Deep spatial-omics analysis of Head & Neck carcinomas provides alternative therapeutic targets and rationale for treatment failure.

Immune checkpoint inhibitor (ICI) therapy has had limited success (<30%) in treating metastatic recurrent Head and Neck Oropharyngeal Squamous Cell Carcinomas (OPSCCs). We postulate that spatial determinants in the tumor play a critical role in cancer therapy outcomes. Here, we describe the case of a male patient diagnosed with p16+ OPSCC and extensive lung metastatic disease who failed Nivolumab and Pembrolizumab/Lenvatinib therapies. Using advanced integrative spatial proteogenomic analysis on the patient's recurrent OPSCC tumors we demonstrate that: (i) unbiased tissue clustering based on spatial transcriptomics (ST) successfully detected tumor cells and enabled the investigation of phenotypic traits such as proliferation or drug-resistance genes in the tumor's leading-edge and core; (ii) spatial proteomic imagining used in conjunction with ST (SpiCi, Spatial Proteomics inferred Cell identification) can resolve the profiling of tumor infiltrating immune cells, (iii) ST data allows for the discovery and ranking of clinically relevant alternative medicines based on their interaction with their matching ligand-receptor. Importantly, when the spatial profiles of ICI pre- and post-failure OPSCC tumors were compared, they exhibited highly similar PD-1/PD-L1low and VEGFAhigh expression, suggesting that these new tumors were not the product of ICI resistance but rather of Lenvatinib dose reduction due to complications. Our work establishes a path for incorporating spatial-omics in clinical settings to facilitate treatment personalization.

Effect of a home-based inspiratory muscle training programme on functional capacity in postdischarged patients with long COVID: the InsCOVID trial.

BACKGROUND: Fatigue and exercise intolerance are the most common symptoms in patients with long COVID. AIMS: This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) programme improves maximal functional capacity in patients' long COVID after a previous admission due to SARS-CoV-2 pneumonia. METHODS: This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week IMT or usual care alone (NCT05279430). The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention.The primary endpoint was the change in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CIx- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints. RESULTS: The mean age of the sample and time to first visit after discharge were 50.4±12.2 years and 362±105 days, respectively. A total of 11 (42.3%) were female. At baseline, the mean of peakVO2, ventilatory efficiency and CIx were 18.9±5 mL/kg/min, 29.4±5.2 and 0.64±0.19, respectively. The IMT arm improved their peakVO2 significantly compared with usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p<0.001). Similar positive findings were found when evaluating changes for CIx and some QoL dimensions. We did not find significant changes in ventilatory efficiency. CONCLUSION: In long COVID patients with a previous admission due to SARS-CoV-2 pneumonia, IMT was associated with marked improvement in exercise capacity and QoL. TRIAL REGISTRATION NUMBER: NCT05279430.

Microencapsulation of Phenolic Extract from Sea Grape (Coccoloba uvifera L.) with Antimutagenic Activity.

This study aimed to microencapsulate the sea grape ethanolic extract by the spray drying process, characterizing the obtained powder, and evaluating its antimutagenicity activity. Microparticles showed a mean size of 6.28 µm and a spherical shape with a smooth surface. The powder had a low moisture content (4.02±0.92 %) and water activity (0.27±0.01), and high solubility (76±3.60 %). Moreover, hygroscopicity (14.75±2.63 g/100 g of powder) and bulk density (0.63±0.03 g/cm3 ) values suggested that this powder can be easily handled at a pilot or industrial scale. In addition, microencapsulation protected the extract against oxidation by ultraviolet light, improved its thermal stability, and its antimutagenicity activity was similar to fresh sea grape extract. In conclusion, the microencapsulation with maltodextrin by spray drying technique is an alternative to protect bioactive compounds from sea grapes against environmental conditions, maintaining their antimutagenic activity.

Clinical and Economic Impact of Long-Term Inhaled Corticosteroid Withdrawal in Patients with Chronic Obstructive Pulmonary Disease Treated with Triple Therapy in Spain.

