Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: A Study on Behalf of the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy Group (GETH).

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed.

Genome organization around nuclear speckles drives mRNA splicing efficiency.

The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies1,2. One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing3. What functional role, if any, speckles might play in the process of mRNA splicing is unclear4,5. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.

Considering the cellular landscape in marrow stimulation techniques for cartilage repair.

BACKGROUND: Marrow stimulation is a common reparative approach to treat injuries to cartilage and other soft tissues (e.g., rotator cuff). It involves the recruitment of bone marrow elements and mesenchymal stem cells (MSCs) into the defect, theoretically initiating a regenerative process. However, the resulting repair tissue is often weak and susceptible to deterioration with time. The populations of cells at the marrow stimulation site (beyond MSCs), and their contribution to inflammation, vascularity, and fibrosis, may play a role in quality of the repair tissue. SUMMARY: In this review, we accomplish three goals: 1) systematically review clinical trials on the augmentation of marrow stimulation and evaluate their assumptions on the biological elements recruited; 2) detail the cellular populations in bone marrow and their impact on healing; and 3) highlight emerging technologies and approaches that could better guide these specific cell populations towards enhanced cartilage or soft tissue formation. KEY MESSAGES: We found that most clinical trials do not account for cell heterogeneity, nor do they specify the regenerative element recruited, and those that do typically utilize descriptions such as "clots", "elements", and "blood". Furthermore, our review of bone marrow cell populations demonstrates a dramatically heterogenous cell population, including hematopoietic cells, immune cells, fibroblasts, macrophages, and only a small population of MSCs. Finally, the field has developed numerous innovative techniques to enhance the chondrogenic potential (and reduce the anti-regenerative impacts) of these various cell types. We hope this review will guide approaches that account for cellular heterogeneity and improve marrow stimulation techniques to treat chondral defects.

Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Designing an antimicrobial film for wound applications incorporating bacteriophages and ε-poly-l-lysine.

Alginate-based dressings have been shown to promote wound healing, leveraging the unique properties of alginate. This work aimed to develop and characterize flexible individual and bilayered films to deliver bacteriophages (phages) and ε-Poly-l-lysine (ε-PLL). Films varied in different properties. The moisture content, swelling and solubility increased with higher alginate concentrations. The water vapour permeability, crucial in biomedical films to balance moisture levels for effective wound healing, reached optimal levels in bilayer films, indicating these will be able to sustain an ideal moist environment. The bilayer films showed improved ductility (lower tensile strength and increased elongation at break) compared to individual films. The incorporated phages maintained viability for 12 weeks under vacuum and refrigerated conditions, and their release was sustained and gradual. Antibacterial immersion tests showed that films with phages and ε-PLL significantly inhibited Pseudomonas aeruginosa PAO1 growth (>3.1 Log CFU/cm2). Particle release was influenced by the swelling degree and diffusional processes within the polymer network, providing insights into controlled release mechanisms for particles of varying size (50 nm to 6 µm) and charge. The films developed, demonstrated modulated release capabilities for active agents, and may show potential as controlled delivery systems for phages and wound healing adjuvants.

Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Coherent control of two Jaynes-Cummings cavities.

We uncover new features on the study of a two-level atom interacting with one of two cavities in a coherent superposition. The James-Cummings model is used to describe the atom-field interaction and to study the effects of quantum indefiniteness on such an interaction. We show that coherent control of the two cavities in an undefined manner allows novel possibilities to manipulate the atomic dynamics on demand which are not achievable in the conventional way. In addition, it is shown that the coherent control of the atom creates highly entangled states of the cavity fields taking a Bell-like or Schrödinger-cat-like state form. Our results are a step forward to understand and harness quantum systems in a coherent control, and open a new research avenue in the study of atom-field interaction exploiting quantum indefiniteness.

Active Low-Density Polyethylene-Based Films by Incorporating α-Tocopherol in the Free State and Loaded in PLA Nanoparticles: A Comparative Study.

