in this sample, approximating that of prisoners in this setting, perhaps suggesting within prison TB transmission in this facility. Formal TB control programmes for personnel and prisoners alike are urgently needed within the Malaysian correctional system.
MATERIALS: Four hundred and ninety-five consecutive paediatric intensive care unit (PICU) admissions were analysed. multiple organ dysfunction syndrome was defined as simultaneous dysfunction of >/= 2 organ system and sepsis by the American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference definition.
RESULTS: Eighty-four patients developed MODS. The incidence of sepsis, severe sepsis and septic shock in these patients was 10.7%, 23.8% and 17.9%, respectively. Worsening categories of sepsis were associated with: (1) a higher mean admission Paediatric Risk of Mortality (PRISM II): 36.6 +/- 25.9, 56.8 +/- 32.1 and 73.6 +/- 28.5%, respectively (P = 0. 005), (2) a larger number of organ dysfunctions: mean MODS index of 37%, 46% and 58%, respectively (P = 0.007), and (3) a higher mortality: 22.2%, 65% and 80%, respectively (P = 0.03).
CONCLUSION: Presence of sepsis, severe sepsis and septic shock was associated with an increasing severity of illness, increased number of organ dysfunctions and a distinct risk of mortality among critically ill children.