Non-Redundant Roles of T Cell Costimulation Pathways in Inflammatory Arthritis Revealed by Dual Blockade of ICOS and CD28 with Acazicolcept (ALPN-101).

OBJECTIVE: CD28 and inducible T cell costimulator (ICOS) appear to have nonredundant roles in T cell activation and adaptive immunity. We undertook this study to characterize in vitro and in vivo the therapeutic potential of acazicolcept (ALPN-101), an Fc fusion protein of a human variant ICOS ligand (ICOSL) domain designed to inhibit both CD28 and ICOS costimulation, in inflammatory arthritis. METHODS: Acazicolcept was compared in vitro with inhibitors of either the CD28 or ICOS pathways (abatacept and belatacept [CTLA-4Ig], prezalumab [anti-ICOSL monoclonal antibody]) in receptor binding and signaling assays, and in a collagen-induced arthritis (CIA) model. Acazicolcept was also compared in cytokine and gene expression assays of peripheral blood mononuclear cells (PBMCs) from healthy donors or rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients stimulated with artificial antigen-presenting cells (APCs) expressing CD28 and ICOS ligands*. RESULTS: Acazicolcept bound CD28 and ICOS, prevented ligand binding, and inhibited human T cell functional interactions, matching or exceeding the activity of CD28 or ICOS costimulatory single-pathway inhibitors tested individually or in combination. Acazicolcept administration significantly reduced disease in the CIA model and more potently than abatacept. Acazicolcept also inhibited proinflammatory cytokine production from stimulated PBMCs in cocultures with artificial APCs and demonstrated unique effects on gene expression distinct from those induced by abatacept, prezalumab, or a combination of both. CONCLUSION: Both CD28 and ICOS signaling play critical roles in inflammatory arthritis. Therapeutic agents such as acazicolcept that coinhibit both ICOS and CD28 signaling may mitigate inflammation and/or disease progression in RA and PsA more effectively than inhibitors of either pathway alone.

The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity.

Despite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4-CD80/CD86 interactions. We demonstrate that by combining CD28 costimulation and dual checkpoint inhibition, ALPN-202 enhances T cell activation and anti-tumor efficacy in cell-based assays and mouse tumor models more potently than checkpoint blockade alone and thus has the potential to generate potent, clinically meaningful anti-tumor immunity in humans.

The depth of Jupiter's Great Red Spot constrained by Juno gravity overflights.

Jupiter's Great Red Spot (GRS) is the largest atmospheric vortex in the Solar System and has been observed for at least two centuries. It has been unclear how deep the vortex extends beneath its visible cloud tops. We examined the gravity signature of the GRS using data from 12 encounters of the Juno spacecraft with the planet, including two direct overflights of the vortex. Localized density anomalies due to the presence of the GRS caused a shift in the spacecraft line-of-sight velocity. Using two different approaches to infer the GRS depth, which yielded consistent results, we conclude that the GRS is contained within the upper 500 kilometers of Jupiter's atmosphere.

Living at the Confluence of Stigmas: PrEP Awareness and Feasibility Among People Who Inject Drugs in Two Predominantly Rural States.

We explored knowledge, beliefs, and acceptability of pre-exposure prophylaxis (PrEP) for HIV prevention with reference to stigma among people who inject drugs (PWID) in two predominately rural U.S. states. We conducted interviews with 65 current or former PWID aged 18 years or older and living in Arizona or Indiana. Most (63%) of the interviewees were not aware of PrEP. They often confused PrEP with HIV treatment, and many believed that PrEP was only for sexual risk or gay sexual risk. Once they understood that PrEP was recommended for PWID, the participants held a positive view of PrEP and felt that a once-daily pill was feasible. Experiences of stigma about drug use remained a crucial barrier to accessing healthcare and PrEP. This was often linked with anticipated or expressed homophobia. PrEP interventions among PWID must focus on education and the confluence of stigmas in which PWID find themselves when considering PrEP.

RESUMEN: Exploramos el conocimiento, las creencias y la aceptabilidad de la profilaxis previa a la exposición (PrEP) para la prevención del VIH con referencia al estigma entre las personas que inyectan drogas (PWID) en dos Estados Unidos predominantemente rurales. estados. Realizamos entrevistas con 65 PWID actuales o anteriores de 18 años o más y viviendo en Arizona o Indiana. Más (63%) de los entrevistados no estaban al tanto de la PrEP. A menudo confundieron la PrEP con el tratamiento del VIH, y muchos creían que la PrEP era sólo por riesgo sexual o riesgo sexual gay. Una vez que entendieron que la PrEP se recomendaba para PWID, los participantes tenían una visión positiva de la PrEP y sentían que una vez-píldora diaria era factible. Las experiencias de estigma sobre el consumo de drogas siguieron siendo una barrera crucial para acceder a la atención médica y a la PrEP. Esto a menudo estaba relacionado con la homofobia anticipada o expresada. Las intervenciones de la PrEP entre PWID deben centrarse en la educación y la confluencia de estigmas en los que PWID se encuentra al considerar la PrEP.

