X-Rays from Superbubbles in the Large Magellanic Cloud. V. The H II Complex N11

The large H II complex N11 in the Large Magellanic Cloud contains OB associations at several different stages in their life histories. We have obtained ROSAT PSPC and HRI X-ray observations, Curtis Schmidt CCD images, echelle spectra in H-alpha and [N II] lines, and IUE interstellar absorption line observations of this region. The central bubble of N11 has an X-ray luminosity a factor of only 3-7 brighter than predicted for an energy-conserving superbubble, making this the first detection of X-ray emission from a superbubble without a strong X-ray excess. The region N11B contains an extremely young OB association analogous to the central association of the Carina nebula, apparently still embedded in its natal molecular cloud. We find that N11B emits diffuse X-ray emission, probably powered by stellar winds. Finally, we compare the tight cluster HD32228 in N11 to R136 in 30 Dor. The latter is a strong X-ray source, while the former is not detected, showing that strong X-ray emission from compact objects is not a universal property of such tight clusters.Comment: submitted to ApJ 1 April 1997, uses aasms4.sty, 20 pages, 10 figures (figure 3 is color; figures 1a and 4 are gifs; original postscript available from http://www.mpia-hd.mpg.de/MPIA/Projects/THEORY/maclow/papers/n11/n11.htm

Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer

We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population

Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH: Extracolonic cancer risks for people with biallelic and monoallelicMUTYHmutations

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier’s risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age, and histories of cancer from their 1,903 first- and 3,255 second-degree relatives, were analysed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer, 19(3.7–97); and ovarian cancer, 17(2.4–115). The HRs (95%CI) for monoallelic MUTYH mutation carriers were: gastric cancer, 9.3(6.7–13); hepatobiliary cancer, 4.5(2.7–7.5); endometrial cancer, 2.1(1.1–3.9); and breast cancer, 1.4(1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95%CI) to age 70 years for biallelic mutation carriers were: bladder cancer, 25%(5%–77%) for males and 8%(2%–33%) for females; and ovarian cancer, 14%(2%–65%). The cumulative risks (95%CI) for monoallelic mutation carriers were: gastric cancer, 5%(4%–7%) for males and 2.3%(1.7%–3.3%) for females; hepatobiliary cancer, 3%(2%–5%) for males and 1.4%(0.8%–2.3%) for females; endometrial cancer, 3%(2%–6%); and breast cancer 11%(8%–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene

The Impact of Mercenaries and Private Military and Security Companies on Civil War Severity between 1946 and 2002

Research has long abandoned the view that only states wage war. On the contrary, civil war research has produced an impressive body of literature on violent non-state actors. Still, a particular group of actors—mercenaries—has been widely neglected so far, although they have participated in numerous conflicts in the second half of the twentieth century. Whether their presence aggravated or improved the situation is a matter of dispute. Some believe that the additional military capabilities provided by mercenaries help to end civil wars quickly without increased bloodshed, while others deem mercenaries greedy and bloodthirsty combatants who contribute to making civil wars more brutal, while a third opinion differentiates between different types of mercenaries. This article tests the impact of mercenaries on civil war severity. The evidence indicates that the presence of both mercenaries and private military and security contractors increases its severity

Diagnosis of cancer as an emergency: a critical review of current evidence

Many patients with cancer are diagnosed through an emergency presentation, which is associated with inferior clinical and patient-reported outcomes compared with those of patients who are diagnosed electively or through screening. Reducing the proportion of patients with cancer who are diagnosed as emergencies is, therefore, desirable; however, the optimal means of achieving this aim are uncertain owing to the involvement of different tumour, patient and health-care factors, often in combination. Most relevant evidence relates to patients with colorectal or lung cancer in a few economically developed countries, and defines emergency presentations contextually (that is, whether patients presented to emergency health-care services and/or received emergency treatment shortly before their diagnosis) as opposed to clinically (whether patients presented with life-threatening manifestations of their cancer). Consistent inequalities in the risk of emergency presentations by patient characteristics and cancer type have been described, but limited evidence is available on whether, and how, such presentations can be prevented. Evidence on patients' symptoms and health-care use before presentation as an emergency is sparse. In this Review, we describe the extent, causes and implications of a diagnosis of cancer following an emergency presentation, and provide recommendations for public health and health-care interventions, and research efforts aimed at addressing this under-researched aspect of cancer diagnosis

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570