Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer:A Randomized Clinical Trial

PURPOSE:Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking.METHODS:Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior &lt;.0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality.RESULTS:Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior =.0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior =.0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P =.4940).CONCLUSION:On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.</p

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF.The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF.Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

What Design Research Does ... : 62 Cards Highlighting the Power and Impact of UK-based Design Research in Addressing a Range of Complex Social, Economic, Cultural and Environmental Issues

Design research makes a significant contribution to the UK economy and society as a whole. Ever since the establishment of the Government Schools of Design in the nineteenth century, the UK has been widely acknowledged as an international leader in design research. Following this lead, the What Design Research Does… cards highlight the wide range of social, economic, cultural and environmental impacts that design research, funded and based in the UK, makes all over the world. The 62 cards illustrate unambiguously the positive changes that contemporary UK-based design researchers are making in many complex issues. Each What Design Research Does… card lists the challenges and issues faced by the design researchers, who they collaborated with, the research methods and approaches taken, the outcomes of the design research, what the main results and findings have been, and what impact the design research has had. In short, the What Design Research Does… cards clearly articulate the breadth of social, economic, cultural and environmental impacts that UK-based design researchers are achieving today

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Allometry of carbon and nitrogen content and growth rate in a diverse range of coccolithophores

As both photoautotrophs and calcifiers, coccolithophores play important roles in ecosystems and biogeochemical cycles. Though some species form blooms in high-latitude waters, low-latitude communities exhibit high diversity and niche diversification. Despite such diversity, our understanding of the clade relies on knowledge of Emiliana huxleyi. To address this, we examine carbon (C) and nitrogen (N) content of strains (n = 9) from the main families of the calcifying Haptophyceae, as well as allometry and cell size frequency across extant species. Coccolithophore cell size is constrained, with ~71% of 159 species smaller than 10 μm in diameter. Growth rates scale with cell biovolume (μ = 1.83 × cell volume(−0.19)), with an exponent close to metabolic theory. Organic carbon (C) per cell is lower than for other phytoplankton, providing a coccolithophore-specific relationship between cell organic C content and biovolume (pg C cell(−1) = 0.30 × cell volume(0.70)). Organic C to N ratios (~8.3 mol:mol) are similar to other phytoplankton, implying little additional N cost for calcification and efficient retention and recycling of cell N. Our results support observations that coccolithophores are efficient competitors in low-nutrient conditions, able to photosynthesize, calcify and run the routine metabolic machinery necessary without any additional need for N relative to noncalcifying algae

Emerging themes in Aboriginal child and adolescent mental health : findings from a qualitative study in Sydney, New South Wales

Objective: To explore emerging themes related to the mental health of Aboriginal children and adolescents ("young people") arising from focus groups conducted in Sydney, New South Wales. Design, setting and participants: A qualitative study was conducted between April 2008 and September 2009 in three Aboriginal community-controlled health organisations in Sydney. A semi-structured approach was used in focus groups and small group interviews to elicit the views of 15 Aboriginal parents and 32 Aboriginal workers from a variety of health and social work backgrounds on important factors surrounding the mental health of Aboriginal young people. Results: Major themes identified were the centrality of family and kinship relationships, the importance of identity, confounding factors in the mental health of Aboriginal young people, and issues related to service access and implementation. Conclusion: Clinicians working with Aboriginal young people should be mindful of the critical importance of family and identity issues and should assess possible physical health or social factors that may complicate a diagnosis. Improvements in access to mental health services for Aboriginal families and a more holistic approach to mental health treatment are urgently required