Jupiter's Overturning Circulation: Breaking Waves Take the Place of Solid Boundaries.

Cloud-tracked wind observations document the role of eddies in putting momentum into the zonal jets. Chemical tracers, lightning, clouds, and temperature anomalies document the rising and sinking in the belts and zones, but questions remain about what drives the flow between the belts and zones. We suggest an additional role for the eddies, which is to generate waves that propagate both up and down from the cloud layer. When the waves break they deposit momentum and thereby replace the friction forces at solid boundaries that enable overturning circulations on terrestrial planets. By depositing momentum of one sign within the cloud layer and momentum of the opposite sign above and below the clouds, the eddies maintain all components of the circulation, including the stacked, oppositely rotating cells between each belt-zone pair, and the zonal jets themselves.

ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist.

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.

Small lightning flashes from shallow electrical storms on Jupiter.

Lightning flashes have been observed by a number of missions that visited or flew by Jupiter over the past several decades. Imagery led to a flash rate estimate of about 4 × 10-3 flashes per square kilometre per year (refs. 1,2). The spatial extent of Voyager flashes was estimated to be about 30 kilometres (half-width at half-maximum intensity, HWHM), but the camera was unlikely to have detected the dim outer edges of the flashes, given its weak response to the brightest spectral line of Jovian lightning emission, the 656.3-nanometre Hα line of atomic hydrogen1,3-6. The spatial resolution of some cameras allowed investigators to confirm 22 flashes with HWHM greater than 42 kilometres, and to estimate one with an HWHM of 37 to 45 kilometres (refs. 1,7-9). These flashes, with optical energies comparable to terrestrial 'superbolts'-of (0.02-1.6) × 1010 joules-have been interpreted as tracers of moist convection originating near the 5-bar level of Jupiter's atmosphere (assuming photon scattering from points beneath the clouds)1-3,7,8,10-12. Previous observations of lightning have been limited by camera sensitivity, distance from Jupiter and long exposures (about 680 milliseconds to 85 seconds), meaning that some measurements were probably superimposed flashes reported as one1,2,7,9,10,13. Here we report optical observations of lightning flashes by the Juno spacecraft with energies of approximately 105-108 joules, flash durations as short as 5.4 milliseconds and inter-flash separations of tens of milliseconds, with typical terrestrial energies. The flash rate is about 6.1 × 10-2 flashes per square kilometre per year, more than an order of magnitude greater than hitherto seen. Several flashes are of such small spatial extent that they must originate above the 2-bar level, where there is no liquid water14,15. This implies that multiple mechanisms for generating lightning on Jupiter need to be considered for a full understanding of the planet's atmospheric convection and composition.

A Survey of Small-Scale Waves and Wave-Like Phenomena in Jupiter's Atmosphere Detected by JunoCam.

In the first 20 orbits of the Juno spacecraft around Jupiter, we have identified a variety of wave-like features in images made by its public-outreach camera, JunoCam. Because of Juno's unprecedented and repeated proximity to Jupiter's cloud tops during its close approaches, JunoCam has detected more wave structures than any previous surveys. Most of the waves appear in long wave packets, oriented east-west and populated by narrow wave crests. Spacing between crests were measured as small as ~30 km, shorter than any previously measured. Some waves are associated with atmospheric features, but others are not ostensibly associated with any visible cloud phenomena and thus may be generated by dynamical forcing below the visible cloud tops. Some waves also appear to be converging, and others appear to be overlapping, possibly at different atmospheric levels. Another type of wave has a series of fronts that appear to be radiating outward from the center of a cyclone. Most of these waves appear within 5° of latitude from the equator, but we have detected waves covering planetocentric latitudes between 20°S and 45°N. The great majority of the waves appear in regions associated with prograde motions of the mean zonal flow. Juno was unable to measure the velocity of wave features to diagnose the wave types due to its close and rapid flybys. However, both by our own upper limits on wave motions and by analogy with previous measurements, we expect that the waves JunoCam detected near the equator are inertia-gravity waves.

I could take the judgment if you could just provide the service: non-prescription syringe purchase experience at Arizona pharmacies, 2018.

