Deciphering cell states and genealogies of human haematopoiesis.

The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems2-5, simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging. Here we introduce an improved, single-cell lineage-tracing system based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as both differences in total HSC output and biases towards the production of different mature cell types. We also find that the diversity of HSC clones decreases markedly with age, leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides a clonally resolved and cell-state-aware atlas of human haematopoiesis at single-cell resolution, showing an unappreciated functional diversity of human HSC clones and, more broadly, paving the way for refined studies of clonal dynamics across a range of tissues in human health and disease.

Management of Air Leaks and Residual Spaces Following Lung Resection.

Air leaks and residual airspaces following lung resection are common problems in thoracic surgery. Prolonged air leaks frequently necessitate extended hospitalization. This is true whether the surgery was done in an open fashion or with video-/robot-assisted thoracic surgery. In this review, the authors present common risk factors that predispose to prolonged air leaks and discuss the management options for air leaks by focusing on intraoperative maneuvers, postoperative considerations, and options for difficult-to-manage air leaks and spaces. They also discuss options to prevent such spaces and present management approaches to take care of patients with these challenging problems.

Novel techniques for management of portal system hemorrhage in acute pancreatitis.

Current management of infected pancreatic necrosis is focused on a minimally invasive step-up approach. The step-up approach consists of initial percutaneous or endoscopic drainage of infected pancreatic necrosis, followed, if necessary, by minimally invasive surgical or endoscopic debridement. While there is reduced morbidity and mortality, vascular complications can be life-threatening. Reported vascular complications have been limited to arterial bleeding. Venous bleeding has not been previously reported. We present two cases of portal venous bleeding in patients who underwent treatment for infected pancreatic necrosis with a step-up approach. We discuss the clinical presentation, diagnosis, and initial management. Moreover, we present two different techniques that can be used to successfully manage venous bleeding in patients who have percutaneous drains in place as part of a step-up approach. These techniques involve tamponading the cavity or drain tract with topical hemostatics and direct embolization of the bleeding vein. These experiences can serve as a guide for managing portal venous bleeding in patients with infected pancreatic necrosis.

Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia.

Lifelong maintenance of the blood system requires equilibrium between clearance of damaged hematopoietic stem cells (HSCs) and long-term survival of the HSC pool. Severe perturbations of cellular homeostasis result in rapid HSC loss to maintain clonal purity. However, normal homeostatic processes can also generate lower-level stress; how HSCs survive these conditions remains unknown. Here we show that the integrated stress response (ISR) is uniquely active in HSCs and facilitates their persistence. Activating transcription factor 4 (ATF4) mediates the ISR and is highly expressed in HSCs due to scarcity of the eIF2 translation initiation complex. Amino acid deprivation results in eIF2α phosphorylation-dependent upregulation of ATF4, promoting HSC survival. Primitive acute myeloid leukemia (AML) cells also display eIF2 scarcity and ISR activity marks leukemia stem cells (LSCs) in primary AML samples. These findings identify a link between the ISR and stem cell survival in the normal and leukemic contexts.