The effects of a prehabilitation programme based on therapeutic exercise, back care education, and pain neuroscience education in patients scheduled for lumbar radiculopathy surgery: A study protocol for a randomised controlled trial.

The aim of this present clinical trial is to evaluate the effectiveness of a multicomponent prehabilitation programme administered through educational videos versus another programme based on written exercise recommendations, in patients scheduled for lumbar radiculopathy surgery. This study will be a multicentre, controlled, randomised, parallel clinical trial. One hundred participants undergoing lumbar radiculopathy surgery who meet the established inclusion criteria will be recruited at different Spanish hospitals. The experimental group will follow a 4-week prehabilitation programme combining therapeutic exercise, back care education, and pain neuroscience education delivered through videos designed for consumption at home. The control group will be provided with written instructions to perform therapeutic exercises during the same prehabilitation time period. The primary outcome of the study will be disability, assessed using the Spanish version of the Oswestry Disability Index. The secondary outcomes will be pain perception, health-related quality of life, fear avoidance, kinesiophobia, catastrophising, anxiety, depression, physical activity, and the treatment satisfaction of the patients. This study will provide evidence for the effectiveness of a home-based multicomponent prehabilitation programme that addresses some already identified barriers to patient attendance in face-to-face programmes. Understanding the medium and long-term effects of pre-surgery lumbar muscle training and pain neuroscience education administered via instructional videos watched by patients at home, will help improve the design of prehabilitation programmes in this population while also improving the cost-effectiveness of such interventions.

Three-dimensional imaging analysis of CAD/CAM custom-milled versus prefabricated allogeneic block remodelling at 6 months and long-term follow-up of dental implants: A retrospective cohort study.

AIM: This retrospective cohort study aimed to volumetrically investigate the bone stability rate of prefabricated allogeneic bone blocks (PBB) and computer-aided design (CAD)/computer-aided manufacturing (CAM) custom-milled allogeneic bone blocks (CCBB) for ridge augmentation. MATERIALS AND METHODS: Nineteen patients were treated with 20 allografts: 11 CCBB, 9 PBB; 10 in the maxilla and 10 in the mandible. Clinical treatment history and cone beam computed tomography scans before surgery (t0), directly after graft surgery (t1) and after 6 months of healing prior to implant insertion (t2) were evaluated using a three-dimensional evaluation software for absolute bone volume, stability as well as vertical and horizontal bone gain. Furthermore, the inserted implants were analysed for survival, marginal bone loss (MBL) and complications for a mean follow-up period of 43.75 (±33.94) months. RESULTS: A mean absolute volume of 2228.1 mm3 (±1205) was grafted at t1. The bone stability rate was 87.6% (±9.9) for CCBB and 83.0% (±14.5) for PBB. The stability was higher in the maxilla (91.6%) than in the mandible (79.53%). Surgery time of PBB was longer than for CCBB (mean Δ = 52 min). The survival rate of the inserted implants was 100% with a mean MBL of 0.41 mm (±0.37). CONCLUSION: The clinical performance of both allograft block designs was equally satisfactory for vertical and horizontal bone grafting prior to implant placement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT06027710.

Differences in clinical outcomes of bloodstream infections caused by Klebsiella aerogenes, Klebsiella pneumoniae and Enterobacter cloacae: a multicentre cohort study.

BACKGROUND: Klebsiella aerogenes has been reclassified from Enterobacter to Klebsiella genus due to its phenotypic and genotypic similarities with Klebsiella pneumoniae. It is unclear if clinical outcomes are also more similar. This study aims to assess clinical outcomes of bloodstreams infections (BSI) caused by K. aerogenes, K. pneumoniae and Enterobacter cloacae, through secondary data analysis, nested in PRO-BAC cohort study. METHODS: Hospitalized patients between October 2016 and March 2017 with monomicrobial BSI due to K. aerogenes, K. pneumoniae or E. cloacae were included. Primary outcome was a composite clinical outcome including all-cause mortality or recurrence until 30 days follow-up. Secondary outcomes were fever ≥ 72 h, persistent bacteraemia, and secondary device infection. Multilevel mixed-effect Poisson regression was used to estimate the association between microorganisms and outcome. RESULTS: Overall, 29 K. aerogenes, 77 E. cloacae and 337 K. pneumoniae BSI episodes were included. Mortality or recurrence was less frequent in K. aerogenes (6.9%) than in E. cloacae (20.8%) or K. pneumoniae (19.0%), but statistical difference was not observed (rate ratio (RR) 0.35, 95% CI 0.08 to 1.55; RR 0.42, 95% CI 0.10 to 1.71, respectively). Fever ≥ 72 h and device infection were more common in K. aerogenes group. In the multivariate analysis, adjusted for confounders (age, sex, BSI source, hospital ward, Charlson score and active antibiotic therapy), the estimates and direction of effect were similar to crude results. CONCLUSIONS: Results suggest that BSI caused by K. aerogenes may have a better prognosis than E. cloacae or K. pneumoniae BSI.

