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.

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.

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.

Microvascular dysfunction following deferred stenting strategy in ST-segment elevation myocardial infarction: a case report.

Background: ST-segment elevation myocardial infarction (STEMI) has traditionally been managed with immediate reperfusion of the culprit artery, primarily through percutaneous coronary intervention and stent placement. Emerging data are highlighting the crucial importance of post-infarct microcirculatory function assessment. Case summary: This report presents a patient with an inferior STEMI who was successfully reperfused without stent implantation. Tools such as optical coherence tomography, fractional flow reserve, and positron emission tomography computed tomography N-13 ammonia were utilized, offering comprehensive insights into the anatomical and functional characteristics of both the epicardial vessel and microcirculation. Discussion: The recovery of the reversible component of microcirculatory dysfunction, observable as early as 5 days post-infarction, might carry significant implications for clinical decision-making. Such insights can potentially influence contemporary treatment strategies, including the consideration of deferred stenting. This case underscores the significance of post-infarct microcirculatory function and its potential impact on therapeutic approaches.

Left ventricular remodeling in premature ventricular contraction-induced cardiomyopathy: Effect of coupling intervals and atrioventricular dissociation.

Background: Left ventricular dyssynchrony (LVD) and postextrasystolic potentiation (PESP) associated with premature ventricular contractions (PVCs) may play a role in the development of premature ventricular contraction-induced cardiomyopathy (PVC-CM). Long-coupled (LC) PVCs have a greater LVD than short-coupled (SC) PVCs, whereas SC-PVCs have a stronger PESP than LC-PVCs. Objective: The purpose of this study was to compare SC-PVCs and LC-PVCs to evaluate the roles of LVD, PESP, and atrioventricular dissociation (AVD) in the development of PVC-CM. Methods: Thirty-six canines underwent pacemaker implantation to induce bigeminal right ventricular apical epicardial PVCs (50% burden) for 12 weeks. Telemetry assessed PVC burden and AVD. Animals were grouped as SC-PVC (coupling interval [CI] 200-220ms), LC-PVC (CI 330 ms), or sham (control). Echocardiographic changes, AVD, and hemodynamics were monitored for 12 weeks. Results: PVC burden was similar between SC-PVC and LC-PVC groups but was statistically higher in the SC-PVC group (50% vs 47.5%; P = .028). After 12 weeks, left ventricular ejection fraction (LVEF) significantly decreased in both SC-PVC and LC-PVC groups (47.1% ± 1.4% and 45.5% ± 2%, respectively) compared to sham group (61% ± 1.6%; P <.001). Overall AVD was similar between SC-PVC and LC-PVC groups, and there was no significant correlation between AVD and reduction in LVEF at 12 weeks (r = 0.09, P = .5; and r = 0.06, P = .8, respectively). Additionally, both SC-PVC and LC-PVC groups experienced substantial declines in max and min dP/dt after 12 weeks compared to baseline. Conclusion: Neither PVC CI nor AVD played an independent role in the development or severity of PVC-CM. LVD and PESP make equal relative contributions to the development of PVC-CM.

Guiding Clinical Prescription of Topical Extemporaneous Formulations of Sodium Cromoglycate Based on Pharmaceutical Performance.

Cromoglycate (SCG) is widely used for allergy processes, and inflammatory states acting as a mast cell membrane stabilizer that inhibits the histamine and mediator release. Currently, SCG topical extemporaneous compounding formulations are prepared in hospitals and community pharmacies, as no industrial fabricated medicines are available in Spain. The stability of these formulations is unknown. Additionally, there are no clear guidelines on which concentration and vehicle are more suitable to enhance permeation across the skin. In this work, the stability of commonly prescribed topical SCG formulations in clinical practice was evaluated. Different vehicles commonly employed by pharmacists daily for formulating topical SCG were investigated (Eucerinum, Acofar Creamgel, and Beeler's base) at different concentrations, ranging from 0.2 to 2%. The stability of topical extemporaneous compounded SCG formulations can be extended for up to three months at room temperature (25 °C). Creamgel 2% formulations significantly improved the topical permeation of SCG across the skin, being 4.5-fold higher than formulations prepared with Beeler's base. The reason attributed to this performance can be related to the lower droplet size formed upon dilution in aqueous media combined with a lower viscosity, which facilitates its application and extensibility on the skin. The higher the SCG concentration in Creamgel formulations, the higher the permeability across both synthetic membranes and pig skin (p-value < 0.05). These preliminary results can be used as a guide to prompt a rational prescription of topical SCG formulations.

