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Management of patients with acute lung injury (ALI) rests on achieving a balance between the gas exchanging benefits of mechanical ventilation and the exacerbation of tissue damage in the form of ventilator-induced lung injury (VILI). Optimizing this balance requires an injury cost function relating injury progression to the measurable pressures, flows, and volumes delivered during mechanical ventilation. With this in mind, we mechanically ventilated naive, anesthetized, paralyzed mice for 4 h using either a low or high tidal volume (Vt) with either moderate or zero positive end-expiratory pressure (PEEP). The derecruitability of the lung was assessed every 15 min in terms of the degree of increase in lung elastance occurring over 3 min following a recruitment maneuver. Mice could be safely ventilated for 4 h with either a high Vt or zero PEEP, but when both conditions were applied simultaneously the lung became increasingly unstable, demonstrating worsening injury. We were able to mimic these data using a computational model of dynamic recruitment and derecruitment that simulates the effects of progressively increasing surface tension at the air–liquid interface, suggesting that the VILI in our animal model progressed via a vicious cycle of alveolar leak, degradation of surfactant function, and increasing tissue stress. We thus propose that the task of ventilating the injured lung is usefully understood in terms of the Vt–PEEP plane. Within this plane, non-injurious combinations of Vt and PEEP lie within a “safe region”, the boundaries of which shrink as VILI develops.

Management of ALI/ARDS involves supportive ventilation at low tidal volumes ( V t ) to minimize the rate at which ventilator induced lung injury (VILI) develops while the lungs heal. However, we currently have few details to guide the minimization of VILI in the ALI/ARDS patient. The goal of the present study was to determine how VILI progresses with time as a function of the manner in which the lung is ventilated in mice. We found that the progression of VILI caused by over-ventilating the lung at a positive end-expiratory pressure of zero is accompanied by progressive increases in lung stiffness as well as the rate at which the lung derecruits over time. We were able to accurately recapitulate these findings in a computational model that attributes changes in the dynamics of recruitment and derecruitment to two populations of lung units. One population closes over a time scale of minutes following a recruitment maneuver and the second closes in a matter of seconds or less, with the relative sizes of the two populations changing as VILI develops. This computational model serves as a basis from which to link the progression of VILI to changes in lung mechanical function.

The identification and development of reliable acute stroke blood biomarkers could limit life-threatening delays stemming from mistriage. Recent investigations have reported a set of 24 plasma circRNAs believed to be released from the brain into circulation during acute ischemic events with potential to serve as such biomarkers. However, limitations associated with the methods employed for biomarker discovery in these studies raise the possibility that these circRNAs actually originate from non-neural sources. Here, we sought to clarify the probability that these 24 plasma circRNAs truly originate from the brain by examining source tissue expression levels. Specifically, we leveraged genome-wide RNA sequencing data from a large cohort of human donors to assess their expression levels in 31 distinct tissue types including brain. 17 of the 24 (70.8%) candidate circRNAs exhibited their single highest expression levels in blood relative to all other tissue types included in our analysis, while only 1 (4.2%) exhibited its single highest expression levels in brain. The observed body-wide expression profiles suggest that a majority of the 24 candidate plasma circRNAs assessed in our analysis originate from circulating white blood cells and not the brain as originally believed, which would dramatically reduce their potential utility as acute stroke biomarkers.

Early initiation of antiretroviral therapy (eiART) can improve clinical outcomes for persons with HIV and reduce onward transmission risk. Baseline drug resistance testing (bDRT) can inform regimen selection upon subsequent treatment initiation. We examined the uptake of eiART and bDRT within 3 months and 30 days of HIV diagnosis. We analyzed a population-based sample from the San Francisco Department of Public Health HIV/AIDS Case Registry of newly-diagnosed HIV/non-AIDS individuals between 2001 and 2015 who received care at publicly-funded facilities (N = 3,124). Uptake of eiART within 3 months of diagnosis increased significantly from 2001 to 2015 (p<0.001), peaking at 74% in 2015. bDRT uptake also increased significantly (p<0.001), peaking at 55% in 2012. eiART uptake was observed to be significantly associated with gender, age, race/ethnicity and transmission risk. There were no significant differences observed in demographic and risk characteristics of persons receiving bDRT in the more recent years. Of 990 persons diagnosed between 2010 and 2015, eiART uptake within 30 days of diagnosis increased from 13% to 38% (p<0.001); bDRT uptake increased from 35% to 39% but the change was not significant (p = 0.141). Observed increases in eiART and bDRT uptake from 2010 to 2015 may reflect the adoption of treatment as prevention and a local public health policy statement in 2010 recommending treatment initiation at time of diagnosis irrespective of CD4 count. Concerns about stigma may underlie disparities in eiART, however such concerns would not bear as directly on a provider-initiated laboratory test like bDRT.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system 1 . We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells 2 , providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10 6 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly 3 . Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG. A phase I dose-escalation trial of GD2-CAR T cells in children and young adults with diffuse midline gliomas to assess the feasibility of manufacturing, safety and tolerability, and to preliminarily assess efficacy.

Yersinia pestis is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of Y. pestis infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of Yersinia pestis pulmonary infections are incompletely understood. Here, we report that Yersinia pestis inhibits neutrophil degranulation during infection, rendering neutrophils ineffective and allowing unrestricted growth of Y. pestis in the lungs. This coordinated inhibition of granule release not only demonstrates the pathogenic benefit of “silencing” lung neutrophils but also reveals specific host processes and pathways that could be manipulated to reduce the severity of primary pneumonic plague. Inhalation of Yersinia pestis causes primary pneumonic plague, the most severe manifestation of plague that is characterized by a dramatic neutrophil influx to the lungs. Neutrophils are ineffective during primary pneumonic plague, failing to control Y. pestis growth in the airways. However, the mechanisms by which Y. pestis resists neutrophil killing are incompletely understood. Here, we show that Y. pestis inhibits neutrophil degranulation, an important line of host innate immune defense. We observed that neutrophils from the lungs of mice infected intranasally with Y. pestis fail to release primary granules throughout the course of disease. Using a type III secretion system (T3SS) injection reporter strain, we determined that Y. pestis directly inhibits neutrophil granule release by a T3SS-dependent mechanism. Combinatorial mutant analysis revealed that a Y. pestis strain lacking both effectors YopE and YopH did not inhibit primary granule release and is killed by neutrophils both in vivo and in vitro . Similarly, Y. pestis strains injecting only YopE or YopH are able to inhibit the majority of primary granule release from human neutrophils. We determined that YopE and YopH block Rac2 activation and calcium flux, respectively, to inhibit neutrophil primary granule release in isolated human neutrophils. These results demonstrate that Y. pestis coordinates the inhibition of neutrophil primary granule release through the activities of two distinct effectors, and this inhibition promotes Y. pestis survival during primary pneumonic plague. IMPORTANCE Yersinia pestis is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of Y. pestis infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of Yersinia pestis pulmonary infections are incompletely understood. Here, we report that Yersinia pestis inhibits neutrophil degranulation during infection, rendering neutrophils ineffective and allowing unrestricted growth of Y. pestis in the lungs. This coordinated inhibition of granule release not only demonstrates the pathogenic benefit of “silencing” lung neutrophils but also reveals specific host processes and pathways that could be manipulated to reduce the severity of primary pneumonic plague.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1 ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models 1 . Arm A of Phase I trial no. NCT04196413 (ref.  2 ) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10 6  kg − 1 ; DL2, 3 × 10 6  kg −1 ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10 6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study ( n  = 3 DL1 (3 DIPG); n  = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M + diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.