Prevalence of frequent premature ventricular contractions and left-ventricular systolic dysfunction in patients receiving Holter monitoring.

BACKGROUND: Premature ventricular contractions (PVCs) are frequently observed with left ventricular (LV) systolic dysfunction, although the prevalence of these associated conditions in the general population remains unknown. OBJECTIVE: We sought to understand the prevalence of frequent PVCs (defined PVCs > 5%) and high burden PVCs (defined PVCs > 10%) and LV systolic dysfunction in patients receiving ambulatory Holter monitors (HM). METHODS: A prospective multicenter (eight US medical centers) cross-sectional study collected demographic and PVC burden data from consecutive patients undergoing 24-h, 48-h, and 14-day HM (July 2018-June 2020). Left ventricle ejection fraction (LVEF) data was collected if obtained within 6 months of HM. Four PVC burden groups were analyzed (<1%, 1%-5%, 5.1%-10%, and >10% burden) and stratified by normal LVEF (≥50%) or presence LVEF < 50%. RESULTS: The prevalence of PVC burden of 5.1%-10% and >10% was 4% and 5%, respectively in the population undergoing HM (n = 6529). Age was significantly different between PVC groups (p < .001). In those with LVEF assessment (n = 3713), the prevalence of LVEF < 50% and both LVEF < 50% and PVC > 5% was 16.4% and 4.2%, respectively. The prevalence of PVC > 5% and PVC > 10% in patients with LVEF < 50% was 26% and 16%, respectively. PVC > 5% were more prevalent in older, male, and Caucasians (p < .001). Females had a lower prevalence of PVC > 5% than males (6% vs. 11%; p < .001), but not among those with LVEF < 50% (24% vs. 26%, p = .10). CONCLUSION: PVC > 5% and PVC > 10% and LVEF < 50% are prevalent in patients undergoing HM. PVC > 5% are associated with older age. Females have a lower prevalence of PVC > 5% than males but similar combined PVC > 5% and LVEF < 50%. CLINICALTRIAL: gov identifier: NCT03228823.

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids.

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 µM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite's plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Application of Accelerated Predictive Stability Studies in Extemporaneously Compounded Formulations of Chlorhexidine to Assess the Shelf Life.

Industrially fabricated medicines have a well-defined shelf life supported by rigorous studies before their approval for commercialization. However, the shelf life of extemporaneous compounding topical formulations prepared at hospitals tends to be shorter, especially when no data are available to prove a longer stability period. Also, the storage conditions are unknown in many circumstances. Accelerated Predictive Stability (APS) studies have been shown to be a useful tool to predict in a faster and more accurate manner the chemical stability of extemporaneously compounded formulations requiring a minimum amount of formulation, thereby reducing the chemical drug waste per study. Shelf life will be allocated based on scientific data without compromising drug efficacy or safety. In this work, the APS approach was applied to the commercially available Cristalmina® (CR) and an extemporaneously compounded formulation of chlorhexidine (DCHX). A different degradation kinetic was found between DCHX and CR (Avrami vs. zero-order kinetics, respectively). This can explain the different shelf life described by the International Council for Harmonisation of Technical Requirements Registration Pharmaceuticals Human Use (ICH) conditions between both formulations. A predicted stability for the DCHX solution was obtained from the extrapolation of the degradation rate in long-term conditions from the Arrhenius equation. The estimated degradation from the Arrhenius equation for DCHX at 5 °C, 25 °C, and 30 °C at 365 days was 3.1%, 17.4%, and 25.9%, respectively. The predicted shelf life, in which the DCHX content was above 90%, was 26.67 months under refrigerated conditions and 5.75 and 2.24 months at 25 and 30 °C, respectively. Currently, the Spanish National Formulary recommends a shelf life of no longer than 3 months at room temperature for DCHX solution. Based on the predicted APS and confirmed by experimental long-term studies, we have demonstrated that the shelf life of DCHX extemporaneously compounded formulations could be prolonged by up to 6 months.

Role of arterial impairment in preeclampsia: should the paradigm shift?