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.

Brachial Blood Pressure Invasively and Non-Invasively Obtained Using Oscillometry and Applanation Tonometry: Impact of Mean Blood Pressure Equations and Calibration Schemes on Agreement Levels.

The use of oscillometric methods to determine brachial blood pressure (bBP) can lead to a systematic underestimation of the invasively measured systolic (bSBP) and pulse (bPP) pressure levels, together with a significant overestimation of diastolic pressure (bDBP). Similarly, the agreement between brachial mean blood pressure (bMBP), invasively and non-invasively measured, can be affected by inaccurate estimations/assumptions. Despite several methodologies that can be applied to estimate bMBP non-invasively, there is no consensus on which approach leads to the most accurate estimation. Aims: to evaluate the association and agreement between: (1) non-invasive (oscillometry) and invasive bBP; (2) invasive bMBP, and bMBP (i) measured by oscillometry and (ii) calculated using six different equations; and (3) bSBP and bPP invasively and non-invasively obtained by applanation tonometry and employing different calibration methods. To this end, invasive aortic blood pressure and bBP (catheterization), and non-invasive bBP (oscillometry [Mobil-O-Graph] and brachial artery applanation tonometry [SphygmoCor]) were simultaneously obtained (34 subjects, 193 records). bMBP was calculated using different approaches. Results: (i) the agreement between invasive bBP and their respective non-invasive measurements (oscillometry) showed dependence on bBP levels (proportional error); (ii) among the different approaches used to obtain bMBP, the equation that includes a form factor equal to 33% (bMBP = bDBP + bPP/3) showed the best association with the invasive bMBP; (iii) the best approach to estimate invasive bSBP and bPP from tonometry recordings is based on the calibration scheme that employs oscillometric bMBP. On the contrary, the worst association between invasive and applanation tonometry-derived bBP levels was observed when the brachial pulse waveform was calibrated to bMBP quantified as bMBP = bDBP + bPP/3. Our study strongly emphasizes the need for methodological transparency and consensus for non-invasive bMBP assessment.

Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics.

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future.

Effect of Clindamycin on Intestinal Microbiome and Miltefosine Pharmacology in Hamsters Infected with Leishmania infantum.

Visceral leishmaniasis (VL), a vector-borne parasitic disease caused by Leishmania donovani and L. infantum (Kinetoplastida), affects humans and dogs, being fatal unless treated. Miltefosine (MIL) is the only oral medication for VL and is considered a first choice drug when resistance to antimonials is present. Comorbidity and comedication are common in many affected patients but the relationship between microbiome composition, drugs administered and their pharmacology is still unknown. To explore the effect of clindamycin on the intestinal microbiome and the availability and distribution of MIL in target organs, Syrian hamsters (120-140 g) were inoculated with L. infantum (108 promastigotes/animal). Infection was maintained for 16 weeks, and the animals were treated with MIL (7 days, 5 mg/kg/day), clindamycin (1 mg/kg, single dose) + MIL (7 days, 5 mg/kg/day) or kept untreated. Infection was monitored by ELISA and fecal samples (16 wpi, 18 wpi, end point) were analyzed to determine the 16S metagenomic composition (OTUs) of the microbiome. MIL levels were determined by LC-MS/MS in plasma (24 h after the last treatment; end point) and target organs (spleen, liver) (end point). MIL did not significantly affect the composition of intestinal microbiome, but clindamycin provoked a transient albeit significant modification of the relative abundance of 45% of the genera, including Ruminococcaceae UCG-014, Ruminococcus 2; Bacteroides and (Eubacterium) ruminantium group, besides its effect on less abundant phyla and families. Intestinal dysbiosis in the antibiotic-treated animals was associated with significantly lower levels of MIL in plasma, though not in target organs at the end of the experiment. No clear relationship between microbiome composition (OTUs) and pharmacological parameters was found.

In Vitro and In Vivo Characteristics of Olive Oil as Excipient for Topical Administration.

