Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. METHODS: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 µg R21 plus 50 µg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. FINDINGS: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites. INTERPRETATION: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. FUNDING: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.

Increased glutamatergic neurotransmission between the retinohypothalamic tract and the suprachiasmatic nucleus of old mice.

Circadian rhythms synchronize to light through the retinohypothalamic tract (RHT), which is a bundle of axons coming from melanopsin retinal ganglion cells, whose synaptic terminals release glutamate to the ventral suprachiasmatic nucleus (SCN). Activation of AMPA-kainate and NMDA postsynaptic receptors elicits the increase in intracellular calcium required for triggering the signaling cascade that ends in phase shifts. During aging, there is a decline in the synchronization of circadian rhythms to light. With electrophysiological (whole-cell patch-clamp) and immunohistochemical assays, in this work, we studied pre- and postsynaptic properties between the RHT and ventral SCN neurons in young adult (P90-120) and old (P540-650) C57BL/6J mice. Incremental stimulation intensities (applied on the optic chiasm) induced much lesser AMPA-kainate postsynaptic responses in old animals, implying a lower recruitment of RHT fibers. Conversely, a higher proportion of old SCN neurons exhibited synaptic facilitation, and variance-mean analysis indicated an increase in the probability of release in RHT terminals. Moreover, both spontaneous and miniature postsynaptic events displayed larger amplitudes in neurons from aged mice, whereas analysis of the NMDA and AMPA-kainate components (evoked by RHT electrical stimulation) disclosed no difference between the two ages studied. Immunohistochemistry revealed a bigger size in the puncta of vGluT2, GluN2B, and GluN2A of elderly animals, and the number of immunopositive particles was increased, but that of PSD-95 was reduced. All these synaptic adaptations could be part of compensatory mechanisms in the glutamatergic signaling to ameliorate the loss of RHT terminals in old animals.

Two-Pole Nature of the Λ(1405) Resonance from Lattice QCD.

This Letter presents the first lattice QCD computation of the coupled channel πΣ-K[over ¯]N scattering amplitudes at energies near 1405 MeV. These amplitudes contain the resonance Λ(1405) with strangeness S=-1 and isospin, spin, and parity quantum numbers I(J^{P})=0(1/2^{-}). However, whether there is a single resonance or two nearby resonance poles in this region is controversial theoretically and experimentally. Using single-baryon and meson-baryon operators to extract the finite-volume stationary-state energies to obtain the scattering amplitudes at slightly unphysical quark masses corresponding to m_{π}≈200 MeV and m_{K}≈487 MeV, this study finds the amplitudes exhibit a virtual bound state below the πΣ threshold in addition to the established resonance pole just below the K[over ¯]N threshold. Several parametrizations of the two-channel K matrix are employed to fit the lattice QCD results, all of which support the two-pole picture suggested by SU(3) chiral symmetry and unitarity.

Advanced Image Stitching Method for Dual-Sensor Inspection.

Efficient image stitching plays a vital role in the Non-Destructive Evaluation (NDE) of infrastructures. An essential challenge in the NDE of infrastructures is precisely visualizing defects within large structures. The existing literature predominantly relies on high-resolution close-distance images to detect surface or subsurface defects. While the automatic detection of all defect types represents a significant advancement, understanding the location and continuity of defects is imperative. It is worth noting that some defects may be too small to capture from a considerable distance. Consequently, multiple image sequences are captured and processed using image stitching techniques. Additionally, visible and infrared data fusion strategies prove essential for acquiring comprehensive information to detect defects across vast structures. Hence, there is a need for an effective image stitching method appropriate for infrared and visible images of structures and industrial assets, facilitating enhanced visualization and automated inspection for structural maintenance. This paper proposes an advanced image stitching method appropriate for dual-sensor inspections. The proposed image stitching technique employs self-supervised feature detection to enhance the quality and quantity of feature detection. Subsequently, a graph neural network is employed for robust feature matching. Ultimately, the proposed method results in image stitching that effectively eliminates perspective distortion in both infrared and visible images, a prerequisite for subsequent multi-modal fusion strategies. Our results substantially enhance the visualization capabilities for infrastructure inspection. Comparative analysis with popular state-of-the-art methods confirms the effectiveness of the proposed approach.