Development and characterization of lipid nanocapsules loaded with iron oxide nanoparticles for magnetic targeting to the blood-brain barrier.

Brain drug delivery is severely hindered by the presence of the blood-brain barrier (BBB). Its functionality relies on the interactions of the brain endothelial cells with additional cellular constituents, including pericytes, astrocytes, neurons, or microglia. To boost brain drug delivery, nanomedicines have been designed to exploit distinct delivery strategies, including magnetically driven nanocarriers as a form of external physical targeting to the BBB. Herein, a lipid-based magnetic nanocarrier prepared by a low-energy method is first described. Magnetic nanocapsules with a hydrodynamic diameter of 256.7 ± 8.5 nm (polydispersity index: 0.089 ± 0.034) and a ξ-potential of -30.4 ± 0.3 mV were obtained. Transmission electron microscopy-energy dispersive X-ray spectroscopy analysis revealed efficient encapsulation of iron oxide nanoparticles within the oily core of the nanocapsules. Both thermogravimetric analysis and phenanthroline-based colorimetric assay showed that the iron oxide percentage in the final formulation was 12 wt.%, in agreement with vibrating sample magnetometry analysis, as the specific saturation magnetization of the magnetic nanocapsules was 12% that of the bare iron oxide nanoparticles. Magnetic nanocapsules were non-toxic in the range of 50-300 µg/mL over 72 h against both the human cerebral endothelial hCMEC/D3 and Human Brain Vascular Pericytes cell lines. Interestingly, higher uptake of magnetic nanocapsules in both cell types was evidenced in the presence of an external magnetic field than in the absence of it after 24 h. This increase in nanocapsules uptake was also evidenced in pericytes after only 3 h. Altogether, these results highlight the potential for magnetic targeting to the BBB of our formulation.

Biological Variation Data in Triathletes for Metabolism and Growth-Related Biomarkers Included in the Athlete Biological Passport.

BACKGROUND: When using biological variation (BV) data, BV estimates need to be robust and representative. High-endurance athletes represent a population under special physiological conditions, which could influence BV estimates. Our study aimed to estimate BV in athletes for metabolism and growth-related biomarkers involved in the Athlete Biological Passport (ABP), by 2 different statistical models. METHODS: Thirty triathletes were sampled monthly for 11 months. The samples were analyzed for human growth hormone (hGH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), insulin, and N-terminal propeptide of type III procollagen (P-III-NP) by immunoassay. Bayesian and ANOVA methods were applied to estimate within-subject (CVI) and between-subject BV. RESULTS: CVI estimates ranged from 7.8% for IGFBP-3 to 27.0% for insulin, when derived by the Bayesian method. The 2 models gave similar results, except for P-III-NP. Data were heterogeneously distributed for P-III-NP for the overall population and in females for IGF-1 and IGFBP-3. BV components were not estimated for hGH due to lack of steady state. The index of individuality was below 0.6 for all measurands, except for insulin. CONCLUSIONS: In an athlete population, to apply a common CVI for insulin would be appropriate, but for IGF-1 and IGFBP-3 gender-specific estimates should be applied. P-III-NP data were heterogeneously distributed and using a mean CVI may not be representative for the population. The high degree of individuality for IGF-1, IGFBP-3, and P-III-NP makes them good candidates to be interpreted through reference change values and the ABP.

Paralytic Shellfish Toxins in Mollusks from Galicia Analyzed by a Fast Refined AOAC 2005.06 Method: Toxicity, Toxin Profile, and Inter-Specific, Spatial, and Seasonal Variations.

