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Background Hypoxia resulting from ascent to high-altitude or pathological states at sea level is known to increase platelet reactivity. Previous work from our group has suggested that this may be adenosine diphosphate (ADP)-specific. Given the clinical importance of drugs targeting ADP pathways, research into the impact of hypoxia on platelet ADP pathways is highly important. Methods Optimul aggregometry was performed on plasma from 29 lowland residents ascending to 4,700 m, allowing systematic assessment of platelet reactivity in response to several platelet agonists. Aggregometry was also performed in response to ADP in the presence of inhibitors of the two main ADP receptors, P2Y1 and P2Y12 (MRS2500 and cangrelor, respectively). Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a key determinant of platelet aggregation, was analysed using the VASPFix assay. Results Hypobaric hypoxia significantly reduced the ability of a fixed concentration of cangrelor to inhibit ADP-induced aggregation and increased basal VASP phosphorylation. However, in the absence of P2Y receptor inhibitors, we did not find evidence of increased platelet sensitivity to any of the agonists tested and found reduced sensitivity to thrombin receptor-activating peptide-6 amide. Conclusion Our results provide evidence of increased P2Y1 receptor activity at high altitude and suggest down-regulation of the P2Y12 pathway through increased VASP phosphorylation. These changes in ADP pathway activity are of potential therapeutic significance to high-altitude sojourners and hypoxic sea level patients prescribed platelet inhibitors and warrant further investigation.

Summary Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting., Graphical Abstract, Highlights • Neutrophils utilize gluconeogenesis (GNG) to generate glycogen stores • Glycogenesis is essential for neutrophil survival and function • Defective glycogen cycling impairs neutrophil function in COPD • Glycogen cycling underpins the metabolic specialization of neutrophils, Neutrophils are required to meet their energy demands at inflamed sites where nutrients may be limited. Sadiku et al. provide evidence of a specialized metabolism that enables neutrophils to utilize glycogen cycling for energy production. This is essential for neutrophil function and survival, and dysregulation is associated with chronic disease states.

Purpose The authors assess the effectiveness of a modified paracanthal or "one-snip" procedure compared with the traditional lateral canthotomy and inferior cantholysis in the reduction of intraocular pressure (IOP) and proptosis in a human cadaveric model of retrobulbar hemorrhage. Methods This study comprised a comparative interventional study in a cadaveric model of retrobulbar hemorrhage. Six orbits of 3 fresh cadavers were included in the study. Baseline measurements of IOP and proptosis were recorded for all 6 orbits before and after simulation of retrobulbar hemorrhage as previously described. Right orbits (n = 3) underwent traditional lateral canthotomy and inferior cantholysis. Left orbits (n = 3) underwent modified paracanthal or "one-snip" procedure. The primary outcome measures were reduction in IOP and proptosis between the 2 techniques. Results Following lateral canthotomy and inferior cantholysis of each right orbit, the average IOP dropped to 14 mm Hg (range of 11-18 mm Hg), corresponding to a mean decrease of 32 mm Hg. Following the "one-snip" procedure of each left orbit, the average IOP dropped to 19 mm Hg with a range of 16 to 23 mm Hg, corresponding to a mean decrease of 22 mm Hg. There was no statistically significant difference in IOP reduction (p = 0.36) or proptosis reduction (p = 0.23) between the 2 treatment groups. Conclusions Compared with traditional lateral canthotomy xand inferior cantholysis, the modified paracanthal or "one-snip" procedure is effective for IOP reduction and led to mild improvement of proptosis in a cadaveric model of retrobulbar hemorrhage. The authors hope this study helps improve orbital compartment syndrome outcomes by providing an option that more providers will feel comfortable performing and therefore decreasing time to surgical decompression.

To summarize the findings of long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy (≥36 months) in patients with exudative age-related macular degeneration.Studies reporting long-term outcomes (≥36 months) of anti-VEGF therapy (n = 11) were identified and analyzed for changes in visual acuity (VA), optical coherence tomography, and safety findings.Six prospective extension studies of Phase 3 clinical trials and five retrospective evaluation studies were identified. The largest improvements in VA with anti-VEGF treatment were found in Years 1 to 2 after treatment initiation. In five studies, VA ultimately declined below patients' pretreatment initial baseline; in three studies, VA ultimately returned to patients' baseline; in three studies, VA decreased but ultimately remained improved over patients' baseline. There was a trend demonstrating that a higher frequency of intravitreous injections showed a better maintenance in VA. Rates of adverse events were similar to previous registration studies of anti-VEGF drugs.The body of evidence to date regarding long-term anti-VEGF treatment indicates a variable course at greater than 36 months follow-up and seems to be dependent on the treatment protocol. Consistent dosing with fluid-free interval is suggested to maintain VA gains in patients with exudative age-related macular degeneration. There is no evidence suggesting that there are additional adverse events from long-term anti-VEGF use.

