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Bioactive Materials Sep 2024Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented...
Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases.
Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) and cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles and an unselective β-adrenergic receptor blocker (propranolol). The two components (i.e., fibrin and alginate) can respond to two triggers (thrombin and Ca, respectively) in postoperative bleeding to gelate, shaping into an interpenetrating network (IPN) featuring high strength. The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function and hamper cytotoxic T cell exhaustion. The reprogrammed TME significantly suppress locally residual and distant tumors, induce strong immune memory effects and thus inhibit lung metastasis. Thus, targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.
PubMed: 38783926
DOI: 10.1016/j.bioactmat.2024.05.022 -
Journal of Clinical Medicine Jun 2024Most recent clinical practice guidelines addressing the management of infantile hemangiomas (IHs) recommend oral propranolol, a non-selective beta-adrenergic...
Most recent clinical practice guidelines addressing the management of infantile hemangiomas (IHs) recommend oral propranolol, a non-selective beta-adrenergic antagonist, as first-line treatment. However, few reports have provided continuous follow-up data regarding cardiac evaluations. Sixty-four patients diagnosed with IHs and treated with oral propranolol before 2 years of age at the Department of Pediatrics, Kangbuk Samsung Hospital (Seoul, Republic of Korea), with regular examinations between 2017 and 2021, were included. Cardiac evaluations, including electrocardiography, Holter monitoring, chest X-ray, and echocardiography, were performed. Sixty-four patients with IHs successfully underwent continuous follow-up cardiac evaluations. The median age at diagnosis was 2 weeks (1 day to 34.3 weeks). The median age at treatment initiation was 13.6 weeks (2.4-87.9 weeks), the mean longitudinal diameter of hemangioma at diagnosis was 2.8 ± 2.1 cm (0.3-12.0 cm), and the mean percentage of size decrease after 1 year of oral propranolol treatment was 71.8%. None of the 64 patients experienced severe adverse side effects during propranolol treatment. There was no statistically significant differences in echocardiographic function and electrocardiographic data after treatment. Propranolol treatment ≥6 months was effective and safe without significant cardiac toxicity in the treatment of patients with infantile hemangiomas.
PubMed: 38893043
DOI: 10.3390/jcm13113332 -
Journal of Ophthalmic & Vision Research 2024Recent studies have reported the promising effect of intravitreal propranolol on retinal neovascularization. However, rapid clearance and short half-life of the drug in...
PURPOSE
Recent studies have reported the promising effect of intravitreal propranolol on retinal neovascularization. However, rapid clearance and short half-life of the drug in the vitreous are the main drawbacks of this therapeutic approach. This study investigates the extension of the residence time of propranolol in the vitreous by polymeric nanoparticles (NPs) with the prospect of improving choroidal neovascularization treatment.
METHODS
The poly (lactic-co-glycolic) acid (PLGA) NPs were fabricated by a modified double emulsion solvent evaporation method and the obtained NPs were characterized for their size, poly dispersity index (PDI), and surface image. The release, cell cytotoxicity, and uptake of NPs were also evaluated. To investigate the effect of the vitreous pharmacokinetic drug loaded NPs versus that of the free propranolol, they were intravitreally injected into the rabbits' eyes and the drug vitreous concentrations in defined intervals were analyzed by high performance liquid chromatography (HPLC).
RESULTS
The spherical NPs with about 230 nm size, and almost 10% drug loading were obtained. Based on the 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium Bromide (MTT) outcomes, 30 µg/ml of propranolol was considered as the guide dosage in the intravitreal injection. Confocal microscopy images verified the presence of labeled NPs in the posterior segment after five days of receiving the injection. assay revealed that the vanishing rate of propranolol in rabbits treated with propranolol NPs was reduced at twice the rate as compared to that of the vanishing rate experienced with only the free drug.
CONCLUSION
PLGA NPs can prolong the existence of propranolol in both vitreous and posterior ocular tissues, and thus, may provide an effective approach in treatment of posterior segment neovascularization.
PubMed: 38638633
DOI: 10.18502/jovr.v19i1.15436 -
The Lancet. Digital Health Oct 2023Diagnosis of skin cancer requires medical expertise, which is scarce. Mobile phone-powered artificial intelligence (AI) could aid diagnosis, but it is unclear how this... (Clinical Trial)
Clinical Trial
Comparison of humans versus mobile phone-powered artificial intelligence for the diagnosis and management of pigmented skin cancer in secondary care: a multicentre, prospective, diagnostic, clinical trial.
BACKGROUND
Diagnosis of skin cancer requires medical expertise, which is scarce. Mobile phone-powered artificial intelligence (AI) could aid diagnosis, but it is unclear how this technology performs in a clinical scenario. Our primary aim was to test in the clinic whether there was equivalence between AI algorithms and clinicians for the diagnosis and management of pigmented skin lesions.