Paralytic shellfish poisoning is an important concern for mollusk fisheries, aquaculture, and public health. In Galicia, NW Iberian Peninsula, such toxicity has been monitored for a long time using mouse bioassay. Therefore, little information exists about the precise toxin analogues and their possible transformations in diverse mollusk species and environments. After the change in the European PSP reference method, a refinement of the Lawrence method was developed, achieving a 75% reduction in chromatogram run time. Since the beginning of 2021, when this refinement Lawrence method was accredited under the norm UNE-EN ISO/IEC 17025, it has been used in the area to determine the toxin profiles and to estimate PSP toxicity in more than 4500 samples. In this study, we have summarized three years of monitoring results, including interspecific, seasonal, and geographical variability of PSP toxicity and toxin profile. PSP was detected in more than half of the samples analyzed (55%), but only 4.4% of the determinations were above the EU regulatory limit. GTX1,4 was the pair of STX analogs that produced the highest toxicities, but GTX2,3 was found in most samples, mainly due to the reduction of GTX1,4 but also by the higher sensitivity of the method for this pair of analogs. STX seems to be mainly a product of biotransformation from GTX2,3. The studied species (twelve bivalves and one gastropod) accumulated and transformed PSP toxins to a different extent, with most of them showing similar profiles except for Spisula solida and Haliotis tuberculata. Two seasonal peaks of toxicity were found: one in spring-early summer and another in autumn, with slightly different toxin profiles during outbreaks in relation to the toxicity during valleys. In general, both the total toxicity and toxin profiles of the southernmost locations were different from those in the northern part of the Atlantic coast and the Cantabrian Sea, but this general pattern is modified by the PSP history of some specific locations.

Marginal changes at bone-level implants supporting dental prostheses with or without intermediate standardised abutments after 36 months: Randomised controlled clinical trial.

OBJECTIVE: The objective of this study is to evaluate the changes at marginal bone level at implants restored with screw-retained prosthesis connected directly to the implants or with an intermediate abutment, after 3-year follow-up. MATERIAL AND METHODS: Thirty-six partially edentulous patients received 72 implants. Each patient received 2 implants and a 2-4-unit screw-retained implant-prosthesis. The test group implants received a screw-retained prosthesis connected directly to the implant shoulder, the control group prosthesis were connected through a 3-mm standardised intermediate abutment. Clinical and radiological data were recorded at baseline and at 6-, 12-, and 36-month follow-up. RESULTS: At 36 months, the mean marginal bone loss was 0.13 ± 0.18 mm for the control group and 0.20 ± 0.24 for the test group, with no significant differences between groups (p > .05). Clinical variables (Probing Pocket Depth, Bleeding on Probing and Plaque Index) at 36 months also showed no significant difference between groups. Minor complications frequency was 6.7% in the control group and 5.3% in test group. None of the groups suffered from mayor complications. Patient Reported Outcomes (PROs) showed a General Satisfaction mean score in the control group of 9.40 (SD 0.82) and 9.37 (SD 1.06) in the test group with no significant differences between groups. CONCLUSIONS: Bone-level implants restored with screw-retained partial prostheses with or without intermediate abutments showed similar radiographic and clinical outcomes after 3 years.

Cyclosporin A-loaded dissolving microneedles for dermatitis therapy: Development, characterisation and efficacy in a delayed-type hypersensitivity in vivo model.

Several drugs can be used for treating inflammatory skin pathologies like dermatitis and psoriasis. However, for the management of chronic and long-term cases, topical administration is preferred over oral delivery since it prevents certain issues due to systemic side effects from occurring. Cyclosporin A (CsA) has been used for this purpose; however, its high molecular weight (1202 Da) restricts the diffusion through the skin structure. Here, we developed a nano-in-micro device combining lipid vesicles (LVs) and dissolving microneedle array patches (DMAPs) for targeted skin delivery. CsA-LVs allowed the effective incorporation of CsA in the hydrophilic DMAP matrix despite the hydrophobicity of the drug. Polymeric matrix composed of poly (vinyl alcohol) (5% w/v), poly (vinyl pyrrolidine) (15% w/v) and CsA-LV dispersion (10% v/v) led to the formation of CsA-LVs@DMAPs with adequate mechanical properties to penetrate the stratum corneum barrier. The safety and biocompatibility were ensured in an in vitro viability test using HaCaT keratinocytes and L929 fibroblast cell lines. Ex vivo permeability studies in a Franz-diffusion cell setup showed effective drug retention in the skin structure. Finally, CsA-LVs@DMAPs were challenged in an in vivo murine model of delayed-type hypersensitivity to corroborate their potential to ameliorate skin inflammatory conditions. Different findings like photon emission reduction in bioluminescence study, normalisation of histological damage and decrease of inflammatory cytokines point out the effectivity of CsA-LVs@DMAPs to treat these conditions. Overall, our study demonstrates that CsA-LVs@DMAPs can downregulate the skin inflammatory environment which paves the way for their clinical translation and their use as an alternative to corticosteroid-based therapies.