In this work, alpha-tocopherol (α-TOC) was encapsulated in poly(lactic acid) nanoparticles (PLA NPs) and added to low-density polyethylene (LDPE) films with the aim of producing an active film for food packaging applications. PLA NPs loaded with α-TOC were produced through nanoprecipitation and dried using two methods (freeze-dryer and oven). LDPE-based films with final polymeric matrix concentrations of 10 and 20 g/kg were then produced through blow extrusion. The results showed that LDPE-based films loaded with α-TOC can be produced using blow extrusion, and a good distribution of PLA NPs can be obtained within the LDPE matrix as observed using scanning electron microscopy (SEM). The mechanical properties were affected by the incorporation of α-TOC and PLA NPs loaded with α-TOC, with the observation of a decrease in tensile strength and Young's Modulus values and an increase in elongation at break. Regarding water vapor permeability, the films showed a reduction in the values with the addition of α-TOC and PLA NPs loaded with α-TOC compared to the LDPE film (control). Films with α-TOC in the free state and loaded in PLA NPs showed antioxidant activity, but their behavior was affected by the encapsulation process.

Sarcopenic obesity in older adults: a clinical overview.

Sarcopenic obesity is characterized by a concurrent decline in muscle mass and function, along with increased adipose tissue. Sarcopenic obesity is a growing concern in older adults owing to significant health consequences, including implications for mortality, comorbidities and risk of developing geriatric syndromes. A 2022 consensus statement established a new definition and diagnostic criteria for sarcopenic obesity. The pathophysiology of this condition involves a complex interplay between muscle, adipose tissue, hormonal changes, inflammation, oxidative stress and lifestyle factors, among others. Sarcopenic obesity is treated with a range of management approaches, such as lifestyle interventions, exercise, nutrition and medical therapies. Emerging therapies that were developed for treating other conditions may be relevant to sarcopenic obesity, including novel pharmacological agents and personalized approaches such as precision medicine. In this Review, we synthesize the current knowledge of the clinical importance of sarcopenic obesity, its assessment and diagnosis, along with current and emerging management strategies.

Resveratrol-loaded octenyl succinic anhydride modified starch emulsions and hydroxypropyl methylcellulose (HPMC) microparticles: Cytotoxicity and antioxidant bioactivity assessment after in vitro digestion.

Hydroxypropyl methylcellulose (HPMC)-based microparticles and modified starch emulsions (OSA-MS) were loaded with resveratrol and characterized regarding their physicochemical and thermal properties. Both delivery systems were subject to an in vitro gastrointestinal digestion to assess the bioaccessibility of resveratrol. In addition, cell-based studies were conducted after in vitro digestion and cytotoxicity and oxidative stress were assessed. HPMC-based microparticles displayed higher average sizes (d) and lower polydispersity index (PDI) (d = 948 nm, PDI < 0.2) when compared to OSA-MS-based emulsions (d = 217 nm, PDI < 0.3). Both proved to protect resveratrol under digestive conditions, leading to an increase in bioaccessibility. Resveratrol-loaded HPMC-microparticles showed a higher bioaccessibility (56.7 %) than resveratrol-loaded emulsions (19.7 %). Digested samples were tested in differentiated co-cultures of Caco-2 and HT29-MTX, aiming at assessing cytotoxicity and oxidative stress, and a lack of cytotoxicity was observed for all samples. Results displayed an increasing antioxidant activity, with 1.6-fold and 1.4-fold increases over the antioxidant activity of free resveratrol, for HPMC-microparticles and OSA-MS nanoemulsions, respectively. Our results offer insight into physiological relevancy due to assessment post-digestion and highlight the protection that the use of micro-nano delivery systems can confer to resveratrol and their potential to be used as functional food ingredients capable of providing antioxidant benefits upon consumption.

Changes in the uninjected contralateral eye after intravitreal brolucizumab for exudative age-related macular degeneration.

PURPOSE: Herein we describe the change in the amount of macular oedema in one eye after contralateral intravitreal brolucizumab injections in a patient with neovascular age-related macular degeneration (nAMD). CASE REPORT: A patient with bilateral nAMD underwent intravitreal bevacizumab injections in both eyes with little improvement in the best-corrected visual acuity (BCVA) and central macular exudation. The treatment was switched to aflibercept, but there was incomplete drying of the macula in both eyes. After uneventful cataract extraction, the central macular thickness (CMT) increased markedly in the operated left eye (LE), which was unresponsive to subtenon triamcinolone and further intravitreal aflibercept. Cataract surgery was also performed in the right eye (RE) combined with an intravitreal sustained-release dexamethasone implant. Nevertheless, the CMT increased. Intravitreal brolucizumab injections were performed in the RE with almost complete disappearance of the oedema in the treated eye. Concurrently, the contralateral uninjected eye showed a remarkable decrease in CMT. Five months after the first brolucizumab injection, the macular exudation increased again in both eyes. A second brolucizumab injection was performed in the RE only, and was followed by a prompt reduction in CMT in both the injected RE and uninjected LE. CONCLUSIONS: Although contralateral retinal changes have been described for many other vascular endothelial growth factor inhibitors, there is little evidence for brolucizumab. We describe a repeated dose- and time-related effect on the uninjected eye in a case of nAMD.

