Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in ∼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer.

Epidemiology of SARS-CoV-2 in Kakuma Refugee Camp Complex, Kenya, 2020-20211.

Understanding SARS-CoV-2 infection in populations at increased risk for poor health is critical to reducing disease. We describe the epidemiology of SARS-CoV-2 infection in Kakuma Refugee Camp Complex, Kenya. We performed descriptive analyses of SARS-CoV-2 infection in the camp and surrounding community during March 16, 2020‒December 31, 2021. We identified cases in accordance with national guidelines.We estimated fatality ratios and attack rates over time using locally weighted scatterplot smoothing for refugees, host community members, and national population. Of the 18,864 SARS-CoV-2 tests performed, 1,024 were positive, collected from 664 refugees and 360 host community members. Attack rates were 325.0/100,000 population (CFR 2.9%) for refugees,150.2/100,000 population (CFR 1.11%) for community, and 628.8/100,000 population (CFR 1.83%) nationwide. During 2020-2021, refugees experienced a lower attack rate but higher CFR than the national population, underscoring the need to prioritize SARS-CoV-2 mitigation measures, including vaccination.

A comparison of the effect of weather and climate on emergency department visitation in Roanoke and Charlottesville, Virginia.

Compared with mortality, the impact of weather and climate on human morbidity is less well understood, especially in the cold season. We examined the relationships between weather and emergency department (ED) visitation at hospitals in Roanoke and Charlottesville, Virginia, two locations with similar climates and population demographic profiles. Using patient-level data obtained from electronic medical records, each patient who visited the ED was linked to that day's weather from one of 8 weather stations in the region based on each patient's ZIP code of residence. The resulting 2010-2017 daily ED visit time series were examined using a distributed lag non-linear model to account for the concurrent and lagged effects of weather. Total ED visits were modeled separately for each location along with subsets based on gender, race, and age. The relationship between the relative risk of ED visitation and temperature or apparent temperature over lags of one week was positive and approximately linear at both locations. The relative risk increased about 5% on warm, humid days in both cities (lag 0 or lag 1). Cold conditions had a protective effect, with up to a 15% decline on cold days, but ED visits increased by 4% from 2 to 5 days after the cold event. The effect of thermal extremes tended to be larger for non-whites and the elderly, and there was some evidence of a greater lagged response for non-whites in Roanoke. Females in Roanoke were more impacted by winter cold conditions than males, who were more likely to show a lagged response at high temperatures. In Charlottesville, males sought ED attention at lower temperatures than did females. The similarities in the ED response patterns between these two hospitals suggest that certain aspects of the response may be generalizable to other locations that have similar climates and demographic profiles.

Scurvy Outbreak Among South Sudanese Adolescents and Young Men - Kakuma Refugee Camp, Kenya, 2017-2018.

Scurvy is a relatively rare micronutrient deficiency disease that can occur among refugees dependent on food aid (1). Inadequate access to fresh fruits and vegetables in refugee camps can result in scurvy (2,3). Kakuma Refugee Camp in Kenya's Turkana District is home to 148,000 refugees, mostly from Somalia and South Sudan, who receive food assistance. In August 2017, a number of South Sudanese adolescent and young adult male refugees were evaluated at a health clinic in the camp for calf pain, chest pain, and gingival swelling. Because the symptoms were nonspecific, no diagnosis was made, and some patients received antibiotics and analgesics. All were managed as outpatients, but symptoms did not improve. During subsequent months, more young men with similar symptoms were reported. On January 20, 2018, the United Nations High Commissioner for Refugees (UNHCR) was informed and conducted clinical examinations. Signs and symptoms included lower limb pain and swelling (in some cases involving joints), lethargy, fatigue, gingival swelling and pain, hyperkeratotic skin changes, and chest pain. Based on these clinical findings, micronutrient deficiency, particularly vitamin C deficiency (scurvy), was considered a possible diagnosis, and an investigation of a possible outbreak was conducted. The suspected scurvy cases all occurred in young men from South Sudan who were living and cooking together in one geographic section of the camp. All patients who received treatment with vitamin C noted improvement of symptoms within <1 week. Patients were provided with food and cash assistance, the latter to allow dietary diversification (i.e., fresh fruits and vegetables). However, both forms of assistance were inadequate to allow access to sufficient amount of calories and the dietary diversification needed for intake of micronutrients, such as vitamin C. It is important to consider these needs when determining the amount of food or cash assistance provided to adolescents and young adult male refugees.

