Prone positioning in combination with the application of low tidal volume and adequate positive end-expiratory pressure (PEEP) improves survival in patients with moderate to severe acute respiratory ...distress syndrome (ARDS). However, the effects of PEEP on end-expiratory transpulmonary pressure (Ptp
) during prone positioning require clarification. For this purpose, the effects of three different PEEP titration strategies on Ptp
, respiratory mechanics, mechanical power, gas exchange, and hemodynamics were evaluated comparing supine and prone positioning.
In forty consecutive patients with moderate to severe ARDS protective ventilation with PEEP titrated according to three different titration strategies was evaluated during supine and prone positioning: (A) ARDS Network recommendations (PEEP
), (B) the lowest static elastance of the respiratory system (PEEP
), and (C) targeting a positive Ptp
(PEEP
). The primary endpoint was to analyze whether Ptp
differed significantly according to PEEP titration strategy during supine and prone positioning.
Ptp
increased progressively with prone positioning compared with supine positioning as well as with PEEP
and PEEP
compared with PEEP
(positioning effect p < 0.001, PEEP strategy effect p < 0.001). PEEP was lower during prone positioning with PEEP
and PEEP
(positioning effect p < 0.001, PEEP strategy effect p < 0.001). During supine positioning, mechanical power increased progressively with PEEP
and PEEP
compared with PEEP
, and prone positioning attenuated this effect (positioning effect p < 0.001, PEEP strategy effect p < 0.001). Prone compared with supine positioning significantly improved oxygenation (positioning effect p < 0.001, PEEP strategy effect p < 0.001) while hemodynamics remained stable in both positions.
Prone positioning increased transpulmonary pressures while improving oxygenation and hemodynamics in patients with moderate to severe ARDS when PEEP was titrated according to the ARDS Network lower PEEP table. This PEEP titration strategy minimized parameters associated with ventilator-induced lung injury induction, such as transpulmonary driving pressure and mechanical power. We propose that a lower PEEP strategy (PEEP
) in combination with prone positioning may be part of a lung protective ventilation strategy in patients with moderate to severe ARDS.
German Clinical Trials Register ( DRKS00017449 ). Registered June 27, 2019. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017449.
Adult zebrafish show a remarkable capacity to regenerate their spinal column after injury, an ability that stands in stark contrast to the limited repair that occurs within the mammalian CNS ...post-injury. The reasons for this interspecies difference in regenerative capacity remain unclear. Here we demonstrate a novel role for Fgf signaling during glial cell morphogenesis in promoting axonal regeneration after spinal cord injury. Zebrafish glia are induced by Fgf signaling, to form an elongated bipolar morphology that forms a bridge between the two sides of the resected spinal cord, over which regenerating axons actively migrate. Loss of Fgf function inhibits formation of this "glial bridge" and prevents axon regeneration. Despite the poor potential for mammalian axonal regeneration, primate astrocytes activated by Fgf signaling adopt a similar morphology to that induced in zebrafish glia. This suggests that differential Fgf regulation, rather than intrinsic cell differences, underlie the distinct responses of mammalian and zebrafish glia to injury.
Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality after major surgery. Intraoperative lung-protective mechanical ventilation has ...the potential to reduce the incidence of postoperative pulmonary complications. This review discusses the relevant literature on definition and methods to predict the occurrence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis on the noninjured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure, and recruitment maneuvers. The authors propose an algorithm for protective intraoperative mechanical ventilation based on evidence from recent randomized controlled trials.
ARHGAP36 is an atypical Rho GTPase-activating protein (GAP) family member that drives both spinal cord development and tumorigenesis, acting in part through an N-terminal motif that suppresses ...protein kinase A and activates Gli transcription factors. ARHGAP36 also contains isoform-specific N-terminal sequences, a central GAP-like module, and a unique C-terminal domain, and the functions of these regions remain unknown. Here we have mapped the ARHGAP36 structure-activity landscape using a deep sequencing-based mutagenesis screen and truncation mutant analyses. Using this approach, we have discovered several residues in the GAP homology domain that are essential for Gli activation and a role for the C-terminal domain in counteracting an N-terminal autoinhibitory motif that is present in certain ARHGAP36 isoforms. In addition, each of these sites modulates ARHGAP36 recruitment to the plasma membrane or primary cilium. Through comparative proteomics, we also have identified proteins that preferentially interact with active ARHGAP36, and we demonstrate that one binding partner, prolyl oligopeptidase-like protein, is a novel ARHGAP36 antagonist. Our work reveals multiple modes of ARHGAP36 regulation and establishes an experimental framework that can be applied towards other signaling proteins.
To determine any long-term effects, 6 and 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the NIMH Collaborative Multisite Multimodal Treatment Study of Children ...With Attention-Deficit/Hyperactivity Disorder (MTA; N = 436); to test whether attention-deficit/hyperactivity disorder (ADHD) symptom trajectory through 3 years predicts outcome in subsequent years; and to examine functioning level of the MTA adolescents relative to their non-ADHD peers (local normative comparison group; N = 261).
Mixed-effects regression models with planned contrasts at 6 and 8 years tested a wide range of symptom and impairment variables assessed by parent, teacher, and youth report.
In nearly every analysis, the originally randomized treatment groups did not differ significantly on repeated measures or newly analyzed variables (e.g., grades earned in school, arrests, psychiatric hospitalizations, other clinically relevant outcomes). Medication use decreased by 62% after the 14-month controlled trial, but adjusting for this did not change the results. ADHD symptom trajectory in the first 3 years predicted 55% of the outcomes. The MTA participants fared worse than the local normative comparison group on 91% of the variables tested.
Type or intensity of 14 months of treatment for ADHD in childhood (at age 7.0-9.9 years) does not predict functioning 6 to 8 years later. Rather, early ADHD symptom trajectory regardless of treatment type is prognostic. This finding implies that children with behavioral and sociodemographic advantage, with the best response to any treatment, will have the best long-term prognosis. As a group, however, despite initial symptom improvement during treatment that is largely maintained after treatment, children with combined-type ADHD exhibit significant impairment in adolescence. Innovative treatment approaches targeting specific areas of adolescent impairment are needed.
Context
Transgender men (TGM) are persons assigned female gender at birth with a male gender identity and are routinely treated with testosterone. Androgen excess is associated with endothelial ...dysfunction among cisgender females (CGF) and is an early sign of atherosclerosis and hypertension.
Objective
To determine the effect of testosterone treatment on endothelial function in TGM.
Setting
The John B. Pierce Laboratory and Yale School of Medicine.
Subjects
Eleven TGM (age 27 ± 5 years; BMI 24.4 ± 3.7 kg/m2) receiving testosterone (T) and 20 CGF (28 ± 5 years; BMI 26.0 ± 5.1 kg/m2) during the early follicular phase of their menstrual cycle.
Design and Outcome Measures
We evaluated brachial vasodilatory responses following stimuli designed to elicit shear stress using 5‐minute occlusion to determine endothelial function (flow‐mediated vasodilation, FMD).
Results
Total T was greater in the TGM compared to CGF (484.6 ± 122.5 vs 1.5 ± 0.7 ng/dL), as was free T (83.9 ± 32.4 vs 1.9 ± 0.8 pg/dL). FMD was markedly lower in the TGM (4.5 ± 2.7%) compared to the CGF (8.1 ± 2.9%, P = .002) indicating significantly diminished endothelial function in TGM.
Conclusions
We have shown for the first time that in TGM the androgen‐dominant hormonal milieu was associated with impaired endothelial function. Endothelial dysfunction precedes clinically detectable atherosclerotic plaque in the coronary arteries, so is an important marker for clinical cardiovascular risk. Therefore, attention to cardiovascular risk factors should be integral to the care of transgender men.
Efficient clearance of pro-inflammatory macrophages from tissues after resolution of a challenge is critical to prevent prolonged inflammation. Defects in clearance can contribute to conditions such ...as inflammatory bowel disease, and thus may be therapeutically targetable. However, the signaling pathways that induce termination of pro-inflammatory macrophages are incompletely defined. We tested whether the ErbB4 receptor tyrosine kinase, previously not known to have role in macrophage biology, is involved in this process. In vitro, pro-inflammatory activation of cultured murine and human macrophages induced ErbB4 expression; in contrast, other ErbB family members were not induced in pro-inflammatory cells, and other innate immune lineages (dendritic cells, neutrophils) did not express detectable ErbB4 levels. Treatment of activated pro-inflammatory macrophages with the ErbB4 ligand neuregulin-4 (NRG4) induced apoptosis. ErbB4 localized to the mitochondria in these cells. Apoptosis was accompanied by loss of mitochondrial membrane potential, and was dependent upon the proteases that generate the cleaved ErbB4 intracellular domain fragment, suggesting a requirement for this fragment and mitochondrial pathway apoptosis. In vivo, ErbB4 was highly expressed on pro-inflammatory macrophages but not neutrophils during experimental DSS colitis in C57Bl/6 mice. Active inflammation in this model suppressed NRG4 expression, which may allow for macrophage persistence and ongoing inflammation. Consistent with this notion, NRG4 levels rebounded during the recovery phase, and administration of exogenous NRG4 during colitis reduced colonic macrophage numbers and ameliorated inflammation. These data define a novel role for ErbB4 in macrophage apoptosis, and outline a mechanism of feedback inhibition that may promote resolution of colitis.
Ultraprotective ventilation in acute respiratory distress syndrome (ARDS) patients with veno-venous extracorporeal membrane oxygenation (VV ECMO) reduces mechanical power (MP) through changes in ...positive end-expiratory pressure (PEEP); however, the optimal approach to titrate PEEP is unknown. This study assesses the effects of three PEEP titration strategies on MP, hemodynamic parameters, and oxygen delivery in twenty ARDS patients with VV ECMO.
PEEP was titrated according to: (A) a PEEP of 10 cmH2O representing the lowest recommendation by the Extracorporeal Life Support Organization (PEEPELSO), (B) the highest static compliance of the respiratory system (PEEPCstat,RS), and (C) a target end-expiratory transpulmonary pressure of 0 cmH2O (PEEPPtpexp).
PEEPELSO was lower compared to PEEPCstat,RS and PEEPPtpexp (10.0 ± 0.0 vs. 16.2 ± 4.7 cmH2O and 17.3 ± 4.0 cmH2O, p < 0.001 each, respectively). PEEPELSO reduced MP compared to PEEPCstat,RS and PEEPPtpexp (5.3 ± 1.3 vs. 6.8 ± 2.0 and 6.9 ± 2.3 J/min, p < 0.001 each, respectively). PEEPELSO resulted in less lung stress compared to PEEPCstat,RS (p = 0.011) and PEEPPtpexp (p < 0.001) and increased cardiac output and oxygen delivery (p < 0.001 each).
An empirical PEEP of 10 cmH2O minimized MP, provided favorable hemodynamics, and increased oxygen delivery in ARDS patients treated with VV ECMO.
German Clinical Trials Register (DRKS00013967). Registered 02/09/2018https://drks.de/search/en/trial/DRKS00013967
•The optimal approach to PEEP titration in VV ECMO patients is unknown.•Adequate PEEP balances between lung protection and hemodynamic stability.•Excessive PEEP causes alveolar overdistension and negative hemodynamic effects.•Empirical moderate PEEP minimizes mechanical power and optimizes hemodynamics.
To determine long-term effects on substance use and substance use disorder (SUD), up to 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the multisite Multimodal ...Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA; n = 436); to test whether medication at follow-up, cumulative psychostimulant treatment over time, or both relate to substance use/SUD; and to compare substance use/SUD in the ADHD sample to the non-ADHD childhood classmate comparison group (n = 261).
Mixed-effects regression models with planned contrasts were used for all tests except the important cumulative stimulant treatment question, for which propensity score matching analysis was used.
The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD. Substance use at all time points, including use of two or more substances and SUD, were each greater in the ADHD than in the non-ADHD samples, regardless of sex.
Medication for ADHD did not protect from, or contribute to, visible risk of substance use or SUD by adolescence, whether analyzed as randomized treatment assignment in childhood, as medication at follow-up, or as cumulative stimulant treatment over an 8-year follow-up from childhood. These results suggest the need to identify alternative or adjunctive adolescent-focused approaches to substance abuse prevention and treatment for boys and girls with ADHD, especially given their increased risk for use and abuse of multiple substances that is not improved with stimulant medication. Clinical trial registration information-Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://clinical trials.gov/; NCT00000388.
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