Anesthetic considerations in the perioperative management of the patient with Jarcho-Levin Syndrome.

Jarcho-Levin syndrome is an eponym used to describe a spectrum of small thoracic skeletal dysplasias with variable involvement of vertebrae and ribs. Initially considered lethal, it is currently compatible with life in its mildest forms. Bone alterations that lead to a restrictive respiratory pattern, recurrent respiratory infections and particular phenotype, can make perioperative anesthetic management difficult. The proper assessment of the airway is of special interest because it presents predictors of a difficult airway, as well as the prevention, early diagnosis and adequate treatment of respiratory failure. We present the case of a patient with Jarcho-Levin Syndrome who underwent vertebral distraction surgery, with its most notable implications in anesthetic management.

Medications mostly associated with hematuria: assessment of the EudraVigilance and Food and Drug Administration pharmacovigilance databases entries.

BACKGROUND: Drugs may have a direct causative role in triggering hematuria. The range of medications which may be responsible for hematuria is wide, but little is known on those which are most frequently involved. The aim of our study was to identify and compare drugs mostly related with hematuria. METHODS: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the EudraVigilance (EV) database were queried to identify the drugs which were associated the most with hematuria individual reports till 30 September 2021. Rivaroxaban, aspirin, warfarin sodium, clopidogrel bisulfate, dabigatran etexilate mesylate, apixaban, warfarin, cyclophosphamide, lansoprazole, enoxaparin sodium, and ibuprofen were analyzed. Analysis per gender, age and severity was performed. Disproportional analysis was performed to compare drugs. RESULTS: Overall, 15,687 reports of hematuria were recorded in the FDA database and 15 007 in the EV database. Rivaroxaban and Warfarin appear to be the most dangerous medications in terms of hematuria when compared to the other medications (PRR>1, P<0.05) while apixaban is the safest one (PRR<1, P<0.05) when compared to the other medications. In terms of severity only 162/15 007 (1.08%) were fatal. Between the drugs analyzed cyclophosphamide 7.2%, enoxaparin (3%) and dabigatran (2.5%) presented a higher number of fatal hematuria episodes when compared to the other drugs (<1%). CONCLUSIONS: Anticoagulants and antiplatelets are more frequently related to hematuria episodes however some differences exist between them. Particularly warfarin and rivaroxaban should be prescribed with caution in patients at increased risk of hematuria. Prescribers should inform those treated with these medications about the risk of hematuria and its sequelae.

Evaluating the long term effectiveness of a Mediterranean marine protected area to tackle the effects of invasive and range expanding herbivorous fish on rocky reefs.

Here we provide evidence, along an 8-year period time-series based on multifaceted data from a Mediterranean marine protected area (MPA), whether protection can tackle invasive and range expanding herbivore fishes, and their effects on the algal resource availability, taking into account the population trends of predatory fishes, fisheries catches of herbivore fishes and sea surface temperature (SST) through time. Our findings pointed out that an ineffective in restoring top-down control process MPA may facilitate, rather than alleviate, the sudden and enduring population burst of invasive and range-expanding herbivorous fishes at tipping points of abrupt change. This subsequently results in the deterioration of rocky reef habitats and the depletion of algal resources, with the tipping points of abrupt change for algal and herbivore fish species not overlapping chronologically. As sea temperature increases, ineffective or recently established MPAs may inadvertently facilitate the proliferation of invasive and range-expanding species, posing a significant challenge to management effectiveness and conservation objectives.

Coculture with porcine luteal cells during in vitro porcine oocyte maturation affects lipid content, cortical reaction and zona pellucida ultrastructure.