Clinical Practice Guideline for Emergency Department Procedural Sedation With Propofol: 2018 Update.

We update an evidence-based clinical practice guideline for the administration of propofol for emergency department procedural sedation. Both the unique considerations of using this drug in the pediatric population and the substantial new research warrant revision of the 2007 advisory. We discuss the indications, contraindications, personnel requirements, monitoring, dosing, coadministered medications, and adverse events for propofol sedation.

The zebrafish reference genome sequence and its relationship to the human genome.

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Cholera Outbreak in Dadaab Refugee Camp, Kenya - November 2015-June 2016.

Dadaab Refugee camp in Garissa County, Kenya, hosts nearly 340,000 refugees in five subcamps (Dagahaley, Hagadera, Ifo, Ifo2, and Kambioos) (1). On November 18 and 19, 2015, during an ongoing national cholera outbreak (2), two camp residents were evaluated for acute watery diarrhea (three or more stools in ≤24 hours); Vibrio cholerae serogroup O1 serotype Ogawa was isolated from stool specimens collected from both patients. Within 1 week of the report of index cases, an additional 45 cases of acute watery diarrhea were reported. The United Nations High Commissioner for Refugees and their health-sector partners coordinated the cholera response, community outreach and water, sanitation, and hygiene (WASH) activities; Médecins Sans Frontiéres and the International Rescue Committee were involved in management of cholera treatment centers; CDC performed laboratory confirmation of cases and undertook GIS mapping and postoutbreak response assessment; and the Garissa County Government and the Kenya Ministry of Health conducted a case-control study. To prevent future cholera outbreaks, improvements to WASH and enhanced disease surveillance systems in Dadaab camp and the surrounding area are needed.

Self-assembled PCBM bilayers on graphene and HOPG examined by AFM and STM.

In this work we report fabrication and characterization of phenyl-C61-butyric acid methyl ester (PCBM) bilayer structures on graphene and highly oriented pyrolytic graphite (HOPG). Through careful control of the PCBM solution concentration (from 0.1 to 2 mg ml-1) and the deposition conditions, we demonstrate that PCBM molecules self-assemble into bilayer structures on graphene and HOPG substrates. Interestingly, the PCBM bilayers are formed with two distinct heights on HOPG, but only one unique representative height on graphene. At elevated annealing temperatures, edge diffusion allows neighboring vacancies to merge into a more ordered structure. This is, to the best of our knowledge, the first experimental realization of PCBM bilayer structures on graphene. This work could provide valuable insight into fabrication of new hybrid, ordered structures for applications to organic solar cells.

Grasping the Ongaonga: When will New Zealand really integrate rural clinical education?

Compared to Australia, substantial rural-based clinical education in New Zealand started small and still has some way to go if it is to fulfil its potential in workforce retention and recruitment to under-served areas. The authors share some of their experiences in rural medical education and then speculate on how it could develop. They discuss the merits of a clinical school composed of a dispersed network of rural sites, which provide and coordinate rural health education.

Correction: Correction to 'Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department' [Annals of Emergency Medicine 66 (2015) 322-333.e31].

Due to a miscommunication during the process of transferring this manuscript from our editorial team to Production, the Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee) were not properly indexed in PubMed. This has now been corrected online. The publisher would like to apologize for any inconvenience caused.

Correction: Correction to 'Clinical Policy: Procedural Sedation and Analgesia in the Emergency Department' [Annals of Emergency Medicine 63 (2014) 247-258.e18].

Due to a miscommunication during the process of transferring this manuscript from our editorial team to Production, the Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee) were not properly indexed in PubMed. This has now been corrected online. This has now been corrected online. The publisher would like to apologize for any inconvenience caused.