Preeclampsia is a worldwide pregnancy complication with serious short- and long-term maternal and neonatal consequences. Our understanding of preeclampsia pathophysiology has significantly evolved over the last decades with the recognition that impaired arterial function and structure may occur early in the course of pregnancy, preceding the clinic-humoral syndrome and driving long-term cardiovascular disease risk in the future of these patients. Although an early abnormal placentation may be the inciting event for a large proportion of cases, there is growing evidence that challenges the placental hypothesis in all affected women, since placental histopathology lesions thought to be characteristic are neither sensitive nor specific markers for the disorder. Recent hemodynamic investigations and studies on left ventricular function and structure in women with preeclampsia further challenge this universal paradigm and propose that placental dysfunction could be secondary to a maternal cardiovascular maladaptation to pregnancy in certain patients. Supporting this hypothesis, certain vascular features, which are characteristically enhanced in normal pregnancy allowing a healthy vascular adaptation, are absent in preeclampsia and comparable to the nonpregnant population. However, arterial biomechanics in preeclampsia may only not cope with hemodynamic demands of pregnancy but also impose additional detrimental loads to the maternal heart ("impaired left-ventricle-aorta coupling") and transmit pressure and flow disturbances into the fetoplacental circulation ("impaired large arteries-microcirculation coupling"). In this review, we analyze the major role of the arterial dysfunction in the cardiovascular maladaptation hypothesis of preeclampsia, shed light on its potential etiopathogenic link, and discuss the complementary nature of the placental and cardiovascular theories.

Effect of enantiomerism on the bioequivalence of a new ibuprofen 600-mg tablet formulation obtained by roller compaction.

The bioequivalence of a new ibuprofen 600-mg film-coated tablet obtained by roller compaction was studied in a crossover study with 22 healthy volunteers. Bioequivalence was analyzed based on (a) the S-enantiomer, (b) the R-enantiomer, and (c) the sum of both enantiomers (representing the results of an achiral assay). The bioequivalence conclusion for ibuprofen products should be based not only on AUC and Cmax but also on tmax since tmax is related to the onset of action. However, it is not possible to ensure if bioequivalence has been demonstrated for tmax as regulators have not defined the acceptance range for the difference between medians of tmax in those cases, where tmax is clinically relevant. In this study, it was possible to conclude bioequivalence for tmax based on S-ibuprofen, though this conclusion might be questioned if the decision is based on R-ibuprofen or the achiral method.

Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis.

Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

Efficacy of a poly-aggregated formulation of amphotericin B in treating systemic sporotrichosis caused by Sporothrix brasiliensis.

In severe cases of sporotrichosis, it is recommended to use amphotericin B deoxycholate (D-AMB) or its lipid formulations and/or in association with itraconazole (ITC). Our aim was to evaluate the antifungal efficacy of a poly-aggregated amphotericin B (P-AMB), a nonlipid formulation, compared with D-AMB on systemic sporotrichosis caused by Sporothrix brasiliensis. In vitro assays showed that Sporothrix schenckii sensu stricto and S. brasiliensis yeast clinical isolates were susceptible to low concentrations of P-AMB and D-AMB. Although P-AMB presented a higher minimal inhibitory concentration (MIC) compared to D-AMB, its cytotoxic effect on renal cells and erythrocytes was lower. For the in vivo assays, male BALB/c mice were intravenously infected with S. brasiliensis yeasts, and P-AMB or D-AMB was administered 3 days post-infection. The efficacy of five therapeutic regimens was tested: intravenous monotherapy with P-AMB or D-AMB, intravenous pulsed-therapy with P-AMB or D-AMB, and intravenous therapy with P-AMB, followed by oral ITC. These treatments increased murine survival and controlled the fungal burden in the liver, spleen, lungs, and kidneys. However, only D-AMB monotherapy or the pulsed-therapies with D-AMB or P-AMB led to 100% survival of the mice 45 days post-infection; only pulsed administration of D-AMB was able to control the fungal load in all organs 45 days post-infection. Accordingly, the histopathological findings showed reductions in the fungal burden and inflammatory reactions in these treatment regimens. Together, our results suggest that the P-AMB formulation could be considered as an alternative drug to D-AMB for treating disseminated sporotrichosis.

Permeability Characteristics of a New Antifungal Topical Amphotericin B Formulation with γ-Cyclodextrins.

Amphotericin B is a low soluble broad-spectrum antifungal agent. Cyclodextrins can be added to amphotericin formulations to enhance both their solubility and antifungal properties. Semisolid amphotericin formulations containing gamma cyclodextrin (AGCD) were prepared and compared with two reference formulations-one of them without any solubility enhancer (A) and the other with DMSO (ADMSO). Rheological, the permeability through hairless mouse skin and antifungal characteristics of the different formulations were evaluated. All three semisolid formulations show low thixotropy characteristics. ADMSO was the formulation with the least consistency, lowest viscosity, and greatest extensibility. The AGCD formulation had the opposite behavior and had both the greatest consistency and viscosity and the lowest extensibility. The lowest permeability was obtained with the reference A formulation while both AGCD and ADMSO had a similar permeability enhancement. According to the antimicrobial in vitro efficacy trials, the AGCD formulation showed 45⁻60% more activity than the reference A formulation. It can be concluded that γ-cyclodextrin is a useful excipient to improve the solubility, permeability, and antifungal activity of amphotericin B in semisolid topical formulations.