CONTEXT: In pigs, in vitro fertilisation (IVF) is associated with high polyspermy rates, and for this reason, in vitro embryo production (IVP) is still an inefficient biotechnology. Coculture with somatic cells is an alternative to improve suboptimal in vitro maturation (IVM) conditions. AIM: This study was conducted to test a coculture system of porcine luteal cells (PLC) and cumulus-oocyte complexes (COC) to improve oocyte metabolism. METHODS: COC were matured in vitro with PLC. Oocyte lipid content, mitochondrial activity, zona pellucida (ZP) digestibility and pore size, cortical reaction and in vitro embryo development were assessed. KEY RESULTS: Coculture reduced cytoplasmic lipid content in the oocyte cytoplasm without increasing mitochondrial activity. Although ZP digestibility and ZP pore number were not different between culture systems, ZP pores were smaller in the coculture. Coculture impacted the distribution of cortical granules as they were found immediately under the oolemma, and more of them had released their content in the ZP. Coculture with porcine luteal cells during IVM increased monospermic penetration and embryo development after IVF. CONCLUSIONS: The coculture of COC with PLC affects the metabolism of the oocyte and benefits monospermic penetration and embryo development. IMPLICATIONS: The coculture system with PLC could be an alternative for the conventional maturation medium in pigs.

Recent advances in oral delivery systems of resveratrol: foreseeing their use in functional foods.

Herein, we review the current state-of-the-art on the use of micro- and nano-delivery systems, a possible solution to some of the drawbacks associated with the incorporation of resveratrol in foods. Specifically, we present an overview of a wide range of micro-nanostructures, namely, lipidic and polymeric, used for the delivery of resveratrol. Also, the gastrointestinal fate of resveratrol-loaded micro-nanostructures, as a critical parameter for their use as functional food, is explored in terms of stability, bioaccessibility, and bioavailability. Different micro-nanostructures are of interest for the development of functional foods given that they can provide different advantages and properties to these foods and even be tailor-made to address specific issues (e.g., controlled or targeted release). Therefore, we discuss a wide range of micro-nanostructures, namely, lipidic and polymeric, used to deliver resveratrol and aimed at the development of functional foods. It has been reported that the use of some production methodologies can be of greater interest than others, for example, emulsification, solvent displacement and electrohydrodynamic processing (EHDP) enable a greater increase in bioaccessibility. Additionally, the use of coatings facilitates further improvements in bioaccessibility, which is likely due to the increased gastric stability of the coated micro-nanostructures. Other properties, such as mucoadhesion, can also help improve bioaccessibility due to the increase in gut retention time. Additionally, cytotoxicity (e.g., biocompatibility, antioxidant, and anti-inflammatory) and possible sensorial impact of resveratrol-loaded micro- and nano-systems in foods are highlighted.

Characterization of Sodium Alginate-Based Films Blended with Olive Leaf and Laurel Leaf Extracts Obtained by Ultrasound-Assisted Technology.

Due to environmental concerns, there is an increasing need to reduce the use of synthetic and non-renewable packaging materials to reduce waste and increase sustainability. This study aimed to characterise sodium alginate edible-based films (SA) incorporated with laurel leaf extract (LLE) and olive leaf extract (OLE) obtained by ultrasound-assisted extraction. Determination of total phenolic content, antioxidant, and antimicrobial activity was performed for the extracts and films. Also, thickness, tensile strength, elongation at break, modulus of elasticity, opacity and colour, moisture content, water vapour permeability (WVP), Fourier-transform infrared spectroscopy (FTIR) spectra, and surface morphology by scanning electron microscope (SEM) analyses were performed for the films. LLE yielded better results in terms of phenolic content (195 mg GAE/g), antioxidant (2.1 TE/g extract) and antimicrobial activity (MIC at 1% for Listeria monocytogenes and Staphylococcus aureus, and 1.8% for Enterococcus faecalis). For the films, the simultaneous incorporation of LLE 1% (w/v) and OLE 1% (w/v) resulted in a significant reduction of approximately 2 log CFU/g against S. aureus. The addition of LLE and OLE extracts also proved to improve barrier properties (lower WVP for SA films with LLE 1% + OLE 1%, 3.49 × 10-11 g m-1 s-1 Pa-1) and promoted changes in resistance and flexibility. The results demonstrated that active alginate-based films can be valuable for enhancing food preservation.