Antibiotic resistance and tolerance: What can drug delivery do against this global threat?

Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding rise in related deaths. Several reasons for this situation can be cited, such as the misuse of traditional antibiotics, the massive use of sanitizing measures, and the overuse of antibiotics in agriculture, fisheries, and cattle. AMR&T management requires a multifaceted approach involving various strategies at different levels, such as increasing the patient's awareness of the situation and measures to reduce new resistances, reduction of current misuse or abuse, and improvement of selectivity of treatments. Also, the identification of new antibiotics, including small molecules and more complex approaches, is a key factor. Among these, novel DNA- or RNA-based approaches, the use of phages, or CRISPR technologies are some potent strategies under development. In this perspective article, emerging and experienced leaders in drug delivery discuss the most important biological barriers for drugs to reach infectious bacteria (bacterial bioavailability). They explore how overcoming these barriers is crucial for producing the desired effects and discuss the ways in which drug delivery systems can facilitate this process.

Monitoring the Velocity of Domain Wall Motion in Magnetic Microwires.

An approach was proposed to control the displacement of domain walls in magnetic microwires, which are employed in magnetic sensors. The velocity of the domain wall can be altered by the interaction of two magnetic microwires of distinct types. Thorough investigations were conducted utilizing fluxmetric, Sixtus-Tonks, and magneto-optical techniques. The magneto-optical examinations revealed transformation in the surface structure of the domain wall and facilitated the determination of the mechanism of external influence on the movement of domain walls in magnetic microwires.

Latest advances in glucose-responsive microneedle-based systems for transdermal insulin delivery.

The development of a self-regulated minimally invasive system for insulin delivery can be considered as the holy grail in the field of diabetes mellitus. A delivery system capable of releasing insulin in response to blood glucose levels would significantly improve the quality of life of diabetic patients, eliminating the need for frequent finger-prick tests and providing better glycaemic control with lower risk of hypoglycaemia. In this context, the latest advances in glucose-responsive microneedle-based transdermal insulin delivery are here compiled with a thorough analysis of the delivery mechanisms and challenges lying ahead in their clinical translation. Two main groups of microneedle-based systems have been developed so far: glucose oxidase-containing and phenylboronic acid-containing systems. Both strategies in combination have also been tested and two other novel strategies are under development, namely electronic closed-loop and glucose transporter-based systems. Results from preclinical studies conducted using these different types of glucose-triggered release systems are comprehensively discussed. Altogether, this analysis from both a mechanistic and translational perspective will provide rationale and/or guidance for future trends in the research hotspot of glucose-responsive microneedle-based insulin delivery systems.

Coexistence of a fluid responsive state and venous congestion signals in critically ill patients: a multicenter observational proof-of-concept study.

BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.

Impact of Rare Earth Elements on CaCO3 Crystallization: Insights into Kinetics, Mechanisms, and Crystal Morphology.

This study investigated the crystallization kinetics and mechanisms of calcium carbonate (CaCO3) in the presence of rare earth elements (REEs) including lanthanum (La), neodymium (Nd), and dysprosium (Dy). Through a comprehensive approach utilizing UV-vis spectrophotometry, powder X-ray diffraction, and high-resolution electron microscopy, we examined the effects of REEs on CaCO3 growth from solution at varying concentrations and combinations of REEs. Our findings highlight that even trace amounts of REEs significantly decelerate the rate of CaCO3 crystallization, also leading to alterations in crystal morphology and mechanisms of growth. The impact of REEs becomes more pronounced at higher concentrations and atomic mass, although the potential formation of poorly ordered REEs carbonate precursor phases can result in a decrease in the REE3+/Ca2+ ratio, influencing the crystallization rate of CaCO3. Vaterite and calcite were identified as the main crystallized polymorphs, with vaterite exhibiting distinct growth defects and calcite developing complex morphologies at higher REEs concentrations and an internal architecture suggesting a nonclassical growth route. We propose that REEs ions selectively adsorb onto different calcite surfaces, impeding growth on specific sites and resulting in intricate morphologies.

Assessment of In Vitro Release Testing Methods for Colloidal Drug Carriers: The Lack of Standardized Protocols.

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters in the development and quality control of drug-loaded nano- and microcarriers. This lack of standardized protocols occurs due to the difficulties encountered in separating the released drug from the encapsulated one. This review aims to compare the most frequent types of release testing methods (i.e., membrane diffusion techniques, sample and separate methods and in situ detection techniques) in terms of the advantages and disadvantages of each one and of the key parameters that influence drug release in each case.

Prevalence, risk factors and echocardiographic predictors of pulmonary hypertension in systemic lupus erythematosus: towards a screening protocol.

BACKGROUND: Systemic lupus erythematosus (SLE) significantly affects the lungs and heart, and pulmonary hypertension (PH) is a severe manifestation that leads to considerable morbidity and mortality. OBJECTIVES: We aimed to determine the prevalence and risk factors of probable SLE-PH, assess the main echocardiographic predictors and develop a potential screening strategy. METHODS: A prospective single-centre study was conducted on 201 patients with SLE who underwent transthoracic echocardiography. Patients meeting PH criteria were referred for right heart catheterisation (RHC). RESULTS: Among patients, 88.56% were women, 85.57% were of Spanish origin and 43.78% had structural heart disease. Out of these, 16 (7.96%) had intermediate or high probability criteria for PH according to European Society of Cardiology (ESC) 2022. Six RHCs confirmed PH with a prevalence of 2.99% for SLE-PH and 1.99% for SLE-pulmonary arterial hypertension (PAH). KEY RISK FACTORS: Key risk factors included age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered pulmonary function tests (PFTs). PH was linked to a higher Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SDI) (mean SDI 4.75 vs 2.05, p<0.001) and increased mortality risk in a 2-year follow-up (12.50% vs 1.08%, p=0.002). CONCLUSION: In our cohort, 7.96% of patients with SLE had an intermediate or high PH probability. By RHC, six patients (2.99%) met the ESC/European Respiratory Society criteria for PH and four (1.99%) for PAH. The main risk factors were older age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered PFTs. PH was a severe SLE complication, suggesting the need for earlier diagnosis through data-driven screening to reduce associated morbidity and mortality.

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci.

AIM: Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at ≤35 years of age was performed. MATERIALS AND METHODS: Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age ≤35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data. RESULTS: The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 × 10-9 ), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p < 10-5 , including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 × 10-8 ). CONCLUSIONS: This study expands the set of known genetic loci for severe periodontitis with an age of onset ≤35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health.

Suppressing the rhamnogalacturonan lyase gene FaRGLyase1 preserves RGI pectin degradation and enhances strawberry fruit firmness.

Plant rhamnogalacturonan lyases (RGLyases) cleave the backbone of rhamnogalacturonan I (RGI), the "hairy" pectin and polymer of the disaccharide rhamnose (Rha)-galacturonic acid (GalA) with arabinan, galactan or arabinogalactan side chains. It has been suggested that RGLyases could participate in remodeling cell walls during fruit softening, but clear evidence has not been reported. To investigate the role of RGLyases in strawberry softening, a genome-wide analysis of RGLyase genes in the genus Fragaria was performed. Seventeen genes encoding RGLyases with functional domains were identified in Fragaria × ananassa. FaRGLyase1 was the most expressed in the ripe receptacle of cv. Chandler. Transgenic strawberry plants expressing an RNAi sequence of FaRGLyase1 were obtained. Three transgenic lines yielded ripe fruits firmer than controls without other fruit quality parameters being significantly affected. The highest increase in firmness achieved was close to 32%. Cell walls were isolated from ripe fruits of two selected lines. The amount of water-soluble and chelated pectins was higher in transgenic lines than in the control. A carbohydrate microarray study showed a higher abundance of RGI epitopes in pectin fractions and in the cellulose-enriched fraction obtained from transgenic lines. Sixty-seven genes were differentially expressed in transgenic ripe fruits when compared with controls. These genes were involved in various physiological processes, including cell wall remodeling, ion homeostasis, lipid metabolism, protein degradation, stress response, and defense. The transcriptomic changes observed in FaRGLyase1 plants suggest that senescence was delayed in transgenic fruits.