Oily excipients are vital components of dermatological products. In this study, the in vitro and in vivo characteristics of Wild Olive Oil (WOO) were compared with two other types of olive oils: Extra Virgin Olive Oil (EVOO) and Virgin Olive Oil (VOO). This work has also included Liquid Paraffin (LP) and Rosehip Oil (RO) as reference oils. Melatonin was used in the study as a model drug to demonstrate the antioxidant capacity of the oils. The melatonin carrier capacity and antioxidant performance was related to the degree of unsaturation of the oils and was highest for RO and WOO and lowest for LP. However, the most stable oil to oxidation was LP. The in vivo performance of the oils in the skin of eight healthy volunteers was investigated with a dermoanalyser. The highest increment of oil and hydration in the skin was obtained with RO. The lowest perception of oiliness was described for WOO, which produced the highest increase in elasticity of the skin area where it was applied. An in vitro-in vivo correlation was therefore performed through multivariable analysis (MVA).

Leishmania infantum infection does not affect the main composition of the intestinal microbiome of the Syrian hamster.

BACKGROUND: Visceral leishmaniasis (VL) is the most severe form of all leishmanial infections and is caused by infection with protozoa of Leishmania donovani and Leishmania infantum. This parasitic disease occurs in over 80 countries and its geographic distribution is on the rise. Although the interaction between the intestinal microbiome and the immune response has been established in several pathologies, it has not been widely studied in leishmaniasis. The Syrian hamster is the most advanced laboratory model for developing vaccines and new drugs against VL. In the study reported here, we explored the relationship between the intestinal microbiome and infection with L. infantum in this surrogate host. METHODS: Male Syrian hamsters (120-140 g) were inoculated with 108 promastigotes of a canine-derived L. infantum strain or left as uninfected control animals. Infection was maintained for 19 weeks (endpoint) and monitored by an immunoglobulin G (IgG) enyzme-linked immunosorbent assay throughout the experiment. Individual faecal samples, obtained at weeks 16, 18 and 19 post-inoculation, were analysed to determine the 16S metagenomic composition (the operational taxonomic units [OTUs] of the intestinal microbiome and the comparison between groups were FDR (false discovery rate)-adjusted). RESULTS: Leishmania infantum infection elicited moderate clinical signs and lesions and a steady increase in specific anti-Leishmania serum IgG. The predominant phyla (Firmicutes + Bacteriodetes: > 90%), families (Muribaculaceae + Lachnospiraceae + Ruminococcaceae: 70-80%) and genera found in the uninfected hamsters showed no significant variations throughout the experiment. Leishmania infantum infection provoked a slightly higher-albeit non-significant-value for the Firmicutes/Bacteriodetes ratio but no notable differences were found in the relative abundance or diversity of phyla and families. The microbiome of the infected hamsters was enriched in CAG-352, whereas Lachnospiraceae UCG-004, the [Eubacterium] ventriosum group and Allobaculum were less abundant. CONCLUSIONS: The lack of extensive significant differences between hamsters infected and uninfected with L. infantum in the higher taxa (phyla, families) and the scarce variation found, which was restricted to genera with a low relative abundance, suggest that there is no clear VL infection-intestinal microbiome axis in hamsters. Further studies are needed (chronic infections, co-abundance analyses, intestinal sampling, functional analysis) to confirm these findings and to determine more precisely the possible relationship between microbiome composition and VL infection.

Wave separation analysis-derived indexes obtained from radial and carotid tonometry in healthy pregnancy and pregnancy-associated hypertension: Comparison with pulse wave analysis-derived indexes.

Background: Increased wave reflections assessed by pulse wave analysis (PWA) was proposed as one of the potential culprits of hypertension seen in women with pregnancy-associated hypertension (PAH). However, this statement has never been confirmed with "Wave Separation Analysis" (WSA), a more sophisticated mathematical approach that analyzes the amplitude and interaction between forward and backward aortic pressure waveform components. Objective: To characterize potential changes in pressure wave components of PAH compared to healthy non-pregnant (NP) women and women with normal pregnancies (HP) by using WSA and compared these findings with PWA-derived indexes; secondarily, to evaluate differences in WSA-derived indexes between subgroups of PAH (i.e., preeclampsia [PE] and gestational hypertension [GH]). Methods: Using radial and carotid applanation tonometry, we quantified in HP (n = 10), PAH (n = 16), and NP (n = 401): (i) PWA-derived indexes; (ii) WSA-derived indexes: forward (Pf) and backward (Pb) waveform components, backward component arrival time (PbAT), reflection magnitude (RM = Pb/Pf) and index [RIx = Pb/(Pf + Pb)]. Results: While PAH was associated with a higher Pf compared to HP and NP, Pb and PbAT were similar between the groups. Both GH and PE showed a higher Pf compared to HP, but only PE had a trend of presenting with higher Pb and lower PbAT compared to the other groups. Finally, PAH showed a trend of having lower RM and RIx compared to NP and HP, with no differences between GH and PE. Conclusion: PAH was associated with higher Pf, but not higher Pb, compared to NP and HP, although PE also demonstrated a trend of higher Pb.

Drug Stability: ICH versus Accelerated Predictive Stability Studies.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and the United States to facilitate the mutual acceptance of stability data that are sufficient for registration by the regulatory authorities in these jurisdictions. Overall, ICH stability studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture. The long-term testing should be performed over a minimum of 12 months at 25 °C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH. The intermediate and accelerated testing should cover a minimum of 6 months at 30 °C ± 2 °C/65% RH ± 5% RH (which is not necessary if this condition was utilized as a long-term one) and 40 °C ± 2 °C/75% RH ± 5% RH, respectively. Hence, the ICH stability testing for industrially fabricated medicines is rigorous and tedious and involves a long period of time to obtain preclinical stability data. For this reason, Accelerated Predictive Stability (APS) studies, carried out over a 3-4-week period and combining extreme temperatures and RH conditions (40-90 °C)/10-90% RH, have emerged as novel approaches to predict the long-term stability of pharmaceutical products in a more efficient and less time-consuming manner. In this work, the conventional ICH stability studies versus the APS approach will be reviewed, highlighting the advantages and disadvantages of both strategies. Furthermore, a comparison of the stability requirements for the commercialization of industrially fabricated medicines versus extemporaneous compounding formulations will be discussed.

Digital phenotyping by wearable-driven artificial intelligence in older adults and people with Parkinson's disease: Protocol of the mixed method, cyclic ActiveAgeing study.

BACKGROUND: Active ageing is described as the process of optimizing health, empowerment, and security to enhance the quality of life in the rapidly growing population of older adults. Meanwhile, multimorbidity and neurological disorders, such as Parkinson's disease (PD), lead to global public health and resource limitations. We introduce a novel user-centered paradigm of ageing based on wearable-driven artificial intelligence (AI) that may harness the autonomy and independence that accompany functional limitation or disability, and possibly elevate life expectancy in older adults and people with PD. METHODS: ActiveAgeing is a 4-year, multicentre, mixed method, cyclic study that combines digital phenotyping via commercial devices (Empatica E4, Fitbit Sense, and Oura Ring) with traditional evaluation (clinical assessment scales, in-depth interviews, and clinical consultations) and includes four types of participants: (1) people with PD and (2) their informal caregiver; (3) healthy older adults from the Helgetun living environment in Norway, and (4) people on the Helgetun waiting list. For the first study, each group will be represented by N = 15 participants to test the data acquisition and to determine the sample size for the second study. To suggest lifestyle changes, modules for human expert-based advice, machine-generated advice, and self-generated advice from accessible data visualization will be designed. Quantitative analysis of physiological data will rely on digital signal processing (DSP) and AI techniques. The clinical assessment scales are the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), Apathy Evaluation Scale (AES), and the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A qualitative inquiry will be carried out with individual and focus group interviews and analysed using a hermeneutic approach including narrative and thematic analysis techniques. DISCUSSION: We hypothesise that digital phenotyping is feasible to explore the ageing process from clinical and lifestyle perspectives including older adults and people with PD. Data is used for clinical decision-making by symptom tracking, predicting symptom evolution, and discovering new outcome measures for clinical trials.

Effect of Primary Packaging Material on the Stability Characteristics of Diazepam and Midazolam Parenteral Formulations.

Diazepam and midazolam are formulated in autoinjectors for parenteral administration to decrease seizures in the case of emergency. However, the compatibility of these lipophilic drugs with the primary packaging material is a key part of drug formulation development. In this work, diazepam and midazolam were packaged in glass syringes as parenteral solutions using two different elastomeric sealing materials (PH 701/50 C BLACK and 4023/50 GRAY). Syringes were stored at three different storage temperatures: 4, 25, and 40 °C. At different time points over 3 years, physical appearance, benzodiazepine sorption on the sealing elastomeric materials, and drug content in solution were assayed. A detailed study on the adsorption profile of both benzodiazepines on the elastomeric gaskets was performed, indicating that the novel rubber material made of bromobutyl derivatives (4023/50 GRAY) is a better choice for manufacturing autoinjectors due to lower drug adsorption. Diazepam showed a better stability profile than midazolam, with the latter solubilised as a hydrochloride salt in an acidic pH that can affect the integrity of the elastomer over time. The amount of drug adsorbed on the surface of the elastomer was measured by NIR and correlated using chemometric models with the amount retained in the elastomeric gaskets quantified by HPLC.

COVID-19-induced latent relapsing hypercoagulable state in the absence of persistent viral infection.

Hypercoagulability in coronavirus disease 2019 infection is already a known fact. But in this article, we have discussed a unique case where the patient had suffered from relapsing thrombus formation. This report describes the case of a patient who presented with chronic coronavirus disease 2019-induced recurrent thrombi refractory to multiple antithrombotic regimens because of multiple recurrent inflammatory flares without any evidence of chronic persistent viral infection. The patient was treated with anticoagulation and anti-inflammatory medications. Still, he had repeated episodes of right ventricular thrombus. Coronavirus disease 2019 can provoke a severe relapsing hypercoagulable state without evidence of persisting viral infection. Rebound inflammatory flares rather than viral recurrence may play a trigger.

Fat-Free Mass Index, Visceral Fat Level, and Muscle Mass Percentage Better Explain Deviations From the Expected Value of Aortic Pressure and Structural and Functional Arterial Properties Than Body Fat Indexes.

Bioelectrical impedance analysis (BIA)-derived indexes [e.g., fat (FMI) and fat-free mass indexes (FFMI), visceral fat level (VFL)] are used to characterize obesity as a cardiovascular risk factor (CRF). The BIA-derived index that better predicts arterial variability is still discussed. Aims: To determine: (1) the association of classical [weight, height, body mass index (BMI), basal metabolic rate (BMR)] and BIA-derived indexes, with arterial properties deviations from expected values (arterial z-scores); (2) maximum arterial variations attributable to BIA-derived indexes; (3) whether the composition of total body, trunk and/or limbs is most closely associated with arterial variations. Methods: Hemodynamic, structural, and functional parameters of different histological types of arteries were assessed (n = 538, 7-85 years). Classical and BIA-derived indexes [fat mass and percentage, FMI, VFL, muscle mass percentage (PMM), FFMI, and percentage] were measured (mono- and multi-segmental devices). Arterial z-scores were obtained using age-related equations derived from individuals not-exposed to CRFs (n = 1,688). Results: First, regardless of the classical index considered, the associations with the arterial properties showed a specific hierarchy order: diameters and local stiffness > aortic and brachial blood pressure (BP) > regional stiffness. Second, all the associations of FMI and FFMI with z-scores were positive. Third, FFMI exceeded the association obtained with BMI and BMR, considering structural z-scores. In contrast, FMI did not exceed the association with z-scores achieved by BMI and BMR. Fourth, regardless of CRFs and classical indexes, arterial z-scores would be mainly explained by FFMI, VFL, and PMM. Fifth, regardless of the body-segment considered, the levels of association between FMI and z-scores did not exceed those found for classic and FFMI. Total fat mass and trunk indexes showed a greater strength of association with z-scores than the FMI of limbs. Sixth, compared to lower limb FFMI indexes, total and upper limbs FFMI showed higher levels of association with z-scores. Conclusions: FFMI (but not FMI) exceeded the strength of association seen between BMI or BMR and structural z-scores. Regardless of the body segment analyzed, the associations between FMI and z-scores did not exceed those found with classic and FFMI. Arterial z-scores could be independently explained by FFMI, VFL, and PMM.

Aging-Related Moderation of the Link Between Compliance With International Physical Activity Recommendations and the Hemodynamic, Structural, and Functional Arterial Status of 3,619 Subjects Aged 3-90 Years.

