Shared decision-making in psoriasis care: Evaluation of how patients' perception of clinicians' delivery of care changes by age and sex.

BACKGROUND: Shared decision-making (SDM) refers to a collaborative process in which clinicians assist patients in making medically informed, evidence-based decisions that align with their values and preferences. There is a paucity of literature on SDM in dermatology. OBJECTIVE: We aim to assess whether male and female psoriasis patients evaluate their clinicians' engagement in SDM differently across different age groups. METHODS: Cross-sectional study using data from the 2014-2017 and 2019 Medical Expenditure Panel Surveys (MEPS). RESULTS: A weighted total of 7,795,608 psoriasis patients were identified. SDM Scores ranged from 1 to 4, with 4 representing the most favorable patient evaluation of their clinicians' engagement in SDM. We conducted multivariate linear regression to compare mean SDM Scores in male psoriasis patients versus female psoriasis patients across different patient age groups. Female patients ages 60-69 perceived significantly greater clinician engagement in SDM compared to age-matched male patients (female patient perception of SDM 3.65 [95%CI:3.61-3.69] vs. male patient perception of SDM 3.50 [95%CI:3.43-3.58], p<0.005). The same trend of older female patients evaluating their clinicians' engagement in SDM significantly higher than their age-matched male counterparts exists for the age group >70 (p<0.005). No significant differences between male and female patients' evaluations of their clinicians' engagement in SDM were demonstrated in subjects younger than 60. All calculations were adjusted for demographic and clinical factors. CONCLUSIONS: Compared to older male psoriasis patients, older female psoriasis patients evaluated their clinicians to be more engaged in shared decision-making.

Row1, a member of a new family of conserved fungal proteins involved in infection, is required for appressoria functionality in Ustilago maydis.

The appressorium of phytopathogenic fungi is a specific structure with a crucial role in plant cuticle penetration. Pathogens with melanized appressoria break the cuticle through cell wall melanization and intracellular turgor pressure. However, in fungi with nonmelanized appressorium, the mechanisms governing cuticle penetration are poorly understood. Here we characterize Row1, a previously uncharacterized appressoria-specific protein of Ustilago maydis that localizes to membrane and secretory vesicles. Deletion of row1 decreases appressoria formation and plant penetration, thereby reducing virulence. Specifically, the Δrow1 mutant has a thicker cell wall that is more resistant to glucanase degradation. We also observed that the Δrow1 mutant has secretion defects. We show that Row1 is functionally conserved at least among Ustilaginaceae and belongs to the Row family, which consists of five other proteins that are highly conserved among Basidiomycota fungi and are involved in U. maydis virulence. We observed similarities in localization between Row1 and Row2, which is also involved in cell wall remodelling and secretion, suggesting similar molecular functions for members of this protein family. Our data suggest that Row1 could modify the chitin-glucan matrix of the fungal cell wall and may be involved in unconventional protein secretion, thereby promoting both appressoria maturation and penetration.

Low-dose ionizing γ-radiation elicits the extrusion of neutrophil extracellular traps.

PURPOSE: Cancer patients frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NETs), we have investigated the mechanisms, consequences and the occurrence of such phenomena in patients undergoing radiotherapy. EXPERIMENTAL DESIGN: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, cancer patients and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice assessing their effects on metastasis. Circulating NETs in irradiated cancer patients were measured by ELISA methods detecting MPO-DNA complexes and citrullinated H3. RESULTS: Very low γ-radiation doses (0.5-1 Gy) given to neutrophils elicit NET formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. CONCLUSIONS: NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.

Growth hormone stimulates the in vitro development and establishment of Haemonchus contortus in sheep.

The physiologic increase in some sex hormones has been associated with an increase in the parasite load caused by Haemonchus contortus in ewes, especially prolactin. In lambs that are especially susceptible to hemonchosis, the levels of sex hormones are low; in contrast, the levels of another pituitary hormone, growth hormone (GH), which is structurally very similar to prolactin, are high. In this study, the in vitro and in vivo effects of GH on H. contortus larvae development and establishment were evaluated. The addition of 20 ng/mL GH for 5 and 10 days to cultures of H. contortus larvae induced an enlargement (p<0.01) and an L3/L4 molting rate (p<0.03) greater than that of untreated larvae or those treated with other concentrations of the hormone. Flow cytometry showed that 3.8% of the largest and most complex cells of newly obtained larvae of H. contortus were positive for the GH receptor, and by immunofluorescence with confocal microscopy, it was observed that these receptors are located in the intestinal region larvae. In the in vivo assay, the administration of recombinant GH to gonadectomized lambs produced an increase in FEC (p<0.03), the number of female adult worms in the abomasum (p<0.05) and the levels of specific antibodies (p<0.04) in relation to the control lambs; however, it did not affect the fertility of H. contortus females. Although many factors affect the development and implantation of H. contortus in the abomasum of sheep, the results of this study strongly suggest that GH participates in the development and establishment of the parasite in sheep, mainly in young sheep.

The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models.

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated. METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq and multiplexed immunofluorescence staining. RESULTS: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype. CONCLUSIONS: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.

Clustering Health Behaviors in Mexican Adolescents: The HELENA-MEX Study.

Purpose: The prevalence of excess weight within the adolescent population is rapidly increasing in Mexico, especially in areas with lower socioeconomic status. The present study aimed to identify lifestyle clustered patterns in adolescents and analyze the associations among these clusters and body composition. Method: A final sample of n=259 participants (13 to 17 years old, 58.7% girls), residents in rural and urban areas, were included. Hierarchical and k-means clusters analyses included moderate to vigorous physical activity (MVPA), cardiorespiratory fitness (CRF), handgrip strength, screen time, sleep time, and diet. The associations between cluster membership and body composition were analyzed through general linear models (ANCOVA), including sex, age, place of residence, and socioeconomic status as covariates. Results: Three different clusters were identified: Cluster 1, [Unhealthy] (low values in all lifestyle patterns), Cluster 2, [Low Physical Fitness] (low values in CRF and handgrip strength) and Cluster 3, [High Physical Activity and CRF] (highest values in CRF, handgrip strength and MVPA). Clusters 2 and 3 showed high values in screen time and industrialized food consumption. There were no differences in sleep between the 3 Clusters. ANCOVA analysis revealed that participants belonging to Cluster 3 showed significantly lower adiposity and a higher Fat Free Mass compared with the other two clusters (p < 0.05). Conclusion: Our findings suggest that a lifestyle characterized by high levels of physical activity and physical fitness and low consumption of industrialized food may be protective against the problem of obesity, which could be helpful to develop interventions to reduce excess weight in Mexican adolescents.

Intratumoral co-injection of NK cells and NKG2A-neutralizing monoclonal antibodies.

NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa-1b in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co-injected with anti-NKG2A and anti-Qa-1b blocking monoclonal antibodies against solid mouse tumor models. Such therapeutic activity was contingent on endogenous CD8 T cells and type-1 conventional dendritic cells (cDC1). Moreover, the anti-tumor effects were enhanced upon combination with systemic anti-PD-1 mAb treatment and achieved partial abscopal efficacy against distant non-injected tumors. In xenografted mice bearing HLA-E-expressing human cancer cells, intratumoral co-injection of activated allogeneic human NK cells and clinical-grade anti-NKG2A mAb (monalizumab) synergistically achieved therapeutic effects. In conclusion, these studies provide evidence for the clinical potential of intratumoral NK cell-based immunotherapies that exert their anti-tumor efficacy as a result of eliciting endogenous T-cell responses.

Efficacy of ethyl-4-bromophenyl carbamate on different Rhipicephalus microplus stages implanted in cattle.

The effect of ethyl-4-bromophenyl carbamate on different Rhipicephalus microplus stages implanted in cattle was evaluated using the pen test with infestation chambers. Twelve steers were distributed into four groups (n = 3), each with four chambers (12 chambers per group), where approximately 1,000 R. microplus larvae were placed in each chamber. The chambers of the first group were sprayed with a solution of ethyl-4-bromophenyl carbamate (0.668 mg/mL) on day 2 post-infestation (PI) (exposed larvae). The chambers of the second group were sprayed with the same solution on day 8 PI (exposed nymphs), and the chambers of the third group were sprayed on day 16 PI (exposed adults) with the same solution. The chambers of the fourth group were used as controls. The percentages of engorged females, egg laying, egg production and egg hatching were evaluated in all groups. The percentage of cumulative reduction of hatched larvae was 98.3, 96.1 and 94.4% when larvae, nymph and adult stages were treated, respectively. The average cumulative reduction of hatched larvae, considering the three treated stages, was 96.3%, whereby the reproductive potential of this tick was drastically reduced. In conclusion, ethyl-4-bromophenyl carbamate acted as an ixodicide (lethal effect) when larval stages were sprayed and as a growth regulator when nymphal and adult stages were sprayed. The sum of these effects had a direct impact on the efficacy of the product in the pen test, and future studies will indicate the potential use of this product for tick control.

Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists.

Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor ß (TGF-ß) and CD137 (4-1BB). Several neutralizing TGF-ß agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-ß and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8+ T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade.

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects.

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137's cytoplasmic tail.

Canakinumab in addition to phosphate-binding and phosphaturia-inducing therapy were effective in achieving remission in a child with a large familial calcinotic tumour.

We describe the clinical evolution of a patient with tumoral calcinosis due to a pathogenic variant in the GALNT3 gene presented with a large mass overlying her left hip associated complicated by inflammatory flares. Therapy (sevelamer, acetazolamide, and probenecid) was unsuccessful in preventing tumour surgeries, therefore, interleukin-1ß monoclonal antibody therapy was added; this was successful in the prevention of tumour re-growth. This case highlights the importance of assessing and treating the inflammatory aspect of calcinotic tumour.

Subclinical experimental infection with Taenia hydatigena in sheep is associated with production losses.

The effect of experimental infection by Taenia hydatigena metacestodes on different productive parameters in sheep was evaluated. Seventeen male Columbia lambs distributed in three groups were used. The lambs of the first group (n = 5) were orally inoculated with 1000 T. hydatigena eggs (low dose). The lambs of the second group (n = 5) were inoculated orally with all the eggs of the last proglottid of an adult cestode (high dose). The lambs of the third group (n = 7) only received a placebo and were used as a control group. All lambs were humanely euthanized at week 13 postinfection, and carcass yield and conformation were evaluated. The infection rates of the lambs from the high-dose infected group and the low-dose infected group were 100% and 40%, respectively, with a mean of 2.4 ± 0.6 and 1 ± 0.7 metacestodes of T. hydatigena in the abdominal cavity, respectively. In a first multivariate study (MANOVA) considering the under the curve (AUC) values of body condition, weight gain, and feed consumption, as well as the final feed conversion values, showed a highly significant (p < 0.0001) group effect (high dose/low dose/uninfected). In a second multivariate study (MANOVA) considering the AUC values of eosinophils blood count, packed cell volume and alkaline phosphatase showed a highly significant (p < 0.0001) group effect (high dose/low dose/uninfected). The increase in serum ALP is a consequence of liver damage that had a strong negative correlation (r = -0.63, p < 0.007) with the body condition of the lambs. Despite these findings, we did not observe obvious clinical manifestations in any of the infected lambs. In general, no differences (p > 0.1) were observed between the lambs of the control group and the lambs of the low-dose infected group in the parameters evaluated. The results of this study show that the infection of T. hydatigena metacestodes subclinically produces a decrease in productive efficiency, alterations of some hematological and biochemical values, and a slight deterioration in the general appearance of the infected lambs. The above aspects are rarely detected by most farmers, but they have a negative impact on the productivity of infected lambs.

Percepciones sobre salud (física, mental y bucal) en un grupo de mujeres en situación de prostitución en la ciudad de Medellín

Introducción: las mujeres y las personas trans que han ejercido el trabajo sexual se encuentran vulneradas puesto que son víctimas de discriminación por su condición laboral, por su género y por los riesgos que acarrea esta labor, y esto impacta en su situación de salud. Este estudio tuvo como objetivo conocer las percepciones sobre salud (física, mental y bucal) en cuatro mujeres que ejercen la prostitución en Medellín, a partir de sus experiencias de vida y aquellas relacionadas con su contexto social. Métodos: se realizó una investigación cualitativa con enfoque etnográfico para analizar las situaciones mencionadas de acuerdo con el objetivo general. Se contó con la participación de cuatro mujeres: dos de nacionalidad venezolana y dos de nacionalidad colombiana; se llevaron a cabo entrevistas semiestructuradas. Se realizó análisis de contenido cualitativo, lo cual permitió la generación de cuatro categorías (salud mental, salud bucal, salud general y calidad de vida). Resultados: sus discursos permitieron elucidar la conexión entre las condiciones de vida y la situación de salud. La falta de oportunidades laborales, un proceso migratorio de profundos cambios económicos y sociales, y una Colombia con inequidades y barreras de acceso a servicios de salud y sociales, son procesos determinantes de orden general, particular y singular de las precarias condiciones de salud bucal y general. Conclusiones: la población participante se encuentra en situación de vulnerabilidad social y de salud, lo cual evidencia la necesidad de políticas públicas y estrategias basadas en la realidad social que contribuyan a generar equidad en salud.

Introduction: women and trans people who have engaged in sex work are triply vulnerable since they are victims of discrimination due to their employment status, their gender, and the risks that this work entails, this impacts their health situation. This study aimed to know the perceptions about health (physical, mental, and oral) of four women who work in prostitution in Medellin, based on their life experiences and those related to their social context. Methods: qualitative research with an ethnographic approach was conducted to analyze the situations mentioned. Four women participated, two Venezuelans and two Colombians, and semi-structured interviews were conducted. Qualitative content analysis was performed, which allowed the generation of four categories (mental health, oral health, general health, and quality of life). Results: her discourses made it possible to elucidate the connection between the living conditions and the health situation. Lack of job opportunities, a migratory process of profound economic and social changes, and a Colombia with inequities and barriers to access to health and social services are determining processes of a general and singular order of the precarious conditions of oral health and general. Conclusions: the participating population is in a situation of social and health vulnerability, which shows the need for public policies and strategies based on the social reality that contribute to generating equity in health.

Intratumoral neoadjuvant immunotherapy based on the BO-112 viral RNA mimetic.

BO-112 is a poly I:C-based viral mimetic that exerts anti-tumor efficacy when intratumorally delivered in mouse models. Intratumoral BO-112 synergizes in mice with systemic anti-PD-1 mAbs and this combination has attained efficacy in PD1-refractory melanoma patients. We sought to evaluate the anti-tumor efficacy of BO-112 pre-surgically applied in neoadjuvant settings to mouse models. We have observed that repeated intratumoral injections of BO-112 prior to surgical excision of the primary tumor significantly reduced tumor metastasis from orthotopically implanted 4T1-derived tumors and subcutaneous MC38-derived tumors in mice. Such effects were enhanced when combined with systemic anti-PD-1 mAb. The anti-tumor efficacy of this neoadjuvant immunotherapy approach depended on the presence of antigen-specific effector CD8 T cells and cDC1 antigen-presenting cells. Since BO-112 has been successful in phase-two clinical trials for metastatic melanoma, these results provide a strong rationale for translating this pre-surgical strategy into clinical settings, especially in combination with standard-of-care checkpoint inhibitors.

Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma.

Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.

Disfagia orofaríngea neurogénica: caracterización clínica y percepción de síntomas en Antioquia, Colombia entre los años 2019 a 2021

Introducción: la disfagia es un trastorno de la deglución, el cual es habitualmente desatendido por profesionales de la salud, en especial la disfagia orofaríngea neurogénica, que es capaz de producir varios síntomas, signos y complicaciones secundarias en los pacientes. Objetivo: realizar una caracterización clínica incluyendo percepción de síntomas de disfagia en pacientes con disfagia orofaríngea neurogénica de causas neurológicas y neuromusculares en Antioquia, Colombia entre los años 2019 y 2021. Metodología: estudio transversal realizado en 80 pacientes con disfagia orofaríngea neurogénica confirmada a través de la herramienta Eating Assessment Tool-10, evaluación clínica y/o resultados de video fluoroscopia de la deglución. Resultados: 71 pacientes presentaron causas neurológicas centrales. La enfermedad cerebrovascular y la enfermedad de Parkinson fueron las etiologías más frecuentes. Solo 18% de los pacientes con causas neurológicas y 33% con causas neuromusculares reportaron tolerancia a todas las consistencias de alimentos. Mediana de 16 puntos en cuanto a autopercepción de síntomas de disfagia mediante el instrumento Eating Assessment Tool-10, con puntuaciones más altas en pacientes con presencia de gastrostomía, antecedente de neumonía, odinofagia y alteración en la oclusión mandibular al examen físico. En los pacientes con causas neurológicas hubo mayor presencia de signos motores linguales y apraxias orofaciales. Conclusión: existen características clínicas como sensación de comida pegada, dificultad para tragar alimentos sólidos, tos y ahogo al tragar, que son útiles en el reconocimiento de casos de disfagia orofaríngea, y apoyan que esta genera más síntomas que signos al examen físico en pacientes con condiciones neurológicas y neuromusculares.

Introduction: dysphagia is a swallowing disorder that is usually neglected by health professionals, especially neurogenic oropharyngeal dysphagia, which can produce various symptoms, signs and secondary complications in patients. Objective: to perform a clinical characterization, including perception of dysphagia symptoms, in patients with neurogenic oropharyngeal dysphagia of neurological and neuromuscular causes in Antioquia, Colombia between 2019 and 2021. Methodology: cross-sectional study conducted in 80 patients with neurogenic oropharyngeal dysphagia confirmed through the Eating Assessment Tool-10, clinical assessment and/ or video fluoroscopy results of swallowing. Results: 71 patients presented central neurological causes. Cerebrovascular disease and Parkinson's disease were the most frequent etiologies. Only 18% of patients with neurological causes and 33% with neuromuscular causes reported tolerance to all food consistencies. Median of 16 points in terms of self-perception of dysphagia symptoms using the Eating Assessment Tool-10, with higher scores in patients with gastrostomy, a history of pneumonia, odynophagia, and abnormal mandibular occlusion on physical examination. In patients with neurological causes, there was a greater presence of lingual motor signs and orofacial apraxia. Conclusion: there are clinical characteristics such as a sensation of stuck food, difficulty swallowing solid foods, coughing, and choking when swallowing, which are useful in recognizing cases of oropharyngeal dysphagia, and support that this generates more symptoms than signs on physical examination in patients with neurological and neuromuscular conditions.