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Aims: This study aimed to assess the impact of adenosine on quantitative myocardial blood flow (MBF) in a rapid stress-rest protocol compared with a rest-stress protocol using 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI) and to gain insights into the time dependency of such effects., Methods and Results: Quantitative MBF at rest (rMBF) and during adenosine-induced stress (sMBF) and myocardial flow reserve (MFR) were obtained from 331 retrospectively identified patients who underwent 13N-ammonia PET MPI for suspected chronic coronary syndrome and who all exhibited no perfusion defects. Of these, 146 (44.1%) underwent a rapid stress-rest protocol with a time interval (Δtstress-rest) of 20 ± 4 min between adenosine infusion offset and rest imaging, as per clinical routine. The remaining 185 (55.9%) patients underwent a rest-stress protocol and served as the reference. Groups did not differ regarding demographics, risk factors, medication, left ventricular function, and calcium scores. rMBF was significantly higher in the stress-rest vs. the rest-stress group [0.80 (interquartile range 0.66-1.00) vs. 0.70 (0.58-0.83) mL·min-1·g-1, P < 0.001], and, as sMBF was identical between groups [2.52 (2.20-2.96) vs. 2.50 (1.96-3.11), P = 0.347], MFR was significantly lower in the stress-rest group [3.07 (2.43-3.88) vs. 3.50 (2.63-4.10), P = 0.007]. There was a weak correlation between Δtstress-rest and rMBF (r = -0.259, P = 0.002) and between Δtstress-rest and MFR (r = 0.163, P = 0.049), and the proportion of patients with abnormally high rMBF was significantly decreasing with increasing Δtstress-rest., Conclusion: Intravenously applied adenosine induces a long-lasting hyperaemic effect on the myocardium. Consequently, rapid stress-rest protocols could lead to an overestimation of rMBF and an underestimation of MFR., Competing Interests: Conflict of interest: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Prcis: Noninferiority of efficacy was demonstrated for a preservative-free bimatoprost 0.01% compared with BAK-containing bimatoprost 0.01% following a 12-week treatment period in patients with open angle glaucoma or ocular hypertension. Improved tolerability, in particular conjunctival hyperemia, was also observed., Purpose: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a preservative-free bimatoprost 0.01% ophthalmic gel (PFB 0.01% gel) compared with preserved bimatoprost 0.01% (PB 0.01%)., Design: Phase III, international, multicenter, randomized, 2-parallel group, investigator-masked, 3-month treatment duration., Methods: Patients with glaucoma or ocular hypertension were randomized after a 7-week run-in/washout period to receive once-daily PFB 0.01% gel (n=236) or PB 0.01% (n=249) for 3 months. The primary efficacy measure was changed from baseline in IOP at week 12. Safety measures included adverse events (AEs) and assessment of conjunctival hyperemia., Results: The mean changes from baseline in IOP at week 12 in the PFB 0.01% gel and PB 0.01% were -9.72±2.97 and -9.47±3.06 mm Hg, respectively, at 8 am , -9.41±3.03 and -9.19±3.12 mm Hg at 10 am , and -8.99±3.36 and -8.54±3.44 mm Hg at 4 pm . Noninferiority of PFB 0.01% gel to PB 0.01% was demonstrated at week 12 based on predetermined criteria (upper 95% CI margin of 1.5 mmHg at all time points). The most frequently reported AE was conjunctival hyperemia; 13 (5.5%) patients with PFB 0.01% gel and 17 (6.8%) patients with PB 0.01%. The percentage of patients experiencing a worsening from baseline in conjunctival hyperemia score was lower with PFB 0.01% gel compared to PB 0.01% at week 6 (20.1% vs. 29.3%, respectively) and week 12 (18.3% vs. 30.4%, respectively)., Conclusions: PFB 0.01% ophthalmic gel has the same efficacy in lowering IOP as PB 0.01% and demonstrated less aggravation of conjunctival hyperemia at weeks 6 and 12., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To compare objective ocular redness measured using OCULUS Keratograph 5 M before and after 0.2% brimonidine instillation in glaucoma patients under topical hypotensive treatment., Methods: 60 eyes from 60 subjects diagnosed with glaucoma or ocular hypertension under hypotensive ocular topical treatment were analyzed. Basal Ophthalmological examination was performed.Outcome variables were OCULUS Keratograph 5 M redness scores (RS) before and after 0.2% brimonidine instillation; overall, bulbar temporal (BT), bulbar nasal (BN), limbar temporal (LT), and limbar nasal (LN); non-invasive average tear film breakup time (Nia-BUT), non-invasive first tear film breakup time (Nif-BUT) and meibography. In addition, the following clinical data were collected: intraocular pressure, type, duration, amount, and preservatives/or not of hypotensive treatment, fluorescein corneal staining score and lower tear meniscus height., Results: All eyes were under topical medication. All redness scores were reduced after brimonidine instillation, mean RS differences were BT 0.82 ± 0.62, BN hyperemia 1.03 ± 0.55, LN hyperemia 0.84 ± 0.49, LT hyperemia 0.71 ± 0.50 and total hyperemia 0.91 ± 0.52 (all p < 0.001). 30 min after brimonidine instillation mean overall RS reduction was 47.97 ± 12.39% (p < 0.001) and after 1 h there was a persistent reduction of overall RS of 45.92 ± 14.27% (p < 0.001). Hyperemia reduction was significant and comparable between preservative and preservative-free group 0.12 ± 0.14 (p > 0.392) and between patient with combination therapy and monotherapy 0.16 ± 0.14 (p > 0.258)., Conclusion: A significant reduction of conjunctival hyperemia was objectively found in glaucoma patients under topical hypotensive treatment before and after brimonidine instillation. Its fast and long-lasting effect may be useful preoperatively in glaucoma patients to reduce intraoperative bleeding and associated complications., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The aim of this study was to demonstrate the efficacy of cyclosporine A 0.1% cationic emulsion (CsA CE) eye drops 4 times a day in pediatric patients affected by a moderate form of vernal keratoconjunctivitis (VKC)., Methods: This was a prospective study of pediatric patients, aged 5-16 years, with an active moderate form of VKC who were poor responders to topical antihistamines treatment and were treated 4 times a day with CsA CE. The clinical signs were graded for analysis as follows: hyperemia, tarsal papillae, and limbal papillae., Results: Twenty-eight patients (22 males and 6 females) with a minimum follow-up period of 3 months were included in the analysis. Statistical analysis excluded tarsal papillae because of the very low baseline value. The clinical score of hyperemia and limbal papillae improved from the first evaluation and was maintained over the follow-up. No side effects were noted., Conclusion: CsA CE has been proposed as a treatment for severe forms of VKC. This study has shown that administration 4 times a day is also effective in the treatment of moderate forms of VKC in children., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Post-occlusive reactive hyperemia (PORH) typically requires caffeine abstinence. For habitual users, it is unknown if abstinence affects PORH., Objective: Compare PORH after habitual users consume or abstain from caffeine., Methods: On separate visits (within-subject), PORH was measured in 30 participants without abstinence from typical caffeine doses (CAFF) and with abstinence (ABS). Measurements included baseline and peak hyperemic velocity, tissue saturation index slopes during ischemia (Slope 1) and following cuff deflation (Slope 2), resting arterial occlusion pressure (AOP), heart rate (HR), systolic (SBP), and diastolic (DBP) blood pressure. All variables were compared using Bayesian paired t-tests. BF10 = likelihood of alternative vs null. Results are mean±SD., Results: Comparing baseline velocity (cm/s) between CAFF (9.3±4.8) and ABS (7.5±4.9) yielded anecdotal evidence (BF10 = 1.0). Peak hyperemic velocity (cm/s) was similar (CAFF = 77.3±16.7; ABS = 77.6±19.0, BF10 = 0.20). For slopes (TSI% /s), CAFF Slope 1 = -0.11±0.04 and Slope 2 = 1.9±0.46 were similar (both BF10≤0.20) to ABS Slope 1 = -0.12±0.03 and Slope 2 = 1.8±0.42. SBP and DBP (mmHg) were both similar (CAFF SBP = 116.0±9.8, DBP = 69.6±5.8; ABS SBP = 115.5±10.7, DBP = 69.5±5.4; both BF10≤0.22). Comparing AOP (mmHg) (CAFF = 146.6±15.0; ABS = 143.0±16.4) yielded anecdotal evidence (BF10 = 0.46). HR (bpm) was similar (CAFF = 66.5±12.3; ABS = 66.9±13.0; BF10 = 0.20)., Conclusions: In habitual users, consuming or abstaining from typical caffeine doses does not appear to affect post-occlusive reactive hyperemia.

Introduction: Multidrug regimens for glaucoma treatment often result in adherence issues due to inconvenience; these issues may be improved with fixed-dose combination drugs. The ophthalmic solution of ripasudil-brimonidine fixed-dose combination (RBFC; K-232) is the first treatment combining a Rho kinase inhibitor and an α 2 -adrenoceptor agonist, and has demonstrated ability to lower intraocular pressure (IOP) and have various effects on conjunctival hyperemia and corneal endothelial cell morphology. This study evaluates the pharmacologic effects of RBFC treatment versus its separate components-ripasudil or brimonidine., Methods: This single-center, prospective, randomized, open-label, blinded endpoint study with 3 × 3 crossover design randomly assigned healthy adult men to three groups (1:1:1) to undergo consecutive 8-day administration phases (with drug-free intervals of at least 5 days). Subjects received twice-daily instillation of RBFC → ripasudil → brimonidine (group A), ripasudil → brimonidine → RBFC (group B), or brimonidine → RBFC → ripasudil (group C). Endpoints included change in IOP, severity of conjunctival hyperemia, corneal endothelial cell morphology, pupil diameter, and pharmacokinetics., Results: Eighteen subjects were assigned in total (six to each group). RBFC significantly reduced IOP from baseline at 1 h post-instillation on days 1 and 8 (12.7 vs. 9.1 and 9.0 mmHg, respectively; both P < 0.001), and provided significantly greater IOP reductions than ripasudil or brimonidine at several time points. The most common adverse drug reaction with all three treatments was mild conjunctival hyperemia, which transiently increased in severity with RBFC or ripasudil, peaking at 15 min post-instillation. In post hoc analyses, conjunctival hyperemia scores were lower with RBFC than with ripasudil at several time points. Transient morphologic changes in corneal endothelial cells occurred for up to several hours with RBFC or ripasudil, but not with brimonidine. Pupil diameter did not change with RBFC., Conclusion: RBFC significantly reduced IOP compared with each agent alone. A combination of each agent's pharmacologic profile was observed in that of RBFC., Trial Registration: Japan Registry of Clinical Trials; Registration No. jRCT2080225220., (© 2023. The Author(s).)

Aims: Systemic venous congestion is associated with an increased risk of acute kidney injury (AKI) in critically ill patients. Venous Excess Ultrasound Score (VExUS) has been proposed as a non-invasive score to assess systemic venous congestion. We aimed to evaluate the association between VExUS and AKI in patients with acute coronary syndrome (ACS)., Methods and Results: This is a prospective study including patients with the diagnosis of ACS (both ST elevation and non-ST elevation ACS). VExUS was performed during the first 24 h of hospital stay. Patients were classified according to the presence of systemic congestion (VExUS 0/≥1). The primary objective of the study was to determine the occurrence of AKI, defined by KDIGO criteria. A total of 77 patients were included. After ultrasound assessment, 31 (40.2%) patients were categorized as VExUS ≥1. VExUS ≥1 was more frequently found in inferior vs. anterior myocardial infarction/non-ST-segment elevation acute myocardial infarction (48.3 vs. 25.8 and 22.5%, P = 0.031). At each increasing degree of VExUS, a higher proportion of patients developed AKI: VExUS = 0 (10.8%), VExUS = 1 (23.8%), VExUS = 2 (75.0%), and VExUS = 3 (100%; P < 0.001). A significant association between VExUS ≥1 and AKI was found [odds ratio (OR): 6.75, 95% confidence interval (CI): 2.21-23.7, P = 0.001]. After multivariable analysis, only VExUS ≥1 (OR: 6.15; 95% CI: 1.26-29.94, P = 0.02) remained significantly associated with AKI., Conclusion: In patients hospitalized with ACS, VExUS is associated with the occurrence of AKI. Further studies are needed to clarify the role of VExUS assessment in patients with ACS., Competing Interests: Conflict of interest: A.A.-M. has received institutional research grants from Novo Nordisk, Boehringer Ingelheim, CSL Behring, and reports speaking fees from Astra Zeneca, Boehringer Ingelheim, Novartis, Servier, and Sanofi. R.G.-N. reports speaking fees from Novartis. J.L.B.-D.l.C. reports speaking fees from Astra Zeneca, Bayer, Boehringer Ingelheim, Novartis, Menarini, and Sanofi. D.S.-L.M. reports speaking fees from Bayer and Novo Nordisk. D.A.-G. has received institutional research grants from Novartis and reports speaking fees from Abbott, Asofarma, Astra Zeneca, Boehringer Ingelheim, Eurofarma, Merck, Medix, Novartis, and Servier. All other authors report no pertinent conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Allergic conjunctivitis is an immune-mediated inflammatory disease of the conjunctiva that is induced by antigens. Allergic conjunctivitis can cause various symptoms such as ocular itching, hyperemia and edema. Developing experimental animal models that show clinical symptoms and methods for quantitative and objective evaluation is important for understanding allergic conjunctivitis. Therefore, this study aimed to develop an ovalbumin (OVA)-induced mouse model of allergic conjunctivitis and a useful method for evaluating symptoms of allergic conjunctivitis., Methods: ICR mice were sensitized by an intraperitoneal injection of OVA in PBS containing alum on days 0 and 5. Subsequently, local sensitization was then performed once daily from days 14 to 28, by instilling OVA in PBS into the both eyes. Drug treatment was administered once daily from days 14 to 28. Mice were randomly assigned topical treatment groups: Group 1, 0.1% betamethasone; Group 2, 0.025% levocabastine; Group 3 PBS (control)., Results: Mice showed marked eye scratching behavior, hyperemia, edema, infiltration of eosinophils into tears and increased antigen-specific immunoglobulin E antibody levels in tears and the serum. These symptoms were inhibited by instillation of levocabastine and betamethasone, which are used clinically for the treatment of allergic conjunctivitis., Discussion: This method may be useful for evaluation of the symptoms of allergic conjunctivitis in experimental and clinical settings. In particular, the developed method, which measures the number of eosinophils in tears collected with phenol red threads, may enable the quantitative, objective, and noninvasive evaluation of the severity of allergic conjunctivitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The VISIONARY study demonstrated statistically significant intraocular pressure (IOP) reductions with the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% (PF tafluprost/timolol FC) in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients, sub-optimally controlled with topical prostaglandin analogue (PGA) or beta-blocker monotherapy. Current subanalyses have examined these data according to the baseline monotherapy., Methods: A European, prospective, observational study included adults (aged ≥ 18 years) with OAG or OHT, who were switched to the PF tafluprost/timolol FC from PGA or beta-blocker monotherapy. Treatment outcomes were reported according to prior monotherapy subgroup: beta-blocker, preserved latanoprost, PF-latanoprost, bimatoprost, tafluprost, and travoprost. Endpoints included the mean change from baseline regarding IOP, conjunctival hyperemia, and corneal fluorescein staining (CFS) at Week 4 and Week 12, and at Month 6., Results: The subanalysis included 577 patients. All prior monotherapy subgroups demonstrated statistically significant IOP reductions from baseline at Week 4, that were maintained through Month 6 (p < 0.001). Mean (SD) IOP change at Month 6 was 6.6 (4.16), 6.3 (4.39), 5.6 (3.67), 4.9 (2.97), 4.6 (4.39), and 4.7  (3.64) mmHg for prior beta-blocker, preserved latanoprost, PF-latanoprost, tafluprost, bimatoprost, and travoprost subgroups, respectively. The largest IOP change was observed in the preserved latanoprost subgroup for each of the ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% IOP reduction categories at Month 6, demonstrating respective reductions of 8.06, 9.20, 10.64, and 11.55 mmHg. CFS was significantly reduced at Month 6 in the prior bimatoprost subgroup (p = 0.0013). Conjunctival hyperemia severity was significantly reduced at each study visit for prior preserved latanoprost users (p < 0.001)., Conclusion: PF tafluprost/timolol FC therapy provided statistically and clinically significant IOP reductions from Week 4 over the total 6-month period, in patients with OAG/OHT, regardless of the type of prior PGA or beta-blocker monotherapy used. Conjunctival hyperemia severity and CFS decreased significantly in prior bimatoprost and preserved latanoprost users, respectively., Clinical Study Number: European Union electronic Register of Post-Authorization Studies (EU PAS) register number: EUPAS22204., (© 2022. The Author(s).)

Introduction: Ocular redness, or conjunctival hyperemia, is a common ophthalmic sign associated with reduced quality of life. For redness without apparent underlying pathology, topical ophthalmic decongestants have been widely used., Areas Covered: Brimonidine tartrate was approved in 2017 as a topical vasoconstrictor at a 0.025% concentration for relief of ocular redness. Since then, investigators have reported on efficacy and safety findings from studies evaluating low-dose brimonidine for reducing ocular redness., Expert Opinion: Brimonidine is highly selective for α 2 -adrenergic receptors. Clinical trials have so far shown that the drug in low doses significantly reduces ocular redness in comparison to vehicle for up to 8 hours. Brimonidine-treated eyes did not present side effects of other vasoconstrictors, such as hypotension, cardiac arrhythmia, or drowsiness. Ocular adverse events, such as allergic reactions and redness rebound, were also minimal. In this review, we examine in detail published literature on the mechanism of brimonidine tartrate and its efficacy and safety in relieving conjunctival hyperemia.

Background: Administration of intracoronary (IC) adenosine allows an easily feasible, inexpensive, and more rapid alternative method for fractional flow reserve (FFR). It is common practice in many centers worldwide. Nicardipine is a strong coronary vasodilator but its efficacy and safety for assessing FFR is not established. The purpose of present study was to compare the efficacy and safety of IC nicardipine and adenosine for assessing FFR., Methods: One hundred and fifty-nine patients with a total of 193 vessels undergoing clinically indicated FFR assessment of intermediate coronary stenoses were included. For the initial assessment of FFR, hyperemia was induced by an IC adenosine. After a washout period of 3 min, FFR was reassessed using 200 μg of IC nicardipine., Results: Hyperemic efficacy among two different stimuli was compared. The mean FFR with IC adenosine was 0.83 ± 0.09 and that with an IC nicardipine was 0.84 ± 0.09. The median FFR with an IC adenosine was 0.83 (0.78-0.91) and that with an IC nicardipine was 0.85 (0.79-0.91) (p-value 0.246). Both FFR values showed an excellent correlation (R 2  = 0.982, p < 0.001). Nicardipine produced fewer changes in heart rate, less chest pain and less flushing than adenosine. Transient atrioventricular block occurred in 29 patients with IC adenosine and none with IC nicardipine., Conclusions: IC bolus injection of nicardipine could be introduced as a safe and practical alternative method of inducing hyperemia during FFR measurements. Compared to IC adenosine, IC nicardipine has a similar hyperemic efficacy and excellent side-effect profile., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Bimatoprost 0.03% is an intraocular pressure (IOP) lowering prostaglandin analog with different adverse side effects such as potential ocular inflammatory effect and ocular hyperemia., Case Presentation: We report a case of 80-year-old woman diagnosed with bilateral glaucomatous uveitis, and choroidal detachment in the left eye after topical bimatoprost administration. During the patient's hospitalization, Bimatoprost treatment was discontinued and local steroid therapy was administrated. After 1 week we reported a marked improvement of visual acuity, IOP measurement was 12 mmHg in both eyes. Anterior segment examination showed complete resolution of conjunctival and pericheratic hyperemia with significant reduction of endothelial precipitates in both eyes., Conclusions: In our case, the anterior granulomatous uveitis occurred in both pseudophakic eyes and the choroidal detachment (CD) in the eye that previously had trabeculectomy. Probably the scar tissue of the trabeculectomy allowed a better penetration of the Bimatoprost or a greater sensitivity due to an altered trabecular tissue. This work confirms that the onset physiopathology mechanism of granulomatous uveitis and CD following instillation of Bimatoprost remains uncertain.

Sore throat is one of the most frequent complaints with which patients seek medical help from an otorhinolaryngologist, therapist and pediatrician., Objective: To evaluate the efficacy and safety of a combined topical drug with flurbiprofen and cetylpyridinium chloride compared with a monocomponent drug in patients with sore throat associated with manifestations of acute pharyngitis, tonsillitis or with exacerbation of chronic forms of pharyngitis or tonsillitis., Material and Methods: A prospective, multicenter, open, randomized, comparative study in parallel groups included 266 adult patients aged 18 to 60 years with an established diagnosis of acute pharyngitis or acute tonsillitis with the main complaint of sore throat caused by viral infections of the upper respiratory tract. The patients included in the study were randomized into two groups of 133 participants each: the 1st group included patients who received the combined agent flurbiprofen 8.75 mg and cetylpyridinium chloride 1.0 mg in the form of tablets for resorption; the 2nd group included patients who received cetylpyridinium chloride 1.2 mg in the form of medicinal lozenges. The effectiveness was evaluated on three scales - STPIS, TPA, STPR, reflecting indicators of the dynamics of the disease., Results: The studied combination turned out to be more effective than the monocomponent remedy and was characterized by a more pronounced decrease in the intensity of sore throat within 2 hours after taking the drug and a decrease in pharyngeal hyperemia., Conclusion: According to results of the study, the use of a drug based on the combination of flurbiprofen and cetylpyridinium chloride was accompanied by a rapid and pronounced decrease in the intensity of sore throat and pharyngeal hyperemia in patients with upper respiratory tract infections.

Sore throat is one of the most frequent complaints with which patients seek medical help from an otorhinolaryngologist, therapist and pediatrician., Objective: To evaluate the efficacy and safety of a combined topical drug with flurbiprofen and cetylpyridinium chloride in patients with sore throat caused by upper respiratory tract infections., Material and Methods: A prospective multicenter open randomized comparative study in parallel groups included 266 adult patients with an established diagnosis of acute pharyngitis or acute tonsillitis aged 18 to 60 years with the main complaint of sore throat caused by viral infections of the upper respiratory tract. The patients included in the study were randomized into two groups of 133 participants each: the 1st group included patients who received the combined agent flurbiprofen 8.75 mg and cetylpyridinium chloride 1.00 mg in the form of tablets for resorption, the 2nd group included patients who received cetylpyridinium chloride 1.2 mg in the form of medicinal lozenges. The effectiveness was evaluated on several scales (RADT, STPIS, TPA, STPR) reflecting subjective and objective indicators of the dynamics of the disease., Results: The studied combination proved to be more effective than the monocomponent agent and was characterized by a more pronounced decrease in sore throat within 2 hours after taking the drug and a decrease in pharyngeal hyperemia., Conclusion: According to the results of the study, the use of a drug based on a combination of flurbiprofen and cetylpyridinium chloride was accompanied by a rapid and pronounced decrease in sore throat and pharyngeal hyperemia in patients with upper respiratory tract infections.

Fractional flow reserve (FFR) is considered the standard for assessment of the physiological significance of coronary artery stenosis. Intracoronary papaverine (PAP) is the most potent vasodilator used for the achievement of maximal hyperemia. However, its use can provoke ventricular tachycardia (VT) due to excessive QT prolongation. We evaluated the clinical efficacy and safety of the administration of PAP after nicorandil (NIC), a potassium channel opener that prevents VT, for optimal FFR measurement.A total of 127 patients with 178 stenoses were enrolled. The FFR values were measured using NIC (NIC-FFR) and PAP (PAP-FFR). We administered PAP following NIC (NIC-PAP). Changes in the FFR and electrogram parameters (baseline versus NIC versus PAP) were assessed and the incidence of arrhythmias after PAP was evaluated. In addition, we analyzed another 41 patients with 51 stenoses by assessing the FFR using PAP before NIC (PAP-NIC). After propensity score matching, the electrogram parameters between 2 groups were compared.The mean PAP-FFR was significantly lower than the mean NIC-FFR (0.82 ± 0.11 versus 0.81 ± 0.11, P < 0.05). The mean baseline-QTc, NIC-QTc, and PAP-QTc values were 425 ± 37 ms 1/2 , 424 ± 41 ms 1/2 , and 483 ± 54 ms 1/2 , respectively. VT occurred in only 1 patient (0.6%). Although PAP induced QTc prolongation (P < 0.05), the PAP-QTc duration was significantly shorter in NIC-PAP compared to PAP-NIC (P < 0.05).The administration of PAP with NIC may induce sufficient hyperemia and prevent fatal arrhythmia through reductions in the PAP-induced QTc prolongation during FFR measurement.

This study aimed to test the effect of a 7-day high-salt (HS) diet on autonomic nervous system (ANS) activity in young healthy individuals and modulation of ANS on microvascular endothelial function impairment. 47 young healthy individuals took 7-day low-salt (LS) diet (3.5 g salt/day) followed by 7-day high-salt (HS) diet (~14.7 g salt/day). ANS activity was assessed by 24-h urine catecholamine excretion and 5-min heart rate variability (HRV). Skin post-occlusive reactive hyperemia (PORH) and acetylcholine-induced dilation (AChID) were assessed by laser Doppler flowmetry (LDF). Separately, mental stress test (MST) at LS and HS condition was conducted, followed by immediate measurement of plasma metanephrines' level, 5-min HRV and LDF microvascular reactivity. Noradrenaline, metanephrine and normetanephrine level, low-frequency (LF) HRV and PORH and AChID significantly decreased following HS compared to LS. MST at HS condition tended to increase HRV LF/HF ratio. Spectral analysis of PORH signal, and AChID measurement showed that MST did not significantly affect impaired endothelium-dependent vasodilation due to HS loading. In this case, 7-day HS diet suppressed sympathetic nervous system (SNS) activity, and attenuated microvascular reactivity in salt-resistant normotensive individuals. Suppression of SNS during HS loading represents a physiological response, rather than direct pathophysiological mechanism by which HS diet affects microvascular endothelial function in young healthy individuals.

Purpose: In this study, we wanted to retrospectively evaluate the effect of the use of topical brimonidine on intraoperative bleeding and surgical hemostasis before strabismus surgery. Methods: Brimonidine tartrate 0.15% (Brimogut, Bilim Ilac, Turkey) eye drops were applied 6 and 3 min before surgery to 44 eyes of 22 patients in group 1 for vasoconstriction. Drops were not applied to 46 eyes of 23 patients in group 2. Preoperative and postoperative photographs and video images were taken. Black-and-white images were used to define the surface areas of the blood vessels. The surface area was calculated by counting the black pixels with ImageJ software. Results: In group 1, redness of eye was observed, on average, at preoperative 339.25 ± 11.52 pixels and intraoperative 247.93 ± 10.63 pixels ( P  < 0.001). But there was no change in group 2 (preoperative 338.87 ± 8.45 pixels to intraoperative 339.71 ± 9.52 pixels, P  > 0.05). The incidence of intraoperative bleeding evaluated by the number of eyes on which cautery was used shows that it was significantly less in group 1 than in group 2 ( P  < 0.001). Conclusions: The use of topical brimonidine before strabismus surgery facilitates clear monitoring of anatomical structures during surgery by effectively controlling hemorrhage. In the postoperative period, it significantly reduces subconjunctival hemorrhage.

Background: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases and has aesthetic, physical, and emotional-social sequelae when left untreated., Objective: To classify the most common adverse reactions associated with dupilumab treatment in patients with AD., Methods: The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for common adverse reactions associated with dupilumab, topical pimecrolimus, and topical tacrolimus. Phase III clinical trial data were used to compare the rate of herpes infections between the treatment group and placebo group., Results: The most common adverse reaction associated with dupilumab was ocular complications. Herpes infections were extremely rare in the patients with AD being treated with dupilumab., Limitations: Prescribing information for dupilumab, topical pimecrolimus, and topical tacrolimus is not available. Adverse effects are reported by patients, health care providers, and pharmaceutical companies, they have not been corroborated., Conclusions: Ocular complications are the most common complication associated with dupilumab. The rate of herpes infection is low in patients being treated with dupilumab, topical pimecrolimus, and topical tacrolimus. There is no significant difference for the rate of herpes infection between, placebo, dupilumab, topical pimecrolimus, and the topical tacrolimus treatment group, suggesting that dupilumab does not affect herpes infection rates., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The resting full-cycle ratio (RFR) is a novel resting index which in contrast to the gold standard (fractional flow reserve (FFR)) does not require maximum hyperemia induction. The objectives of this study were to evaluate the agreement between RFR and FFR with the currently recommended thresholds and to design a hybrid RFR-FFR ischemia detection strategy, allowing a reduction of coronary vasodilator use., Materials and Methods: Patients subjected to invasive physiological study in 9 Spanish centers were prospectively recruited between April 2019 and March 2020. Sensitivity and specificity studies were made to assess diagnostic accuracy between the recommended levels of RFR ≤0.89 and FFR ≤0.80 (primary objective) and to determine the RFR "grey zone" in order to define a hybrid strategy with FFR affording 95% global agreement compared with FFR alone (secondary objective)., Results: A total of 380 lesions were evaluated in 311 patients. Significant correlation was observed ( R 2  = 0.81; P < 0.001) between the two techniques, with 79% agreement between RFR ≤ 0.89 and FFR ≤ 0.80 (positive predictive value, 68%, and negative predictive value, 80%). The hybrid RFR-FFR strategy, administering only adenosine in the "grey zone" (RFR: 0.86 to 0.92), exhibited an agreement of over 95% with FFR, with high predictive values (positive predictive value, 91%, and negative predictive value, 92%), reducing the need for vasodilators by 58%., Conclusions: Dichotomous agreement between RFR and FFR with the recommended thresholds is significant but limited. The adoption of a hybrid RFR-FFR strategy affords very high agreement, with minimization of vasodilator use., Competing Interests: The authors have no conflicts of interest regarding this paper., (Copyright © 2021 Juan Casanova-Sandoval et al.)

Context: Gonadotropin-releasing hormone agonist (GnRH-a) serves as an alternative to human chorionic gonadotropin (hCG) to trigger final oocyte maturation, while it significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS), probably by attenuating vascular/endothelial activation., Objectives: The objectives of this work are to compare the effect of different modes of final follicular maturation (hCG vs GnRH-a) following ovarian stimulation (OS) for in vitro fertilization (IVF) on endothelial function., Design and Setting: A prospective cohort study was conducted at a tertiary medical center., Participants: Patients age 37 years or younger, undergoing OS for IVF, were allocated into 2 groups according to the type of final follicle maturation: the hCG group (n = 7) or the GnRH-a group (n = 8)., Intervention: Endothelial function was assessed by measurement of the peripheral arterial tonometry in reaction to temporary ischemia at 3 study points: day 3 of menstrual cycle (day 0), day of hCG/GnRH-a administration (day trigger) and day of oocyte pick-up (day OPU). The ratio of arterial tonometry readings before and after ischemia is called the reactive hyperemia index (RHI). Decreased RHI (< 1.67) indicates endothelial dysfunction., Main Outcome Measures: The main outcomes measures of this study included endothelial function at 3 study points during OS with different modes of triggering final follicular maturation., Results: The mean RHI values at day 0 were within the normal range for all patients and comparable between both groups (hCG: 1.7 ± 0.3 vs GnRH-a: 1.79 ± 0.4, P = .6). All patients presented a decrease in RHI values on day trigger, which did not differ between the 2 groups (1.62 ± 0.3 vs 1.4 ± 0.2, respectively, P = .2). However, the hCG group demonstrated a further decrease in RHI on day OPU, whereas patients who received GnRH-a had restored normal endothelial function reflected by increased RHI values (1.4 ± 0.2 vs 1.75 ± 0.2, respectively, P = .03)., Conclusions: Triggering final follicular maturation with GnRH-a restored normal endothelial function, whereas hCG trigger resulted in a decrease in endothelial function., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study evaluated whether caffeine abstention is required before fractional flow reserve (FFR) measurement by intravenous adenosine triphosphate (ATP) administration in Japanese patients., Methods: This study was a subanalysis of a previously published study and a total of 208 intermediate lesions that underwent FFR measurements were enrolled for this analysis. Hyperemia was induced by continuous intravenous ATP infusion at 150 μg/kg/min (IVATP150) and 210 μg/kg/min (IVATP210), and by intracoronary administration of nicorandil 2 mg (ICNIC2mg) as a reference standard., Results: The degree of change in the FFR value after ICNIC2mg and IVATP210 was similar between the caffeine and non-caffeine groups (0.00 ± 0.02 vs. 0.01 ± 0.02). In patients who consumed caffeine before the FFR measurement, the degree of FFR change was independent of the time interval (<12 h, 12-24 h, and 24-48 h) between caffeine intake and catheterization both after IVATP150 and ICNIC2mg and after IVATP210 and ICNIC2mg., Conclusion: When compared with the FFR value after ICNIC2mg, the degree of change in the FFR value after IVATP210 were similar regardless of caffeine intake. Strict caffeine abstention before intravenous ATP-induced FFR measurement may not be required in clinical practice., (Copyright © 2020. Published by Elsevier Ltd.)

We investigated the diagnostic utility and safety of intracoronary bolus administration of nicorandil compared with intravenous administration of adenosine for evaluating FFR in patients with intermediate (40-70%) coronary stenosis. The FFR values obtained with nicorandil and adenosine showed linear relationship. This correlation is statistically significant with regression coefficient of 0.932 (R2 = 0.834, p < 0.001). The side effects such as bronchospasm, hypotension, and bradycardia were significantly higher after administration of adenosine compared to nicorandil (20% vs. 1.66%, p = 0.001). Intracoronary use of nicorandil seems to be promising in offering the advantages of lesser side effects, similar efficacy, and lesser cost as compared to adenosine., Competing Interests: Declaration of competing interest All authors have none to declare., (Copyright © 2020 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

We investigated the effect of the papaverine dose increment method to confirm maximal hyperemia for fractional flow reserve (FFR) measurements. We evaluated 115 consecutive patients involving 200 lesions. FFR was measured after intracoronary papaverine injection into the left (12 mg) and right (8 mg) coronary arteries as standard doses. Except for 2 patients who had ventricular tachyarrythmia (VTA), we administered a higher papaverine dose (2 mg added to the standard dose). We compared the FFR values after using different papaverine doses. VTA incidence and electrocardiogram parameters were compared according to the papaverine doses used. The QTU interval and corrected QTU were significantly prolonged after using a higher dose compared with a standard dose. VTA occurred in one patient (0.9%) at the higher dose. There was no significant difference with a strong correlation between the FFR values in the 2 doses (r = 0.963, P < 0.001). Maximal hyperemia was achieved in most patients at the standard papaverine dose. However, 19 lesions changed ischemic diagnosis at the higher dose (12 lesions changed from ischemia negative to positive, and 7 lesions changed from positive to negative). Therefore, to confirm the appropriate ischemia diagnosis for borderline FFR values, it may be favorable to perform another FFR measurement at an incremental papaverine dose.

Purpose: JV-GL1 is an efficacious, potent, and long-acting antiglaucoma agent, according to studies in ocular normotensive and hypertensive monkeys. As an obligatory step in the drug development process, studies with exaggerated doses and an accelerated dosing schedule for JV-GL1 were performed in a second species (dog). Methods: Intraocular pressure (IOP) was measured by pneumatonometry in conscious Beagle dogs, which remained conscious throughout the study and gently restrained by hand. Pupil diameter was measured with an Optistick. Ocular surface hyperemia was visually assessed and scored according to a 1-3 assessment scale. Results: JV-GL1, as a 0.01% eye drop, produced significantly greater reductions in IOP than the original clinical dose of bimatoprost (0.03%). JV-GL1 and its free acid enzymatic hydrolysis product PGN 9856, over a 0.01%-0.1% dose range, reduced IOP to ≤10 mm Hg. JV-GL1 and PGN 9856 produced no miosis but a similar degree of ocular surface hyperemia to bimatoprost. Although PGN 9862, a close congener of PGN 9856, was very active as the free acid, esterification essentially abolished its ocular hypotensive activity and ocular surface redness. Conclusion: JV-GL1 was confirmed as a highly effective and potent ocular hypotensive, exceeding the activity of bimatoprost. A similar degree of ocular surface redness was apparent for both compounds, given as eye drops, but no other effects occurred. Results with PGN 9862 and its isopropyl ester confirmed that PGN 9862-isopropyl ester is not bioavailable in the eye and not susceptible to enzymatic hydrolysis in ocular tissues, a first for C1 ester prodrugs in the eye.

Background: Adenosine and adenosine triphosphate (ATP) are widely used to induce hyperemia for fractional flow reserve (FFR) measurements. Caffeine attenuates their hyperemic effects, but not those of nicorandil and papaverine. No studies have systematically compared the hyperemic efficacies of nicorandil, papaverine, and ATP with and without caffeine abstention., Methods: FFRs were measured using nicorandil 2 mg (FFR NC2 ), nicorandil 4 mg (FFR NC4 ), and papaverine (FFR PAP ) in 40 patients (group 1), and using nicorandil 2 mg, ATP (FFR ATP ), ATP plus nicorandil (FFR ATP+NC 2 ), and papaverine in 20 patients with (group 2) and in 20 patients without caffeine abstention (group 3)., Results: In group 1, FFR NC2 and FFR NC4 did not differ (p = 0.321) and were higher than FFR PAP (p < 0.001 and p = 0.0026). Likewise, FFR NC2 was higher than FFR PAP in groups 2 (p = 0.049) and 3 (p < 0.010). In the whole group, Bland-Altman analysis showed a modest mean difference (0.015, p < 0.001) and narrow 95% limits of agreement (-0.025 and 0.056). FFR NC2 and FFR PAP strongly correlated (r = 0.975, p < 0.001). Compared with FFR PAP , FFR ATP and FFR ATP+NC2 did not differ in group 2 (p = 1.0 and p = 0.780), but they were higher (p = 0.002 and p = 0.02) in group 3. Adjunctive nicorandil did not decline FFR further in groups 2 (p = 0.942) and 3 (p = 0.294)., Conclusions: Nicorandil 2 mg is a safe and practical alternative for patients who consume caffeine-containing products before the test or have contraindications for adenosine/ATP. Increasing the nicorandil dose to 4 mg or administering adjunctive nicorandil during ATP infusions does not offer any clinical advantages compared with administering nicorandil 2 mg alone., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Prosthetic valve thrombosis (PVT) is a serious complication among patients with prosthetic heart valves. Thrombolytic therapy (TT) is now widely used as first-line treatment for PVT. Endothelial dysfunction has previously been reported in patients with PVT. The aim of this study was to investigate the changes in endothelial function soon after TT in PVT patients., Methods: The study group included 85 patients with PVT [female: 53 (62.3%); age: 48.7±13.9 years] who were evaluated prospectively before and shortly after TT. All of the patients were evaluated using transthoracic and transesophageal echocardiography. TT was administered in all cases with a low-dose, ultra-slow infusion regimen. Endothelial function was evaluated using a noninvasive measurement of flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia., Results: The study population included 38 (44.7%) obstructive and 47 (55.3%) non-obstructive PVT patients. The obstructive PVT patients had lower baseline FMD values than the non-obstructive PVT group (5.31±0.76% vs. 5.87±0.84%; p=0.003). TT was successful in 79 patients (92.9%). FMD was significantly increased in the successfully thrombolyzed patients after TT (5.65±0.86% vs. 7.13±1.26%; p<0.001). There was no significant difference in the FMD values after TT in patients who were unresponsive to TT (5.07±0.61% vs. 5.38±0.95%; p=0.371). There was a significant increase in FMD values after TT in patients with obstructive PVT (5.31±0.76% vs. 8.22±1.15%; p<0.001). However, this difference was not statistically significant for patients with non-obstructive PVT (5.87±0.84% vs. 6.11±0.95%; p=0.276)., Conclusion: This study demonstrated that successful TT may contribute to improvement of impaired endothelial function in patients with obstructive PVT.

We describe a case of a 37-year-old veteran with recurrent conjunctival hyperemia 5 years after an eye-whitening conjunctivectomy procedure with mitomycin C who desired to have a repeat procedure by the original surgeon. Instead, the patient was counseled and successfully fitted with white sclera painted contact lenses to mask the regrowth of his conjunctival vasculature with excellent cosmetic results and comfort. Further eye-whitening surgery was, therefore, avoided. We conclude that hand-painted white sclera contact lenses with regular ocular surface health monitoring can be offered as a cosmetic, safer, and economical alternative to patients in order to avoid eye-whitening procedures known to induce ocular ischemia.

Background: The index of microcirculatory resistance is an invasive measure of coronary microvascular function that has to be calculated during maximal hyperemia, classically achieved with intravenous adenosine (IV). The aim of this study was to evaluate the use of intracoronary (IC) adenosine for the calculation of IMR., Methods and Results: 31 patients with stable coronary artery disease were included in the study. Coronary pressure and thermodilution measurements were obtained at rest and during maximal hyperemia using a pressure-temperature sensor-tipped coronary guidewire. Duplicate measurements were performed using first IC and then IV adenosine. Dispersion of transit times was comparable for IC and IV adenosine. IMR values based on IC vs IV adenosine showed a high level of agreement and an intraclass correlation coefficient of 0.90. Applying an upper normal limit of 25, misclassification of IMR using IC adenosine was seen in just one patient in whom IC adenosine resulted in a lower value. A simplified procedure based on a single bolus dose of saline did not change the level of agreement or the rate of misclassification., Conclusions: We found an excellent agreement between IMR values measured during hyperemia induced by IC as compared to IV adenosine. The use of IC adenosine may facilitate invasive assessment of microvascular function and is potentially time- and cost-saving with less patient discomfort as compared to IV infusion. The trail is registered with NCT03369184., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Irene Santos-Pardo et al.)

Purpose: A prospective, open-label study in 20 professional swimmers evaluated the efficacy and safety of an ophthalmic solution containing crosslinked hyaluronic acid, coenzyme Q10, and vitamin E TPGS in releasing eye irritation and restoring ocular surface damages after prolonged exposure to chlorinated water., Methods: Individually, one eye was instilled with the ophthalmic solution and the other used as a comparator. Eye drops were self-administered three times a day for 2 months. Tear film breakup time (primary endpoint), Schirmer I test, beating of eyelashes/min, tear osmolarity, corneal and conjunctival staining with fluorescein, Ocular Surface Disease Index questionnaire, subject satisfaction, visual acuity (secondary endpoints), and Efron Grading Scale were evaluated at screening/baseline (V1), week 1 (V2), week 2 (V3), week 4 (V4), and week 8 (V5)., Results: After 2 months, breakup time test significantly improved in the treated eyes (+1.67 s) compared to control (-3.00 s) ( p  = 0.0002). Corneal and conjunctival surfaces of treated eyes recovered significantly compared to control eyes when assessed by fluorescein staining ( p  < 0.0001), Ocular Surface Disease Index ( p  < 0.05), and visual analog scale ( p  = 0.0348) scores. Improvements were also observed with Schirmer I test, beating of eyelashes, and tear osmolarity, despite without statistical significance. Efron Grading Scale was consistent with the other tests. The ocular tolerability was excellent., Conclusion: The adequate combination of crosslinked hyaluronic acid, coenzyme Q10, and vitamin E TPGS, contained in the ophthalmic solution VisuXL ® , has been shown to protect ocular surface from potential damages originating from prolonged exposure to chlorinated water. VisuXL may represent a compelling treatment in other situations beyond dry eye syndrome.

