Background The COVID-19 pandemic is challenging advanced health systems, which are dealing with an overwhelming number of patients in need of intensive care for respiratory failure, often requiring intubation. Prone positioning in intubated patients is known to reduce mortality in moderate-to-severe acute respiratory distress syndrome. We aimed to investigate feasibility and effect on gas exchange of prone positioning in awake, non-intubated patients with COVID-19-related pneumonia. MethodsIn this prospective, feasibility, cohort study, patients aged 18-75 years with a confirmed diagnosis of COVID-19related pneumonia receiving supplemental oxygen or non-invasive continuous positive airway pressure were recruited from San Gerardo Hospital, Monza, Italy. We collected baseline data on demographics, anthropometrics, arterial blood gas, and ventilation parameters. After baseline data collection, patients were helped into the prone position, which was maintained for a minimum duration of 3 h. Clinical data were re-collected 10 min after prone positioning and 1 h after returning to the supine position. The main study outcome was the variation in oxygenation (partial pressure of oxygen [PaO 2 ]/fractional concentration of oxygen in inspired air [FiO 2 ]) between baseline and resupination, as an index of pulmonary recruitment. This study is registered on ClinicalTrials.gov, NCT04365959, and is now complete. Findings Between March 20 and April 9, 2020, we enrolled 56 patients, of whom 44 (79%) were male; the mean age was 57•4 years (SD 7•4) and the mean BMI was 27•5 kg/m² (3•7). Prone positioning was feasible (ie, maintained for at least 3 h) in 47 patients (83•9% [95% CI 71•7 to 92•4]). Oxygenation substantially improved from supine to prone positioning (PaO 2 /FiO 2 ratio 180•5 mm Hg [SD 76•6] in supine position vs 285•5 mm Hg [112•9] in prone position; p<0•0001). After resupination, improved oxygenation was maintained in 23 patients (50•0% [95% CI 34•9-65•1]; ie, responders); however, this improvement was on average not significant compared with before prone positioning (PaO 2 /FiO 2 ratio 192•9 mm Hg [100•9] 1 h after resupination; p=0•29). Patients who maintained increased oxygenation had increased levels of inflammatory markers (C-reactive protein: 12•7 mg/L [SD 6•9] in responders vs 8•4 mg/L [6•2] in non-responders; and platelets: 241•1 × 10³/µL [101•9] vs 319•8 × 10³/µL [120•6]) and shorter time between admission to hospital and prone positioning (2•7 days [SD 2•1] in responders vs 4•6 days [3•7] in non-responders) than did those for whom improved oxygenation was not maintained. 13 (28%) of 46 patients were eventually intubated, seven (30%) of 23 responders and six (26%) of 23 non-responders (p=0•74). Five patients died during follow-up due to underlying disease, unrelated to study procedure. Interpretation Prone positioning was feasible and effective in rapidly ameliorating blood oxygenation in awake patients with COVID-19-related pneumonia requiring oxygen supplementation. The effect was maintained after resupina...

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.

In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.