Robust Multi-Modal Image Registration for Image Fusion Enhancement in Infrastructure Inspection.

Efficient multi-modal image fusion plays an important role in the non-destructive evaluation (NDE) of infrastructures, where an essential challenge is the precise visualizing of defects. While automatic defect detection represents a significant advancement, the determination of the precise location of both surface and subsurface defects simultaneously is crucial. Hence, visible and infrared data fusion strategies are essential for acquiring comprehensive and complementary information to detect defects across vast structures. This paper proposes an infrared and visible image registration method based on Euclidean evaluation together with a trade-off between key-point threshold and non-maximum suppression. Moreover, we employ a multi-modal fusion strategy to investigate the robustness of our image registration results.

Skeletal and Mechanistic Diversity in Ir-Catalyzed Cycloisomerizations of Allene-Tethered Pyrroles and Indoles.

Pyrroles and indoles bearing N-allenyl tethers participate in a variety of iridium-catalyzed cycloisomerization processes initiated by a C-H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro-indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane-fused tetrahydroindolizines can be obtained. Moreover, by using chiral ligands, these cascade processes can be carried out in an enantioselective manner. DFT studies provide insights into the underlying mechanisms and justify the observed chemo- regio- and stereoselectivities.

Gold(III) Auracycles featuring C(sp3)-Au-C(sp2) Bonds: Synthesis and Mechanistic Insights into the Cycloauration Step.

The direct auration of arenes is a key step in numerous gold-catalyzed reactions. Although reported more than 100 years ago, understanding of its underlying mechanism has been hampered by the difficulties in the isolation of relevant intermediates given the propensity of gold(III) species to undergo reductive elimination. Here, we report the synthesis and isolation of a new family of intriguing zwitterionic [C(sp3)^C(sp2)]-auracyclopentanes, as well as of their alkyl-gold(III) precursors and demonstrate their value as mechanistic probes to study the Csp2-Au bond-forming event. Experimental investigations employing Kinetic Isotope Effects (KIE), Hammett plot, and Eyring analysis provided important insights into the formation of the auracycle. The data suggest a SEAr mechanism wherein the slowest step might be the p-coordination between the arene and the gold(III) center, en route to the Wheland intermediate. We also show that these auracyclopentanes can work as catalysts in several gold-promoted transformations.

2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVES: Fatigue is prevalent in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and recognised as one of the most challenging symptoms to manage. The existence of multiple factors associated with driving and maintaining fatigue, and the evidence about what improves fatigue has led to a multifaceted approach to its management. However, there are no recommendations for fatigue management in people with I-RMDs. This lack of guidance is challenging for those living with fatigue and health professionals delivering clinical care. Therefore, our aim was to develop EULAR recommendations for the management of fatigue in people with I-RMDs. METHODS: A multidisciplinary taskforce comprising 26 members from 14 European countries was convened, and two systematic reviews were conducted. The taskforce developed the recommendations based on the systematic review of evidence supplemented with taskforce members' experience of fatigue in I-RMDs. RESULTS: Four overarching principles (OAPs) and four recommendations were developed. OAPs include health professionals' awareness that fatigue encompasses multiple biological, psychological and social factors which should inform clinical care. Fatigue should be monitored and assessed, and people with I-RMDs should be offered management options. Recommendations include offering tailored physical activity and/or tailored psychoeducational interventions and/or, if clinically indicated, immunomodulatory treatment initiation or change. Patient-centred fatigue management should consider the individual's needs and preferences, their clinical disease activity, comorbidities and other psychosocial and contextual factors through shared decision-making. CONCLUSIONS: These 2023 EULAR recommendations provide consensus and up-to-date guidance on fatigue management in people with I-RMDs.