PURPOSE: To compare needle and microcannula injection techniques in regards to the microanatomical location of hyaluronic acid gel injected in the upper lip vermillion border of cadaver specimens. METHODS: The upper lip vermillion border was injected transcutaneously with hyaluronic acid gel in 8 fresh hemifaces of 4 female human cadavers. Each hemiface was injected by a single experienced injector, the right side using a 27-gauge microcannula and the left side using a 30-gauge needle. A 2cm region of each lip was excised lateral to a point 1cm lateral to the philtrum. Specimens were fixed in 95% alcohol, embedded in paraffin, and stained with hematoxylin and eosin for histologic examination. RESULTS: The majority of hyaluronic acid injected with either a needle or microcannula was located within the orbicularis oris muscle, and the remaining hyaluronic acid resided within the subcutaneous fat. In 3/4 right (microcannula) hemifaces, 100% of the hyaluronic acid was located within the muscle. Only 2/4 left (needle) hemifaces had at least 95% of the hyaluronic acid located within the muscle. Overall, in right (microcannula) hemifaces 93% of the filler was located within the muscle and in left (needle) hemifaces 79% of the filler was located within the muscle (p =0.14 ). CONCLUSIONS: The majority of hyaluronic acid filler injected into the vermillion border after either microcannula or needle injection resides within the orbicularis oris muscle rather than in a subcutaneous/submucosal location. Injection with a microcannula shows a trend for more uniform intramuscular location compared to needle injection.

Purpose: To evaluate long-term visual and anatomical outcomes of anti–vascular endothelial growth factor (VEGF) therapy for macular edema (ME) secondary to retinal vein occlusion (RVO) in routine clinical practice. Methods: Patients with ME secondary to hemi-RVO (HRVO), central RVO (CRVO), or branch RVO (BRVO) after initiating anti-VEGF therapy were followed for at least 36 months. Main outcomes were change in best visual acuity (BVA) and mean absolute change in central subfield thickness (CST) at 12, 24, 36, and 48 months. Results: Patients with BRVO showed significant increases in BVA that were maintained after 12, 24, 36, and 48 months (+11.03, +12.06, +10.71, and +9.26 letters, respectively; P < .05). CST significantly decreased after 12, 24, 36, and 48 months (−83.51, −67.93, −97.52, −127.85 µm, respectively; P < .05). In patients with CRVO/HRVO, significant improvements in BVA were seen at 12 and 24 months (+9.39 and +8.54 letters, respectively; P = .023). At 36 and 48 months, the visual gain was not significant (+2.64 and +3.42 letters, respectively; P > .05). For CST changes, there were significant decreases at 12, 24, and 36 months (−146.23, −149.54, and −166.44 µm, respectively; P < .05). At 48 months (−97.66 µm, P = .130), changes in CST were not significant. Conclusions: In routine clinical practice, visual and anatomical benefits of anti-VEGF agents in patients with BRVO were sustained at 36 and 48 months. For patients with CRVO/HRVO, anatomical improvements were maintained for 36, but not 48 months, while visual improvements were no longer maintained by 36 months.

BACKGROUND AND OBJECTIVE: To evaluate the repeatability of retinal thickness and vascular density measurements using split-spectrum amplitude-decorrelation angiography (SSADA) with optical coherence tomography (OCT). PATIENTS AND METHODS: Forty patients were divided into seven categories according to their diagnosis: no retinopathy (control), retinal vein occlusion, diabetes with no retinopathy, diabetes with retinopathy, non-exudative age-related macular degeneration (AMD), exudative AMD, and epiretinal membrane. Capillary density and retinal thickness measurements were taken and evaluated for reliability by determination of statistically significant differences and coefficient of variability (CoV) between measurements. RESULTS: No significant differences ( P > .05) were found in any of the within-visit measurements. CoVs ranged from 0.26% to 52.76%, depending on the measure and the disease settings. CONCLUSION: The SSADA OCT angiography analysis has a low level of variability between measurements and, thus, is a reliable tool for evaluation of retinal perfusion. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:e9–e19.]

One of the rare but serious complications observed with deoxycholic acid administration is damage to the marginal mandibular nerve. In this study, we evaluated if deoxycholic acid directly induces histologic damage to fresh cadaveric marginal mandibular nerve. A segment of marginal mandibular nerve was harvested from 12 hemifaces of 6 fresh cadavers. The nerve specimen was exposed to either 0.9% sterile saline for 24 h, deoxycholic acid (10 mg/ml) for 20 min, or deoxycholic acid (10 mg/ml) for 24 h. The nerve specimens were then fixed in glutaraldehyde for a minimum of 24 h. Toluidine blue stained sections were evaluated for stain intensity using light microscopy and color deconvolution image analysis. Supraplatysmal fat was harvested as a positive control and exposed to the same treatments as the marginal mandibular nerve specimens, then evaluated using transmission electron microscopy. Toluidine blue staining was less in the marginal mandibular nerve exposed to deoxycholic acid when compared to saline. The specimen exposed to deoxycholic acid for 24 h showed less toluidine blue staining than that of the nerve exposed to deoxycholic acid for 20 min. Transmission electron microscopy of submental fat exposed to deoxycholic acid revealed disruption of adipocyte cell membrane integrity and loss of cellular organelles when compared to specimens only exposed to saline. Deoxycholic acid (10 mg/ml) damages the marginal mandibular nerve myelin sheath in fresh human cadaver specimens. Direct deoxycholic acid neurotoxicity may cause marginal mandibular nerve injury clinically. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .