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Background: A coronary function test (CFT) is the recommended diagnostic test to identify coronary vasomotor dysfunction as a cause of symptoms in patients with angina and nonobstructive coronary arteries (ANOCA). Acetylcholine is the commonly used pharmacological agent for spasm provocation. We aimed to investigate an association between severity of symptoms and provocative acetylcholine dose., Methods and Results: We included ANOCA patients undergoing clinically indicated CFT from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing: NL-CFT. Patients with epicardial spasm (n=251) were divided according to acetylcholine spasm triggering dose: low (2-20 mcg, EpiLOW), middle (100 mcg, EpiMIDDLE) or high (200 mcg, EpiHIGH). Patients with microvascular spasm (n=157) were analyzed irrespective of triggering dose. The patient groups were compared to each other and to a control group with negative CFT results (n=101). We assessed mean Seattle Angina Questionnaire angina frequency and summary scores at baseline and follow-up and the proportion of patients improving or deteriorating. An inverse relationship between provocation dosage and angina frequency at baseline was found in epicardial spasm: the lower the triggering dose, the more frequently patients experienced angina (EpiLOW 48±20, EpiMIDDLE 53±21, EpiHIGH 57±19, microvascular spasm 61±21, controls 64±21, overall P =0.003). A trend was seen toward most patients improving in the high triggering dose group, and most patients deteriorating in the low triggering dose group., Conclusions: A significant dose-dependent relationship between spasm provocation and anginal complaints exists. Acetylcholine provocation dose could be incorporated as a risk stratification factor or surrogate outcome in future clinical trials., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06083155.

Background: Invasive coronary angiography via the radial approach is commonly performed following radial artery spasm prophylaxis (RASP). It is however unknown, whether RASP influences the results of coronary spasm provocation testing performed after diagnostic angiography. We aimed to investigate the effects of RASP on vasomotor responses during intracoronary acetylcholine (ACh) testing., Methods: We retrospectively screened 372 consecutive patients (51 % female, mean age 61 ± 11 years) with angina and non-obstructive coronary arteries, who underwent intracoronary provocation with ACh according to a standardized protocol. During testing, dose-dependent clinical discomfort and concomitant ischemic electrocardiographic changes were recorded in addition to visual reductions of epicardial lumen diameters. Of these patients, 156 (42 %) received RASP (i.e. 200 μg nitroglycerin and 2.5 mg verapamil), while no RASP was administered in 216 (58 %) patients. Both groups were compared regarding age, sex, cardiovascular risk factors and ACh-test results., Results: ACh provocation testing revealed a pathological test result in 71 patients (46 %) with RASP and 103 patients (48 %) without (p = 0.752) [epicardial spasm: in 20 patients (28 %) with RASP and 42 patients (41 %) without (p = 0.120); microvascular spasm: in 51 patients (72 %) with RASP and 61 patients (59 %) without (p = 0.362)]. Overall, RASP did not significantly alter coronary artery vasomotor responses, neither regarding the frequency (p = 0.752) or type of coronary spasm (microvascular vs. epicardial; p = 0.108) nor regarding the ACh dose leading to spasm (p = 0.151)., Conclusions: RASP does not significantly affect coronary vasomotor responses to ACh, suggesting that radial artery spasm prophylaxis can be routinely administered even in patients in whom intracoronary spasm testing is performed., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The no-reflow phenomenon is a significant complication during excimer laser coronary angioplasty (ELCA) procedures, which can lead to adverse outcomes. This study explores the efficacy of intracoronary administration of a cocktail solution comprising nitroglycerin, heparin, and verapamil on preventing no-reflow during ELCA in patients with in-stent restenosis (ISR)., Methods: This study included patients undergoing ELCA with contrast infusion for ISR. Based on whether receiving the intracoronary cocktail solution during ELCA, participants were divided into two groups: the cocktail (+) group and the cocktail (-) group. The primary endpoint was the incidence of no-reflow, which was defined as the cessation of blood flow into the distal coronary artery in the absence of a clear angiographic explanation for impairment of flow., Results: A total of 54 lesions in 51 patients were included. The mean age of the study population was 61.8 ± 9.7 years, with 84.3 % male. Baseline clinical characteristics were well-balanced. The incidence of no-reflow was significantly lower in the cocktail (+) group compared to the cocktail (-) group (0 % vs. 17.9 %, P = 0.024). No cases of hypotension, major bleeding or coronary perforation in either group. Major adverse cardiac events (MACE) within 6-month were no significant difference between the groups (4.0 % vs. 3.8 %, P = 0.977)., Conclusions: The pilot study suggests that intracoronary administration of a cocktail comprising heparin, nitroglycerin, and verapamil may reduce the incidence of no-reflow during ELCA in patients with ISR. However, given the limited sample size and the non-randomized design, these findings should be considered hypothesis-generating. Future validation needs to be confirmed through multicenter studies with larger sample sizes., Competing Interests: Conflict of interest statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Chronic anal fissures (CAFs) are the second most common anorectal disease. Non-surgical treatment includes several options with controversial efficacy. The aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate., Methods: A phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with CAF. The enrollment started after local ethics committee approval (study n. 6461, protocol approval n. 0045085). Eligible consecutive patients were randomized to one of three different groups, each receiving a different ointment. The efficacy of the treatment was evaluated with the REALISE score., Results: Nine patients were treated with cream A (median age 47 years, IQR 40-56, 22% female), nine with cream B (median age 52 years, IQR 49-57, 33% female), and nine with cream C (median age 58 years, IQR 46-62, 55% female). In group A, REALISE scores decreased significantly from a median of 22 (IQR 12-25) to 6 (IQR 4-8) (p < 0.05) after 40 days. In group B, REALISE scores improved significantly from a median of 20 (IQR 17-22) to 5 (IQR 4-9) (p < 0.05). In group C, REALISE scores decreased significantly from a median of 19 (IQR 19-20) to 4 (4-5) (p < 0.05). No statistically differences were recorded. The healing rate was 77% with creams A and C, while it was 44% with cream B., Conclusion: Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. Ethics approval and consent to participate: The local ethics committee of Hospital University of Bari approved this study (n. 6461) and protocol (approval n. 0045085/17.05.2022). The methods were carried out in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants and/or their legal guardian(s). Consent for publication: Written informed consent was obtained from all participants., (© 2025. Springer Nature Switzerland AG.)

The structural and functional integrity of conduits used for coronary artery bypass grafting is critical for graft patency. Disruption of endothelial integrity and endothelial dysfunction are incurred during conduit harvesting subsequent to mechanical or thermal injury and during conduit storage prior to grafting, leading to acute thrombosis and early graft failure. Late graft failure, in particular that of vein grafts, is precipitated by progressive atherogenesis. Intra-operative management includes appropriate selection of conduit-specific harvesting techniques and storage solutions. Arterial grafts are prone to vasospasm subsequent to surgical manipulation, and application of intra-operative vasodilatory protocols is critical. Post-operative management includes continuation of oral vasodilator therapy and selection of antithrombotic and lipid-lowering agents to attenuate atherosclerotic disease progression in conduits. In this review, the scientific evidence underlying the key aspects of intra- and post-operative management of conduits for coronary artery bypass grafting is examined. Clinical consensus statements for best clinical practice are provided, and areas requiring further research are highlighted., (This article has been co-published with permission in the European Heart Journal and the European Journal of Cardio-Thoracic Surgery. © 2024 the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article.)

Purpose: We studied the effect of a platelet-rich fibrin matrix (PRFM) combined with prostaglandin E-1 (PGE-1) injection on erectile function in patients refractory to response for phosphodiesterase type 5 inhibitors (PDE5-Is)., Methods: This randomized, double-blind, placebo-controlled study included 80 patients. The patients were randomly assigned to four groups and blinded together with the administrating physicians to the nature of the intracorporeal injection (ICI) therapies. Group (1) received saline, group (2) received platelet-rich fibrin matrix (PRFM), group (3) received prostaglandin E-1 (PGE-1), and group (4) received a combination of PRFM + PGE-1. The patients received ICI therapy weekly for 8 consecutive weeks. Clinical information and follow-up data were obtained at 1, 2, 3, and 6 months., Results: A significant increase occurred in the validated Arabic version of the International Index of Erectile Function (ArIIEF-5) score in group (4) compared to the other three groups (p value = 0.037). There was a significant difference in erection hardness scale (EHS) scores among all groups after receiving the different treatments (p = 0.004). A significant increase was seen in the ArIIEF-5 score in groups 4 and 3 compared to that in groups 1 and 2 (p < 0.001). There was also a significant increase in the arterial dilatation % in groups 4 and 3 compared to that in groups 1 and 2 (p = 0.019)., Conclusion: The combination of PRFM plus PGE-1 had shown significant improvement in the ArIIEF-5 score, yet the patients still had mild to moderate ED., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the local ethical committee. Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Persistent Pulmonary Hypertension of the newborn (PPHN) is characterized by sustained elevated Pulmonary Artery Pressure (PAP). Drug resistance and the adverse effects of current therapeutic agents warrant investigation of other targeted therapies. Bosentan has shown benefits in affected neonates. However, trials reported the association with unwanted effects. Thus, in this study, we assess another agent in the same family, Macitentan. However, its efficacy in the treatment of PPHN is not yet reported. Hence, this study evaluated the effect of Macitentan compared to Bosentan in terms of efficacy and safety in the treatment of PPHN., Methods: This randomized, double-blinded non-inferiority clinical trial was conducted in Shahid Akbar Abadi hospital, Tehran, Iran. Sixty clinically stable neonates with signs suggestive of PPHN were randomly allocated into two groups (n = 30 in each group) and they received either Bosentan 1 mg/kg/dose BD (twice daily) or Macitentan 1 mg/kg/dose BD simultaneously with sildenafil. The echocardiographic and laboratory indices of efficacy and safety were compared between groups. SPAP (systolic pulmonary artery pressure) was used to assess the non-inferiority of the Macitentan compared to the Bosentan in their respective doses used in the study., Results: Participants' mean (SD) age was 3.53 (1.21) days, and 55% were female. No mortality case occurred. SPAP was reduced in both Bosentan and Macitenan groups with the mean difference in SPAP of 9 (95% CI: 7.34-10.65) in Bosentan and SPAP mean difference of 14 (95% CI: 12.12-15.86) in Macitentan group. Categorical comparison of primary outcome improvement showed that Macitentan was superior to Bosentan with a 10% non-inferiority margin. Similar results were obtained in other echocardiographic indices. Also, no significant alterations were observed in laboratory safety parameters., Conclusion: Macitentan 1 mg/kg/dose BD (twice daily) is non-inferior to Bosentan 1 mg/kg/dose BD in improving echo outcomes of PPHN and it was even more effective in improving some of these. Also, it is non-inferior to Bosentan in terms of safety. TRIAL REGISTRY NUMBER: (IRCT20160120026115N9)., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Importance: The results of small studies suggest that off-label use of low-dose oral minoxidil (LDOM) may be safe and effective for patients with hair loss, but larger trials and standardized guidelines are lacking., Objective: To create an expert consensus statement for LDOM prescribing for patients with hair loss., Evidence Review: The current literature on the pharmacological properties, adverse effect profile, and use of LDOM for patients with hair loss was reviewed. Topics of interest were identified, and a modified Delphi consensus process was created. A total of 43 hair loss specialist dermatologists from 12 countries participated in a modified Delphi process. Consensus was reached if at least 70% agreed or strongly agreed on a 5-point Likert scale., Findings: Over 4 survey rounds, 180 items in the first round, 121 items in the second round, 16 items in the third round, and 11 items in the fourth round were considered and revised. A total of 76 items achieved consensus including diagnoses for which LDOM may provide direct or supportive benefit, indications for LDOM compared to topical minoxidil, dosing for adults (18 years and older) and adolescents (aged 12 to 17 years), contraindications, precautions, baseline evaluation, monitoring, adjunctive therapy, and specialty consultation. Pediatric use and dosing items for children younger than 12 years, and LDOM titration protocols fell short of consensus., Conclusions and Relevance: This international expert consensus statement regarding the off-label prescribing of LDOM for patients with hair loss can help guide clinical practice until more data emerge. Hair loss experts with experience treating pediatric patients were underrepresented on this expert panel. Future research should investigate best practices for LDOM use in pediatric patients. Other critical topics for further investigation include the comparative efficacy of topical minoxidil vs oral minoxidil, the safety of oral minoxidil for patients with a history of allergic contact dermatitis to topical minoxidil, the long-term safety of LDOM, and the use of other off-label forms of minoxidil, such as compounded formulations of oral minoxidil and sublingual minoxidil. As additional evidence-based data emerge, these recommendations should be updated.

Coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) obtained through coronary bolus thermodilution are used to assess and treat patients with angina and no obstructive coronary artery disease. Previous studies demonstrate comparable results assessing epicardial ischemia by fractional flow reserve using intravenous (IV) or intracoronary (IC) adenosine. It is unknown if there is a similarity between IC and IV hyperemia with adenosine when performing coronary reactivity testing (CRT). We reviewed CRT data and baseline demographics in a cohort of patients who underwent CRT for ischemia and no obstructive coronary artery disease. We evaluated CFR and IMR in patients whereby maximal hyperemia was obtained by both IC and IV means using linear regression, one-way analysis of variance, Wilcoxon, and Bland-Altman analysis. We assessed 62 patients with a median age of 60.5 years (50 to 67), and 72% were females. The average CFR with IC adenosine was 3.12 (2.31 to 4.06) and 2.71 (2.0 to 3.88) with IV adenosine, with an R 2 value of 0.50 (p <0.0001). The average IMR with IC adenosine was 28.23 (16.24 to 50.72) and 22.27 (14.79 to 37.0) with IV adenosine, with an R 2 value of 0.33 (p <0.0001). Average intra-method variability between IC and IV adenosine was nonsignificant (p = 0.31 for CFR and p = 0.55 for IMR). Bland-Altman analysis showed reasonable agreement between IV and IC adenosine for CFR and IMR with slightly higher values using IC adenosine. Therefore, in CRT with bolus thermodilution, CFR and IMR values obtained with IC adenosine correlate well with those obtained with IV adenosine. This presents a potential alternative to IV adenosine for bolus thermodilution CRT., Competing Interests: Declaration of competing interest Dr. Widmer discloses personal payments for work as a consultant/advisor for Abbott, Philips, and Medtronic. He also discloses having received payments for work as a speaker/proctor for Abbott and Gore. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Excess exercise ventilation (high ventilation (V̇ E )/carbon dioxide output (V̇CO 2 )) contributes significantly to dyspnea and exercise intolerance since the earlier stages of chronic obstructive pulmonary disease (COPD). A selective pulmonary vasodilator (inhaled nitric oxide) has shown to increase exercise tolerance secondary to lower V̇ E /V̇CO 2 and dyspnea in this patient population. We aimed to assess whether a clinically more practical option - oral sildenafil - would be associated with similar beneficial effects. In a randomized, placebo-controlled study, twenty-four patients with mild-to-moderate COPD completed, on different days, two incremental cardiopulmonary exercise tests (CPET) one hour after sildenafil or placebo. Eleven healthy participants performed a CPET in a non-interventional visit for comparative purposes with patients when receiving placebo. Patients (FEV 1 = 69.4 ± 13.5 % predicted) showed higher ventilatory demands (V̇ E /V̇CO 2 ), worse pulmonary gas exchange, and higher dyspnea during exercise compared to controls (FEV 1 = 98.3 ±11.6 % predicted). Contrary to our expectations, however, sildenafil (50 mg; N= 15) did not change exertional V̇ E /V̇CO 2 , dead space/tidal volume ratio, operating lung volumes, dyspnea, or exercise tolerance compared to placebo (P>0.05). Due to the lack of significant beneficial effects, nine additional patients were trialed with a higher dose (100 mg). Similarly, active intervention was not associated with positive physiological or sensory effects. In conclusion, acute oral sildenafil (50 or 100 mg) failed to improve gas exchange efficiency or excess exercise ventilation in patients with predominantly moderate COPD. The current study does not endorse a therapeutic role for sildenafil to mitigate exertional dyspnea in this specific patient subpopulation. Clinical trial registry: https://ensaiosclinicos.gov.br/rg/RBR-4qhkf4 Web of Science Researcher ID: O-7665-2019., Competing Interests: Declaration of Competing Interest No authors declare conflicts of interest related to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Iontophoresis studies face challenges due to the unknown absolute drug dose delivered and the possible effect of the current used in drug delivery on the microvessels, known as current-induced vasodilation. This study aimed to investigate how various concentrations of acetylcholine (ACh), delivered through transdermal iontophoresis using repeated current pulses, impact the recovery profile of the microvascular response., Methods: The study included fifteen healthy volunteers, and microvascular responses to five concentrations of iontophorised ACh (ranging from 0.0055 mM to 55 mM) and sterile water were assessed at six forearm skin sites using polarized reflectance spectroscopy. Iontophoresis at each concentration involved three consecutive pulses separated 8 recovery periods., Results: Current-induced responses were more pronounced for lower concentrations of ACh and for sterile water. With repeated pulses, lower concentrations of ACh exhibited a recovery profile more akin to higher concentrations., Perspective: Through repeated iontophoresis of ACh, microvascular responses exhibit variation based on the drug concentration and the number of pulses administered. These variations are likely attributed to changes in skin conductivity and permeability., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hot flashes, common during menopause, affect up to 80% of the Western menopausal women and are reported to contribute to sleep disturbances in midlife. Few prospective data are available to confirm the specific role of hot flashes in disrupting sleep in midlife women, however, or confirm whether changes in hot flashes in response to clinical therapies result in improvement in sleep., Objective: To examine the effects of continuous nitroglycerin therapy on sleep quality in perimenopausal and postmenopausal women with frequent hot flashes (pre-specified secondary trial endpoint) and to examine prospective associations between hot flashes and sleep disruption in this population., Study Design: Sleep data were analyzed from a randomized, double-blinded, placebo-controlled trial of continuous transdermal nitroglycerin (NTG) therapy to suppress nitric oxide-mediated vasodilation in perimenopausal or postmenopausal women with hot flashes. Participants were randomized to uninterrupted use of transdermal NTG (0.2-0.6 mg/hour) or placebo for 12 weeks. Nocturnal hot flashes awakening participants from sleep were evaluated using 7-day symptom diaries at baseline, 5 weeks, and 12 weeks. Sleep disruption (wakefulness after sleep onset, WASO) was assessed using validated sleep diaries, and global sleep quality was assessed by the validated Pittsburgh Sleep Quality Index (PSQI: range 0 [best] 21 [worst]) questionnaire. Mixed linear models examined changes in sleep quality and disruption, as well as the strength of associations between nocturnal hot flash frequency and sleep outcomes, over 5 and 12 weeks, adjusting for baseline values, age, race, and ethnicity., Results: Among the 141 participants (70 to NTG and 71 to placebo, mean age 54.6 [±3.9] years), the mean baseline hot flash frequency was 10.8 (±3.5) per day, including 2.6 (±1.7) nocturnal hot flashes awakening participants. At baseline, hot flashes were the most commonly reported reason for nocturnal awakening, with 62.6% of participants reporting waking due to hot flashes at least twice nightly. Over 5 and 12 weeks, mean frequency of nocturnal hot flashes causing awakenings decreased in both groups (NTG: -0.9 episodes/night, placebo: -1.0 episodes/night). Sleep disruption as measured by average nightly WASO also decreased (NTG: -10.1 minutes, placebo: -7.3 minutes), and mean PSQI score improved (NTG: -1.3 points, placebo: -1.2 points). No significant between-group differences in change in sleep outcomes were detected from baseline to 5 and 12 weeks, including PSQI sleep quality score as a prespecified secondary trial endpoint (P≥.05 for all). Greater improvement in nocturnal hot flash frequency over 5 and 12 weeks was associated with greater improvement in PSQI sleep quality score (β= -0.30, P=.01) and sleep disruption reflected by WASO (β= -1.88, P=.02) in the combined sample., Conclusion: Among menopausal women in a randomized trial of continuous NTG therapy for hot flashes, hot flashes were the most frequently reported cause of nocturnal awakenings. Compared to placebo, continuous NTG therapy did not result in greater improvements in sleep quality from baseline to 5 and 12 weeks. Based on night-by-night symptom diaries and questionnaires, however, greater improvement in nocturnal hot flash frequency in both groups was associated with greater improvement in sleep quality and disruption., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The primary aim of this study was to evaluate the effects of vasodilator administration on CT angiography (CTA) prostatic artery diameter and peak opacification in dogs with prostatic carcinoma prior to prostatic artery embolization (PAE)., Materials and Methods: A prospective clinical trial was performed. Ten dogs with naturally occurring prostatic carcinoma and no evidence of cardiovascular disease were enrolled. Each dog underwent multiphase CTA of the prostate before and after IV vasodilator (glyceryl trinitrate [GTN] or clevidipine butyrate [clevidipine]) administration, and cardiovascular parameters were monitored. PAE was performed the following day. Prostatic arterial anatomy was characterized by CTA. Prostatic artery lumen diameter and peak opacification were measured on pre- and post-vasodilator CTA by a blinded radiologist. The percent change of these measurements was calculated and assessed for significance., Results: Glyceryl trinitrate and clevidipine were administered in 5 dogs each with subsequent blood pressure reduction documented in all dogs. No significant difference was detected in prostatic artery diameter or peak opacification between pre- vs. post-vasodilator CTA. Good agreement in prostatic arterial branch number, origin, and course was documented between pre- and post-vasodilator CTA images., Clinical Significance: Study findings do not support the routine use of vasodilator administration during pre-PAE CTA in dogs, though larger sample sizes and protocol alterations may be needed to detect a clinically relevant utility., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Griffin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Coronary Artery Spasm (CAS) often presents in the epicardial coronary arteries. The anterior septal branch is distributed within the myocardium, and occurrences of spasms are rare. Currently, there is no available literature on this topic, and the onset of symptoms remains elusive, potentially leading to misdiagnosis., Case Presentation: We present a case of acute myocardial infarction (AMI) caused by spasm in the anterior septal branch, accompanied by transient right bundle branch block (RBBB). The administration of nitroglycerin via intracoronary injection resulted in the alleviation of spasm in the anterior septal branch and the disappearance of RBBB. After the administration of anti-coronary spasm medications, the patient exhibited favorable recovery outcomes. No episodes of myocardial ischemia were observed during the six-month follow-up., Conclusions: The presence of new RBBB in patients may warrant consideration of anterior septal coronary artery spasm, which necessitates urgent coronary angiography to clarify the underlying cause and facilitate the prompt initiation of anti-spasm treatment., Competing Interests: Declarations. Ethics approval and consent to participate: The studies involving human participants were reviewed and approved by Ethics Committee of Wuhan Asia Heart Hospital (2024-B014). Consent for publication: Consent for publication Written informed consent was obtained from the patient for publication of this case report. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Delayed cerebral ischemia (DCI) is one of the main contributors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Endovascular spasmolysis with intra-arterial nimodipine (IAN) may resolve angiographic vasospasm, but its effect on infarct prevention and clinical outcome is still unclear. We report the effect of IAN on infarction rates and functional outcome in a consecutive series of SAH patients., Methods: To assess the effectiveness of IAN, we collected functional outcome data of all SAH patients referred to a single tertiary center since its availability (2011-2020). IAN was primarily reserved as a last tier option for DCI refractory to induced hypertension (iHTN). Functional outcome was assessed after 12 months according to the Glasgow Outcome Scale (GOS, favorable outcome = GOS4-5)., Results: Out of 376 consecutive SAH patients, 186 (49.5%) developed DCI. Thereof, a total of 96 (25.5%) patients remained unresponsive to iHTN and received IAN. DCI-related infarction was observed in 44 (45.8%) of IAN-treated patients with a median infarct volume of 111.6 mL (Q 1 : 51.6 to Q 3 : 245.7). Clinical outcome was available for 84 IAN-treated patients. Of those, a total of 40 (47.6%) patients reached a favorable outcome after 1 year. Interventional complications were observed in 9 (9.4%) of the IAN-treated patients., Conclusion: Intra-arterial spasmolysis using nimodipine infusion was associated with low treatment specific complications. Despite presenting a subgroup of severely affected SAH patients, almost half of IAN-treated patients were able to lead an independent life after 1 year of follow-up., Trial Registration Number: German Clinical Trial Register DRKS00030505., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Purpose: Subarachnoid hemorrhage (SAH) is a rare but life-threatening clinical event for pediatric patients. Cerebral vasospasm is a common complication of SAH that often leads to poor outcomes. This case report describes the use of dual intraventricular (IVT) vasodilators in a pediatric patient., Summary: An 11-year-old male presented with traumatic diffuse SAH and cerebral vasospasm. Despite treatment with IVT nicardipine, intravenous (IV) milrinone by continuous infusion, enteral nimodipine, and intraarterial verapamil and milrinone given during digital subtraction angiography, transcranial Doppler (TCD) mean velocities continued to rise. IVT milrinone was then added to IVT nicardipine and IV milrinone. The combination of IVT nicardipine, IV milrinone, and rescue therapy with IVT milrinone was continued for a total of 7 days. TCD mean velocities decreased into the mild to moderate range within 2 days of the patient receiving this combined regimen and remained globally low thereafter., Conclusion: This case illustrates the potential benefit of using dual IVT vasodilators to improve outcomes for pediatric patients with refractory cerebral vasospasm., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Purpose: Vasospasm is a common iatrogenic event during mechanical thrombectomy (MT). In such circumstances, intra-arterial nimodipine administration is occasionally considered. However, its use in the treatment of iatrogenic vasospasm during MT has been poorly studied. We investigated the impact of iatrogenic vasospasm treated with intra-arterial nimodipine on outcomes after MT for large vessel occlusion stroke., Methods: We conducted a retrospective analysis of the multicenter observational registry Endovascular Treatment in Ischemic Stroke (ETIS). Consecutive patients treated with MT between January 2015 and December 2022 were included. Patients treated with medical treatment alone, without MT, were excluded. We also excluded patients who received another in situ vasodilator molecule during the procedure. Outcomes were compared according to the occurrence of cervical and/or intracranial arterial vasospasm requiring intraoperative use of in situ nimodipine based on operator's decision, using a propensity score approach. The primary outcome was a modified Rankin Scale (mRS) score of 0-2 at 90 days. Secondary outcomes included excellent outcome (mRS score 0-1), final recanalization, mortality, intracranial hemorrhage and procedural complications. Secondary analyses were performed according to the vasospasm location (intracranial or cervical)., Results: Among 13,678 patients in the registry during the study period, 434 received intra-arterial nimodipine for the treatment of MT-related vasospasm. In the main analysis, comparable odds of favorable outcome were observed, whereas excellent outcome was significantly less frequent in the group with vasospasm requiring nimodipine (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.63-0.97). Perfect recanalization, defined as a final modified Thrombolysis In Cerebral Infarction score of 3 (aOR 0.63, 95% CI 0.42-0.93), was also rarer in the vasospasm group. Intracranial vasospasm treated with nimodipine was significantly associated with worse clinical outcome (aOR 0.64, 95% CI 0.45-0.92), in contrast to the cervical location (aOR 1.37, 95% CI 0.54-3.08)., Conclusion: Arterial vasospasm occurring during the MT procedure and requiring intra-arterial nimodipine administration was associated with worse outcomes, especially in case of intracranial vasospasm. Although this study cannot formally differentiate whether the negative consequences were due to the vasospasm itself, or nimodipine administration or both, there might be an important signal toward a substantial clinical impact of iatrogenic vasospasm during MT., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Contrast-induced nephropathy (CIN) is a potential complication associated with the administration of intravenous contrast agents. The objective of this study was to evaluate the effectiveness of remote ischemic preconditioning (RIPC) and two pharmacological interventions in preventing CIN., Methods: Randomized controlled trials (RCTs) examining the efficacy of RIPC, nicorandil, and trimetazidine in treating CIN were searched within databases such as PubMed, Cochrane Library, Embase, and Web of Science. The primary outcome was the incidence of CIN. The consistency model was used to address heterogeneity and enhance model fit. The assessment of consistency between direct and indirect evidence was conducted through the node-splitting method. Posterior probability estimates and surface under the cumulative ranking area (SUCRA) ranked interventions based on their effectiveness in preventing CIN. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to grade the quality of evidence., Results: Based on hydration therapy, RIPC, nicorandil, and trimetazidine all showed prophylactic effects on CIN compared to control groups. The SUCRA results showed that RIPC (SUCRA = 37.7%, PrBest = 0.4%), nicorandil (SUCRA = 91.2%, PrBest = 74.7%), and trimetazidine (SUCRA = 71.0%, PrBest = 24.9%). However, there were no significant differences between the nicorandil, RIPC, and trimetazidine groups. Subgroup analysis suggested that there was still a protective effect in populations with mean estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m 2 or with a high prevalence of diabetes mellitus., Conclusions: Nicorandil, trimetazidine, and RIPC all showed renal protective effects. Based on hydration, nicorandil, trimetazidine, and RIPC may show better prophylaxis against CIN than hydration alone after intravenous contrast administration.

Purpose: The clinical importance and management of vasospasm as a complication during endovascular stroke treatment (EVT) has not been well studied. We sought to investigate the effect of adding nimodipine to the guiding catheter flush (GCF) to prevent vasospasm during EVT., Methods: This is a single-center retrospective analysis including patients with EVT (stent-retriever and/or distal aspiration) treated for anterior or posterior circulation intracranial vessel occlusion from January 2018 to June 2023. Exclusion criteria were intracranial or extracranial stenosis, intra-arterial alteplase, patient age over 80 years. Study groups were patients with (nimo+) and without (nimo-) nimodipine in the GCF. They were compared for occurrence of vasospasm as primary endpoint and clinical outcome in univariate analysis., Results: 477 patients were included in the analysis (nimo+ n = 94 vs. nimo- n = 383). Nimo+ patients experienced less vasospasm during EVT (e.g. vasospasm in target vessel n (%): nimo- = 113 (29.6) vs. nimo+ = 9 (9.6), p < 0.001; extracranial vasospasm, n (%): nimo- = 68 (17.8) vs. nimo+ = 7 (7.4), p = 0.017). Patients of the two study groups had a comparable clinical outcome (90 day mRS, median (IQR): 3 (1-6) for both groups, p = 0.896). In general, patients with anterior circulation target vessel occlusion (TVO) experienced more vasospasm (anterior circ. TVO 38.7% vs. posterior circ. 7.5%, p = 0.006)., Conclusion: Prophylactic adding of nimodipine reduces the risk of vasospasm during EVT without affecting the clinical outcome. Patients with anterior circulation TVO experienced more vasospasm compared to posterior circulation TVO., Competing Interests: Declarations Conflict of interest L.J. Sommer, J. Jesser, O. Nikoubashman, T.N. Nguyen, J. Pinho, A. Reich, M. Wiesmann and C.S. Weyland declare that they have no competing interests. Ethical standards Informed consent: Written informed consent was waived by the local ethics committee. Ethical approval: Ethical approval for the stroke database was provided by the local ethics committee (Ethikkommission der Medizinischen Fakultät der Universität Aachen; 35/333). Written informed consent was waived in view of the retrospective study design., (© 2024. The Author(s).)

Flap surgery is an integral part of plastic surgery, and ischemia-reperfusion (I/R) injury significantly affects the viability of the flap. Carvedilol (CRV), a nonselective beta-blocker with alpha-1 blocking and antioxidant properties, and known for its potential in reducing I/R damage, was chosen as the active substance for our study. The aim of this study was to investigate the vasodilator and antioxidant effects of CRV on rat inferior epigastric artery skin flap using orally disintegrating tablets (ODTs). The optimized ODT formulation was subjected to in vivo experiments using Sprague-Dawley female rats (n = 24) divided into three groups: Group I (control, I/R), Group II (treatment, I/R + CRV), and Group III (treatment, I/R), I/R + CRV ODT). Reperfusion was then observed following the release of the microclamp from the pedicle, and the flap was then re-adapted to its original position. Control rats were given oral isotonic solution via gavage and were subjected to 8 h of ischemia and 12 h of reperfusion. Group II was given 2 mg/kg CRV oral tablets for 7 days before and after surgery. Group III was given 2 mg/kg/day CRV ODT for the same period. Biopsies were taken from the flap and histopathological and biochemical analyses including superoxide dismutase, glutathionenitric oxide, malondialdehyde, paraoxonase 1, total oxidant, and total antioxidant capacities were performed. This study demonstrates that CRV ODTs significantly increased flap viability by approximately 25% compared to the control group, highlighting their promising therapeutic potential., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Aims: This study evaluated the sex differences of sequential changes in coronary blood flows and microvascular function in patients with suspected angina but with no obstructed coronary arteries., Methods: A total of 202 consecutive patients who experienced chest pain but had no significant coronary artery stenosis and who underwent adenosine stress echocardiography were included in the study. Coronary blood flow (CBF) velocities were measured at 1, 2, and 3 min after adenosine infusion., Results: The mean age was 61 years, and 138 (68%) were women. Approximately 40% of patients had coronary microvascular dysfunction (CMD, coronary flow velocity reserve < 2.3), with women exhibiting higher CMD prevalence. The left ventricular (LV) mass index was similar between men and women, while women exhibited higher baseline rate pressure products (RPP). At baseline, coronary blood flow velocities were similar between the sexes. However, CBF velocities in women gradually increased during the examination; and in men, the increase was abrupt and steep during the early stages of examination (p = 0.015 for interaction between time and sex), even with similar RPP in stress. Coronary flow velocity reserve was steadily lower in women compared to men (1 min, 2.09 ± 0.86 vs 2.44 ± 0.87; 2 min, 2.39 ± 0.72 vs 2.63 ± 0.85; 3 min, 2.45 ± 0.70 vs 2.68 ± 0.73)., Conclusions: In patients with suspected angina but with no obstructed coronary arteries, CMD was especially prevalent among women. Women exhibited higher oxygen consumption, while exhibiting slower and gradual increases in CBF velocities. Conversely, men exhibited faster and steeper increases in CBF velocities even with similar RPP in stress., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests. Ethical approval and consent to participate: This study was fully reviewed and approved by the Ethics Institutional Review Board of Korea University Anam Hospital. Consent for publication: Not applicable., (© 2023. The Author(s).)

Complication after carotid artery revascularization is mainly represented by stroke. Reversible cerebral vasoconstriction syndrome triggering by carotid artery revascularization is exceptional but it is an unrecognized aetiology of stroke. It could be associated with brain edema and henceforth, a posterior reversible encephalopathy syndrome can be confused with post-carotid artery revascularization cerebral hyperperfusion syndrome. We reported three cases about reversible cerebral vasoconstriction syndrome following revascularization therapy whose one had also a posterior reversible encephalopathy syndrome. This complication occurred within two weeks after carotid artery revascularization. All took nimodipine and all had a functional improvement at 3-months follow-up. Reversible cerebral vasoconstriction syndrome with posterior reversible encephalopathy syndrome after carotid artery revascularization may mimic cerebral hyperperfusion syndrome. After a comprehensive review, nineteen cases of reversible cerebral vasoconstriction syndrome post-carotid artery revascularization have been reported in the literature mainly after symptoms. It occurs mainly in women around sixty years of age. The onset is expected four days after revascularization., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The discovery of nitric oxide's role in biological processes like platelet function, vasodilation, cell permeability, and inflammation has advanced our understanding of organic nitrate therapy's hemodynamic and nonhemodynamic effects. Short-term use of organic nitrates prevents left ventricular enlargement and infarct expansion. However, information on their long-term impact on LV remodeling in post-acute cardiac dysfunction patients is limited. In this study, we utilized an innovative active hydrogel with gelatin (Gel)/polyethylene glycol (PEG)/polylactic acid (PLA) encapsulating gold nanoparticles (AuNPs)-based drug delivery system for the sustained release of nitroglycerin (NTG). Gel/PEG/PLA/NTG/AuNPs hydrogel-based system is a non-transplant surgical method that can adhere to the surface of the heart and deliver the drug directly to the epicardium. Cardiac dysfunction was induced by ligating the left anterior descending coronary artery. Echocardiograms were used to study the pre- and post-operative hemodynamics. Hematoxylin and eosin (H&E) and Masson's trichrome stain (MTS) staining revealed that the acute myocardial infarction (AMI) rats' group had irregularly shaped fibers and a lack of transverse striations, whereas Gel/PEG/PLA/NTG/AuNPs hydrogel group showed significant improvement. Rats in the Gel/PEG/PLA hydrogel group demonstrated marked vasodilation, compared to the AMI group. Mechanistically, we determined that hydrogel disrupts the initiation of post-cardiac dysfunction via inhibiting Wnt/β-catenin transcriptional activation. Hence, the Gel/PEG/PLA/NTG/AuNPs hydrogel group effectively protected against ischemic injury and inflammation in AMI, demonstrating a novel method for treating acute cardiac dysfunction., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Identification of the Adamkiewicz artery before aortic surgery is important for preventing postoperative complications due to spinal cord ischemia. The Adamkiewicz artery is difficult to identify due to its small diameter. Nitroglycerin has a vasodilatory effect and is used clinically to improve visualization of blood vessels on coronary computed tomography (CT) angiography. We investigated whether the vasodilatory effect of nitroglycerin could improve the ability to visualize the Adamkiewicz artery., Methods: We extracted 33 cases wherein contrast-enhanced CT images were taken before and after aortic aneurysm surgery. Nitroglycerin was administered for coronary artery evaluation on the preoperative CT. However, no nitroglycerin was administered before the postoperative CT. Aortic contrast-to-noise ratio, CT value, image noise, and diameter of the Adamkiewicz artery and anterior spinal artery were measured. The depiction of the Adamkiewicz artery was graded into four grades and evaluated. These measurements were performed by two independent reviewers., Results: In nitroglycerin-administered cases, the contrast-to-noise ratio and CT values were significantly higher (P < 0.001, P < 0.001, respectively); the Adamkiewicz artery and anterior spinal artery diameters were dilated (P = 0.005, P = 0.001, respectively). The Adamkiewicz artery score also improved significantly (P < 0.001). No significant difference was found in image noise., Conclusion: Nitroglycerin contributed to improving the Adamkiewicz artery's visualization., Competing Interests: Declarations. Ethics approval: The Institutional Review Board approved this retrospective study. Informed consent: The need for informed patient consent was waved. Conflict of interest: We declare that we have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre-specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT-2) was assessed., Methods: RIGHT-2 was a pre-hospital-initiated multicentre randomized sham-controlled blinded-endpoint trial that randomized patients with presumed ultra-acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2)., Results: In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre-morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70-3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09-13.59)., Conclusions: Pre-hospital ultra-acute transdermal GTN did not improve overall functional outcome in patients with investigator-diagnosed TIA compared with sham treatment., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Chronic wounds have a high disease burden and significantly influence patient quality of life. The development of chronic wounds is multifactorial and thus adequate management and care is often difficult to achieve. Chronic diseases, malnutrition, smoking, immune dysregulation, and age contribute to chronic wound development. Treatment options include adequately addressing underlying conditions and selecting appropriate topical preparations which enhance and promote healing of different wounds based on an understanding of wound healing pathophysiology. Puerarin, a naturally occurring flavinoid, may offer therapeutic potential for addressing etiologies as well as managing wound beds due to its anti-inflammatory, anti-oxidative, pro-angiogenic, and anesthetic properties., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Pulmonary hypertension (PH) is a progressive hemodynamic condition associated with significant morbidity and mortality, especially in patients undergoing cardiac surgery. Therefore, the objective of this network meta-analysis (NMA) is to compare the efficacy of various pulmonary vasodilators in perioperative control of PH among patients undergoing mitral valve replacement surgery (MVRS), aiming to address the existing knowledge gap and improve perioperative outcomes., Methods: Electronic databases including PubMed, Cochrane Central Registry of Controlled Trials, Scopus, Embase, and Web of Science (WOS) from inception to 17 September 2024. Only randomized controlled trials (RCTs) evaluating vasodilators in PH patients undergoing MVRS were included. We used netmeta package in RStudio to analyze the outcome data with their corresponding mean difference (MD) and confidence intervals (CI)., Results: Seventeen RCTs including 862 patients were analyzed. Prostacyclin, nitric oxide (NO), and sodium nitroprusside (SN) significantly reduced mean pulmonary arterial pressure with effect sizes [MD, 95% confidence interval (CI)] of (11.77, - 18.78; - 4.76; - 8.3, - 15.9; - 0.6; - 11.02, - 20.1; - 3.8, respectively). While no treatment showed significant efficacy on pulmonary capillary wedge pressure, systolic pulmonary arterial pressure, or heart rate, nitroglycerin, NO, and prostacyclin, showed significant increases in cardiac index with effect sizes (MD, 95% CI) of (1, 0.3; 1.7; 1.2 0.8; 1.6; 1.2 0.8; 1.6, respectively). Additionally, NO, prostacyclin, SN, and nitroglycerin demonstrated significant reductions in systemic vascular resistance (SVR), with effect sizes of. (- 0.54, - 0.82; - 0.26, - 0.37, - 0.65; - 0.09; - 0.47, - 0.77; - 0.16; - 0.14, - 0.24; - 0.03, respectively)., Conclusions: This NMA highlights prostacyclin, nitroglycerin, NO, and SN as consistently effective in improving hemodynamics for patients with PH undergoing MVRS, and provides valuable insights for surgeons to choose the suitable vasodilator for these surgeries. However, limitations and the need for further RCTs are acknowledged., Competing Interests: Declarations. Competing interests: The authors declare that they have no competing interests. Ethics approval: Not applicable Consent to participate: Not applicable Consent for publication: Not applicable Availability of data and material: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Authors’ contribution: A.E. conceived and designed the study, interpreted data, drafted the manuscript, and supervised the entire project; A.M. contributed to the study design, data acquisition, statistical modeling and analysis, interpretation of results, and critically revised the manuscript; A.R. was involved in data extraction, interpretation, and critical revision of the manuscript; N.G.H. assisted with data extraction, statistical analysis, and manuscript drafting; M.S. contributed to literature search, screening, and drafting of the results; S.K.K. assisted in methodological design, quality assessment, and manuscript revisions; B.E.M. participated in statistical analysis, data interpretation, and manuscript revision; A.A.S. contributed to literature review and manuscript preparation; M.N.K. assisted with data collection, quality assessment, and manuscript revisions; A.A.A. was involved in data extraction and screening and contributed to manuscript drafting; L.A.H. contributed to data curation, literature search, and manuscript development; A.Z. assisted with literature search, data analysis, and manuscript feedback; M.A.Z. contributed to quality assessment and analysis refinement; W.A. participated in the writing and revision of the manuscript; S.N. provided critical input on study design and wrote and revised the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work., (© 2024. The Author(s).)

Background: Bolus thermodilution and intravenous adenosine are established methods for coronary microcirculatory assessment. Yet, its adoption remains low, partly due to procedural time and patient discomfort associated with intravenous adenosine. We investigated differences between intracoronary and intravenous adenosine using bolus thermodilution in terms of microcirculatory indices, procedural time, and side effects associated with adenosine in patients with myocardial ischemia and nonobstructive coronary arteries., Methods and Results: In this prospective, observational study, 102 patients with suspected myocardial ischemia and nonobstructive coronary arteries underwent measurements of mean transit time, coronary flow reserve, index of microcirculatory resistance, procedure time and patient tolerability with low-dose intracoronary adenosine, high-dose intracoronary adenosine (HDIC), and intravenous adenosine. HDIC induced greater hyperemia compared with low-dose intracoronary IC adenosine and intravenous adenosine with a shorter hyperemic mean transit time, P <0.0001. Coronary flow reserve was higher and index of microcirculatory resistance lowest with HDIC, compared with low-dose intracoronary IC adenosine and intravenous adenosine, P <0.05. Low coronary flow reserve was downgraded from 21% with intravenous adenosine to 10% with HDIC adenosine ( P =0.031); high index of microcirculatory resistance was downgraded from 23% with intravenous adenosine to 14% with HDIC ( P =0.098). Intracoronary adenosine was associated with lower procedural times ( P <0.0001). More patients experienced chest pain with intravenous adenosine ( P <0.01) and the chest pain intensity was higher compared with intracoronary adenosine ( P <0.0001)., Conclusions: In patients with suspected myocardial ischemia and nonobstructive coronary arteries undergoing coronary microcirculatory assessment with bolus thermodilution, the use of HDIC compared with intravenous adenosine was associated with enhanced induction of hyperemia. The use of intracoronary adenosine allowed for a shorter procedure time and was better tolerated., Registration+: URL: clinicaltrials.gov; Unique Identifier: NCT04827498.

Background: This study investigates the dose-response relationship of acetylcholine (ACh) on healthy human gingival blood flow (GBF). Understanding this dose-response relationship contributes to studying vasodilatory mechanisms in various pathological conditions., Methods: The study involved 22 young healthy men (21 - 32 years) to investigate the dose-response relationship of ACh on GBF. Semi-circular wells were created on the labial surface of the upper right second incisor (FDI #12) and upper left first incisor (FDI #21), including the gingival sulcus, for the application of drugs. ACh-chloride solutions at 0.1, 1, and 10 mg/mL were administered to the gingival sulcus of tooth FDI #12 with a Hamilton syringe. Physiological saline was applied on the contralateral side to FDI #21 as a control. The GBF was measured non-invasively by the laser speckle contrast imaging method in four 1mm high adjacent regions: coronal, midway1, midway2, and apical, and was expressed in a laser speckle perfusion unit (LSPU). After the baseline blood flow recording, ACh doses were applied sequentially, with washout periods in between. Data were statistically analyzed using a linear mixed model., Results: The GBF did not change on the saline site throughout the experiment. The GBF was significantly higher at the coronal region after all ACh doses (baseline: 218±31 LSPU, and 227±38 LSPU p < 0.05, 239±40 LSPU p < 0.001, 291±54 LSPU p < 0.001, respectively) compared to the saline. It was also elevated following 1 and 10 mg/mL at the midway1 (245±48 LSPU, p < 0.05, 293±65 LSPU p < 0.001). At midway2 and apical, only the 10 mg/mL dose was effective (285±71 LSPU, p < 0.001; 302±82 LSPU, p < 0.001)., Conclusions: Our findings suggest a dose-dependent vasodilation to ACh, emphasizing its role in human gingival microcirculation. Only the 10 mg/mL ACh could evoke remote vasodilation 3 mm from the application. The described method could facilitate the investigation of endothelium-dependent vasodilation in disorders affecting microcirculation, such as periodontitis or diabetes., Competing Interests: Declarations Ethics approval and consent to participate Informed consent to participate was obtained from all of the participants in the study. The investigation adhered to the principles outlined in the Declaration of Helsinki. The investigation received ethical approval from the Medical Scientific Council, a specialist authority ethical committee for the Hungarian National Public Health and Medical Officer Service (57734-7/2022/EÜIG). Each participant received written information detailing the measurement process and any potential risks. Consent for publication All participants agreed to the publication of non-identifiable photographs in an open-access journal. The publication does not include any images that could enable the identification of individual participants. The participants have obtained informed consent for the publication of their data. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The accurate assessment of drug concentrations in biodistribution studies is crucial for evaluating the efficacy and toxicity of compounds in drug development. As the concentration of biologics in plasma can be higher than in tissue due to their potentially low volume of distribution, transcardiac perfusion is commonly employed to reduce the influence of excess drugs in residual blood. However, there is a lack of consistency in the literature on the conditions and methods of perfusion. To enhance blood removal during transcardiac perfusion, sodium nitrite (NaNO 2 ), a vasodilator, has been widely used with concentrations up to 5% in publications. However, we found that such high NaNO 2 could disrupt the BBB during perfusion, which should be avoided in experiments. In this study, we examined the impact of various vasodilators on blood-brain barrier integrity and vascular permeability using the ratio of FITC-Dextran to Texas Red-Dextran (FITC/Texas Red). Additionally, we optimized perfusion conditions-including euthanasia method and perfusion flow rate-based on hemoglobin levels and the FITC/Texas Red ratio in tissues. Despite the superiority of NaNO 2 in terms of solubility and cost over other vasodilators, we found that 2% NaNO 2 disrupted blood-brain barrier integrity, significantly altering the FITC/Texas Red ratio. In contrast, 100 mM NaNO 2 did not significantly affect this ratio. Moreover, under Ketamine/Xylazine (Ket/Xyl) anesthesia, which reduced blood clot formation compared to CO 2 euthanasia, 100 mM NaNO 2 achieved the lowest hemoglobin levels in the brain. Compared to other vasodilators and the PBS control group, 100 mM NaNO 2 decreased the tissue/plasma ratio (K p,t ) but not brain/plasma ratio (K p,b ) of hIgG1 and human transferrin. We have developed a method to efficiently evaluate blood-brain barrier integrity during transcardiac perfusion. The combination of Ket/Xyl anesthesia and 100 mM NaNO 2 effectively removes residual blood from tissues without significantly affecting blood vessel permeability.

Background: Access to inhaled nitric oxide (iNO) is limited in low resource settings due to non-availability and high cost. There is a need for research on low-cost alternative therapies for management of persistent pulmonary hypertension of the newborn (PPHN). We aimed to compare oral sildenafil and bosentan as monotherapy in the treatment of neonates with PPHN., Study Design: In this single-centre open-label randomized controlled trial (RCT), term and late preterm neonates with PPHN, defined as pulmonary arterial systolic pressure (PASP) > 35 mmHg and requiring fraction of inspired oxygen (FiO 2 ) > 0.21, were randomized to receive oral sildenafil and bosentan. The primary outcome was reduction of PASP by 25% within 48 h after start of drug., Results: Thirty-six neonates were analyzed (18 in each group). Initial PASPs were similar in both groups. The median (IQR) time for the primary outcome (PASP to reduce by 25% within 48 h) was 36 (24-48) h and 96 (48-120) h in sildenafil and bosentan groups respectively (p = 0.008). There was also a higher need to add other pulmonary vasodilators in bosentan group as compared to sildenafil group (p = 0.006)., Conclusion: Sildenafil was associated with quicker reduction of PASP and FiO 2 in neonates with PPHN, as compared to bosentan. Large multicentre blinded trials to assess efficacy and safety of bosentan in comparison with other pulmonary vasodilators would help to get a clearer understanding of its role in the management of PPHN, particularly for use in resource-limited settings that lack iNO., Clinical Trial Registration: https://ctri.nic.in/Clinicaltrials/rmaindet.php? trialid=63997&EncHid=39716.16132&modid=1&compid=19[CTRI/2022/06/043328]., (© 2024. The Author(s).)

Purpose: Testosterone therapy represents the cornerstone of gender affirming hormone therapy (GAHT) among t-AFAB (transgender Assigned Female At Birth) people. Minoxidil is a vasodilator drug approved for topical use for the treatment of androgenetic alopecia. The aim of the present study was to evaluate the efficacy of topical minoxidil in enhancing beard growth in a group of t-AFAB people on GAHT., Methods: Sixteen t-AFAB individuals with an incomplete beard development, on GAHT for at least 6 months, were enrolled. Topical minoxidil was applied to the interested facial areas. Before starting (T0), after 3 (T3) and 6 (T6) months, we evaluated facial hair growth using the Ferriman-Gallwey modified score (FGm)., Results: Subjects were 26 (2.7) years old and on GAHT for 18.5 [15-54] months; using a paired match evaluation, a statistically significant facial hair growth was observed over time, in particular at T6 (median upper lip FGm 3.5 [3-4] vs 2 [1-2] at T0 and chin FGm 4 [3.25-4] vs 1 [1-2] at T0; p ≤ 0.002). Comparing the minoxidil group with a control group (n = 16) matched for age and BMI who developed a full-grown beard only with GAHT, a logistic multivariable analysis identified hirsutism before GAHT was independently positively associated with the development of a full beard [OR 15.22 (95% CI 1.46-158.82); p = 0.023]., Conclusions: This is the first study demonstrating the efficacy of topical minoxidil in enhancing facial hair growth among t-AFAB people on GAHT. Further studies will be necessary to assess whether the obtained improvements will persist after discontinuing the medication., (© 2024. The Author(s).)

Background: Androgenetic alopecia (AGA) is a prevalent type of hair loss that impacts individuals of both genders. Platelet-rich plasma (PRP) and minoxidil have been employed as therapeutic interventions for AGA, yet the efficacy of their concurrent use remains ambiguous., Objective: To perform a comprehensive review and meta-analysis aimed at evaluating the effectiveness of platelet-rich plasma (PRP) in combination with minoxidil for the treatment of androgenetic alopecia (AGA)., Methods: We conducted a comprehensive search of the databases PubMed, Embase, Web of Science, and Cochrane Library, encompassing their complete records up until December 2023. Eligible studies were randomized controlled trials that compared the combination of PRP and minoxidil with minoxidil or PRP alone in patients with AGA. The primary outcome measure was the change in hair growth as assessed by the hair density or hair thickness. Secondary outcome measures included patient satisfaction, and global photographic assessment., Results: A total of 6 studies involving 343 participants were included in this meta-analysis. The results showed that PRP combined with minoxidil significantly improved hair growth compared to minoxidil or PRP alone. The pooled analysis demonstrated a significant increase in hair density (weighted mean difference [WMD] = 9.14; 95% confidence interval [CI]: 6.57-11.70) and hair diameter (WMD = 4.72; 95% CI 3.21-6.23) in the PRP combined with minoxidil group. Moreover, patients receiving PRP combined with minoxidil reported higher satisfaction rates compared to those using minoxidil or PRP alone., Conclusions: This meta-analysis suggests that PRP combined with minoxidil is an effective treatment for AGA, providing significant improvement in hair growth and patient satisfaction., Level of Evidence Iii: 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 ., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Human and Animal Rights: This article does not contain any studies with human participants or animals performed by any of the authors. Informed Consent: For this type of study, informed consent is not required., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: Focal entrapment of the common fibular (peroneal) nerve (CFN) is the most common nerve entrapment in the lower extremity. Accurate diagnosis can be difficult due to co-existent pathology such as low back pathology. A 1% lidocaine block of CFN is often used to confirm the local entrapment pathology and demonstrate possibility of pain relief. A surprising, unexpected and temporary strengthening of CFN supplied ankle and foot muscles is occasionally produced, termed the Phoenix sign. Aetiology of this phenomenon has been puzzling, but restoration of neural circulation and nutrition via improved local blood flow has been postulated to be responsible., Methods: This is a double-blinded, randomized, prospective controlled trial of 20 patients, comparing 2 vasodilating agents and their ability to produce the Phoenix effect. Ultrasound guided infiltration of 0.3 mL 1% lidocaine or papaverine HCl 10 mg/mL was executed adjacent to CFN. Motor strength pre- infiltration and 4 min post-infiltration were measured for anterior compartment muscles utilizing MRC manual motor testing reported on a 0-5 scale. The extensor hallucis longus (EHL) muscle proved to be the most significant., Results: Average motor strength of the EHL improved from 2.2 (+/-0.40) to 4.9 (+/-0.32).) in the lidocaine group. In the papaverine group, pre-infiltration EHL motor strength averaging 2.1 (+/-0.93) improved to 4.4 (+/- 1.01) post-infiltration. Papaverine and lidocaine produced similar statistically significant increases in muscle strength (p = < 0.05)., Conclusion: There was no difference between small local infiltrations of lidocaine or papaverine in production of increased anterior compartment EHL motor strength. It is most likely that the Phoenix Effect is explained by temporary local improvements in the microcirculation of the CFN vasa nervorum., Trial Registration: NCT06637046 10/10/2024 Retrospectively registered., (© 2024. The Author(s).)

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is a major contributor to mortality worldwide, with delayed cerebral ischaemia (DCI) contributing significantly to morbidity in these patients. There are limited evidence-based therapies for DCI. A 2012 case series first recommended the use of intravenous (IV) milrinone in this patient population, stating the need for formal prospective trials. However, uptake of this therapy into clinical practice has proceeded without adequate studies for efficacy and safety., Methods: We sought to determine the effect of IV milrinone on DCI in patients with aSAH in terms of functional outcome through a systematic review using Embase, MEDLINE, and Cochrane Library databases. Quality assessment was performed using MINORS criteria., Results: A total of 2429 studies were screened, with ten studies included in the review. Of these, no randomized trials were identified. Three observational comparative studies were included, and the remaining seven studies were non-comparative in nature, and mainly retrospective. Overall, the quality of evidence for non-comparative studies was poor., Conclusions: This study reveals a paucity of evidence in the literature and highlights the need for high-quality randomized trials to investigate the safety and efficacy of IV milrinone, a commonly utilized treatment in critically ill aSAH patients with DCI. Ultimately, without evidence of efficacy and absence of harm, we caution continued use of intravenous milrinone for the treatment of DCI.

Objectives: We retrospectively analyzed the usefulness and safety of intracoronary acetylcholine (ACh) 200 μg into the left coronary artery (LCA) as vasoreactivity testing compared with intracoronary ACh 100 μg., Methods: We recruited 1433 patients who had angina-like chest pain and intracoronary ACh testing in the LCA, including 1234 patients with a maximum ACh 100 μg and 199 patients with a maximum ACh 200 μg. ACh was injected in incremental doses of 20/50/100/200 μg into the LCA. Positive spasm was defined as ≥ 90% stenosis, usual chest pain, and ischemic electrocardiogram (ECG) changes., Results: The incidence of coronary constriction ≥ 90%, usual chest pain, and ischemic ECG changes with a maximum ACh of 100 μg was markedly higher than that with a maximum ACh of 200 μg. The frequency of unusual chest pain in patients with a maximum ACh of 200 μg was higher than that in those with a maximum ACh of 100 μg (13% vs. 3%, p < 0.001). In patients with rest angina, positive spasm of maximum ACh 100 μg was significantly higher than that of maximum ACh 200 μg, whereas there was no difference regarding positive spasm in patients with atypical chest pain between the two ACh doses. Major complications (1.38% vs. 1.51%, p = 0.8565) and the occurrence of paroxysmal atrial fibrillation (1.81% vs. 2.63%, p = 0.6307) during ACh testing in the LCA were not different between the two maximum ACH doses., Conclusions: Intracoronary ACh 200 μg into the LCA is clinically useful and safe for vasoreactivity testing when intracoronary ACh 100 μg dose not provoke spasms., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition in newborns admitted to the neonatal intensive care units (NICUs). PPHN has still a high mortality and morbidity. Inhaled nitric oxide (iNO) is the first line vasodilator therapy for PPHN in high income countries. In low-to-middle income countries (LMICs), availability of iNO remains scarce and expensive. The purpose of this scoping review was to evaluate the current existing literature for milrinone therapy in PPHN and to identify the knowledge gaps in milrinone use in infants with PPHN. The available evidence for milrinone remains limited both as monotherapy and as an adjuvant to iNO. The studies were heterogeneous, conducted in different settings, with different populations and more importantly the endpoints of these trials were short-term outcomes such as changes in oxygenation and blood pressure. Large prospective studies investigating long-term outcomes, mortality, and the need for Extracorporeal membrane oxygenation (ECMO) are warranted. Randomized controlled trials with milrinone as monotherapy are needed in LMICs where iNO availability remains limited. IMPACT: Milrinone has a potential role in the management of PPHN both as an adjuvant to iNO as well as a monotherapy. This scoping review identified the problems existing in the published literature on milrinone and the barriers to generalization of these results. Multi-centre randomized controlled trials on milrinone, especially involving centers from low- and middle-income countries are needed, where it can be evaluated as first-line pulmonary vasodilator therapy., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Pulmonary hypertension is a pathophysiologic manifestation of a heterogeneous group of diseases, with the main pathophysiologic mechanisms being persistent pulmonary vasoconstriction and irreversible vascular remodeling. The impact significantly affects the prognosis of patients with pulmonary hypertension. If it is not treated and intervened in time, it may lead to right ventricular failure and further endanger the patient's life. Within the past decade or so, nebulized inhalation therapy is considered to have advantages in the treatment of pulmonary hypertension as a safe, limited, and rapid therapy, for example, inhaled vasodilators (prostate analogs, nitroglycerin, carbon monoxide analogs sildenafil, and nitroprusside), inhaled anti-inflammatory and antiproliferative agents (simvastatin, and selatinib), and inhaled peroxides (levocetirizine) have been recognized as emerging therapeutic approaches in the treatment of pulmonary hypertension as emerging therapeutic approaches. Therefore, this article provides a brief review of recent advances in the potential of nebulized inhaled vasodilators, anti-inflammatory and antiproliferative agents, and anti-peroxides for the treatment of pulmonary hypertension, with the aim of providing different therapeutic options for the treatment of pulmonary hypertension, enhancing the quality of survival, alleviating symptoms, and improving the prognosis of patients with this condition., 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 © 2024 Elsevier Inc. All rights reserved.)

Aim: The purpose of this study is to identify the clinical outcomes of patients during acute phase of Peyronie's disease (PD) treated with daily Tadalafil 5 mg associated with non-surgical treatments such as intra-plaque verapamil injections (IVI), vacuum erection devices (VED) or extra corporeal shockwave therapy (ESWT)., Methods: 445 patients with PD in acute stage were treated as it follows: Group 1(G1) 117 men with only Tadalafil 5 mg once a day for 3 months; Group 2(G2) 106 men with IVI plus Tadalafil 5 mg for a period of 12 weeks; Group 3(G3) 124 men that received ESWT for 6 weeks plus Tadalafil with the same protocol of G1; Group 4(G4) 98 men with VED plus Tadalafil 5 mg for 3 months. There were assessed at baseline and follow-up: Erectile dysfunction (ED), presence and severity of painful erections, penile plaque size and penile curvature degree. The results were evaluated at baseline and 3,6,12 months., Results: Not statistically significant differences emerged between the two groups at baseline, except for higher presence of patients with ED in in G3(7.4%) vs other groups(p < 0.001). Three months after the treatment in G3 men had a significant reduction of penile curvature degrees after 1 year by treatments, whereas pain in an erection or during intercourse was resolved completely in 75% of the patients., Conclusions: Our study highlights that multimodal therapy has beneficial long-term effects not only in the decrease of ED symptoms, but also in the relief of the penile curvature and the quality of life., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

After Fontan operation, decreased venous capacitance and venoconstriction are adaptive mechanisms to maintain venous return and cardiac output. The consequent higher venous pressure may adversely impact end-organ function, exercise capacity and result in worse clinical outcomes. This pilot study evaluated the safety and effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after 4 weeks of therapeutic treatment with ISDN. Primary aims were to assess the safety of ISDN and the effect on maximal exercise. We also aimed to evaluate the effect of ISDN on ultrasound-assessed liver stiffness, markers of submaximal exercise, and PVP at rest and peak exercise. Repeated measures t-tests were used to assess change in variables of interest in response to ISDN. Mean age was 23.5 ± 9.2 years (range 11.2-39.0 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO 2 (1401 ± 428 to 1428 ± 436 mL/min, p = 0.128), but VO 2 at the anaerobic threshold increased (1087 ± 313 to 1115 ± 302 mL/min, p = 0.03). ISDN was also associated with a lower peak exercise PVP (22.5 ± 4.5 to 20.6 ± 3.0 mmHg, p = 0.015). Liver stiffness was lower with ISDN, though the difference was not statistically significant (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p = 0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Treatment with ISDN for 4 weeks is well-tolerated in patients with a Fontan circulation. ISDN is associated with an increase in VO 2 at anaerobic threshold, lower peak PVP, and a trend toward lower liver stiffness. Larger, longer duration studies will be necessary to define the impact of ISDN on clinical outcomes in the Fontan circulation.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT04297241., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nitroglycerin has been of considerable interest as a treatment for ischaemic stroke. Recent clinical trials with nitroglycerin transdermal patches during the acute phase of stroke failed to improve functional outcomes. Systematic review and meta-analysis of the effectiveness of nitroglycerin in preclinical models of ischaemic stroke has not previously been reported, despite several clinical trials., Objective: To conduct a systematic review and meta-analysis of preclinical evidence regarding the effect of nitroglycerin on infarct volume in animal models of ischaemic stroke., Summary of Review: The protocol was registered in PROSPERO (CRD42023432644). Our search identified 238 publications. Three publications met inclusion criteria (including 10 comparisons of infarct size). Study quality was modest (median 6 out of 9), with no evidence of publication bias. Nitroglycerin did not significantly reduce infarct volume (NMD point estimate 20.2 % reduction, 95 % CI -1.52-52.7 %, p = 0.068). Subgroup analysis suggested greater efficacy of nitroglycerin with direct intracarotid administration to the ischaemic territory at the time of reperfusion., Conclusions: A small number of studies (three) were included in this review. Overall, nitroglycerin did not reduce infarct volume in experimental stroke models. However, nitroglycerin may be of benefit when administered directly into the ischaemic territory. Given nitroglycerin's short half-life, we propose this route may minimise harmful reduction of cerebral perfusion pressure resulting from hypotension following systemic administration., Competing Interests: Declaration of competing interest D.J.B. is an inventor; and The University of Newcastle is applicant for the patent: Stroke Treatment (WO 2022/072,348), related to the delivery of nitrates to the brain during stroke., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Erectile dysfunction (ED) is a common issue that affects older men and is often associated with various health conditions. Phosphodiesterase 5 inhibitors are commonly used to treat ED; however, their effectiveness may be limited, or the medication may be contraindicated. Therefore, topical gels are being developed as an alternative option for the pharmacologic treatment of ED., Objectives: This review aimed to provide an overview of the efficacy and safety of topical agents for the treatment of ED., Methods: The PubMed, Cochrane, Embase, and Web of Science databases were searched. Articles were included that investigated ED and topical agents operating through the skin of the penis, evaluated the effectiveness of the treatment, and involved patients randomized into groups., Results: Topical alprostadil, glyceryl trinitrate (MED2005), and an over-the-counter formulation (MED3000) were used as alternative treatments for ED in 7 articles, which included 3475 patients. Topical alprostadil induced an erection in 67% to 75% of patients. Adequate erections for vaginal penetration were reported in 38.7% of the alprostadil-treated patients vs 6.9% of the placebo-treated patients. Topical alprostadil significantly and dose dependently improved the total score change on the International Index of Erectile Function as compared with the placebo. MED2005 exhibited a rapid onset of action, with nearly 70% effectiveness within 10 minutes. MED3000 met the minimal clinically important difference threshold of a 4-point increase on the erectile function domain of the International Index of Erectile Function, with an improvement of 5.73 points in 24 weeks. Topical therapy for ED also had acceptable safety profiles., Conclusion: Topical agents via various mechanisms are effective and well-tolerated treatments for ED. A fast-acting drug that significantly reduces side effects as compared with other options has been discovered. However, its efficacy relative to current first-line therapies remains unclear. Topical agents present a viable therapeutic alternative for individuals who are unable or unwilling to take oral phosphodiesterase 5 inhibitors., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Erectile dysfunction is among the most prevalent urologic issues affecting men globally and is characterized by a high incidence rate. This condition significantly affects the quality of life of patients and their sexual partners., Objectives: Due to the interactions, contraindications, and side effects associated with systemic drugs, recent research has increasingly focused on topical and transdermal medications for the treatment of erectile dysfunction., Methods: Based on previous studies, this article examines papaverine in terms of local effectiveness, methods of increasing therapeutic efficiency, possible local side effects, and evaluation of its various formulations., Results: Among these approaches, notable strategies include using novel formulations and nanoformulations as compared with classic ones, employing permeation enhancers, and combining treatments with other oral and topical drugs with synergistic mechanisms. These methods aim to improve transdermal papaverine's bioavailability and therapeutic efficacy while minimizing side effects and enhancing patient compliance., Conclusion: Transdermal papaverine may not be as effective as its injectable form, but the treatment path is more pleasant, with less pain and fewer side effects for patients. For this reason, using solutions that remove the penile skin and fascial absorption barrier can be very effective., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Ischemic stroke disrupts functional connectivity within the brain's resting-state networks (RSNs), impacting recovery. This study evaluates the effects of norepinephrine and hydralazine (NEH), a cerebral perfusion augmentation therapy, on RSN integrity in a hyperacute canine stroke model., Materials and Methods: Fifteen adult purpose-bred mongrel canines, divided into treatment and control (natural history) groups, underwent endovascular induction of acute middle cerebral artery occlusion (MCAO). Postocclusion, the treatment group received intra-arterial norepinephrine (0.1-1.52 µg/kg/min, adjusted for 25-45 mm Hg above baseline mean arterial pressure) and hydralazine (20 mg). Resting-state fMRI (rs-fMRI) data were acquired with a 3T scanner by using a blood oxygen level dependent-EPI sequence (TR/TE = 1400 ms/20 ms, 2.5 mm slices, 300 temporal positions). Preprocessing included motion correction, spatial smoothing (2.5 mm full width at half maximum), and high-pass filtering (0.01 Hz cutoff). Functional connectivity within RSNs were analyzed through group-level independent component analysis and weighted whole-brain ROI-to-ROI connectome, pre- and post-MCAO., Results: NEH therapy significantly maintained connectivity post-MCAO in the higher-order visual and parietal RSNs, as evidenced by thresholded statistical mapping (threshold-free cluster enhancement P corr > .95). However, this preservation was network-dependent, with no significant ( P corr < .95) changes in the primary visual and sensorimotor networks., Conclusions: NEH demonstrates potential as a proof-of-concept therapy for maintaining RSN functional connectivity after ischemic stroke, emphasizing the therapeutic promise of perfusion augmentation. These insights reinforce the role of functional connectivity as a measurable end point for stroke intervention efficacy, suggesting clinical translatability for patients with insufficient collateral circulation., (© 2024 by American Journal of Neuroradiology.)

Objectives: To investigate if daily treatment with glyceryl trinitrate (GTN) ointment, over 24 weeks combined with a 12-week eccentric exercise programme is more effective for chronic mid-portion Achilles tendinopathy than placebo ointment and eccentric exercise., Methods: This was a single-site randomised double-blind placebo-controlled trial at an acute hospital, Dublin, Ireland. Patients with chronic mid-portion Achilles tendinopathy were randomised to either 24 weeks of daily GTN ointment or placebo ointment. Both groups received an identical 12-week eccentric exercise programme. The primary outcome measure was the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire at 24 weeks, which measures pain, function and activity. Secondary outcomes included pain severity, self-reported physical function, calf muscle function, pressure pain thresholds and ultrasound changes. Statistical analyses were performed according to intention-to-treat principles., Results: 76 patients (30 women; 46 men, mean age±SD, 45.6±8.2 years) were recruited for the trial. Significant improvements in VISA-A scores occurred in both groups at 6-week, 12-week and 24-week follow-up. The increase was not significantly different between groups, adjusted mean between-group difference from baseline to week 6, -1.33 (95% CI -6.96 to 4.31); week 12, -1.25 (95% CI -8.0 to 5.49) and week 24, -3.8 (95% CI -10.6 to 3.0); negative values favour GTN. There was no significant between-group difference in any of the secondary outcome measures at 6, 12 and 24 weeks., Conclusions: Adding daily GTN ointment over 24 weeks to a 12-week eccentric exercise programme did not improve pain, function and activity level in patients with chronic mid-portion Achilles tendinopathy when compared with placebo ointment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Iatrogenic acute limb ischaemia (ALI) in neonates is a rare but severe event with potentially deleterious outcomes. In the neonatal intensive care unit, this risk is increased due to the high rate of catheterisation procedures. ALI management includes pharmacological and non-pharmacological interventions, but no commonly accepted clinical guidelines are available. In the present case, a peripheral catheter was erroneously placed in the left brachial artery of a term infant, causing blockage and ischaemia in the limb. The catheter was immediately removed, the affected limb was elevated and warm compresses were applied to the contralateral limb. The patient was treated with fresh frozen plasma, heparin, iloprost and topical nitroglycerin. Three nerve block procedures were also performed. At 6-8 days of age, significant improvement was observed. The patient was discharged at 17 days of age with near-complete resolution, whereas complete resolution was observed at postdischarge follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Kounis syndrome is defined as the concurrence of acute coronary syndromes in the setting of allergic or anaphylactic reactions. It primarily affects men aged 40-70 years and is often associated with chest pain. This syndrome is often unrecognized and undiagnosed in clinical practice due to a low level of awareness. Herein, we present a case of type I Kounis syndrome in a young woman without chest pain., Case Presentation: A 28-year-old Japanese woman with a history of atopic dermatitis received a glycyrrhizin, glutathione, and neurotropin preparation (a preparation of inflamed skin extract from rabbits inoculated with vaccinia virus) at a dermatology clinic to treat pruritus caused by atopic dermatitis. Immediately after the administration, the patient developed abdominal pain and generalized body wheals. The patient was diagnosed with anaphylaxis and was transported to our hospital. She had no chest pain on arrival at our hospital; however, a 12-lead electrocardiogram showed ST elevation in leads I, aVL, V2, and V3, and an echocardiogram showed decreased wall motion in the anterior and lateral walls of the left ventricle. Sublingual nitroglycerin administration improved ST-segment elevation and left ventricular wall motion abnormalities. The patient underwent emergency coronary angiography, which revealed no significant stenosis, and was diagnosed with type I Kounis syndrome., Conclusion: Kounis syndrome without chest pain is rare in young women. Since it can be fatal in cases with severe allergic symptoms such as anaphylaxis, the possibility of concurrent acute coronary syndrome should be considered when treating systemic allergic reactions, regardless of age, sex, or the presence or absence of chest symptoms., (© 2024. The Author(s).)