Achieving clinical outcomes with benralizumab in severe eosinophilic asthma patients in a real-world setting: orbe II study.

BACKGROUND: The ORBE II study aimed to describe the characteristics and clinical outcomes of adult patients with severe eosinophilic asthma (SEA) treated with benralizumab in a real-world setting in Spain. METHODS: ORBE II (NCT04648839) was an observational, retrospective cohort study in adult SEA patients who had been prescribed benralizumab. Demographic and clinical data of 204 SEA patients were collected 12 months prior to benralizumab initiation (baseline) and at follow-up. Exacerbation rate, asthma symptoms, maintenance oral corticosteroid (OCS) use and lung function were evaluated, among other variables. RESULTS: A total of 204 SEA patients were evaluated. Mean (standard deviation, SD) age of the study population was 56.4 (12.4) years, 62.3% were women and mean (SD) duration of asthma was 15.1 (12.7) years. Median (Q1-Q3) follow-up duration was 19.5 (14.2-24.2) months. At baseline, 72.6% of the overall population (OP) presented blood eosinophil counts ≥ 300 cells/µL; 36.8% had comorbid chronic rhinosinusitis with nasal polyps (CRSwNP); 84.8% reported at least one severe exacerbation, and 29.1% were OCS-dependent. At 1 year of follow-up, patients receiving benralizumab treatment had a 85.6% mean reduction in exacerbations from baseline, and 81.4% of patients achieved zero exacerbations. We also found a clinically relevant mean (SD) increase in pre-bronchodilator (BD) FEV1 of 331 (413) mL, with 66.7% of patients achieving a pre-BD FEV1 increase ≥ 100 mL, and 46.3% of patients achieving a pre-BD FEV1 ≥ 80% of predicted. Regarding symptom control, 73.8% of the OP obtained an ACT score ≥ 20 points. After 1 year of follow-up, mean reduction in the daily OCS dose was 70.5%, and complete OCS withdrawal was achieved by 52.8% of the OCS-dependent patients. Almost half (43.7%) of the OP on benralizumab met all four criteria for clinical remission. Patients with concomitant CRSwNP obtained similar or enhanced outcomes. CONCLUSIONS: These data support the real-world benefits of benralizumab in SEA patients, and particularly in those with concomitant CRSwNP. TRIAL REGISTRATION: NCT04648839.

Developmental light deprivation transiently reduces the expression of vGluT2 and GluN2B in the rat ventral suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is the most important circadian clock in mammals. The SCN synchronizes to environmental light via the retinohypothalamic tract (RHT), which is an axon cluster derived from melanopsin-expressing intrinsic photosensitive retinal ganglion cells. Investigations on the development of the nonimage-forming pathway and the RHT are scarce. Previous studies imply that light stimulation during postnatal development is not needed to make the RHT functional at adult stages. Here, we examined the effects of light deprivation (i.e., constant darkness (DD) rearing) during postnatal development on the expression in the ventral SCN of two crucial proteins for the synchronization of circadian rhythms to light: the presynaptic vesicular glutamate transporter type 2 (vGluT2) and the GluN2B subunit of the postsynaptic NMDA receptor. We found that animals submitted to DD conditions exhibited a transitory reduction in the expression of vGluT2 (at P12-19) and of GluN2B (at P7-9) that was compensated at older stages. These findings support the hypothesis that visual stimulation during early ages is not decisive for normal development of the RHT-SCN pathway.

Tumor lysis syndrome is associated with worse outcomes in adult patients with acute lymphoblastic leukemia.