Engineering Oral and Parenteral Amorphous Amphotericin B Formulations against Experimental Trypanosoma cruzi Infections.

Chagas disease (CD) is a parasitic zoonosis endemic in most mainland countries of Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective if received at the early stages of the disease. Only two drugs (benznidazole and nifurtimox) have so far been marketed, and both share various limitations such as variable efficacy, many side effects, and long duration of treatment, thus reducing compliance. The in vitro and in vivo efficacy of poly-aggregated amphotericin B (AmB), encapsulated poly-aggregated AmB in albumin microspheres (AmB-AME), and dimeric AmB-sodium deoxycholate micelles (AmB-NaDC) was evaluated. Dimeric AmB-NaDC exhibited a promising selectivity index (SI = 3164) against amastigotes, which was much higher than those obtained for licensed drugs (benznidazole and nifurtimox). AmB-AME, but not AmB-NaDC, significantly reduced the parasitemia levels (3.6-fold) in comparison to the control group after parenteral administration at day 7 postinfection. However, the oral administration of AmB-NaDC (10-15 mg/kg/day for 10 days) resulted in a 75% reduction of parasitemia levels and prolonged the survival rate in 100% of the tested animals. Thus, the results presented here illustrate for the first time the oral efficacy of AmB in the treatment of trypanosomiasis. AmB-NaDC is an easily scalable, affordable formulation prepared from GRAS excipients, enabling treatment access worldwide, and therefore it can be regarded as a promising therapy for trypanosomiasis.

Reduction of Myocardial Ischemia-Reperfusion Injury by Inhibiting Interleukin-1 Alpha.

BACKGROUND: Interleukin-1α (IL-1α) released by dying cells is an alarmin that activates the innate immunity. We hypothesized that after myocardial ischemia-reperfusion (I/R) injury, IL-1α amplifies the myocardial damage by activating the inflammasome and caspase-1. METHODS: Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 minutes, after 24 hours of reperfusion. An IL-1α blocking antibody (15 µg/kg intraperitoneally) or matching vehicle was given after reperfusion. A subgroup of mice underwent sham surgery. We assessed the effects of IL-1α blockade on caspase-1 activity, infarct size, cardiac troponin I serum levels, and left ventricular fractional shortening, 24 hours after I/R. RESULTS: I/R led to inflammasome formation, and IL-1α blockade significantly reduced inflammasome formation, reflected by a >50% reduction in caspase-1 activity versus vehicle (P = 0.03). IL-1α blockade also reduced the infarct size (-52% infarct expressed as percentage of area at risk, and -79% for cardiac troponin I serum levels, P < 0.001 vs. vehicle) and preserved the left ventricular fractional shortening (31 ± 3% vs. 25 ± 2%, P < 0.001 vs. vehicle). CONCLUSION: IL-1α blockade after I/R reduces the inflammasome activation, decreases the infarct size, and preserves the left ventricular function. IL-1α blockade may therefore represent a novel therapeutic strategy to reduce I/R injury.

Emotional Self-Regulation of Individuals with Autism Spectrum Disorders: Smartwatches for Monitoring and Interaction.

In this paper, we analyze the needs of individuals with Autism Spectrum Disorders (ASD) to have a pervasive, feasible and non-stigmatizing form of assistance in their emotional self-regulation, in order to ease certain behavioral issues that undermine their mental health throughout their life. We argue the potential of recent widespread wearables, and more specifically smartwatches, to achieve this goal. Then, a smartwatch system that implements a wide range of self-regulation strategies and infers outburst patterns from physiological signals and movement is presented, along with an authoring tool for smartphones that is to be used by caregivers or family members to create and edit these strategies, in an adaptive way. We conducted an intensive experiment with two individuals with ASD who showed varied, representative behavioral responses to their emotional dysregulation. Both users were able to employ effective, customized emotional self-regulation strategies by means of the system, recovering from the majority of mild stress episodes and temper tantrums experienced in the nine days of experiment in their classroom.

Agitation Rate and Time for Complete Dissolution in BCS Biowaivers Based on Investigation of a BCS Biowaiver for Dexketoprofen Tablets.

The objective of the present work is to investigate the validity of the existing requirements for BCS biowaivers of immediate release products containing a class I drug in relation to the agitation rate (50 or 75 rpm in the paddle apparatus) and the time limit for complete dissolution (30 min) in the current biowaivers in vitro dissolution tests. Further, the possibility of extensions will be examined since it has been proposed that the time limit for complete dissolution should be revised to 60 min, and also, if cone formation occurs with apparatus 2 at 50 rpm, then a higher agitation rate is acceptable to eliminate it. The development of four generic dexketoprofen immediate release tablets is described. Dexketoprofen is the eutomer of ketoprofen. According to the BCS, dexketoprofen is a class I drug. Three out of the four products failed to show bioequivalence for Cmax in the initial bioequivalence study conducted with the product despite similar but nonrapid dissolution profiles at 50 rpm in the paddle apparatus, or similar and very rapid dissolution profiles at 75 rpm. In conclusion, these data indicate that BCS biowaivers for class I drugs should be granted only when dissolution with the paddle apparatus is complete in 30 min at 50 rpm. The time limit for complete dissolution should not be extended to 60 min. Furthermore, the agitation rate should not be increased to 75 rpm, even in the case of a coning effect.

Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles.

There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within N-palmitoyl-N-methyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index.

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics).

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY.

Unraveling the Impact of the Oil Phase on the Physicochemical Stability and Skin Permeability of Melatonin Gel Formulations.

Melatonin's antioxidant properties make it a valuable component in anti-aging semisolid topical products. This study explores the role of Pemulen®, an acrylic-based viscosifying agent, in stabilizing cream-gel formulations. Remarkably, even at low concentrations (0.4%), Pemulen® successfully produced physicochemical stable topical formulations. In this work, the impact of the ratio of the oily phase-comprising olive oil and isopropyl myristate from 0 to 20%-was investigated to understand the internal microstructure effect on skin permeability, rheological properties, and stability. The formulations exhibited pseudoplastic behavior, with a significant positive correlation (p-value < 0.1) between the oily phase ratio, viscosity, spreadability, skin adhesiveness, and permeability. Formulations without the oil phase exhibited greater skin permeability. However, higher oily phase content enhanced viscosity, spreadability, and skin adhesion. Given that melatonin primarily degrades through oxidation, incorporating antioxidant excipients in semisolid formulations is crucial for maintaining its chemical stability. A quality by design (QbD) approach was used to assess the impact of four excipients-(a) DL-α-tocopheryl acetate (0.05%), (b) ascorbic acid (0.1%), (c) ethylene diamine tetraacetic acid (0.1%), and (d) sodium metabisulphite (0.5%)-on melatonin's stability. Our findings indicate that maintaining the physical stability of the formulation with a 20% oil phase is more critical for protecting melatonin from oxidation than merely adding antioxidant excipients.

Impact of VA-ECMO on Dynamic LV Outflow Obstruction After Transcatheter Aortic Valve Replacement.

Dynamic left ventricular outflow obstruction is a rare but severe complication of transcatheter aortic valve replacement. It presents as a paradoxical hemodynamic collapse after relieving the left ventricular afterload. Considering its unique pathophysiology, this entity dictates counterintuitive treatments. We describe a case of left ventricular outflow obstruction treated with venoarterial extracorporeal membrane oxygenation and discuss its management principles.

"A stratified pathway to stent-free reperfusion: Selecting suitable patients in ST-elevation myocardial infarction".

BACKGROUND: The DANAMI-3 DEFER study demonstrated that deferring stent implantation in ST-elevation myocardial infarction (STEMI) is safe, although not superior to immediate stenting. It is possible that an individualized revascularization strategy in STEMI, achieved through appropriate patient selection, could be feasible and effective. METHODS: This prospective, non-randomized study included 198 patients with STEMI who underwent primary percutaneous coronary intervention (PCI) between October 2019 and November 2021. Patients were assigned to either the deferred stenting (DS) group (n = 19) or the control group (C) undergoing immediate stenting (n = 179) based on a multimodal approach integrating coronary angiography, intravascular imaging, physiological assessments, and clinical judgment. The primary endpoints included all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE). RESULTS: The DS group showed a significantly lower rate of stent implantation (10.5 % vs. 97.7 %, p < 0.001) and a higher use of thrombus aspiration (89.5 % vs. 30.7 %, p < 0.001) and glycoprotein IIb/IIIa inhibitors (31.6 % vs. 6.7 %, p < 0.001) compared to the C group. No significant differences were observed between the groups in terms of all-cause mortality (5.3 % vs. 8.9 %, p = 0.59) or MACCE (10.5 % vs. 8.4 %, p = 0.71). CONCLUSIONS: This study demonstrates the feasibility of implementing individualized reperfusion strategies in STEMI within a real-world clinical setting. The findings, while limited by the study design, generate valuable hypotheses that warrant further investigation to refine patient selection criteria and optimize outcomes.

Aortic Stenosis Management in Patients With Acute Hip Fracture.

The treatment of severe aortic stenosis (SAS) has evolved rapidly with the advent of minimally invasive structural heart interventions. Transcatheter aortic valve replacement has allowed patients to undergo definitive SAS treatment achieving faster recovery rates compared to valve surgery. Not infrequently, patients are admitted/diagnosed with SAS after a fall associated with a hip fracture (HFx). While urgent orthopedic surgery is key to reduce disability and mortality, untreated SAS increases the perioperative risk and precludes physical recovery. There is no consensus on what the best strategy is either hip correction under hemodynamic monitoring followed by valve replacement or preoperative balloon aortic valvuloplasty to allow HFx surgery followed by valve replacement. However, preoperative minimalist transcatheter aortic valve replacement may represent an attractive strategy for selected patients. We provide a management pathway that emphasizes an early multidisciplinary approach to optimize time for hip surgery to improve orthopedic and cardiovascular outcomes in patients presenting with HFx-SAS.

Acute Hemodynamic Compromise After Transcatheter Aortic Valve Replacement Due to Dynamic Left Ventricle Obstruction: A Systematic Review.

Acute hemodynamic compromise after transcatheter aortic valve replacement (TAVR) because of dynamic left ventricle (LV) obstruction (LVO), also known as suicide LV, is an infrequent but severe complication of TAVR that is poorly defined in previous studies. Understanding this complication is essential for its prompt diagnosis and optimal treatment. We conducted a systematic literature review using PubMed, Embase, Web of Science, and Medline databases for studies describing acute hemodynamic compromise after TAVR because of dynamic LVO or suicide LV. Each study was reviewed by 2 authors individually for eligibility, and a third author resolved disagreements. From a total of 506 studies, 25 publications were considered for the final analysis. The majority of patients with this condition were women demonstrating a hypertrophic septum, a small ventricle, and hyperdynamic contractility on pre-TAVR echocardiographic assessment. An intraventricular gradient before TAVR was found in half of the cases. Acute hemodynamic compromise after TAVR because of dynamic LVO manifested mainly as significant hypotension and occurred most often immediately after valve deployment. The LV outflow tract was the most common site of obstruction. Advanced therapies were required in nearly 65% of the cases. In conclusion, acute hemodynamic compromise after TAVR because of dynamic LVO occurred almost invariably in women. Echocardiography before TAVR may offer essential information to anticipate this complication. LV outflow tract obstruction appears to carry the highest risk of developing this phenomenon. Advanced therapies should be promptly considered as a bailout strategy in patients with hemodynamic collapse refractory to medical therapy.

Leveraging 3D-printed microfluidic micromixers for the continuous manufacture of melatonin loaded SNEDDS with enhanced antioxidant activity and skin permeability.

Vesicants are chemical warfare agents (CWAs) capable of causing severe skin damage and systemic toxicity. Melatonin, known for its anti-inflammatory and antioxidant properties, can mitigate the effects of these agents. Self-nano-emulsifying drug delivery systems (SNEDDS) containing a high melatonin concentration (5 %, 50 mg/g) were optimized using a quality-by-design approach from biocompatible, non-irritant excipients with a particle size of about 100 nm. The melatonin-loaded SNEDDS showed a 43-fold greater permeability than a conventional melatonin cream. Chemical stability at ambient temperature (25 °C) was maintained for one year. The preparation of optimised melatonin-loaded SNEDDS using a simple mixing method was compared to microfluidic micromixers. Mixing was successfully achieved using a 3D-printed (fused deposition modeling or stereolithography) T-shaped toroidal microfluidic chip (with a channel geometry optimized by computational fluid dynamics), resulting in a scalable, continuous process for the first time with a substantial reduction in preparation time compared to other conventional mixing approaches. No statistically significant differences were observed in the key quality attributes, such as particle size and melatonin loading, between mixing method till kinetic equilibrium solubility is reached and mixing using the 3D-printed micromixers. This scalable, continuous, cost-effective approach improves the overall efficiency of SNEDDS production, reduces the cost of quality control for multiple batches, and demonstrates the potential of continuous microfluidic manufacture with readily customizable 3D-printed micromixers at points of care, such as military bases.