Purpose: To determine the clinical and economic impact of inhaled corticosteroid (ICS) withdrawal in Spanish patients with COPD receiving triple therapy (TT) with ICS, long-acting ß2-agonist (LABA), and long-acting muscarinic antagonist (LAMA). Patients and Methods: This was an observational, retrospective study of BIG-PAC database medical records. Patients aged ≥40 years receiving TT from 2016 to 2018 were followed for 1 year. Two cohorts were identified: patients continuing TT (ICS+LABA+LAMA), and patients receiving TT with ICS withdrawn (LABA+LAMA). Variables included medication, exacerbations (moderate and severe), pneumonia, mortality, health resource use (HRU), and cost per patient/year. Cohorts were compared using propensity score matching (PSM). Multivariate statistical analysis using analysis of covariance and Cox proportional risks was conducted. Results: Of 6541 patients included, 5740 (87.8%) continued TT and 801 (12.2%) had ICS withdrawn. Patients with ICS withdrawal were younger, had lower disease burden, higher ICS doses, and more exacerbations compared with those continuing ICS. PSM matched 795 patients in each cohort. Mean age was 68.5 years (SD: 11.2), 69.9% were male, and mean Charlson index was 2.0. Patients with ICS withdrawal had more total exacerbations in the 12 months following withdrawal compared with patients continuing TT (36.6% vs 31.4%; p=0.030). No significant differences were found for pneumonia (3.3% vs 3.6%; p=0.583) and mortality (9.9% vs 7.5%; p=0.092). Median time to first exacerbation was shorter in patients with ICS withdrawal compared with those continuing ICS (HR: 0.69, 95% CI: 0.57-0.83; p<0.001). Mean health cost per patient/year among patients with ICS withdrawal was higher than those continuing TT (€2993 vs €2130; p<0.001). Conclusion: ICS withdrawal in patients with COPD receiving TT was associated with increased exacerbations, HRU, and costs compared with continuing TT, with health and economic impacts on patients and the Spanish National Healthcare System, respectively. Pneumonia and mortality rates were similar between groups.

Poly(hydrophobic Amino Acids) and Liposomes for Delivery of Vaccine against Group A Streptococcus.

Adjuvants and delivery systems are essential components of vaccines to increase immunogenicity against target antigens, particularly for peptide epitopes (poor immunogens). Emulsions, nanoparticles, and liposomes are commonly used as a delivery system for peptide-based vaccines. A Poly(hydrophobic amino acids) delivery system was previously conjugated to Group A Streptococcus (GAS)-derived peptide epitopes, allowing the conjugates to self-assemble into nanoparticles with self adjuvanting ability. Their hydrophobic amino acid tail also serves as an anchoring moiety for the peptide epitope, enabling it to be integrated into the liposome bilayer, to further boost the immunological responses. Polyleucine-based conjugates were anchored to cationic liposomes using the film hydration method and administered to mice subcutaneously. The polyleucine-peptide conjugate, its liposomal formulation, and simple liposomal encapsulation of GAS peptide epitope induced mucosal (saliva IgG) and systemic (serum IgG, IgG1 and IgG2c) immunity in mice. Polyleucine acted as a potent liposome anchoring portion, which stimulated the production of highly opsonic antibodies. The absence of polyleucine in the liposomal formulation (encapsulated GAS peptide) induced high levels of antibody titers, but with poor opsonic ability against GAS bacteria. However, the liposomal formulation of the conjugated vaccine was no more effective than conjugates alone self-assembled into nanoparticles.

Antimicrobial Effects of Aqueous Extract from Calyces of Hibiscus sabdariffa in CD-1 Mice Infected with Multidrug-Resistant Enterohemorrhagic Escherichia coli and Salmonella Typhimurium.

To determinate the antimicrobial effect of chloramphenicol and aqueous extract against multidrug-resistant enterohemorrhagic Escherichia coli (EHEC) and Salmonella enterica serovar Typhimurium in CD-1 mice. Aqueous extract was isolated from Hibiscus sabdariffa calyces. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of chloramphenicol and aqueous extract were determined for EHEC and S. Typhimurium. Nine groups of six mice each were formed. Three groups were inoculated orally with 1 × 104 colony-forming units (CFU) of S. Typhimurium, three groups were inoculated with 1 × 104 CFU of EHEC and the remaining three groups were not inoculated. Six hours postinoculation, the mice of some groups were orally administered solutions of aqueous extract (50 mg/mL), chloramphenicol (82 µg/mL), or isotonic saline. The EHEC and S. Typhimurium concentration in all mice feces was determined. For both pathogens, the MIC and MBC values of aqueous extract were 20 y 50 mg/mL, respectively; for chloramphenicol, they were between 17.5 and 82 µg/mL. EHEC and S. Typhimurium were not detected in the feces of mice that were administered aqueous extract on the 2nd and 3rd days posttreatment. Furthermore, these mice recovered from the infection. In contrast, in mice not treated, or treated with chloramphenicol alone, pathogens were isolated from their feces throughout the study, and some mice died. The H. sabdariffa calyx extracts could be an alternative to control multidrug-resistant bacteria in humans and animals.