INTRODUCTION: Tumor lysis syndrome (TLS) occurs frequently during induction therapy for acute lymphoblastic leukemia (ALL). Patients are categorized into intermediate or high risk based on lactate dehydrogenase (LDH) value and white blood cell (WBC) count according to an expert panel, although no effort has been made to analyze TLS in ALL and its potential consequences. METHODS: We retrospectively analyzed TLS, variables associated with its occurrence and its impact in overall survival and mortality during induction in a cohort of ALL patients in their first induction regimen. RESULTS: A total of 138 patients were included. 52.9% were male and median age at diagnosis was 34 years. Most of them were treated with Hyper-CVAD (39.1%) or a modified CALGB 10403 regimen (37.7%). TLS was identified in 42 patients (30.4%), and half of them fulfilled criteria for clinical TLS (C-TLS). Median overall survival (OS) was the lowest in C-TLS patients. An LDH 3 times greater its upper normal limit (ULN) value and a WBC count equal or greater than 50✕109/l were associated with TLS development, and being male, hyperuricemia and an LDH 3 times greater its ULN value were associated with C-TLS development. C-TLS and AKI were associated with excess mortality during induction. CONCLUSION: TLS was identified in almost a third of ALL patients during induction therapy. Different thresholds for LDH value and WBC count as well as other variables that could identify patients at risk to developing this complication, which is associated with shorter OS. C-TLS confers a higher risk for mortality during induction.

Effectiveness of Land- and Water-based Exercise on Fatigue and Sleep Quality in Women With Fibromyalgia: The al-Ándalus Quasi-Experimental Study.

OBJECTIVE: To assess the effectiveness of 24 weeks of land- and water-based exercise on fatigue and sleep quality in women with fibromyalgia, and the persistence of changes 12 weeks after exercise cessation. DESIGN: Quasi-experimental study. SETTING: University facilities and fibromyalgia associations. PARTICIPANTS: Women with fibromyalgia (N=250; 50.8±7.6 years old). INTERVENTIONS: Participants were assigned to land-based exercise (n=83), water-based exercise (n=85), or no exercise control (n=82) groups. The intervention groups engaged in a similar multicomponent exercise program for 24 weeks. MAIN OUTCOME MEASURES: The Multidimensional Fatigue Inventory and Pittsburgh Sleep Quality Index were used. RESULTS: Intention-to-treat analyses revealed that, compared with the control group, at week 24: (i) the land-based exercise group improved physical fatigue (mean difference -0.9 units; 95% confidence interval -1.7 to -0.1; Cohen's d=0.4) and (ii) the water-based exercise group improved general fatigue (-0.8; -1.4 to -0.1, d=0.4), and global sleep quality (-1.6; -2.7 to -0.6, d=0.6). Additionally, compared with the land-based exercise group, the water-based exercise group improved global sleep quality (-1.2; -2.2 to -0.1, d=0.4). Changes were generally not sustained at week 36. CONCLUSION: Land-based multicomponent exercise improved physical fatigue, whereas water-based exercise improved general fatigue and sleep quality. The magnitude of the changes was small-to-medium, and no benefits were maintained after exercise cessation.

Longitudinal association of sedentary time and physical activity with pain and quality of life in fibromyalgia.

OBJECTIVE: To analyze changes over time and the predictive value of baseline and changes of sedentary time (ST) and physical activity (PA) on pain, disease impact, and health-related quality of life (HRQoL) at 2- and 5-year follow-up in women with fibromyalgia. METHODS: This is a longitudinal and exploratory study with three time points. A total of 427 women with fibromyalgia (51.4 ± 7.6 years) were followed after 2 (n = 172) and 5 years (n = 185). ST and PA (light and moderate-to-vigorous [MVPA]) were assessed using triaxial accelerometers. Pain, disease impact, and HRQoL were measured using: pressure pain threshold, the pain subscale of the revised fibromyalgia impact questionnaire (FIQR), the bodily pain subscale of the 36-item short-form health survey (SF-36), a visual analog scale (VAS), the FIQR, and the SF-36 physical and mental components. RESULTS: Over 5 years, pressure pain threshold, ST, light PA, and MVPA variables were worsened, while FIQR and SF-36 variables were improved (Cohen's d < 0.1-0.3). Baseline ST or light PA were not associated with future outcomes, whereas greater MVPA at baseline was associated with better SF-36 bodily pain at 5-year follow-up (ß = 0.13). Reducing ST and increasing light PA were associated with better bodily pain (ß = -0.16 and 0.17, respectively) and SF-36 physical component (ß = -0.20 and 0.17, respectively) at 5-year follow-up. Increasing MVPA was associated with less pain (pressure pain threshold, VAS, and FIQR-pain) and better SF-36 physical component at 2- and 5-year follow-up (ß's from -0.20 to 0.21). CONCLUSIONS: Objectively measured variables slightly worsened over years, while for self-reported outcomes there was a trend for improvement. Reductions in ST and increases in light PA and MVPA were associated with better HRQoL at 5-year follow-up, and increases in MVPA were additionally associated with better pain and HRQoL at 2-year follow-up.

