Key points• In awake humans, when CO 2 is maintained above normal levels, exposure to acute intermittent hypoxia causes a sustained elevation in ventilation that persists when normoxic breathing is resumed.• In this study we have demonstrated that when CO 2 is maintained above normal levels, exposure to acute continuous hypoxia also causes a sustained elevation in ventilation when normoxic breathing is resumed.• This sustained elevation in ventilation following both acute intermittent hypoxia and acute continuous hypoxia is maintained by mechanisms other than increased activity of the carotid body.• These results help develop our understanding of respiratory control in humans and may aid future development of treatments for respiratory control disorders, such as obstructive sleep apnoea.Abstract In awake humans, long-term facilitation of ventilation (vLTF) following acute intermittent hypoxia (AIH) is only expressed if CO 2 is maintained above normocapnic levels. vLTF has not been reported following acute continuous hypoxia (ACH) and it is not known whether this might be unmasked by elevated CO 2 . Twelve healthy participants completed three trials. In all trials end-tidal pressure of CO 2 was elevated 4-5 mmHg above normocapnic levels. During Trial 1 (AIH) participants were exposed to eight 4 min episodes of hypoxia. During Trial 2 (ACH) participants were exposed to continuous hypoxia for 32 min. In Trial 3 (Control) participants were exposed to euoxia throughout. To assess the contribution of the carotid body (CB) in observed ventilatory responses, CB afferent discharge before and after each trial was transiently inhibited with hyperoxia. Minute ventilation (V E ) increased following all trials, but was significantly greater in Trials 1 and 2 when compared with Trial 3 (Trial 1: 4.96 ± 0.87, Trial 2: 5.07 ± 0.7, Trial 3: 2.55 ± 0.98 l min −1 , P < 0.05). Hyperoxia attenuatedV E to a similar extent in baseline and recovery in all trials (Trial 1: 3.0 ± 0.57 vs. 3.27 ± 0.68, Trial 2: 1.97 ± 0.62 vs. 2.56 ± 0.62, Trial 3: 2.23 ± 0.49 vs. 2.15 ± 0.55 l min −1 , P > 0.05). Data are means ± SEM. In awake humans with elevated CO 2 , ACH evokes a sustained increase in ventilation that is comparable to that evoked by AIH. However, a gradual positive drift in ventilation in response to elevated CO 2 accounts for approximately half of this apparent vLTF. Additionally, our data support the view that the CB is not directly involved in maintaining vLTF.

New Findings r What is the central question of this study?Pulmonary arterial pressure is higher in older than younger humans and predicts mortality. It is also increased by acute hypoxia, which causes constriction of the pulmonary vasculature. We asked whether this pulmonary vascular response to hypoxia is greater in older humans. r What is the main finding and its importance?Using Doppler echocardiography in 12 younger (ß20 years old) and nine older men (ß55 years old) exposed to 20 min of moderate isocapnic hypoxia, we demonstrated that older men showed a significantly greater rise in pulmonary arterial pressure during alveolar hypoxia than younger men. Future studies should examine the pathophysiological importance of increased hypoxic pulmonary vasoconstriction with age.Resting pulmonary arterial pressure increases with age in humans. In the general population, higher values are associated with increased mortality, and in common cardiopulmonary diseases, such as congestive heart failure and chronic obstructive pulmonary disease, the presence of pulmonary arterial hypertension portends a worse outcome. Pulmonary arterial pressure increases during alveolar hypoxia, as a consequence of constriction in the pulmonary vasculature. We hypothesized that older men have more vigorous hypoxic pulmonary vasoconstriction than younger men. Twelve younger (20.5 ± 0.5 years old) and nine older men (55.8 ± 2.1 years old) were exposed for 20 min on different days to isocapnic hypoxia (end-tidal P O 2 = 50 mmHg) and isocapnic euoxia (end-tidal P O 2 = 100 mmHg); each was preceded (baseline) and followed by 5 min of isocapnic euoxia. Systolic pulmonary arterial pressure and cardiac output were measured continuously using Doppler echocardiography. Systolic pulmonary arterial pressure was greater during baseline euoxic measurements in older participants (27.8 ± 0.8 versus 24.1 ± 0.7 mmHg, P = 0.001) and also increased more during hypoxia in older participants (15.2 ± 1.3 versus 9.6 ± 0.9 mmHg, P = 0.011). Cardiac output did not differ between the two groups during baseline measurements (P = 0.60) or hypoxia (P = 0.49). All data are means ± SEM. The increased magnitude of hypoxic pulmonary vasoconstriction demonstrated with age has implications for individuals wishing to ascend to high altitude or travel by air, for those suffering from conditions in which global alveolar hypoxia is a feature and for patients requiring general anaesthesia.

Introduction: DLBCL subtypes may be classified by gene expression corresponding to germinal centre (GCB) or activated peripheral blood (ABC) B-cells. Treatment outcomes with R-CHOP therapy were inferior for ABCs in retrospective series, and this study investigated whether adding bortezomib could reverse the adverse prognosis. The trial used gene expression profiling (GEP) to stratify cases, with adaptive design to analyse the outcome by subtypes at predefined timepoints. Methods: Newly diagnosed patients with DLBCL underwent staging and commenced standard R-CHOP. During cycle 1, formalin-fixed paraffin-embedded (FFPE) tissue was used to extract messenger RNA for GEP using the Illumina DASL array platform. Cases were allocated to GCB, ABC or Unclassifiable (Unc) type before starting cycle 2, using an established algorithm based upon 20 genes. Patients with successful GEP were randomised 1:1 to receive R-CHOP +/- bortezomib 1.6 mg/m2 s/c on days 1+8 in cycles 2-6. The study was powered to detect a difference in progression-free survival (PFS) of 10% with bortezomib, with a 2-sided significance, 5% and 90% power. The adaptive design allowed for closure of randomization for GCB cases if 1-year PFS was <70% after 55 received RB-CHOP (interim safety analysis) or if 1-year PFS was <85% after 73 received RB-CHOP and followed for 1 year (futility analysis). Results: Between 6/2011 and 5/2015 1132 patients were enrolled from 109 sites, with 1078 samples analysed. Of these, 157 (15%) biopsies had inadequate material for GEP, but the remaining 921 were classified as 246 (27%) ABC, 476 (52%) GCB and 199 (22%) Unc. Successful classification was possible from both surgical and needle core biopsies. Median laboratory turnaround time was 12 working days and all results were available prior to the scheduled administration of cycle 2. Characteristics of the patients of different subtypes are shown in the table. Following both interim analyses the DMEC recommended continued recruitment of patients with a GCB phenotype. Table. ABC GCB Unc Age (years): median 67 63 63 Age (years) : range 23 to 86 20 to 82 20 to 85 % performance status 0-1 88 88 90 % at least one extranodal site 53 54 62 % bone marrow involved 15 14 23 % LDH>ULN 69 76 79 % IPI score 0/1 29 27 26 % IPI score 2/3 57 55 55 % IPI score 4/5 15 19 19 % B symptoms 46 43 49 % Bulk>10cm 17 26 21 Conclusions: This study has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy in a large multicentre trial. Although patients with ABC type lymphoma were in general slightly older, they did not appear to have other adverse prognostic features at diagnosis vs GCB. All patients will have completed therapy by the time of the meeting, allowing the initial response and toxicity data to be available for presentation. Disclosures Davies: GIlead: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; CTI: Honoraria; Takeda: Honoraria, Research Funding; Bayer: Research Funding; GSK: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: The addition of bortezomib to R-CHOP chemotherapy in diffuse large B-cell lymphoma. Pocock:Janssen: Honoraria. Jack:Jannsen: Research Funding. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding.

Childhood pulmonary embolism (PE) is a rare but serious condition marked by hypoxemia, shock, right-sided heart failure, and significant risk for fatality. Recommended treatment options include surgical embolectomy, anticoagulation, and thrombolysis. This report describes the successful use of recombinant tissue plasminogen activator to treat PE associated with urosepsis in a 34-day-old infant and reverse severe hemodynamic compromise. Diagnosis of proximal PE and monitoring its treatment were successfully achieved by echocardiography.