Purpose: Rho-associated kinase-inhibitor ripasudil 0.4% eye drops are reportedly effective for the reduction of intraocular pressure (IOP) in glaucoma patients. However, the previous studies investigated the efficacy of IOP reduction for only about 1 year. Here, we evaluated the safety and efficacy of long-term ripasudil instillation in Japanese open-angle glaucoma (OAG) patients. Methods: This study involved 312 eyes of 312 Japanese OAG patients newly initiated with ripasudil treatment at Kyoto Prefectural University of Medicine and Oike-Ikeda Eye Clinic, Kyoto, Japan. In all patients, adverse events leading to discontinuation of ripasudil treatment were investigated. Of the 312 patients, 129 patients able to continue ripasudil administration for over 12-months post-treatment initiation were enrolled to investigate the long-term efficacy. IOP data at 0-, 1-, 3-, 6-, 12-, 18-, and 24-months post initiation of continuous ripasudil use were obtained, and the IOP values at each time point were then compared. The first period (from 1-6 months) and second period (from 12-24 months) IOP data were also compared based on the mixed model. Results: IOP at each time-point post-treatment initiation was significantly reduced compared with that at pre initiation ( P  < 0.05). Differences in IOP between the first and second periods of the study were not statistically significant ( P  = 0.058). Adverse events leading to discontinuation of treatment included blepharitis (15.7%) and conjunctival hyperemia (9.0%). Conclusions: We found that in Japanese OAG patients, 24-month ripasudil eye drop instillation is both safe and effective for lowering IOP and that blepharitis is the primary adverse event for discontinuation of use.

Objective: Ambient exposure to fine particles is associated with increased cardiovascular morbidity and mortality. Associations between occupational particulate matter (PM) exposure and cardiovascular disease have been studied less. The objective of this study was to examine associations between PM exposure and endothelial function among workers in Norwegian smelters., Methods: We examined endothelial function with Endo-PAT equipment after a working day (WD) and on a day off (DO) in 59 furnace workers recruited from three metal smelters in Norway. The difference in baseline pulse amplitude (BPA) and reactive hyperemia index (RHI) between the 2 days was analysed in relation to individual exposure to PM < 250 nm (PM 250 ) or the respirable aerosol fraction of particles, and adjusted for relevant covariates., Results: The exposure to PM 250 ranged from 0.004 to 5.7 mg/m 3 . The mean BPA was significantly higher on WD relative to DO (772 vs. 535, p = 0.001). This difference was associated with PM concentrations among participants ≥ 34 years, but not among the younger workers. Reactive hyperemia was significantly lower on workdays relative to days off (1.70 vs. 1.84, p = 0.05). This difference was observed only among participants above the age 34. No associations with PM exposure were observed., Conclusions: PM exposure was associated with higher BPA among participants older than 34 years. BPA reflects microvessel pulsatility. Our results may indicate an age-dependent cardiovascular susceptibility to PM exposure. Endothelial function measured by RHI was reduced on WD among participants 34 years and older, but we found no associations between PM exposure and RHI.

Purpose: Preservatives in glaucoma medications have been associated with ocular toxicity. We compared ocular signs and symptoms in patients with open-angle glaucoma or ocular hypertension treated in monotherapy with preserved or preservative-free prostaglandin analogues., Methods: Observational cross-sectional clinical study in real life. 82 patients treated for at least 6 months with prostaglandin analogue were assessed for intraocular pressure, ocular symptoms and ocular signs including conjunctival hyperaemia, tear break-up time and tear meniscus height measured using objective and non-invasive methods (OCULUS Keratograph 5M). Patients presenting with symptoms of ocular toxicity with preserved prostaglandin analogues were switched to preservative-free latanoprost, and a second assessment was processed 6 months after., Results: At inclusion, 30 (36.6%) patients were treated with preservative-free latanoprost, 25 (30.5%) with preserved latanoprost, 16 (19.5%) with preserved travoprost and 11 (13.4%) with preserved bimatoprost. Patients treated with preservative-free latanoprost reported significantly less ocular symptoms upon instillation (mainly burning) and between instillations than patients treated with preserved prostaglandin analogues. The mean conjunctival hyperaemia (limbal + bulbar) was significantly lower with preservative-free latanoprost (2.08 ± 0.55) compared to preserved latanoprost (2.50 ± 0.7, p = 0.0085), preserved travoprost (2.67 ± 0.82, p = 0.0083) and preserved bimatoprost (2.68 ± 0.67, p = 0.0041). There were no relevant between-group differences in mean tear meniscus height and break-up time. Ocular symptoms and conjunctival hyperaemia improved when preserved prostaglandin analogues were switched to preservative-free latanoprost for 6 months while intraocular pressure reduction was maintained., Conclusion: Overall, this study suggests a better subjective and objective ocular tolerance when patients were treated with preservative-free latanoprost than with other preserved prostaglandin analogues monotherapy. Switching to preservative-free latanoprost maintained intraocular pressure at the same level as preservative prostaglandin analogue, but improved ocular surface tolerance.

Purpose: To compare the biocompatibility and subjective symptoms of four multipurpose solutions marketed in Palestine with hydrogel contact lenses., Methods: 50 habitual soft contact lens wearers were recruited in this interventional crossover study. Subjects were asked to attend the optometry clinic five times. A new pair of hydrogel lenses (Bioxifilcon-B) were fitted each time. This pair was soaked randomly overnight in one of the following four-multipurpose solutions (NEOPLUS ® , AvizorUnicaSensitive ® , ReNuMultiPlus ® and COMPLETERevitaLens ® ) which contain different disinfecting agents (PHMB, Phx, PAPB, and PQ-1+Alexidine, respectively), or non-preserved saline. At each visit, corneal staining, ocular redness and subjective symptoms were assessed., Results: The percentage of corneal staining increased significantly (P≤0.050) after soaking the lenses with PHMB (86%), PAPB (64%) and Phx (32%) based-solutions. However, a non-significant increase was noticed after the use of PQ-1+Alexidine based solution (30%, P=0.083). Ocular redness evaluation showed a significant increase (P≤0.050) in limbal hyperemia after the use of all solutions, while bulbar redness was significantly increased after the use of biguanide-based solutions (P≤0.050). The subjective assessment analysis showed a non-significant change in comfort, dryness, photophobia and scratchiness (P≥0.050) at 2-h intervention using all solutions, except for the PHMB based solution which showed a significant change in subjective symptoms (P≤0.050)., Conclusion: The combination of Bioxifilcon-B hydrogel contact lenses and solution containing PHMB, PAPB and Phx-disinfectants induced a significant increase in corneal staining after 2h of CL-wear with a higher severity when the PHMB-based solution was used, while the PQ-1+Alexidine-based solution did not. Only the PHMB-based solution triggered a significant change in subjective symptoms which might which suggests that it might be related to the severity of staining rather than the induction of staining., (Copyright © 2019 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.)

Background: This study will evaluate the efficacy of travoprost for patients with glaucoma systematically., Methods: A comprehensive literature search will be carried from following literature sources from inception to the present: Cochrane Library, MEDLINE, EMBASE, Web of Science, Google scholar, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. We will only consider randomized controlled trials on assessing the efficacy and safety of travoprost for glaucoma for inclusion. We will use Cochrane risk of bias tool for the methodological quality assessment for each qualified study. If it is possible, we will pool the outcome data, and will perform meta-analysis., Results: This study will systematically evaluate the efficacy and safety of travoprost for glaucoma. Primary outcomes include intraocular pressure (IOP), mean IOP, and mean reduction of IOP. Secondary outcomes consist of diastolic ocular perfusion pressure, central corneal thickness, and quality of life, as measured by 36-Item Short Form Health Survey, and treatment-related adverse events included hyperemia, eye pain, and eye pruritus., Conclusion: The findings of the present study will summarize the updated evidence of travoprost for patients with glaucoma.PROSPERO registration number: PROSPERO CRD42019126956.