Oncological and functional outcomes of transoral laser surgery for hypopharyngeal carcinoma.

BACKGROUND: Surgical resection or radiotherapy (RT) are standard approaches for early-staged hypopharyngeal squamous cell carcinoma (HPSCC). Transoral laser microsurgery (TOLMS) seems to provide good oncological and functional results with few local complications. The aim of our study was to analyze the outcomes of TOLMS, with or without neck dissection or RT, in the treatment of HPSCC in a tertiary referral center. METHODS: A retrospective study was conducted in patients with early T-category (T1-T2) HPSCC treated by TOLMS. RESULTS: A total of 34 patients were included in the study. The series includes 17 (50%) T1 and 17 (50%) T2 classified tumors. The 5-year overall survival and disease-specific survival rates were 51% and 66%, respectively, with a 5-year local control rate of 92%. All patients reassumed oral diet and none of them had a tracheostomy at the end of the follow-up. CONCLUSIONS: TOLMS offers an effective treatment option in terms of oncologic control and function preservation in locally circumscribed HPSCC.

Complications related to the Cook-Swartz implantable Doppler probe use in head and neck microvascular reconstruction: a systematic review.

PURPOSE: Vascular perfusion research has been dedicated to identify inexpensive, effective, and easy to use methods to assess free flap perfusion for both buried and non-buried flaps. METHODS: Systematic review of complications in patients underwent Head and Neck microsurgical reconstruction and vascular implantable Doppler monitoring. RESULTS: Sixteen articles were included for qualitative analysis. 2535 (92.2%) patients received IDP monitorization. Venous thrombosis was the most common vascular complication effecting 28 (1.1%). Regarding complications potentially related to the use of the IDP, just one study described the presence of granuloma formation along the suture line in 2 (0.07%) patients. CONCLUSIONS: Our findings indicated that Cook-Swartz IDP will represents a safe and effective device for FF monitoring in HN reconstructive micro-surgery. A detailed prospective registration of the results and complications related to the use of IDP remains mandatory to precisely estimate results, cost, and complications.

The use of a thin guide-wire for urethral definition in prostate SBRT treatments with Cyberknife.

PURPOSE: To study and analyze the effect of the use of a thin guide-wire instead of a Foley catheter for urethral definition in prostate stereotactic body radiation therapy (SBRT) treatments and to compare treatment parameters in both situations. MATERIAL AND METHODS: Thirty-seven prostate SBRT patients were employed in this study. A Foley catheter was employed in nine of them, and a guide-wire was employed in the other 28 patients. For each of the 28 patients in which the guide-wire was employed, a comparison between urethral positions in both situations was performed, allowing for a margin definition of the urethra when a Foley catheter was employed. Displacements of the prostate during treatment were obtained, allowing for an analysis of prostate positions in both situations. Also, different treatment parameters such as the number of treatment interruptions, couch movements performed, and x-rays needed were gathered. RESULTS: Large differences between urethral positions can be found in the anterior-posterior (AP) directions compared to those in the lateral (LAT) direction. Differences are also larger in areas closer to the base of the prostate, where margins applied in the case of using a Foley catheter are 16 mm with a mean displacement of 6 mm in the posterior direction. No differences in the treatment parameters were found during treatment in both situations. The difference found in absolute prostate pitch rotations suggests that the Foley catheter provokes a shift of the prostate position, which does not occur when employing the guide-wire. CONCLUSIONS: Foley catheters shift the urethral position, making them a wrong surrogate of the urethra when no catheters are present. The margins needed to assess uncertainties introduced by the use of a Foley catheter are larger than those usually applied. The use of a Foley catheter did not present any additional difficulty during treatment delivery in terms of images employed or interruptions produced.