METHODS
In this multicentre, prospective, diagnostic, clinical trial, we included specialist and novice clinicians and patients from two tertiary referral centres in Australia and Austria. Specialists had a specialist medical qualification related to diagnosing and managing pigmented skin lesions, whereas novices were dermatology junior doctors or registrars in trainee positions who had experience in examining and managing these lesions. Eligible patients were aged 18-99 years and had a modified Fitzpatrick I-III skin type; those in the diagnostic trial were undergoing routine excision or biopsy of one or more suspicious pigmented skin lesions bigger than 3 mm in the longest diameter, and those in the management trial had baseline total-body photographs taken within 1-4 years. We used two mobile phone-powered AI instruments incorporating a simple optical attachment: a new 7-class AI algorithm and the International Skin Imaging Collaboration (ISIC) AI algorithm, which was previously tested in a large online reader study. The reference standard for excised lesions in the diagnostic trial was histopathological examination; in the management trial, the reference standard was a descending hierarchy based on histopathological examination, comparison of baseline total-body photographs, digital monitoring, and telediagnosis. The main outcome of this study was to compare the accuracy of expert and novice diagnostic and management decisions with the two AI instruments. Possible decisions in the management trial were dismissal, biopsy, or 3-month monitoring. Decisions to monitor were considered equivalent to dismissal (scenario A) or biopsy of malignant lesions (scenario B). The trial was registered at the Australian New Zealand Clinical Trials Registry ACTRN12620000695909 (Universal trial number U1111-1251-8995).
FINDINGS
The diagnostic study included 172 suspicious pigmented lesions (84 malignant) from 124 patients and the management study included 5696 pigmented lesions (18 malignant) from the whole body of 66 high-risk patients. The diagnoses of the 7-class AI algorithm were equivalent to the specialists' diagnoses (absolute accuracy difference 1·2% [95% CI -6·9 to 9·2]) and significantly superior to the novices' ones (21·5% [13·1 to 30·0]). The diagnoses of the ISIC AI algorithm were significantly inferior to the specialists' diagnoses (-11·6% [-20·3 to -3·0]) but significantly superior to the novices' ones (8·7% [-0·5 to 18·0]). The best 7-class management AI was significantly inferior to specialists' management (absolute accuracy difference in correct management decision -0·5% [95% CI -0·7 to -0·2] in scenario A and -0·4% [-0·8 to -0·05] in scenario B). Compared with the novices' management, the 7-class management AI was significantly inferior (-0·4% [-0·6 to -0·2]) in scenario A but significantly superior (0·4% [0·0 to 0·9]) in scenario B.
INTERPRETATION
The mobile phone-powered AI technology is simple, practical, and accurate for the diagnosis of suspicious pigmented skin cancer in patients presenting to a specialist setting, although its usage for management decisions requires more careful execution. An AI algorithm that was superior in experimental studies was significantly inferior to specialists in a real-world scenario, suggesting that caution is needed when extrapolating results of experimental studies to clinical practice.
FUNDING
MetaOptima Technology.
Topics: Humans; Artificial Intelligence; Australia; Cell Phone; Melanoma; Prospective Studies; Secondary Care; Sensitivity and Specificity; Skin Neoplasms
PubMed: 37775188
DOI: 10.1016/S2589-7500(23)00130-9 -
World Journal of Gastrointestinal... Mar 2024In this editorial we comment on the in-press article in the about the role of computed tomography (CT) for the prediction of esophageal variceal bleeding. The mortality...
In this editorial we comment on the in-press article in the about the role of computed tomography (CT) for the prediction of esophageal variceal bleeding. The mortality and morbidity are much increased in patients with chronic liver diseases when complicated with variceal bleeding. Predicting the patient at a risk of bleeding is extremely important and receives a great deal of attention, paving the way for primary prophylaxis either using medical treatment including carvedilol or propranolol, or endoscopic band ligation. Endoscopic examination and the hepatic venous pressure gradient are the gold standards in the diagnosis and prediction of variceal bleeding. Several non-invasive laboratory and radiological examinations are used for the prediction of variceal bleeding. The contrast-enhanced multislice CT is a widely used non-invasive, radiological examination that has many advantages. In this editorial we briefly comment on the current research regarding the use of CT as a non-invasive tool in predicting the variceal bleeding.
PubMed: 38577645
DOI: 10.4253/wjge.v16.i3.98 -
Frontiers in Neurology 2023Given the substantial disease burden, appropriate and effective management of migraine is a public health priority. To gain insights into real-world migraine management...
OBJECTIVES
Given the substantial disease burden, appropriate and effective management of migraine is a public health priority. To gain insights into real-world migraine management practices in Taiwan, current treatment patterns, costs, and health care resource use were assessed.
METHODS
This was a retrospective, longitudinal study using the Taiwan National Health Insurance Research Database. Included patients had an initial diagnosis of migraine (defined using International Classification of Diseases codes) between 1 January 2013 and 31 December 2017. Data analyzed included demographics; the use, number, and type of acute and preventive medications; and drug and medical services costs. Data were stratified according to migraine type (chronic [CM] or episodic [EM] migraine).
RESULTS
A total of 312,718 patients were included in the analyses: 53,992 (17.3%) had CM and 258,726 (82.7%) had EM. Most patients (81.7%) had used acute and/or preventive medications; acute medications used more frequently than preventive medications (78.0% vs. 20.2%). Acute medications were used by 81.6 and 77.3% of patients with CM and EM, respectively. Commonly used acute medications were acetaminophen (68.8%), ergots (49.4%), and non-steroidal anti-inflammatory drugs (38.4%); the use of triptans (6.0%), tramadol (3.1%), and other opioids (0.2%) was less common. A total of 28.6 and 18.5% of patients with CM and EM, respectively, used preventive medications. Flunarizine (68.9%), propranolol (40.7%), and topiramate (16.0%) were the most commonly used preventive medications. Most patients had used 1-2 acute or preventive medications, with the use of ≥3 acute or preventive medications more common in patients with CM than EM. Average total medical cost was 4,169 New Taiwan Dollars (NTDs) per CM patient and 2,928 NTDs per EM patient, with CM patients having higher costs associated with medical service utilization and acute medication use.
CONCLUSION
These real-world data suggest unmet needs for Taiwanese patients with migraine, including under-utilization of preventive medications and greater costs and health care resource use for patients with CM versus EM. These findings provide important information on treatment patterns, cost, and health care resource use for patients with migraine in Taiwan.
PubMed: 37654430
DOI: 10.3389/fneur.2023.1222912 -
Iranian Journal of Child Neurology 2023Epidemiologic studies point to an increased prevalence of migraine in children in recent decades. Migraine treatment involves acute and prophylactic therapy. Recently,...
OBJECTIVES
Epidemiologic studies point to an increased prevalence of migraine in children in recent decades. Migraine treatment involves acute and prophylactic therapy. Recently, such anti-epileptic drugs as Levetiracetam have been used to treat adult migraines. The present study aimed to compare the efficacy of Levetiracetam, Sodium Valproate, and Propranolol in preventing migraine headaches in children.
MATERIALS & METHODS
In this clinical trial, children with migraine were randomly divided into three groups. Each group consisted of 13 children. Two groups were treated with Propranolol and Sodium Valproate, respectively. Another group (the case) was treated with Levetiracetam. The patients were assessed based on headache score, PedMIDAS, and headache frequency before and three months after the intervention. Finally, the data was analyzed using descriptive and analytical statistical methods.
RESULTS
Levetiracetam significantly reduced the headache severity (P=0.026), frequency (P=0.024), and PedMIDAS score (P=0.001) in children with migraine. However, no significant difference was found between the three groups. The percentage of patients who experienced pain relief was detected as 69.24%, 92.31%, and 30.76% in the Propranolol, Sodium Valproate, and Levetiracetam groups, respectively.
CONCLUSION
This study concluded that Levetiracetam can be used as a migraine prophylaxis drug in children.
PubMed: 38074934
DOI: 10.22037/ijcn.v17i1.21330 -
European Journal of Pharmacology Dec 2023Recent studies suggest that lower urinary tract dysfunction may arise due to changes in local perfusion. Phosphodiesterase-5 inhibitors can improve urinary bladder blood...
Recent studies suggest that lower urinary tract dysfunction may arise due to changes in local perfusion. Phosphodiesterase-5 inhibitors can improve urinary bladder blood flow, although the local mechanisms have not been fully elucidated. The aim was to pharmacologically characterise the vascular supply to the bladder and determine the mechanisms underlying the effects of the phosphodiesterase-5 inhibitors tadalafil and sildenafil. Responses of isolated rings of porcine superior vesical arteries to electrical field stimulation (EFS) were measured in the absence and presence of inhibitors of key neurotransmitter systems. Vasodilation responses to nitric oxide (NO) donors were also recorded, and the effects of phosphodiesterase-5 inhibitors on all responses determined. EFS caused biphasic responses with an initial vasoconstriction and a slower developing vasodilation. Vasoconstriction was mediated by ATP (55%) and noradrenaline (45%) release, whilst vasodilation was reduced by L-NNA (100 μM) (80%) and propranolol (1 μM) (20%). The nitrergic component was inhibited (81%) by L-NPA, a selective inhibitor of neuronal nitric oxide synthase (nNOS). Endothelial removal did not affect vasodilation. Tadalafil and sildenafil depressed noradrenaline-evoked vasoconstriction (by 26.8% and 35.5% respectively, P < 0.01), enhanced vasodilation to EFS (by 27.8% and 51.8% respectively, p < 0.01) and enhanced responses to NO donors nitroprusside, SIN-1, and SNAP, increasing pIC values (P < 0.01), without affecting maximal responses. In conclusion, neuronal NOS has a predominant role in regulating vascular tone of the porcine superior vesical artery and potentiation of nNO-mediated vasodilation is the primary mechanism underlying effects of phosphodiesterase-5 inhibitors in the bladder vasculature.
Topics: Animals; Swine; Sildenafil Citrate; Tadalafil; Phosphodiesterase 5 Inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 5; Urinary Bladder; Vasodilation; Norepinephrine; Nitric Oxide
PubMed: 37925131
DOI: 10.1016/j.ejphar.2023.176152 -
Journal of the Academy of... 2024Acute disturbance is a broad term referring to escalating behaviors secondary to a change in mental state, such as agitation, aggression, and violence. Available... (Review)
Review
Effectiveness and Safety of Intravenous Medications for the Management of Acute Disturbance (Agitation and Other Escalating Behaviors): A Systematic Review of Prospective Interventional Studies.
Acute disturbance is a broad term referring to escalating behaviors secondary to a change in mental state, such as agitation, aggression, and violence. Available management options include de-escalation techniques and rapid tranquilization, mostly via parenteral formulations of medication. While the intramuscular route has been extensively studied in a range of clinical settings, the same cannot be said for intravenous (IV); this is despite potential benefits, including rapid absorption and complete bioavailability. This systematic review analyzed existing evidence for effectiveness and safety of IV medication for management of acute disturbances. It followed a preregistered protocol (PROSPERO identification CRD42020216456) and is reported following the guidelines set by Preferred Reporting Items for Systematic Review and Meta-Analysis. APA PsycINFO, MEDLINE, and EMBASE databases were searched for eligible interventional studies up until May 30th, 2023. Data analysis was limited to narrative synthesis since primary outcome measures varied significantly. Results showed mixed but positive results for the effectiveness of IV dexmedetomidine, lorazepam, droperidol, and olanzapine. Evidence was more limited for IV haloperidol, ketamine, midazolam, chlorpromazine, and valproate. There was no eligible data on the use of IV clonazepam, clonidine, diazepam, diphenhydramine, propranolol, ziprasidone, fluphenazine, carbamazepine, or promethazine. Most studies reported favorable adverse event profiles, though they are unlikely to have been sufficiently powered to pick up rare serious events. In most cases, evidence was of low or mixed quality, accentuating the need for further standardized, large-scale, multi-arm randomized controlled trials with homogeneous outcome measures. Overall, this review suggests that IV medications may offer an effective alternative parenteral route of administration in acute disturbance, particularly in general hospital settings.
Topics: Humans; Administration, Intravenous; Psychomotor Agitation; Aggression; Antipsychotic Agents; Prospective Studies
PubMed: 38309683
DOI: 10.1016/j.jaclp.2024.01.004 -
Case Reports in Ophthalmology 2023PHACE(S) syndrome is a neurocutaneous disorder with a hallmark finding of an infantile facial hemangioma (IFH) >5 cm. Eye examination of patients with PHACE(S) syndrome...
PHACE(S) syndrome is a neurocutaneous disorder with a hallmark finding of an infantile facial hemangioma (IFH) >5 cm. Eye examination of patients with PHACE(S) syndrome with no IFH at periorbital region is reported to be of low yield. We report a unique case of the syndrome with ocular manifestations without periorbital IFH or systemic findings. A 3-week-old female infant with right periauricular IFH >5 cm, extending to the neck and cheek and lower lip IFH was presented. Examination revealed pseudoptosis due to microphthalmia with esotropia and hypertropia. Both corneas were clear with diameters of 5 mm and 10 mm, right eye (RE) and left eye (LE), respectively. There was a posterior polar cataract with a poor view of the fundus RE. Ocular B-scan and magnetic resonance imaging (MRI) findings were suggestive of a dysmorphic globe, vitreous hemorrhage, spherophakia and persistent fetal vasculature RE and normal findings LE. Clinical evaluation, MRI, and MR angiography revealed no other systemic abnormalities. Subsequent follow-up visits revealed progressive clouding of the cornea with neovascularization and the development of phthisis bulbi RE at which point an ocular prosthesis was placed. The IFH was managed with dye laser and with oral propranolol. At 1 year, the patient has remained stable with no development of new local or systemic anomalies, regression of the periauricular and lip IFH, and normal development of the orbital structure RE with an ocular prosthesis in situ. Ocular involvement in patients with PHACE(S) syndrome may be present without periorbital IFH. Regardless of the location of the IFH and the presence or absence of a periocular component, it is recommended that they receive a full initial ophthalmological assessment.
PubMed: 37901638
DOI: 10.1159/000533887