Background: Achievement of maximal hyperemia is mandatory for an accurate calculation of fractional flow reserve (FFR) and it is obtained with adenosine given either as an intravenous infusion or as an intracoronary bolus., Aims: The purpose of this study was to compare the infusion of adenosine with intracoronary adenosine bolus dose escalation in the optimal assessment of peak FFR., Methods: We enrolled consecutive patients with borderline coronary lesions that were assessed by FFR with the use of adenosine intracoronary boluses (100, 200, 400 and 600 µg) and intravenous infusion of 140 µg/kg/min and 280 µg/kg/min. FFR values were assessed and compared., Results: Fifty patients with 125 borderline coronary artery stenoses were enrolled. Physiological severity assessed with: intravenous adenosine infusion at 140 µg/kg/min was mean 0.82 ± 0.09; infusion at 280 µg/kg/min - 0.81 ± 0.09; intracoronary bolus of 100 µg, 200 µg, 400 µg and 600 µg - 0.83 ± 0.09; 0.83 ± 0.09, 0.83 ± 0.09; and 0.83 ± 0.09, respectively. There was a strong linear correlation between FFR values obtained from 140 µg/kg/min infusion and adenosine intracoronary 100, 200, 400 and 600 µg bolus injection (r = 0.989, r = 0.99, r = 0.993, r = 0.994, respectively, p < 0.001 for all)., Conclusions: FFR values achieved with intracoronary boluses of adenosine are very similar, but not identical to those obtained using intravenous adenosine administration. The values of FFR may vary between escalating doses of intracoronary boluses and intravenous infusion.

Background: Fractional Flow Reserve (FFR) is currently indicated as a first line strategy for the functional assessment of intermediate coronary stenoses. However, the protocol for inducing hyperemia still lacks standardization. Intracoronary adenosine boli, with a progressive increase to high-dosage, have been proposed as a sensitive and accurate strategy for the classification of coronary stenoses, although being potentially affected by the achievement of plateau of the effect and by a less prolonged and stable hyperemia as compared to intravenous administration. Therefore, the aim of the present study was to define the conditioning parameters and assess the impact of increasing-dose intracoronary adenosine on peak hyperemia duration in patients undergoing FFR for intermediate coronary stenoses., Methods: FFR was assessed in patients with intermediate (40 to 70%) lesions by pressure-recording guidewire (Prime Wire, Volcano), after induction of hyperemia with intracoronary boli of adenosine (from 60 to 1440 μg, with dose doubling at each step). Hyperemic duration was defined as the time for the variation form minimum FFR ± 0.02 and time to recovery till baseline values., Results: We included 87 patients, undergoing FFR evaluation of 101 lesions. Mean peak hyperemia duration and time to recovery significantly increased with adenosine doses escalation (p = 0.02 and p < 0.001). Peak hyperemia duration and time to recovery with 1440 μg adenosine were 14.5 ± 12.6 s and 45.2 ± 30.7 s, respectively. Hyperemia duration was not related to Quantitative Coronary Angiography (QCA) parameters or FFR values. In fact, a similar increase in the time of hyperemic peak was noted when comparing patients with positive or negative FFR (p between  = 0.87) or patients with lesions < or ≥20 mm (p between  = 0.92) and lesions involving left main coronary or proximal left anterior descending artery (LAD) (p between  = 0.07). A linear relationship was observed between time to recovery and FFR variations, with a greater time to baseline required in patients with FFR ≤ 0.80 (p = 0.003) and in lesions ≥ 20 mm (p = 0.006), but not in LAD/LM lesions (p = 0.55)., Conclusions: The present study shows a progressive raise in the duration of peak hyperemia and time to recovery, after the administration of increasing doses of intracoronary adenosine for the assessment of FFR. Therefore, considering the potential advantages of a high-dose adenosine protocol, allowing a more prolonged hyperemia and a more precise and reliable measurement of FFR, further larger studies with such FFR strategy should certainly be advocated to confirm its safety and benefits, before its routinely use recommendation., (Copyright © 2018. Published by Elsevier B.V.)

Glaucoma leads to irreversible blindness. Numerous anti-glaucoma eye drops have been developed. Unfortunately, many patients with glaucoma still suffer from progressive visual disorders. Recently, ripasudil hydrochloride hydrate, a selective Rho-associated protein kinase inhibitor, was launched for the treatment of glaucoma. However, adverse events, such as conjunctival hyperemia, are often noted in clinical trials using healthy subjects. Therefore, we investigated the onset, offset, and kinetic changes of conjunctival hyperemia induced by ripasudil ophthalmic solution in patients with open-angle glaucoma or ocular hypertension who had already been treated with anti-glaucoma eye drops other than ripasudil. Conjunctival hyperemia was evaluated by both clinical grading by 3 ophthalmic physicians and pixel coverage of conjunctival blood vessels determined by conjunctival hyperemia-analyzing software. Conjunctival hyperemia appeared within 10 min post-instillation in most of the participants. Clinical grade and pixel coverage increased significantly 10 min post-instillation and then decreased. In most of the participants, hyperemia resolved within 2 h. Median conjunctival hyperemia offset was 90 min. A tendency of monotonic increase was observed between clinical grade and pixel coverage. Taken altogether, hyperemia induced by ripasudil was transient in glaucoma patients who had already been treated with anti-glaucoma eye drops other than ripasudil.

Purpose: The purpose of this study was to investigate the IOP-lowering effects of the ITRI-E-212, a new Rho-associated protein kinase (ROCK) inhibitor. ITRI-E-212 improved fluid outflow through the trabecular meshwork and reduced IOP with transient and mild conjunctival hyperemia. ITRI-E-212 can potentially be developed into new antiglaucoma agents., Methods: ITRI-E-212 was selected from more than 200 amino-isoquinoline structures because of its adequate solubility and drug-loading percentage in eye drops. ITRI-E-212 has less than 50% inhibitory concentration (IC50) against ROCK2. The in vitro kinase inhibition was evaluated using the ADP-Glo kinase assay. A comprehensive analysis of the kinase inhibitor selectivity of ITRI-E-212 was performed using the KINOMEscan methodology. The IOP-lowering effect and tolerability of ITRI-E-212 were investigated in normotensive and ocular hypertensive rabbits. The pharmacokinetics study was performed in vivo in the aqueous humor (AH), and hyperemia was assessed., Results: ITRI-E-212 showed high in vitro inhibitory activity against ROCK2 and high specificity against AGC kinases. The mean IOP-lowering effect of ITRI-E-212 in normotensive and ocular hypertensive models was 24.9% and 28.6%, respectively; 1% ITRI-E-212 produced notable reductions in IOP that were sustained for at least 6 hours after each dose once per day. Only transient, mild hyperemia was observed. The compound extracted from the AH reached 78.4% ROCK2 kinase inhibition at 1 hour after dose administration and was sustained for 4 hours., Conclusions: ITRI-E-212 is a novel and highly specific ROCK2 inhibitor with the ability to lower IOP in animal models. It has favorable pharmacokinetic and ocular tolerability profiles with only minimal conjunctival hyperemia.

Background: Tumor necrosis factor inhibitors decrease the risk of cardiovascular events in moderate to severe psoriasis, but the association between their effects on endothelial function and those on skin lesions has not been well studied. We investigated the association between infliximab effects on endothelial function during the loading phase and those on skin lesions in patients with psoriasis., Methods: We evaluated endothelial function with reactive hyperemia-peripheral arterial tonometry index (RHI) in 15 patients with psoriasis before the first and third infusions of infliximab. Patients were stratified into two groups; those who maintained Psoriasis Area and Severity Index (PASI) 75 response for more than 6 months (defined as responders) and the others (defined as nonresponders)., Results: Six weeks after the initiation of infliximab (before the third infusion), PASI scores were significantly improved compared with baseline, while RHI values were not altered in the whole patient group. However, when the responders and the nonresponders were analyzed separately, RHI values tended to be decreased before the third infusion compared with baseline in the nonresponders, while being unchanged in the responders. Importantly, the difference in ∆RHI reached a statistical significance between the two groups, and the cutoff value (mean - 2 standard deviation of RHI values in the responders) identified the nonresponders with 67% of sensitivity and 100% of specificity., Conclusions: The decrease in RHI values before the third infusion may serve as a predictor for the long-term unfavorable effect of infliximab on psoriatic skin lesions., (© 2018 The International Society of Dermatology.)