Background: Compliance with physical activity recommendations (CPARs) is associated with better health indicators. However, there are only few studies to date that have comprehensively analyzed the association between CPARs and cardiovascular status "as a whole" (e.g., analyzing hemodynamic, structural, and functional properties, and different arterial territories). The relationship between CPARs and cardiovascular properties could be strongly influenced by the growth and aging process. Aim: The goal of the study is to investigate the association between CPAR and cardiovascular properties by placing special emphasis on: (i) identifying if there is an independent association, (ii) if the association is "moderated" by age, and (iii) to what extent the association depends on the arterial parameter (hemodynamic vs. structural vs. functional) and/or the arterial segment (e.g., central vs. peripheral; elastic vs. transitional vs. muscular arteries). Methods: A total of 3,619 subjects (3-90 years of age) were studied. Extensive cardiovascular evaluations were performed. Cardiovascular risk factors (CRFs) and physical activity (PA) levels were determined. The subjects were categorized as compliant (n = 1, 969) or non-compliant (n = 1,650) with World Health Organization-related PA recommendations. Correlation and multiple regression models (including CPAR*Age interaction) were obtained, and Johnson-Neyman technique was used to produce regions of significance. Results: The independent association between CPARs and cardiovascular characteristics were strongly moderated by age. The moderation was observed on a wide range of age but particularly notorious on the extremes of life. Certain arterial characteristics demonstrated opposite effects in relation to CPAR status depending on the range of age considered. The association between CPAR and cardiovascular characteristics was independent of CRFs and moderated by age. In subjects younger than 45-55 years, CPAR status was associated with lower central and peripheral blood pressure (i.e., the younger the subject, the higher the reduction). During adult life, as age increases in the subjects, CPARs was associated with a beneficial hemodynamic profile, which is not related with variations in pressure but strongly related with lower levels of waveform-derived indexes and ventricular afterload determinants. Conclusions: The independent associations between CPARs and arterial properties were strongly moderated by age. Data provided by blood pressure levels and waveform-derived indexes would be enough to evaluate the independent association between CPARs and the vascular system in the general population.

Influence of Epoch Length and Recording Site on the Relationship Between Tri-Axial Accelerometry-Derived Physical Activity Levels and Structural, Functional, and Hemodynamic Properties of Central and Peripheral Arteries.

Background: It remains to be established to what extent physical activity (PA) levels among individuals are independently associated with deviations from the "optimal" state of the arterial system. Accelerometers have been proposed as means to obtain reliable, objective, and more comprehensive data of PA. Decisions at the time of data collection/processing could influence the association between accelerometry-derived indices and arterial properties. Objectives: (i) To identify to what extent the strength of association between arterial properties and accelerometer-derived indices depend on the recording site and/or the epoch length; (ii) to determine whether some arterial characteristics (hemodynamic vs. structural vs. functional) or regions (elastic vs. transitional vs. muscular arteries; central vs. peripheral) have higher levels of association with accelerometry-derived indices. Methods: Physical activity (PA), cardiovascular risk factors (CRFs), and cardiovascular properties were evaluated in 60 volunteers (general population; age: 23-62 years; women: 43%). PA was measured daily for 7 days (free-living situation; triaxial-accelerometers ActiGraph-GT3X+; hip and wrist; "Worn-to-wrist" option) and raw data was converted at epoch lengths of 1, 5, 10, 30, and 60-s. PA-related energy expenditure, daily time in moderate-to-vigorous PA, steps/minute, and counts-per-minute for vector magnitude were calculated. The cardiovascular evaluation included hemodynamic (central and peripheral pressure), structural (diameters and intima-media thickness), and functional (local and regional stiffness) parameters of carotids, femoral, and brachial arteries, and carotid-femoral and carotid-radial pathways. Arterial z-scores were obtained using age-related equations derived from healthy participants not exposed to CRFs (n = 1,688; age: 2-84 years; female: 51.2%) to evaluate at which degree each parameter deviates from the "optimal" value. Methods: In general, hip recordings outperformed those obtained on the wrist regarding the strength of association with arterial parameters. Accelerometer-derived indices and their association with arterial properties vary depending on the recording site and epoch length. PA indices are stronger associated with functional (local) than structural variables and with central than peripheral arteries. Conclusions: Regardless of the PA index, there were independent associations with central artery characteristics, which reinforces that these territories would be the most related to PA levels. Differences in data acquisition and processing could lead to differences in conclusions when addressing the association between accelerometer-derived indices and the cardiovascular system.