Encapsulation by Electrospraying of Anticancer Compounds from Jackfruit Extract (Artocarpus heterophyllus Lam): Identification, Characterization and Antiproliferative Properties.

BACKGROUND: Compounds with biological activities had been reported in the jackfruit. These compounds are susceptible to structural changes such as isomerization and/or loss of bonds due to environmental factors. Then, the encapsulation for protecting is a necessary process. OBJECTIVE: In this study, encapsulation of High-Value Biological Compounds (HVBC) was performed using High Degree of Polymerization Agave Fructans (HDPAF) and Whey Protein (WP) as encapsulating materials to preserve the biological properties of the HVBC. METHODS: The extract was characterized by HPLC-MS in order to show the presence of compounds with preventive or therapeutic effects on chronic degenerative diseases such as cancer. The micrographs by Scanning Electron Microscopy (SEM), Thermal Analysis (TGA and DSC), photostabilization and antiproliferation of M12.C3.F6 cell line of capsules were evaluated. RESULTS: The micrographs of the nanocapsules obtained by Scanning Electron Microscopy (SEM) showed spherical capsules with sizes between 700 and 800nm. No cracks, dents or deformations were observed. The Thermogravimetric Analysis (TGA) evidenced the decomposition of the unencapsulated extract ranging from 154 to 221°C. On the other hand, the fructan-whey protein mixture demonstrated that nanocapsules have a thermoprotective effect because the decomposition temperature of the encapsulated extract increased 32.1°C. Differential Scanning Calorimetry (DSC) exhibited similar values of the glass transition temperature (Tg) between the capsules with and without extract; which indicates that the polymeric material does not interact with the extract compounds. The photoprotection study revealed that nanocapsules materials protect the jackfruit extract compounds from the UV radiation. Finally, the cell viability on the proliferation of M12.C3.F6 cell line was not affected by powder nanocapsules without jackfruit extract, indicating that capsules are not toxic for these cells. However, microcapsules with jackfruit extract (50µg/ml) were able to inhibit significantly the proliferation cells. CONCLUSION: The encapsulation process provides thermoprotection and photostability, and the antiproliferative activity of HVBC from jackfruit extract was preserved.

Rapid progression of carotid stenosis was rare in a large integrated healthcare system during an eight-year period.

OBJECTIVE: Few studies have evaluated the rapid progression of carotid stenosis on a large scale. We created a custom software algorithm to analyze an electronic medical record database to examine the natural progression of carotid stenosis, identify a subset of patients with rapid progression, and evaluate the specific patient risk factors associated with this rapid progression. METHODS: Patients in a large integrated healthcare system who had undergone two or more carotid ultrasound scans from August 2010 to August 2018 were identified. We did not distinguish between those with an established carotid stenosis diagnosis and those with a screening ultrasound scan. We used our novel algorithm to extract data from their carotid ultrasound reports. The degrees of carotid stenosis were categorized as follows: level 1, 0% to 39%; level 2, 40% to 59%; level 3, 60% to 79%; level 4, 80% to 99%; and level 5, complete occlusion. The primary endpoint was rapid vs slow progression of carotid stenosis, with rapid progression defined as an increase of two or more levels within any 18-month period of the study, regardless of the date of the initial ultrasound scan. The association of the demographic and clinical characteristics with rapid progression was assessed by univariable and multivariable logistic regression. RESULTS: From a cohort of 4.4 million patients, we identified 4982 patients with two or more carotid ultrasound scans and a median follow-up period of 13.1 months (range, 0.1-93.7 months). Of the 4982 patients, 879 (17.6%) had shown progression of carotid stenosis. Only 116 patients (2.3%) had had progression to level 4 (80%-99% stenosis) from any starting level during a median of 11.5 months. A total of 180 patients (3.6%) were identified as experiencing rapid progression during a median follow-up of 9.9 months. The final multivariable analysis showed that younger age (P < .01), white race (P = .02), lower body mass index (P = .01), a diagnosis of peripheral arterial disease (P = .03), and a diagnosis of transient ischemic attack (P < .01) were associated with rapid progression. CONCLUSIONS: Using a novel algorithm to extract data from >4 million patient records, we found that rapid progression of carotid stenosis appears to be rare. Although 17.6% of patients showed any degree of progression, only 3.6% had experienced rapid progression. Among those with any disease progression, 20.5% had experienced rapid progression. Although the overall incidence of rapid progression was low, patients with any progression might warrant close follow-up, especially if they have the associated risk factors for rapid progression. The custom software algorithm might be a powerful tool for creating and evaluating large datasets.

In vitro larvicidal and in vivo anthelmintic effects of Oxalis tetraphylla (Oxalidaceae) hydroalcoholic extract against Haemonchus contortus in lambs.

The in vitro larvicidal and in vivo anthelmintic effects of Oxalis tetraphylla hydroalcoholic extract (HE), against Haemonchus contortus in experimentally infected lambs, were assessed. We used a microtitration plate method, comprising the following two stages. Stage 1: 20 µl of water containing 200 sheathed H. contortus infective larvae (ShHcl) were deposited in every well of three series; then, the series 2 and 3 wells were treated with 80 µl 1% ivermectin and O. tetraphylla HE at 20 mg/ml, respectively. Stage 2: the same procedure was performed replacing the ShHcl with exsheathed larvae (ExShHcl). Evaluations were performed after 24 and 48 h. The total numbers of dead and live larvae were counted. A second experiment evaluated the reduction in nematode egg populations in the faeces of lambs treated orally with the O. tetraphylla HE. The 27 lambs used were divided into Groups 1, 2 and 3 (n = 9), which were administered water (positive control), levamisole 1 m (7.5 mg/kg body weight (BW), as a unique dose) and O. tetraphylla HE (20 mg/kg BW), respectively. The plant HE was administered daily for 8 days. The in vitro assay showed 80.9% and 86.5% larval mortality of ShHcl after 24 and 48 h, respectively, while the corresponding mortality values for ExShHcl were 97 and 99%, respectively. The in vivo assay showed variability in the eggs/gram of faeces (epg) values; however, at the end of the trial, the average reduction in the epg values of the O. tetraphylla HE group was 45.6% (P < 0.05). Oxalis tetraphylla HE contains compounds that belong to the flavonol group with anthelmintic activity.

Risk Analysis of a Fuel Storage Terminal Using HAZOP and FTA.

The size and complexity of industrial chemical plants, together with the nature of the products handled, means that an analysis and control of the risks involved is required. This paper presents a methodology for risk analysis in chemical and allied industries that is based on a combination of HAZard and OPerability analysis (HAZOP) and a quantitative analysis of the most relevant risks through the development of fault trees, fault tree analysis (FTA). Results from FTA allow prioritizing the preventive and corrective measures to minimize the probability of failure. An analysis of a case study is performed; it consists in the terminal for unloading chemical and petroleum products, and the fuel storage facilities of two companies, in the port of Valencia (Spain). HAZOP analysis shows that loading and unloading areas are the most sensitive areas of the plant and where the most significant danger is a fuel spill. FTA analysis indicates that the most likely event is a fuel spill in tank truck loading area. A sensitivity analysis from the FTA results show the importance of the human factor in all sequences of the possible accidents, so it should be mandatory to improve the training of the staff of the plants.

Resedronato: eficacia en la Enfermedad de Paget. Experiencia del Hospital General Universitario y Hospital Universitario La Fe de Valencia / Risedronate: efficacy in Paget's disease, experience of the General University Hospital and the University Hospital and the University Hospital la Fe de Valencia

La enfermedad ósea de Paget (osteítis deformante) es la osteopatía más frecuente en nuestro medio tras la osteoporosis, calculándose que en España está afectada un 1,5 por ciento de la población mayor de 50 años. Su mayor pico de incidencia es en los 65 años y en un gran número de casos se diagnostica de forma casual, ante una elevación de fosfatasas alcalinas en paciente asintomático y sin deformidades, lo que ocasiona su remisión y estudio en los servicios de Reumatología. En la enfermedad de Paget, han demostrado su eficacia terapéutica distintos bifosfonatos, así como la calcitonina. Hemos querido comprobar la eficacia de risedronato, para lo cual hemos estudiado 18 pacientes tratados con 30 mg diarios durante dos meses, valorando su efectividad mediante la medición de las fosfatasas alcalinas antes y después del tratamiento. La edad media de los pacientes fue de 60,1 años (50-79 años), siendo 12 hombres y 6 mujeres. Presentaban afectación poliostótica 13 casos y monostótica 5. En 7 casos existía actividad moderada y en 11 casos la actividad era alta. En todos los casos hemos constatado una respuesta positiva, siendo parcial en 6 casos (40 por ciento), buena en 7 (40 por ciento) y completa en 5 (20 por ciento). Consideramos el risedronato como un tratamiento eficaz de la enfermedad de Paget, siendo cómoda su administración y sin efectos adversos (ninguna intolerancia digestiva) (AU)

Miasmas / Miasmas

Se confecciona un folleto de homeopatía sobre el tema miasma, de gran importancia en este campo. Se define el concepto, la clasificación, se presenta la sinopsis de los síntomas y signos dentro de los diferentes tipos de miasmas crónicos (AU)

Acupuntura con estimulación manual VS electroacumpuntura en la analgesia quirúrgica acupuntural en cirugía oftálmica / Acupuncture with handy stimulation versus electroacupuncture in acupunctural surgical analgesia in ophthalmic surgery

Se realizó un estudio explicativo experimental en el Hospital Universitario "Dr. Celestino Hernández Robau" en el período comprendido entre mayo de 2001 y marzo de 2002, con el objetivo de determinar la efectividad de la acupuntura con estimulación manual y eléctrica en la cirugía oftálmica; en los pacientes que fueron operados mediante cirugía mayor electiva empleando la acupuntura como método analgésico, se utilizaron los puntos acupunturales Intestino Grueso 4 y San Jiao 5. Los pacientes se asignaron de forma aleatoria en dos grupos: en el I se empleó la estimulación eléctrica, y en el II la estimulación manual. La analgesia transoperatoria lograda fue buena en 84,0 por ciento del total de la muestra y sólo en 16,0 por ciento ésta fue regular; la analgesia postoperatoria fue buena en 82,0 por ciento y en 18,0 por ciento la misma fue catalogada de regular. Llama la atención que del total de la muestra estudiada, 66,0 por ciento presentó cifras tensionales elevadas con diferencias en ambos grupos, y la incidencia fue superior en el grupo de pacientes que recibió estimulación eléctrica de las agujas, lo que nos llevó a plantear que la estimulación manual fue más efectiva que la electroacupuntura(AU)

Miasmas / Miasmas

Se confecciona un folleto de homeopatía sobre el tema miasma, de gran importancia en este campo. Se define el concepto, la clasificación, se presenta la sinopsis de los síntomas y signos dentro de los diferentes tipos de miasmas crónicos

Artritis reumatoide de inicio tardío / Late onset rheumatoid arthritis

Objetivo: Pretendemos valorar las características de la artritis reumatoide de inicio en mayores de 60 años. Método: Se estudian retrospectivamente un grupo de 33 enfermos con artritis reumatoide de inicio en una edad igual o superior a los 60 años (inicio tardío o ARIT), comparado con otro grupo de 33 pacientes con artritis reumatoide diagnosticada antes de los 60 años (adulto joven o ARAJ), recogidos de forma sucesiva en los últimos tres años. Se valoran los siguientes parámetros: edad, sexo, rigidez matutina, forma de inicio, localización de la artritis, nódulos reumatoideos, hemoglobina, plaquetas, VSG, factor reumatoideo, anticuerpos antinucleares, capacidad funcional y alteraciones radiológicas. Resultados: Se obtuvieron diferencias estadísticamente significativas entre ambos grupos en: una mayor rigidez articular, mayor número de luxaciones articulares, más alteraciones radiológicas, peor capacidad funcional y más afectación de pequeñas articulaciones de las manos en el grupo ARAJ; y por otro lado se observa mayor afectación de hombros en el ARIT, manteniéndose esta diferencia cuando nos referimos al sexo masculino y también cuando el FR es positivo; cuando es negativo se superpone a una entidad característica como es la polimialgia reumática (PMR). Conclusiones: Según el momento de aparición de la Artritis Reumatoide (más o menos de 60 años), podemos encontrar unas diferencias propias de cada una, y una similitud con otro tipo de enfermedades como la PMR (AU)