Genetic basis of Y-linked hearing impairment.

A single Mendelian trait has been mapped to the human Y chromosome: Y-linked hearing impairment. The molecular basis of this disorder is unknown. Here, we report the detailed characterization of the DFNY1 Y chromosome and its comparison with a closely related Y chromosome from an unaffected branch of the family. The DFNY1 chromosome carries a complex rearrangement, including duplication of several noncontiguous segments of the Y chromosome and insertion of ∼160 kb of DNA from chromosome 1, in the pericentric region of Yp. This segment of chromosome 1 is derived entirely from within a known hearing impairment locus, DFNA49. We suggest that a third copy of one or more genes from the shared segment of chromosome 1 might be responsible for the hearing-loss phenotype.

The patterns and dynamics of genomic instability in metastatic pancreatic cancer.

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

The movement of multidrug-resistant tuberculosis across borders in East Africa needs a regional and global solution.

Kevin Cain and colleagues reflect on the cross border movement of people from Somalia with MDR-TB and the implications for MDR-TB programs in East Africa.

Complex landscapes of somatic rearrangement in human breast cancer genomes.

Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.

DNA methylation profiling of human chromosomes 6, 20 and 22.

DNA methylation is the most stable type of epigenetic modification modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation. We find that 17% of the 873 analyzed genes are differentially methylated in their 5' UTRs and that about one-third of the differentially methylated 5' UTRs are inversely correlated with transcription. Despite the fact that our study controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

Combined use of inactivated and oral poliovirus vaccines in refugee camps and surrounding communities - Kenya, December 2013.

Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988, circulation of indigenous wild poliovirus (WPV) has continued without interruption in only three countries: Afghanistan, Nigeria, and Pakistan. During April-December 2013, a polio outbreak caused by WPV type 1 (WPV1) of Nigerian origin resulted in 217 cases in or near the Horn of Africa, including 194 cases in Somalia, 14 cases in Kenya, and nine cases in Ethiopia (all cases were reported as of March 10, 2014). During December 14-18, 2013, Kenya conducted the first-ever campaign providing inactivated poliovirus vaccine (IPV) together with oral poliovirus vaccine (OPV) as part of its outbreak response. The campaign targeted 126,000 children aged ≤59 months who resided in Somali refugee camps and surrounding communities near the Kenya-Somalia border, where most WPV1 cases had been reported, with the aim of increasing population immunity levels to ensure interruption of any residual WPV transmission and prevent spread from potential new importations. A campaign evaluation and vaccination coverage survey demonstrated that combined administration of IPV and OPV in a mass campaign is feasible and can achieve coverage >90%, although combined IPV and OPV campaigns come at a higher cost than OPV-only campaigns and require particular attention to vaccinator training and supervision. Future operational studies could assess the impact on population immunity and the cost-effectiveness of combined IPV and OPV campaigns to accelerate interruption of poliovirus transmission during polio outbreaks and in certain areas in which WPV circulation is endemic.

Clinical policy: procedural sedation and analgesia in the emergency department.

This clinical policy from the American College of Emergency Physicians is the revision of a 2005 clinical policy evaluating critical questions related to procedural sedation in the emergency department.1 A writing subcommittee reviewed the literature to derive evidence-based recommendations to help clinicians answer the following critical questions: (1) In patients undergoing procedural sedation and analgesia in the emergency department,does preprocedural fasting demonstrate a reduction in the risk of emesis or aspiration? (2) In patients undergoing procedural sedation and analgesia in the emergency department, does the routine use of capnography reduce the incidence of adverse respiratory events? (3) In patients undergoing procedural sedation and analgesia in the emergency department, what is the minimum number of personnel necessary to manage complications? (4) Inpatients undergoing procedural sedation and analgesia in the emergency department, can ketamine, propofol, etomidate, dexmedetomidine, alfentanil and remifentanil be safely administered? A literature search was performed, the evidence was graded, and recommendations were given based on the strength of the available data in the medical literature.