Objective: Fractional flow reserve (FFR) using adenosine has been the gold standard in the functional assessment of intermediate coronary stenoses in the catheterization laboratory. We aim to study the correlation of adenosine-free indices such as whole cycle Pd/Pa [the ratio of mean distal coronary pressure (Pd) to the mean pressure observed in the aorta (Pa)], instantaneous wave-free ratio (iFR), and contrast-induced submaximal hyperemia (cFFR) with FFR., Methods: This multicenter, prospective, observational study included patients with stable angina or acute coronary syndrome (>48 h since onset) with discrete intermediate coronary lesions (40-70% diameter stenosis). All patients underwent assessment of whole cycle Pd/Pa, iFR, cFFR, and FFR. We then evaluated the correlation of these indices with FFR and assessed the diagnostic efficiencies of them against FFR ≤0.80., Results: Of the 103 patients from three different centers, 83 lesions were included for analysis. The correlation coefficient (r value) of whole cycle Pd/Pa, iFR, and cFFR in relation to FFR were +0.84, +0.77, and +0.70 (all p values < 0.001), respectively, and the c-statistic against FFR ≤0.80 were 0.92 (0.86-0.98), 0.89(0.81-0.97), and 0.91 (0.85-0.97) (all p values < 0.001), respectively. The best cut-off values identified by receiver-operator characteristic curve for whole cycle Pd/Pa, iFR, and cFFR were 0.94, 0.90, and 0.88, respectively, for an FFR ≤0.80. By the concept of "adenosine-free zone" (iFR = 0.86-0.93), 59% lesions in this study would not require adenosine., Conclusion: All the three adenosine-free indices had good correlation with FFR. There is no difference in the diagnostic accuracies among the indices in functional evaluation of discrete intermediate coronary stenoses. However, further validation is needed before adoption of adenosine-free pressure parameters into clinical practice., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Patients who experienced cardiovascular side effects during cancer therapy with carfilzomib for multiple myeloma had relapsed multiple myeloma, so have be previously treated with other cancer therapies. The present is a single center cohort study to evaluate early cardiovascular effects of administration of irreversible proteasome inhibitor carfilzomib in naïve patients. We included 24 patients and collected cardiovascular side effects, echocardiographic parameters and endothelial function at baseline and after 4 cycles. At early follow up we observed increase in blood arterial pressure values (mean change in systolic pressure of 10 mmHg (P-value < 0.01; diastolic arterial pressure and mean arterial pressure of 3.3 mmHg and 5.4 mmHg, both P-value < 0.01). Reactive hyperemia PAT index was reduced in the whole cohort by a mean of 0.46 points (P-value < 0.01); diastolic function was changed: E-wave-deceleration-time (EDT) was reduced by 49,96 ± 31 ms, P-value < 0.05 and early diastolic tissue Doppler velocity (e') by a mean value of 1.46 cm/s, P - value 0.04. At early follow up we did not observe events of grade 3 or 4. We observe correlation between events and endothelial dysfunction at baseline and age (OR 1.9, CI 95% 0.05-5.804, P- value: 0.038 for RHI<1.67; OR 1,4, CI 95%0.99-2.56, P- value: 0.04 for age). Our results suggest that therapy with carfilzomib when used as first line therapy is responsible for increase in systemic blood pressure, alteration of endothelium-mediated vascular dilatation and early myocardial diastolic dysfunction., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To examine correlations between ocular redness scores provided by the Keratograph 5M and those determined using two image-based grading scales., Methods: Observational prospective cross-sectional study. Two hundred and twenty six eyes of two hundred and twenty six participants (175 patients using anti-glaucoma eye drops and 51 subjects untreated). All subjects were scored automatically using the keratograph 5M. These redness scores (RS) were then correlated with the gradings provided by the Efron and McMonnies/Chapman-Davies scale (MC-D) scales (two observers)., Results: Excellent reproducibility was observed for both the Efron (weighted K=0.897, 95% CI 0.823-0.904) and MC-D (weighted K=0.783, 95% CI 0.752-0.795) scales. Keratograph RS and the scores obtained with both Efron (Spearman's Rho=0.43, P<0.001) and MC-D (Spearman's Rho=0.48, P<0.001) scales were significantly correlated. RS for the bulbar and limbal - nasal and temporal quadrants also correlated moderately with the two subjective scales. Through Bland Altman analysis, poor agreement was detected between the objective and subjective methods: agreement values for the Efron scale or MC-D scale (matching scorers between observers) versus overall RS showed high biases (-15.58 and -22.05 respectively) and wide limits of agreement (LOA) (-46.169 to 15.005 and -52.534 to 8.19 respectively). Lowest bias was observed between temporal limbal RS and Observer 2 Efron score (-0.04)., Conclusions: Although it emerged as a reliable objective method, the keratograph 5M overestimated the scores compared with the subjective grading scales when used to grade the degree of ocular redness. Therefore, they should not be interchangeable methods., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: We hypothesized that CO 2 and H + stimulate capillaries and arterioles to produce local and conducted vasodilations required to coordinate the distribution of blood flow to contracting skeletal muscle fibers., Methods: CO 2 and H + independently and in combination were applied to 2A arterioles (first branch order from the 1A feed arteriole) and capillaries of the in situ, blood-perfused hamster cremaster muscle. The resulting local and conducted vasodilations were measured., Results: H + (pH: 7.2-6.6) and CO 2 (5% and 10%) applied to the vascular network induced 2A arteriolar vasodilations, while 15% CO 2 produced vasoconstriction. Localized application of H + produced 2A arteriolar vasodilation, while 15% CO 2 resulted in a variable response. Simultaneous application of CO 2 and H + did not result in the predicted additive effects. Application of CO 2 and H + alone or combined on arterioles or capillaries did not induce a conducted response., Conclusions: CO 2 and H + produce arteriolar vasodilation but, critically, cannot stimulate the spread of vasodilation throughout the network, thus limiting their ability to coordinating blood flow to contracting skeletal muscle fibers. Given their potential for interaction, the importance of CO 2 and H + may lie in their ability to modify the effects of other vasodilators., (© 2018 John Wiley & Sons Ltd.)

Introduction Growing evidence supports ischemia-guided management of chest pain, with invasive and non-invasive tests reliant upon achieving adenosine-induced coronary hyperemia (defined as increased blood flow to an organ's perfusion bed). In the non-invasive setting, surrogate markers of hyperemia, such as increases in heart rate, are often used, despite not being formally validated. We tested whether heart rate and other non-invasive indices are reliable markers of coronary hyperemia. Methods The first part involved Doppler flow-based validation of the best pressure-wire markers of hyperemia in 53 patients. Subsequently, using these validated pressure-derived parameters, 265 pressure-wire traces were analysed to determine whether heart rate and other non-invasive parameters correlated with hyperemia. Results In the flow derivation cohort, the best determinant of hyperemia came from having 2 out of 3 of: (1) Ventriculisation of the distal pressure waveform, (2) disappearance of distal dicrotic pressure notch, (3) separation of mean aortic and distal pressures. Within the 244 patients demonstrating hyperemia, non-invasive markers of hyperemia, such as change in heart rate (p = 0.77), blood pressure (p = 0.60) and rate-pressure product (p = 0.86), were poor correlates of coronary hyperemia, with only 37.3% demonstrating a ≥ 10% increase in heart rate that is commonly used to adjudge adenosine-induced hyperemia in the non-invasive setting. Conclusions We demonstrate, by correlation with Doppler-flow data, a validated method of identifying coronary hyperemia within the catheter laboratory using the pressure-wire. We subsequently show that non-invasive parameters, such as heart rate change, are poor predictors of coronary hyperemia during stress imaging protocols that rely upon achieving adenosine-induced hyperemia.

Purpose: The aim is discussing the origins of worsening of external eye condition (EEC) and of tear film (TF) instability after wear of silicone-hydrogel contact lenses (CLs) with hydrogen-peroxide (H 2 O 2 ) care system., Methods: EEC and TF stability were evaluated before and after 15days of wear combined with different care systems: (1) H 2 O 2 , (2) detergent solution and H 2 O 2 , (3) multipurpose solution (MPS), (4) H 2 O 2 and artificial tears. In-vitro cell mortality tests were performed after 24h cell incubation with CLs treated with H 2 O 2 . Photon correlation spectroscopy (PCS) was carried out on tears of non-wearers and CL wearers who used MPS or H 2 O 2 solution., Results: Worsening of EEC was observed only for the group using H 2 O 2 (group 1). In-vitro, cell mortality was found higher for worn CL than for unworn CLs. Worsening of TF stability was observed regardless of care system and also PCS results on tears of CL wearers were found different compared to non-wearers regardless of care system. The only observed remedy for tear instability of CL wearers was found to be the administration of artificial tears., Conclusions: Worsening of EEC of CL wearers using H 2 O 2 is attributed to H 2 O 2 scarce cleaning efficacy, which can be solved by adding a CL detergent solution. The origin of TF instability is found to be different. A remedy was found to be the administration of artificial tears, whose effect could be attributed either to the role of specific components or to rinsing and replacement of TF during wear., (Copyright © 2017 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)