BACKGROUND: Community pharmacies are important for health access by rural populations and those who do not have optimum access to the health system, because they provide myriad health services and are found in most communities. This includes the sale of non-prescription syringes, a practice that is legal in the USA in all but two states. However, people who inject drugs (PWID) face significant barriers accessing sterile syringes, particularly in states without laws allowing syringe services programming. To our knowledge, no recent studies of pharmacy-based syringe purchase experience have been conducted in communities that are both rural and urban, and none in the Southwestern US. This study seeks to understand the experience of retail pharmacy syringe purchase in Arizona by PWID. METHODS: An interview study was conducted between August and December 2018 with 37 people living in 3 rural and 2 urban Arizona counties who identified as current or former users of injection drugs. Coding was both a priori and emergent, focusing on syringe access through pharmacies, pharmacy experiences generally, experiences of stigma, and recommendations for harm reduction services delivered by pharmacies. RESULTS: All participants reported being refused syringe purchase at pharmacies. Six themes emerged about syringe purchase: (1) experience of stigma and judgment by pharmacy staff, (2) feelings of internalized stigma, (3) inconsistent sales outcomes at the same pharmacy or pharmacy chain, (4) pharmacies as last resort for syringes, (5) fear of arrest for syringe possession, and (6) health risks resulting from syringe refusal. CONCLUSIONS: Non-prescription syringe sales in community pharmacies are a missed opportunity to improve the health of PWID by reducing syringe sharing and reuse. Yet, current pharmacy syringe sales refusal and stigmatization by staff suggest that pharmacy-level interventions will be necessary to impact pharmacy practice. Lack of access to sterile syringes reinforces health risk behaviors among PWID. Retail syringe sales at pharmacies remain an important, yet barrier-laden, element of a comprehensive public health response to reduce HIV and hepatitis C among PWID. Future studies should test multilevel evidence-based interventions to decrease staff discrimination and stigma and increase syringe sales.

Evidence for low density holes in Jupiter's ionosphere.

Intense electromagnetic impulses induced by Jupiter's lightning have been recognised to produce both low-frequency dispersed whistler emissions and non-dispersed radio pulses. Here we report the discovery of electromagnetic pulses associated with Jovian lightning. Detected by the Juno Waves instrument during its polar perijove passes, the dispersed millisecond pulses called Jupiter dispersed pulses (JDPs) provide evidence of low density holes in Jupiter's ionosphere. 445 of these JDP emissions have been observed in snapshots of electric field waveforms. Assuming that the maximum delay occurs in the vicinity of the free space ordinary mode cutoff frequency, we estimate the characteristic plasma densities (5.1 to 250 cm-3) and lengths (0.6 km to 1.3 × 105 km) of plasma irregularities along the line of propagation from lightning to Juno. These irregularities show a direct link to low plasma density holes with ≤250 cm-3 in the nightside ionosphere.

Novel Immunomodulatory Proteins Generated via Directed Evolution of Variant IgSF Domains.

Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all immune cell subsets, making the IgSF an attractive family of proteins for therapeutic targeting in human diseases. We have developed a directed evolution platform capable of engineering IgSF domains to increase affinities for cognate ligands and/or introduce binding to non-cognate ligands. Using this scientific platform, ICOSL domains have been derived with enhanced binding to ICOS and with additional high-affinity binding to the non-cognate receptor, CD28. Fc-fusion proteins containing these engineered ICOSL domains significantly attenuate T cell activation in vitro and in vivo and can inhibit development of inflammatory diseases in mouse models. We also present evidence that engineered ICOSL domains can be formatted to selectively provide costimulatory signals to augment T cell responses. Our scientific platform thus provides a system for developing therapeutic protein candidates with selective biological impact for treatments of a wide array of human disorders including cancer and autoimmune/inflammatory diseases.

A complex dynamo inferred from the hemispheric dichotomy of Jupiter's magnetic field.

The Juno spacecraft, which is in a polar orbit around Jupiter, is providing direct measurements of the planet's magnetic field close to its surface1. A recent analysis of observations of Jupiter's magnetic field from eight (of the first nine) Juno orbits has provided a spherical-harmonic reference model (JRM09)2 of Jupiter's magnetic field outside the planet. This model is of particular interest for understanding processes in Jupiter's magnetosphere, but to study the field within the planet and thus the dynamo mechanism that is responsible for generating Jupiter's main magnetic field, alternative models are preferred. Here we report maps of the magnetic field at a range of depths within Jupiter. We find that Jupiter's magnetic field is different from all other known planetary magnetic fields. Within Jupiter, most of the flux emerges from the dynamo region in a narrow band in the northern hemisphere, some of which returns through an intense, isolated flux patch near the equator. Elsewhere, the field is much weaker. The non-dipolar part of the field is confined almost entirely to the northern hemisphere, so there the field is strongly non-dipolar and in the southern hemisphere it is predominantly dipolar. We suggest that Jupiter's dynamo, unlike Earth's, does not operate in a thick, homogeneous shell, and we propose that this unexpected field morphology arises from radial variations, possibly including layering, in density or electrical conductivity, or both.

Prevalent lightning sferics at 600 megahertz near Jupiter's poles.

Lightning has been detected on Jupiter by all visiting spacecraft through night-side optical imaging and whistler (lightning-generated radio waves) signatures1-6. Jovian lightning is thought to be generated in the mixed-phase (liquid-ice) region of convective water clouds through a charge-separation process between condensed liquid water and water-ice particles, similar to that of terrestrial (cloud-to-cloud) lightning7-9. Unlike terrestrial lightning, which emits broadly over the radio spectrum up to gigahertz frequencies10,11, lightning on Jupiter has been detected only at kilohertz frequencies, despite a search for signals in the megahertz range 12 . Strong ionospheric attenuation or a lightning discharge much slower than that on Earth have been suggested as possible explanations for this discrepancy13,14. Here we report observations of Jovian lightning sferics (broadband electromagnetic impulses) at 600 megahertz from the Microwave Radiometer 15 onboard the Juno spacecraft. These detections imply that Jovian lightning discharges are not distinct from terrestrial lightning, as previously thought. In the first eight orbits of Juno, we detected 377 lightning sferics from pole to pole. We found lightning to be prevalent in the polar regions, absent near the equator, and most frequent in the northern hemisphere, at latitudes higher than 40 degrees north. Because the distribution of lightning is a proxy for moist convective activity, which is thought to be an important source of outward energy transport from the interior of the planet16,17, increased convection towards the poles could indicate an outward internal heat flux that is preferentially weighted towards the poles9,16,18. The distribution of moist convection is important for understanding the composition, general circulation and energy transport on Jupiter.

Health System Creation and Integration at a Health Sciences University: A Five-Year Follow-up.

EXECUTIVE SUMMARY: Shifting healthcare market forces and regulation have exerted near-constant pressure on U.S. academic health centers (AHCs) attempting to successfully execute their traditional tripartite mission. A governance structure and organizational alignment that works well under one set of conditions is rarely optimal when conditions change. Thus, the degree and type of alignment of an AHC's clinical, educational, and faculty practice organizations have changed regularly within the sector, typically landing near one end or the other on a continuum from fully aligned with centralized governance to largely independent with separate governance. The authors examine the case of Georgia Regents University and Health System in this context. In step with industry trends, the institution's governance structure swung from fully aligned/centralized governance in the early 1990s to essentially separate and decentralized by 2000. In 2010, the Georgia Regents University organizations achieved rapid realignment by creating a governance structure of sufficient strength and flexibility to absorb and adjust to continuing external upheaval. The hospitals, clinics, and physician-faculty practice group were combined into one integrated health system, then aligned with the university to form the state's only public AHC under aligned, but distinct, corporate and management structures. The years since reorganization have seen significant growth in patient volumes and complexity, improved service quality, and enhanced faculty physician satisfaction, while also significantly increasing economic contributions from the health system to the academic mission. This case study offers observations and lessons learned that may be useful to other higher education institutions considering reorganization.

Implications of the ammonia distribution on Jupiter from 1 to 100 bars as measured by the Juno microwave radiometer.

The latitude-altitude map of ammonia mixing ratio shows an ammonia-rich zone at 0-5°N, with mixing ratios of 320-340 ppm, extending from 40-60 bars up to the ammonia cloud base at 0.7 bars. Ammonia-poor air occupies a belt from 5-20°N. We argue that downdrafts as well as updrafts are needed in the 0-5°N zone to balance the upward ammonia flux. Outside the 0-20°N region, the belt-zone signature is weaker. At latitudes out to ±40°, there is an ammonia-rich layer from cloud base down to 2 bars which we argue is caused by falling precipitation. Below, there is an ammonia-poor layer with a minimum at 6 bars. Unanswered questions include how the ammonia-poor layer is maintained, why the belt-zone structure is barely evident in the ammonia distribution outside 0-20°N, and how the internal heat is transported through the ammonia-poor layer to the ammonia cloud base.

Polyarteritis nodosa-induced pancreaticoduodenal artery aneurysmal rupture.

Polyarteritis nodosa (PAN) is a systemic, necrotizing vasculitis of small- and medium-sized arteries typically with multiorgan involvement. Most cases of PAN are idiopathic, although hepatitis B or C virus infections and hairy cell leukemia are important in the pathogenesis of some cases. PAN is characterized as segmental transmural inflammation of muscular arteries. Diagnosis is based on clinical suspicion, a negative immunofluorescence test for antineutrophil cytoplasmic antibodies, and whenever possible, biopsy conformation. Angiographic images may reveal microaneurysms affecting the renal, hepatic, or mesenteric vasculature. Aneurysmal formation and rupture are important complications that can be fatal. Treatment may warrant immunosuppression with steroids and cyclophosphamide. If left untreated, PAN can be fatal. To our knowledge, we report the second documented case of PAN-induced ruptured inferior pancreaticoduodenal artery aneurysm.

Venous cystic adventitial disease presenting as an enlarging groin mass.

Venous cystic adventitial disease is an exceedingly rare vascular disorder, with 12 cases reported in the past decade. A 60-year-old woman presented with a painful, palpable groin mass without leg swelling. She was initially thought to have a nonreducible inguinal hernia. A computed tomography scan was obtained that revealed a cystic mass involving the right common femoral vein. Previous imaging revealed that the mass had enlarged over time. In the operating room, the cyst wall was excised without compromising vein integrity. The patient had an uneventful recovery and her pain resolved. We review the presentation, diagnosis, and treatment of this condition. We believe that the rapid evolution of this lesion suggests that an unknown inciting factor triggers its onset and growth.

Biomechanical strain characteristics of soft tissue biceps tenodesis and bony tenodesis.

BACKGROUND: Biomechanical analysis of biceps tenodesis procedures has historically focused on load to failure models. Minimal data exists for the analysis of biomechanical strain properties of the biceps tendon in a sub-failure, physiologic cadaver model. HYPOTHESIS: Tendon strain characteristics are different between bony and soft tissue tenodesis surgery, and the soft tissue tenodesis procedure reproduces a strain pattern more similar to the native biceps tendon. METHODS: Eight fresh frozen cadaver upper extremities were mounted onto a custom device that controls shoulder abduction and rotation. Strain on the tendon was measured using a differential variable reluctance transducer as the arm was moved through cycles of abduction and external rotation. Each arm was mounted once, and all 3 testing procedures were performed on each of the 8 specimens. Statistical analysis was completed using ANOVA, followed by multiple comparisons with Bonferroni correction. RESULTS: The bony tenodesis model placed higher strain on the biceps tendon than the soft tissue tenodesis (p = 0.025). Also, the bony tenodesis model increased the strain on the biceps tendon when compared to the native tendon (p = 0.031). In contrast, the soft tissue tenodesis did not significantly alter strain when compared to the native tendon (p = 0.089). CONCLUSION: The soft tissue tenodesis procedure better maintained the native strain environment when compared to the bony tenodesis using an interference screw. Due to this closer approximation of native biceps tendon biomechanics, the soft tissue procedure may be more preferable clinically than the bony tenodesis. LEVEL OF EVIDENCE: 1, Controlled Laboratory Study.

Neer Award 2012: cerebral oxygenation in the beach chair position: a prospective study on the effect of general anesthesia compared with regional anesthesia and sedation.

BACKGROUND: Devastating neurologic ischemic episodes, such as stroke and deafness, have occurred in patients undergoing shoulder surgery in the beach chair position. We hypothesized that awake patients would be able to avoid significant cerebral deoxygenation events (CDEs) compared with anesthetized patients when procedures were performed in the beach chair position. MATERIALS AND METHODS: Sixty patients underwent elective shoulder surgery in the beach chair position. Thirty patients underwent an interscalene block and monitored sedation (awake group); 30 patients underwent general anesthesia (asleep group). Cerebral oxygenation saturation (Scto2) was measured during the procedure. Scto2 values below critical thresholds were defined as CDEs and treated. RESULTS: Baseline mean arterial pressure and Scto2 values were lower in the asleep group during the operation (P < .0001). A higher incidence of CDEs was seen in the asleep group (56.7% vs 0% awake group), and more CDEs were seen per patient (2.97 in asleep vs 0 awake, P < .0001). Scto2 below a threshold value of 55% was seen in 23.3% in the asleep group vs 3.3% in the awake group. A total of 89 combined desaturation events were documented in the asleep vs 1 in the awake group (P < .0001). CONCLUSIONS: Patients in the beach chair position treated with regional anesthesia and sedation had almost no cerebral desaturation events, unlike patients who had general anesthesia. Avoidance of general anesthesia in the beach chair position may reduce the risk of ischemic neurologic injury.