Catching mono- and poly-ADP-ribose readers with synthetic ADP-ribose baits.

ADP-ribosylation is an essential post-translational modification that comes in two varieties: mono-ADP-ribosylation (MAR) and poly-ADP-ribosylation (PAR). Modular interaction domains that read MAR and PAR modifications are critical for interpreting the language of ADP-ribosylation. Kliza et al. (2021) use a chemical biology approach to identify distinct MAR and PAR readers.

Interplay between compartmentalized NAD+ synthesis and consumption: a focus on the PARP family.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a substrate for signaling enzymes. When used as a substrate by signaling enzymes, it is consumed, necessitating the recycling of NAD+ consumption products (i.e., nicotinamide) via a salvage pathway in order to maintain NAD+ homeostasis. A major family of NAD+ consumers in mammalian cells are poly-ADP-ribose-polymerases (PARPs). PARPs comprise a family of 17 enzymes in humans, 16 of which catalyze the transfer of ADP-ribose from NAD+ to macromolecular targets (namely, proteins, but also DNA and RNA). Because PARPs and the NAD+ biosynthetic enzymes are subcellularly localized, an emerging concept is that the activity of PARPs and other NAD+ consumers are regulated in a compartmentalized manner. In this review, I discuss NAD+ metabolism, how different subcellular pools of NAD+ are established and regulated, and how free NAD+ levels can control signaling by PARPs and redox metabolism.

Chemical genetic methodologies for identifying protein substrates of PARPs.

Poly-ADP-ribose-polymerases (PARPs) are a family of 17 enzymes that regulate a diverse range of cellular processes in mammalian cells. PARPs catalyze the transfer of ADP-ribose from NAD+ to target molecules, most prominently amino acids on protein substrates, in a process known as ADP-ribosylation. Identifying the direct protein substrates of individual PARP family members is an essential first step for elucidating the mechanism by which PARPs regulate a particular pathway in cells. Two distinct chemical genetic (CG) strategies have been developed for identifying the direct protein substrates of individual PARP family members. In this review, we discuss the design principles behind these two strategies and how target identification has provided novel insight into the cellular function of individual PARPs and PARP-mediated ADP-ribosylation.

Chemical gradients in human enamel crystallites.

Dental enamel is a principal component of teeth1, and has evolved to bear large chewing forces, resist mechanical fatigue and withstand wear over decades2. Functional impairment and loss of dental enamel, caused by developmental defects or tooth decay (caries), affect health and quality of life, with associated costs to society3. Although the past decade has seen progress in our understanding of enamel formation (amelogenesis) and the functional properties of mature enamel, attempts to repair lesions in this material or to synthesize it in vitro have had limited success4-6. This is partly due to the highly hierarchical structure of enamel and additional complexities arising from chemical gradients7-9. Here we show, using atomic-scale quantitative imaging and correlative spectroscopies, that the nanoscale crystallites of hydroxylapatite (Ca5(PO4)3(OH)), which are the fundamental building blocks of enamel, comprise two nanometric layers enriched in magnesium flanking a core rich in sodium, fluoride and carbonate ions; this sandwich core is surrounded by a shell with lower concentration of substitutional defects. A mechanical model based on density functional theory calculations and X-ray diffraction data predicts that residual stresses arise because of the chemical gradients, in agreement with preferential dissolution of the crystallite core in acidic media. Furthermore, stresses may affect the mechanical resilience of enamel. The two additional layers of hierarchy suggest a possible new model for biological control over crystal growth during amelogenesis, and hint at implications for the preservation of biomarkers during tooth development.

Publisher Correction: Chemical gradients in human enamel crystallites.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Decreased Beta Power and OFC-STN Phase Synchronization During Reactive Stopping in Freely Behaving Rats.

During natural behavior, an action often needs to be suddenly stopped in response to unexpected sensory input - referred to as reactive stopping. Reactive stopping has been mostly investigated in humans, which led to hypotheses about the involvement of different brain structures, in particular the hyperdirect pathway. Here, we directly investigate the contribution and interaction of two key regions of the hyperdirect pathway, the orbitofrontal cortex (OFC) and subthalamic nucleus (STN), using dual-area, multi-electrode recordings in male rats performing a stop-signal task. In this task rats have to initiate movement to a go-signal, and occasionally stop their movement to the go-signal side after a stop-signal, presented at various stop-signal delays.Both the OFC and STN show near-simultaneous field potential reductions in the beta frequency range (12-30 Hz) compared to the period preceding the go-signal and the movement period. These transient reductions (∼200 ms) only happen during reactive stopping, which is when the stop-signal was received after action initiation, and are well-timed after stop-signal onset and before the estimated time of stopping. Phase synchronization analysis also showed a transient attenuation of synchronization between the OFC and STN in the beta range during reactive stopping.The present results provide the first direct quantification of local neural oscillatory activity in the OFC and STN and interareal synchronization specifically timed during reactive stopping.Significance Statement Different studies observed increases in oscillatory beta activity and suggested increased synchronization between the orbitofrontal cortex (OFC) and subthalamic nucleus (STN) during reactive stopping. However, there has been inconsistency in the timing of beta modulations, and no study has yet investigated phase synchronization during stopping in both the OFC and STN with anatomical and temporal precision. Using dual-area recordings during a stopping task, we observed substantial decreases in beta power in both the OFC and STN at the time of stopping, alongside a decrease in beta phase synchronization. Rather than increased beta-band activity, the OFC and STN appear to facilitate stopping through local and inter-areal desynchronization. This may enable functionally specific neuronal activity to selectively inhibit motor behavior downstream.

Proximity-dependent mapping of the HCMV US28 interactome identifies RhoGEF signaling as a requirement for efficient viral reactivation.

Human cytomegalovirus (HCMV) encodes multiple putative G protein-coupled receptors (GPCRs). US28 functions as a viral chemokine receptor and is expressed during both latent and lytic phases of virus infection. US28 actively promotes cellular migration, transformation, and plays a major role in mediating viral latency and reactivation; however, knowledge about the interaction partners involved in these processes is still incomplete. Herein, we utilized a proximity-dependent biotinylating enzyme (TurboID) to characterize the US28 interactome when expressed in isolation, and during both latent (CD34+ hematopoietic progenitor cells) and lytic (fibroblasts) HCMV infection. Our analyses indicate that the US28 signalosome converges with RhoA and EGFR signal transduction pathways, sharing multiple mediators that are major actors in processes such as cellular proliferation and differentiation. Integral members of the US28 signaling complex were validated in functional assays by immunoblot and small-molecule inhibitors. Importantly, we identified RhoGEFs as key US28 signaling intermediaries. In vitro latency and reactivation assays utilizing primary CD34+ hematopoietic progenitor cells (HPCs) treated with the small-molecule inhibitors Rhosin or Y16 indicated that US28 -RhoGEF interactions are required for efficient viral reactivation. These findings were recapitulated in vivo using a humanized mouse model where inhibition of RhoGEFs resulted in a failure of the virus to reactivate. Together, our data identifies multiple new proteins in the US28 interactome that play major roles in viral latency and reactivation, highlights the utility of proximity-sensor labeling to characterize protein interactomes, and provides insight into targets for the development of novel anti-HCMV therapeutics.

Aging is associated with maladaptive episodic memory-guided social decision-making.

Older adults are frequent targets and victims of financial fraud. They may be especially susceptible to revictimization because of age-related changes in both episodic memory and social motivation. Here we examined these factors in a context where adaptive social decision-making requires intact associative memory for previous social interactions. Older adults made more maladaptive episodic memory-guided social decisions but not only because of poorer associative memory. Older adults were biased toward remembering people as being fair, while young adults were biased toward remembering people as being unfair. Holding memory constant, older adults engaged more with people that were familiar (regardless of the nature of the previous interaction), whereas young adults were prone to avoiding others that they remembered as being unfair. Finally, older adults were more influenced by facial appearances, choosing to interact with social partners that looked more generous, even though those perceptions were inconsistent with prior experience.

Familiarity Alters the Bandwidth of Perceptual Awareness.

Results from paradigms like change blindness and inattentional blindness indicate that observers are unaware of numerous aspects of the visual world. However, intuition suggests that perceptual experience is richer than these results indicate. Why does it feel like we see so much when the data suggests we see so little? One possibility stems from the fact that experimental studies always present observers with stimuli that they have never seen before. Meanwhile, when forming intuitions about perceptual experience, observers reflect on their experiences with scenes with which they are highly familiar (e.g., their office). Does prior experience with a scene change the bandwidth of perceptual awareness? Here, we asked if observers were better at noticing alterations to the periphery in familiar scenes compared with unfamiliar scenes. We found that observers noticed changes to the periphery more frequently with familiar stimuli. Signal detection theoretic analyses revealed that when observers are unfamiliar with a stimulus, they are less sensitive at noticing (d') and are more conservative in their response criterion (c). Taken together, these results suggest that prior knowledge expands the bandwidth of perceptual awareness. It should be stressed that these results challenge the widely held idea that prior knowledge fills in perception. Overall, these findings highlight how prior knowledge plays an important role in determining the limits of perceptual experience and is an important factor to consider when attempting to reconcile the tension between empirical observation and personal introspection.

A Retrospective Genomic Landscape of 661 Young Adult Glioblastomas Diagnosed Using 2016 WHO Guidelines for Central Nervous System Tumors.

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible.

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-related Macular Degeneration.

OBJECTIVE: To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DESIGN: Phase 1, open-label, single-center, first-in-human clinical study. SUBJECTS: Adult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. METHODS: Patients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. MAIN OUTCOME MEASURES: Safety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. RESULTS: Baseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center-involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. CONCLUSIONS: All 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Surgical Management of Full-Thickness Macular Holes in Macular Telangiectasia Type 2: A Global Multicenter Study.

PURPOSE: To report on macular hole repair in macular telangiectasia type 2 (MacTel2). DESIGN: Global, multicenter, retrospective case series. PARTICIPANTS: Patients undergoing surgery for MacTel2-associated full-thickness macular hole (MTMH). METHODS: Standardized data collection sheet distributed to all surgeons. MAIN OUTCOME MEASURES: Anatomic closure and visual outcomes of MTMH. RESULTS: Sixty-three surgeries in 47 patients with MTMH were included from 30 surgeons. Mean age was 68.1 years, with 62% female, 72% White, 21% East or South Asian, 2% African American, and 2% Hispanic or Latino. Procedures included 34 internal limiting membrane (ILM) peeling alone, 22 ILM flaps, 5 autologous retinal transplantations (ARTs), 1 retinotomy, and 1 subretinal bleb. For ILM peeling, preoperative visual acuity (VA) was 0.667 ± 0.423 logarithm of the minimum angle of resolution (logMAR). Minimum hole diameter (MHD) was 305.5 ± 159.4 µm (range, 34-573 µm). Sixteen of 34 ILM peels (47%) resulted in MTMH closure. At postoperative month 6, VA was stable at 0.602 ± 0.516 logMAR (P = 0.65). VA improved by at least 2 lines in 43% and at least 4 lines in 24%. For ILM flaps, preoperative VA was 0.878 ± 0.552 logMAR. MHD was 440.8 ± 175.5 µm (range, 97-697 µm), which was significantly larger than for ILM peels (P < 0.01). Twenty of 22 ILM flaps (90%) resulted in MTMH closure, which was significantly higher than for ILM peels (P < 0.01). At postoperative month 6, VA improved to 0.555 ± 0.405 logMAR (P < 0.05). VA improved by at least 2 lines in 56% and at least 4 lines in 28%. For ARTs, preoperative VA was 1.460 ± 0.391 logMAR. MHD was 390.2 ± 203.7 µm (range, 132-687 µm). All 5 ARTs (100%) resulted in MTMH closure. At postoperative month 6, VA was stable at 1.000 ± 0.246 logMAR (P = 0.08). Visual acuity improved at least 2 lines in 25%. CONCLUSIONS: Surgical closure of macular holes improved VA in 57% of MTMHs. Internal limiting membrane flaps achieved better anatomic and functional outcomes than ILM peeling alone. Autologous retinal transplantation may be an option for refractory MTMHs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Midfrontal theta dynamics index the monitoring of postural stability.

Stepping is a common strategy to recover postural stability and maintain upright balance. Postural perturbations have been linked to neuroelectrical markers such as the N1 potential and theta frequency dynamics. Here, we investigated the role of cortical midfrontal theta dynamics of balance monitoring, driven by balance perturbations at different initial standing postures. We recorded electroencephalography, electromyography, and motion tracking of human participants while they stood on a platform that delivered a range of forward and backward whole-body balance perturbations. The participants' postural threat was manipulated prior to the balance perturbation by instructing them to lean forward or backward while keeping their feet-in-place in response to the perturbation. We hypothesized that midfrontal theta dynamics index the engagement of a behavioral monitoring system and, therefore, that perturbation-induced theta power would be modulated by the initial leaning posture and perturbation intensity. Targeted spatial filtering in combination with mixed-effects modeling confirmed our hypothesis and revealed distinct modulations of theta power according to postural threat. Our results provide novel evidence that midfrontal theta dynamics subserve action monitoring of human postural balance. Understanding of cortical mechanisms of balance control is crucial for studying balance impairments related to aging and neurological conditions (e.g. stroke).

Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling.

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development [R. T. Moon et al, Development 119, 97-111 (1993); I. Oishi et al, Genes Cells 8, 645-654 (2003)], but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a ß-catenin-independent, ubiquitin-proteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain [M. Flynn, O. Saha, P. Young, BMC Evol. Biol. 11, 235 (2011)], which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

Demographic disparities in children with retropharyngeal and parapharyngeal abscesses.

PURPOSE: To explore the impact that demographic and socioeconomic factors such as age, gender, race, and insurance status have on the diagnosis of retropharyngeal (RPA) and parapharyngeal abscesses (PPA) in the pediatric population. METHODS: The 2016 HCUP KID was searched for all RPA/PPA discharges using the joint ICD-10 code J39.0. Descriptive statistics, univariate, and multivariate analyses were performed to assess the relationship between demographic factors and their impact on RPA/PPA diagnosis. Results were reported with their corresponding odds ratio with a 95 % confidence interval and p-value. RESULTS: 56.4 per 100,000 weighted discharges were discharged with a diagnosis of a RPA/PPA, the average age was 5.7 years old, with a male predominance. Pediatric discharges diagnosed with a RPA/PPA were less likely to identify as Hispanic or Asian/Island Pacific. They were also less likely to be insured by Medicaid and reside in zip codes with a lower median income. CONCLUSION: The analysis of this national pediatric database demonstrated significant demographic differences in children diagnosed with RPA/PPAs. Following the multivariate analysis, children from a higher socioeconomic background and those with private insurance were more likely to be diagnosed with a RPA/PPAs. However, disparities in children's overall hospital course and complications is a potential area for future research.

Relationship between otolaryngology interest groups and residency match results.

BACKGROUND: Many students have limited exposure to otolaryngology-head and neck surgery (OTOHNS) throughout medical school, limiting recruitment of medical students early in their medical careers. OBJECTIVE: To assess the association between otolaryngology interest groups (OIGs) at medical schools and percentage of students matching into OTOHNS residency programs. To characterize specific aspects of OIGs that may impact the percentage of students matching into OTOHNS residency programs from a given medical school. METHODS: Data was obtained from web searches of 141 accredited U.S. allopathic medical schools to see if they possessed OIGs. Information on the various activities and opportunities that OIGs participated in was collected through medical school websites. 2020 NRMP® match results data were obtained. RESULTS: Web searches found that 73 % (103 out of 141) of U.S. allopathic medical schools have OIGs. Medical schools with OIGs were associated with a 35 % increase in the median percentage of OTOHNS matches (P = 0.022). Of the 103 medical schools with OIGs, 53 % (55) of the schools had information on their websites describing activities and opportunities that their OIGs participate in. OIGs with research and/or mentorship opportunities were associated with increases in OTOHNS matches by 32 % (P = 0.043) and 83 % (P = 0.012), respectively. CONCLUSION: The presence of an OIG at a medical school is associated with an increased percentage of students matching into OTOHNS from that medical school. OIGs that provide research or mentorship opportunities are associated with an increased percentage of students matching into OTOHNS from those medical schools.

Reward enhancement of item-location associative memory spreads to similar items within a category.

The experience of a reward appears to enhance memory for recent prior events, adaptively making that information more available to guide future decision-making. Here, we tested whether reward enhances memory for associative item-location information and also whether the effect of reward spreads to other categorically-related but unrewarded items. Participants earned either points (Experiment 1) or money (Experiment 2) through a time-estimation reward task, during which stimuli-location pairings around a 2D-ring were shown followed by either high-value or low-value rewards. All stimuli were then tested for location memory or recognition (yes/no), immediately and after a 24-hour delay. Across both experiments (combined analysis), there was a robust improvement in location memory following high-value rewards, even though evidence supporting this effect was reliable in Experiment 2 but not in Experiment 1. The memory-enhancing effect of reward was observed on both the immediate and delayed location-memory tests. Reward-enhanced memory for both directly rewarded stimuli and categorically related stimuli that were not directly rewarded. No reliable effect of reward value on yes/no recognition-memory performance was observed in either experiment. We hypothesise that reward enhances the consolidation of recent experience and conceptually related memories to make these more available for future decisions.

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly.

Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.

Continuous Positive Airway Pressure in the Treatment of Pediatric High Altitude Pulmonary Edema: A Case Study.

Treatment of high altitude pulmonary edema (HAPE) can be challenging and is further complicated in the pediatric patient in the prehospital environment. The following case presents a decompensating pediatric patient with HAPE in the prehospital aeromedical environment. It illustrates the potential benefit of continuous positive airway pressure (CPAP) as a treatment modality in the treatment of HAPE.