Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Selective left mainstem bronchial intubation in the neonatal intensive care unit

Background: Selective neonatal left mainstem bronchial intubation to treat right lung disease is typically achieved with elaborate maneuvers, instrumentation and devices. This is often attributed to bronchial geometry which favors right mainstem entry of an endotracheal tube deliberately advanced beyond the carina. Case summary: A neonate with severe bullous emphysema affecting the right lung required urgent non-ventilation of that lung. We achieved left mainstem bronchial intubation by turning the endotracheal tube 180° such that the Murphy's eye faced the left instead of the right, and simulated a left-handed intubation by slightly orientating the endotracheal tube such that its concavity faced the left instead of the right as in a conventional right-handed intubation. Conclusion: Urgent intubation of the left mainstem bronchus with an endotracheal tube can be easily achieved by recognizing that it is the position of the endotracheal tube tip and the direction of its concavity that are the chief determinants of which bronchus an endotracheal tube goes when advanced. This is important in critically ill neonates as the margin of safety and time window are small, and the absence of double-lumen tubes. Use of fiberoptic bronchoscope and blockers should be reserved as backup plans. Resumo: Justificativa: A intubação seletiva neonatal do brônquio principal esquerdo para tratar a doença pulmonar direita é tipicamente realizada com elaboradas manobras, instrumentação e dispositivos. Isso é frequentemente atribuído à geometria brônquica que favorece a entrada principal direita de um tubo endotraqueal (TET) deliberadamente avançado para além da carina. Resumo do caso: Recém-nascido com enfisema bolhoso grave afetando o pulmão direito que precisou com urgência da não ventilação desse pulmão. Conseguimos a intubação brônquica esquerda fazendo uma rotação de 180° do TET, de forma que o olho de Murphy ficasse voltada para a esquerda e não para a direita, e simulamos uma intubação à esquerda orientando ligeiramente o TET, de modo que sua concavidade virasse para a esquerda em vez de para a direita, como em uma intubação convencional à direita. Conclusão: A intubação urgente do brônquio principal esquerdo com um TET pode ser facilmente obtida reconhecendo-se que é a posição da ponta do TET e a direção de sua concavidade que determinam para qual brônquio o TET irá quando avançado. Isso é importante em neonatos criticamente doentes diante da margem de segurança e janela de tempo pequenas e na ausência de tubos de duplo lúmen. O uso de broncofibroscópio e bloqueadores deve ser considerado como planos de segurança. Keywords: Bullous emphysema, Endobronchial intubation, Neonate, Palavras-chave: Enfisema bolhoso, Intubação endobrônquica, Recém-nascid

Selective left mainstem bronchial intubation in the neonatal intensive care unit

Abstract Background: Selective neonatal left mainstem bronchial intubation to treat right lung disease is typically achieved with elaborate maneuvers, instrumentation and devices. This is often attributed to bronchial geometry which favors right mainstem entry of an endotracheal tube deliberately advanced beyond the carina. Case summary: A neonate with severe bullous emphysema affecting the right lung required urgent non-ventilation of that lung. We achieved left mainstem bronchial intubation by turning the endotracheal tube 180° such that the Murphy's eye faced the left instead of the right, and simulated a left-handed intubation by slightly orientating the endotracheal tube such that its concavity faced the left instead of the right as in a conventional right-handed intubation. Conclusion: Urgent intubation of the left mainstem bronchus with an endotracheal tube can be easily achieved by recognizing that it is the position of the endotracheal tube tip and the direction of its concavity that are the chief determinants of which bronchus an endotracheal tube goes when advanced. This is important in critically ill neonates as the margin of safety and time window are small, and the absence of double-lumen tubes. Use of fiberoptic bronchoscope and blockers should be reserved as backup plans

Using illness scripts to teach clinical reasoning skills to medical students

Background and Objectives: Most medical students learn clinical reasoning skills informally during clinical rotations that have varying quality of supervision. We conducted a randomized controlled trial to determine if a workshop that uses "illness scripts" could improve students' clinical reasoning skills when making diagnoses of patients portrayed in written scenarios. Methods: In 2007-2008, 53 fourth-year medical students were randomly assigned to either a family medicine (intervention) or psychiatry (control) clerkship at The Chinese University of Hong Kong. Students in the intervention group participated in a 3-hour workshop on clinical reasoning that used illness scripts. The workshop was conducted with small-group teaching using a Web-based set of clinical reasoning problems, individualized feedback, and demonstration of tutors' reasoning aloud. The effectiveness of the intervention was assessed using the Diagnostic Thinking Inventory (DTI) and the measurement of individual students' performance in solving clinical reasoning problems (CRP). Results: The postintervention overall DTI scores between groups were similar (mean difference 0, 95% confidence interval [CI]= -7.4 to 7.4). However, the total scores on the CRP assessment were 14% (95% CI=8% to 21%) higher in the intervention group than in controls. Conclusion: A workshop on illness scripts may have some benefit for improving diagnostic performance in clinical reasoning problems