Adipose Tissue, Non-Communicable Diseases, and Physical Exercise: An Imperfect Triangle.

The study of adipose tissue has received considerable attention due to its importance not just in maintaining body energy homeostasis but also in playing a role in a number of other physiological processes. Beyond storing energy, adipose tissue is important in endocrine, immunological, and neuromodulatory functions, secreting hormones that participate in the regulation of energy homeostasis. An imbalance of these functions will generate structural and functional changes in the adipose tissue, favoring the secretion of deleterious adipocytokines that induce a pro-inflammatory state, allowing the development of metabolic and cardiovascular diseases and even some types of cancer. A common theme worldwide has been the development of professional guidelines for the control and treatment of obesity, with emphasis on hypocaloric diets and exercise. The aim of this review is to examine the pathophysiological mechanisms of obesity, considering the relationship among adipose tissue and two aspects that contribute positively or negatively to keeping a healthy body homeostasis, namely, exercise and noninfectious diseases. We conclude that the relationship of these aspects does not have homogeneous effects among individuals. Nevertheless, it is possible to establish some common mechanisms, like a decrease in pro-inflammatory markers in the case of exercise, and an increase in chronic inflammation in non-communicable diseases. An accurate diagnosis might consider the particular variables of a patient, namely their molecular profile and how it affects its metabolism, routines, and lifestyle; their underling health conditions; and probably even the constitution of their microbiome. We foresee that the development and accessibility of omics approaches and precision medicine will greatly improve the diagnosis, treatment, and successful outcomes for obese patients.

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma.

Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.

New Formulation of Platelet-Rich Plasma Enriched in Platelet and Extraplatelet Biomolecules Using Hydrogels.

Platelet-rich plasma (PRP) is an autologous biologic product used in several fields of medicine for tissue repair due to the regenerative capacity of the biomolecules of its formulation. PRP consists of a plasma with a platelet concentration higher than basal levels but with basal levels of any biomolecules present out of the platelets. Plasma contains extraplatelet biomolecules known to enhance its regenerative properties. Therefore, a PRP containing not only a higher concentration of platelets but also a higher concentration of extraplatelet biomolecules that could have a stronger regenerative performance than a standard PRP. Considering this, the aim of this work is to develop a new method to obtain PRP enriched in both platelet and extraplatelet molecules. The method is based on the absorption of the water of the plasma using hydroxyethyl acrylamide (HEAA)-based hydrogels. A plasma fraction obtained from blood, containing the basal levels of platelets and proteins, was placed in contact with the HEAA hydrogel powder to absorb half the volume of the water. The resulting plasma was characterized, and its bioactivity was analyzed in vitro. The novel PRP (nPRP) showed a platelet concentration and platelet derived growth factor (PDGF) levels similar to the standard PRP (sPRP), but the concentration of the extraplatelet growth factors IGF-1 (p < 0.0001) and HGF (p < 0.001) were significantly increased. Additionally, the cells exposed to the nPRP showed increased cell viability than those exposed to a sPRP in human dermal fibroblasts (p < 0.001) and primary chondrocytes (p < 0.01). In conclusion, this novel absorption-based method produces a PRP with novel characteristics compared to the standard PRPs, with promising in vitro results that could potentially trigger improved tissue regeneration capacity.

Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients.