A Web-Based Intervention to Support the Mental Well-Being of Sexual and Gender Minority Young People: Mixed Methods Co-Design of Oneself.

BACKGROUND: Sexual and gender minority youth are at greater risk of compromised mental health than their heterosexual and cisgender peers. This is considered to be due to an increased burden of stigma, discrimination, or bullying resulting in a heightened experience of daily stress. Given the increasing digital accessibility and a strong preference for web-based support among sexual and gender minority youth, digital interventions are a key means to provide support to maintain their well-being. OBJECTIVE: This paper aims to explicate the co-design processes and underpinning logic of Oneself, a bespoke web-based intervention for sexual and gender minority youth. METHODS: This study followed a 6-stage process set out by Hagen et al (identify, define, position, concept, create, and use), incorporating a systematic scoping review of existing evidence, focus groups with 4 stakeholder groups (ie, sexual and gender minority youth, professionals who directly support them, parents, and UK public health service commissioners), a series of co-design workshops and web-based consultations with sexual and gender minority youth, the appointment of a digital development company, and young adult sexual and gender minority contributors to create content grounded in authentic experiences. RESULTS: Oneself features a welcome and home page, including a free accessible to all animation explaining the importance of using appropriate pronouns and the opportunity to create a user account and log-in to access further free content. Creating an account provides an opportunity (for the user and the research team) to record engagement, assess users' well-being, and track progress through the available content. There are three sections of content in Oneself focused on the priority topics identified through co-design: (1) coming out and doing so safely; (2) managing school, including homophobic, biphobic, or transphobic bullying or similar; and (3) dealing with parents and families, especially unsupportive family members, including parents or caregivers. Oneself's content focuses on identifying these as topic areas and providing potential resources to assist sexual and gender minority youth in coping with these areas. For instance, Oneself drew on therapeutic concepts such as cognitive reframing, stress reduction, and problem-solving techniques. There is also a section containing relaxation exercises, a section with links to other recommended support and resources, and a downloads section with more detailed techniques and strategies for improving well-being. CONCLUSIONS: This study contributes to research by opening up the black box of intervention development. It shows how Oneself is underpinned by a logic that can support future development and evaluation and includes diverse co-designers. More interactive techniques to support well-being would be beneficial for further development. Additional content specific to a wider range of intersecting identities (such as care-experienced Asian sexual and gender minority youth from a minority faith background) would also be beneficial in future Oneself developments. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/31036.

Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Cornual adenomyosis in Essure® device users and in patients hysterectomized for other causes: A retrospective cohort study.

OBJECTIVE: To determine whether adenomyosis is present in the cornual portion of hysterectomies of symptomatic sterilization device users and in patients hysterectomized for different benign causes and who presented with pelvic pain and/or menstrual alterations. METHODS: An observational, analytical, cross-sectional, single-center, retrospective cohort study was conducted in a secondary level hospital. Cohort 1 consisted of women who had Essure® hysteroscopic sterilization devices inserted between 2009 and 2017, who developed gynecologic symptoms (pelvic pain, heavy menstrual bleeding, and/or abnormal uterine bleeding) and who underwent a hysterectomy for explantation of the devices. Cohort 2 consisted of women with the same gynecologic symptoms, who underwent a hysterectomy for other benign causes. All surgeries were performed by the gynecology team between 2018 and 2022. A descriptive and comparative analysis of sociodemographic, clinical characteristics, and pathologic findings between cohorts was made. RESULTS: In total, 96 patients were studied (cohort 1 included 34 women, cohort 2 included 62 women). Pelvic pain was found to be more frequent in the cohort of Essure users (76.47% vs. 50%, P = 0.012), with a ratio of three times higher in this group (odds ratio 3.25, 95% confidence interval 1.27-8.28). Adenomyosis was more frequently found in the Essure group, both at corporal and cornual portions, the latter being five times higher in this cohort (relative risk = 5.47; 95% confidence interval 1.17-25.64). CONCLUSIONS: The present study may be the first to describe cornual adenomyosis related to Essure devices. These devices may play a role in the development of adenomyosis and, consequently, pelvic pain. However, causality is difficult to establish.

Relationship between Body Posture Assessed by Dynamic Baropodometry and Dental Occlusion in Patients with and without Dental Pathology.

Body biomechanics and dental occlusion are related, but this interaction is not fully elucidated. The aim of this study was to investigate the association between body posture and occlusion in patients with and without dental pathology. A cross-sectional study was carried out with 29 patients divided into a control group and a group with pathology (malocclusions). Body posture was evaluated by dynamic baropodometry, analyzing parameters such as the line of gait and the anteroposterior and lateral position of the center of pressure (CoP). Occlusion was classified radiographically according to the sagittal skeletal relationship. Results showed significant differences in mean position phase line between groups (p = 0.01-0.02), with means of 115.85 ± 16.98 mm vs. 95.74 ± 24.47 mm (left side) and 109.03 ± 18.03 mm vs. 91.23 ± 20.80 mm (right side) for controls and pathologies, respectively. The effect size was large (Cohen's d 0.97 and 0.92). There were no differences in the anteroposterior (p = 0.38) or lateral (p = 0.78) position of the CoP. In gait analysis, significant differences were observed in left (548.89 ± 127.50 N vs. 360.15 ± 125.78 N, p < 0.001) and right (535.71 ± 131.57 N vs. 342.70 ± 108.40 N, p < 0.001) maximum heel strength between groups. The results suggest an association between body posture and occlusion, although further studies are needed to confirm this relationship. An integrated postural and occlusal approach could optimize the diagnosis and treatment of dental patients.

Upregulation of the secretory pathway Ca2+/Mn2+-ATPase isoform 1 in LPS-stimulated microglia and its involvement in Mn2+-induced Golgi fragmentation.

Microglia play an important protective role in the healthy nervous tissue, being able to react to a variety of stimuli that induce different intracellular cascades for specific tasks. Ca2+ signaling can modulate these pathways, and we recently reported that microglial functions depend on the endoplasmic reticulum as a Ca2+ store, which involves the Ca2+ transporter SERCA2b. Here, we investigated whether microglial functions may also rely on the Golgi, another intracellular Ca2+ store that depends on the secretory pathway Ca2+/Mn2+-transport ATPase isoform 1 (SPCA1). We found upregulation of SPCA1 upon lipopolysaccharide stimulation of microglia BV2 cells and primary microglia, where alterations of the Golgi ribbon were also observed. Silencing and overexpression experiments revealed that SPCA1 affects cell morphology, Golgi apparatus integrity, and phagocytic functions. Since SPCA1 is also an efficient Mn2+ transporter and considering that Mn2+ excess causes manganism in the brain, we addressed the role of microglial SPCA1 in Mn2+ toxicity. Our results revealed a clear effect of Mn2+ excess on the viability and morphology of microglia. Subcellular analysis showed Golgi fragmentation and subsequent alteration of SPCA1 distribution from early stages of toxicity. Removal of Mn2+ by washing improved the culture viability, although it did not effectively reverse Golgi fragmentation. Interestingly, pretreatment with curcumin maintained microglia cultures viable, prevented Mn2+-induced Golgi fragmentation, and preserved SPCA Ca2+-dependent activity, suggesting curcumin as a potential protective agent against Mn2+-induced Golgi alterations in microglia.

The ABCG2 protein in vitro transports the xenobiotic thiabendazole and increases the appearance of its residues in milk.

Thiabendazole (TBZ) is a broad-spectrum anthelmintic and fungicide used in humans, animals, and agricultural commodities. TBZ residues are present in crops and animal products, including milk, posing a risk to food safety and public health. ABCG2 is a membrane transporter which affects bioavailability and milk secretion of xenobiotics. Therefore, the aim of this work was to characterize the role of ABCG2 in the in vitro transport and secretion into milk of 5-hydroxythiabendazole (5OH-TBZ), the main TBZ metabolite. Using MDCK-II polarized cells transduced with several species variants of ABCG2, we first demonstrated that 5OH-TBZ is efficiently in vitro transported by ABCG2. Subsequently, using Abcg2 knockout mice, we demonstrated that 5OH-TBZ secretion into milk was affected by Abcg2, with a more than 2-fold higher milk concentration and milk to plasma ratio in wild-type mice compared to their Abcg2-/- counterpart.

Retos y estrategias para recuperar y dinamizar la atención primaria. Metodología DAFO (Debilidades, Amenazas, Fortalezas y Oportunidades)-CAME (Corregir, Afrontar, Mantener y Explotar) en un departamento de salud / Challenges and strategies to recover and dynamize primary care: SWOT-CAME analysis in a Health Department

Objetivo: Identificar fortalezas, obstáculos, cambios en el entorno y capacidades de los equipos y unidades de apoyo en atención primaria, con el objetivo de proporcionar atención de alta calidad en un área de salud integrada. Diseño: Estudio de métodos mixtos basado en la matriz DAFO y el análisis CAME. Emplazamiento: Atención primaria, Comunidad Valenciana. Participantes: En total han participado 271 profesionales de los diferentes colectivos y representantes de asociaciones de pacientes, 99 en la fase de captura de ideas, 154 en la fase de elaboración de la matriz DAFO y 18 en la fase de elaboración del análisis CAME. Intervenciones: Se condujo un análisis DAFO-CAME a partir del cual se establecieron líneas de acción. La captura de información se realizó mediante grupos nominales, la fase de consenso integrando al conjunto de profesionales mediante Delphi y conferencia de consenso. Mediciones principales: Priorización de propuestas para mantener las fortalezas, afrontar las amenazas, explotar las oportunidades, corregir las debilidades en el marco de un plan de acción de un área de salud integrada. Resultados: Se propusieron un total de 82 ideas diferentes (20 fortalezas, 40 debilidades, 4 amenazas, 12 oportunidades y 6 amenazas-oportunidades). Este análisis condujo a un plan estratégico con 7 líneas y 33 acciones/intervenciones priorizadas. Conclusiones: Atención integrada buscando fórmulas colaborativas entre niveles asistenciales, redefinición de roles, soluciones digitales, capacitación del personal y mejoras en equipamientos y procesos de soporte, junto a medidas para afrontar el envejecimiento de la población y las necesidades de centros sociosanitarios constituyen los retos sobre los que actuar.(AU)

Objective: To identify strengths, obstacles, changes in the environment, and capabilities of primary care teams and support units, with the aim of providing high-quality care in an integrated healthcare area. Design: Mixed methods study based on the SWOT matrix and CAME analysis. Location: Primary care, Valencian community. Participants: A total of 271 professionals from different collectives and patient association representatives participated. 99 in the idea generation phase, 154 in the SWOT matrix development phase, and 18 in the CAME analysis development phase. Interventions: A SWOT-CAME analysis was conducted, from which action lines were established. Information capture was carried out through nominal groups, and the consensus phase involved integrating all professionals through Delphi and consensus conference techniques. Main measurements: Prioritization of proposals to maintain strengths, address threats, exploit opportunities, and correct weaknesses within the framework of an integrated healthcare area action plan. Results: A total of 82 different ideas were proposed (20 strengths; 40 weaknesses; 4 threats; 12 opportunities; 6 threats-opportunities), which, once prioritized, were translated into 7 lines and 33 prioritized actions/interventions (CAME analysis). Conclusions: Integrated care, seeking collaborative approaches between care levels, redefining roles, digital solutions, staff training, and improvements in equipment and support processes, along with measures to address the aging population and the needs of socio-sanitary centers, constitute the challenges to be addressed.(AU)

Effectiveness and safety of azathioprine for inflammatory pouch disorders: results from the RESERVO study of GETECCU.

Background: The usefulness of thiopurines has been poorly explored in pouchitis and other pouch disorders. Objective: To evaluate the effectiveness and safety of azathioprine as maintenance therapy in inflammatory pouch disorders. Design: This was a retrospective and multicentre study. Methods: We included patients diagnosed with inflammatory pouch disorders treated with azathioprine in monotherapy. Effectiveness was evaluated at 1 year and in the long term based on normalization of stool frequency, absence of pain, faecal urgency or fistula discharge (clinical remission), or any improvement in these symptoms (clinical response). Endoscopic response was evaluated using the Pouchitis Disease Activity Index (PDAI). Results: In all, 63 patients were included [54% males; median age, 49 (28-77) years]. The therapy was used to treat pouchitis (n = 37) or Crohn's disease of the pouch (n = 26). The rate of clinical response, remission and non-response at 12 months were 52%, 30% and 18%, respectively. After a median follow-up of 23 months (interquartile range 11-55), 19 patients (30%) were in clinical remission, and 45 (66%) stopped therapy. Endoscopic changes were evaluated in 19 cases. PDAI score decreased from 3 (range 2-4) to 1 (range 0-3). In all, 21 patients (33%) presented adverse events and 16 (25%) needed to stop therapy. Conclusion: Azathioprine may be effective in the long term for the treatment of inflammatory pouch disorders and could be included as a therapeutic option.

Privacy-preserving federated machine learning on FAIR health data: A real-world application.

Objective: This paper introduces a privacy-preserving federated machine learning (ML) architecture built upon Findable, Accessible, Interoperable, and Reusable (FAIR) health data. It aims to devise an architecture for executing classification algorithms in a federated manner, enabling collaborative model-building among health data owners without sharing their datasets. Materials and methods: Utilizing an agent-based architecture, a privacy-preserving federated ML algorithm was developed to create a global predictive model from various local models. This involved formally defining the algorithm in two steps: data preparation and federated model training on FAIR health data and constructing the architecture with multiple components facilitating algorithm execution. The solution was validated by five healthcare organizations using their specific health datasets. Results: Five organizations transformed their datasets into Health Level 7 Fast Healthcare Interoperability Resources via a common FAIRification workflow and software set, thereby generating FAIR datasets. Each organization deployed a Federated ML Agent within its secure network, connected to a cloud-based Federated ML Manager. System testing was conducted on a use case aiming to predict 30-day readmission risk for chronic obstructive pulmonary disease patients and the federated model achieved an accuracy rate of 87%. Discussion: The paper demonstrated a practical application of privacy-preserving federated ML among five distinct healthcare entities, highlighting the value of FAIR health data in machine learning when utilized in a federated manner that ensures privacy protection without sharing data. Conclusion: This solution effectively leverages FAIR datasets from multiple healthcare organizations for federated ML while safeguarding sensitive health datasets, meeting legislative privacy and security requirements.

New insights in the pathogenic mechanism of multiple sclerosis: Is Epstein-Barr virus associated with optic nerve involvement?

INTRODUCTION: There are no reports in the literature studying the possible relationship between Epstein-Barr virus (EBV) and optic nerve involvement in multiple sclerosis (MS). The aim of our study was to analyze the association between EBV antibodies titres and optical coherence tomography (OCT) and OCT angiography (OCTA) quantitative parameters. METHODS: We conducted a retrospective study. The study included 98 eyes of 49 patients with MS. Years of MS duration, relapse count, history of optic neuritis (ON), and immunoglobulin (Ig) G antibodies to the EBV viral capsid antigen (VCA) were recorded from each patient. Also, OCT analysis (including retinal nerve fibre layer (RNFL) thickness and ganglion cell-inner plexiform layer (GCIPL) thickness) and OCTA analysis (including perfusion density (PD) and flux index (FI) of the radial peripapillary capillary plexus) were performed in each participant. RESULTS: No significant associations were observed between anti-EBV antibody levels and OCT or OCTA parameters (p > 0,05). Correlation analysis between OCT and OCTA measurements showed a significant positive correlation between RNFL thickness and GCIPL thickness with peripapillary PD and FI (p < 0,035). Subgroup analysis revealed a significant diminution of RNFL thickness, GCIPL thickness and peripapillary PD and FI (p < 0,05) in the ON group. CONCLUSION: We were unable to demonstrate a significant association between anti-EBV VCA IgG antibody titres and OCT or OCTA parameters. Nonetheless, further longitudinal studies are needed to explore the possible association of EBV with optic nerve involvement in MS.

Production of Methyl Lactate with Sn-USY and Sn-ß: Insights into Real Hemicellulose Valorization.

Potassium exchanged Sn-ß and Sn-USY zeolites have been tested for the transformation of various aldoses (hexoses and pentoses), exhibiting outstanding catalytic activity and selectivity toward methyl lactate. Insights into the transformation pathways using reaction intermediates-dihydroxyacetone and glycolaldehyde-as substrates revealed a very high catalytic proficiency of both zeolites in aldol and retro-aldol reactions, showcasing their ability to convert small sugars into large sugars, and vice versa. This feature makes the studied Sn-zeolites outstanding catalysts for the transformation of a wide variety of sugars into a limited range of commercially valuable alkyl lactates and derivatives. [K]Sn-ß proved to be superior to [K]Sn-USY in terms of shape selectivity, exerting tight control on the distribution of produced α-hydroxy methyl esters. This shape selectivity was evident in the transformation of several complex sugar mixtures emulating different hemicelluloses-sugar cane bagasse, Scots pine, and white birch-that, despite showing very different sugar compositions, were almost exclusively converted into methyl lactate and methyl vinyl glycolate in very similar proportions. Moreover, the conversion of a real hemicellulose hydrolysate obtained from Scots pine through a simple GVL-based organosolv process confirmed the high activity and selectivity of [K]Sn-ß in the studied transformation, opening new pathways for the chemical valorization of this plentiful, but underutilized, sugar feedstock.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

Optical coherence tomography angiography analysis in patients with intracranial hypertension.

INTRODUCTION: Evidence on peripapillary microvasculature in intracranial hypertension (IH) after the regression of papilledema is still scarce. The aim of this preliminary study was to determine the association between structural changes in the optic nerve and the retina and peripapillary microvasculature in patients with IIH. METHODS: We conducted a retrospective study. The study included 39 eyes of 21 patients with IIH. Treatment for IIH and history of obesity were registered from each patient. Moreover, OCT analysis including retinal nerve fiber layer (RNFL) thickness and ganglion cell-inner plexiform layer (GCIPL) thickness, and OCTA analysis including perfusion density (PD) and flux index (FI) of the radial peripapillary capillary plexus were performed. RESULTS: Correlation analysis revealed a high correlation between GCIPL thickness and peripapillary PD and FI (p < 0,05, r > 0,7), whereas the degree of correlation between RNFL thickness and peripapillary microvascular parameters was low (p < 0,05, r < 0,7). Patients with regressed papilledema had significantly lower GCIPL thickness and peripapillary PD than control subjects (p < 0,05). CONCLUSION: Peripapillary microvascular measurements are highly correlated with GCIPL thickness in patients with IIH. Moreover, GCIPL thickness and peripapillary PD are significantly inferior in patients with regressed papilledema compared to control group. Thus, we suggested that peripapillary microvascular parameters may be an early indicator of optic nerve atrophy in patients with IIH.

Respiratory syncytial virus infection in adults: Differences with influenza.

INTRODUCTION: Respiratory syncytial virus (RSV) causes an acute respiratory illness similar to influenza, although there are few data comparing both of them in adults. The existence of clinical differences between these two infections could have implications for their management. MATERIALS AND METHODS: Retrospective observational cohort study including 63 adults with positive PCR for RSV and 221 for influenza during winter 2018-2019. Epidemiological, clinical characteristics and outcomes were contrasted between both groups. RESULTS: Compared to influenza, RSV-positive patients presented a higher association with active neoplasia (OR=2.9; 95% CI: 1.2-6.9), dependence for basic activities of daily living (OR=3.4; 95% CI: 1.4-8.2) and immunosuppression due to chronic glucocorticoid administration (OR=7.6; 95% CI: 1.6-36.1). At diagnosis, fever was less common (OR=0.3; 95% CI: 0.2-0.7), and C-reactive protein level ≥100mg/l was more frequent (OR=2.1; 95% CI: 1.0-4.5). They developed bacterial co-infection by Staphylococcus aureus in a higher proportion (OR=8.3; 95% CI: 1.5-46.9) and presented a greater need for admission to the intensive care unit (OR=5.4; 95% CI: 1.4-19.2). CONCLUSION: RSV is an important cause of respiratory illness in adults during the influenza season. It especially affects vulnerable patients with chronic underlying diseases, and has a higher morbidity than influenza. For all these reasons, specific detection, prevention and treatment of RSV is necessary in order to reduce the consumption of health care resources due to RSV disease in adults.

An miR164-resistant mutation in the transcription factor gene CpCUC2B enhances carpel arrest and ectopic boundary specification in Cucurbita pepo flower development.

The sex determination process in cucurbits involves the control of stamen or carpel development during the specification of male or female flowers from a bisexual floral meristem, a function coordinated by ethylene. A gain-of-function mutation in the miR164-binding site of CpCUC2B, ortholog of the Arabidopsis transcription factor gene CUC2, not only produced ectopic floral meristems and organs, but also suppressed the development of carpels and promoted the development of stamens. The cuc2b mutation induced the transcription of CpCUC2B in the apical shoots of plants after female flowering but repressed other CUC genes regulated by miR164, suggesting a conserved functional redundancy of these genes in the development of squash flowers. The synergistic androecious phenotype of the double mutant between cuc2b and etr2b, an ethylene-insensitive mutation that enhances the production of male flowers, demonstrated that CpCUC2B arrests the development of carpels independently of ethylene and CpWIP1B. The transcriptional regulation of CpCUC1, CpCUC2, and ethylene genes in cuc2b and ethylene mutants also confirms this conclusion. However, the epistasis of cuc2b over aco1a, a mutation that suppresses stamen arrest in female flowers, and the down-regulation of CpACS27A in cuc2b female apical shoots, indicated that CpCUC2B promotes stamen development by suppressing the late ethylene production.

Long-term use of mepolizumab in a case of chronic eosinophilic pneumonia: extending interval dosing.

INTRODUCTION: Mepolizumab, a humanized anti IL-5 monoclonal antibody, has been used off-label for chronic eosinophilic pneumonia (CEP), inducing disease remission and saving systemic corticosteroids. CASE STUDY: We present a case of CEP, requiring long-term corticosteroids therapy due to relapse upon withdrawal. Mepolizumab was started and maintained for 2 years and 6 months. RESULTS: Corticosteroids could be withdrawn and mepolizumab dose interval was spared up to 10 wk with no disease relapse. CONCLUSION: Mepolizumab is shown to be useful for chronic eosinophilic pneumonia, allowing corticosteroid withdrawal. Dose interval may be individualized under close monitoring, for a more efficient treatment, reducing medical costs while improving patients' quality of life.

Comparative Study of the Effectiveness of Vedolizumab Versus Ustekinumab After Anti-TNF Failure in Crohn's Disease (Versus-CD): Data from the ENEIDA Registry.

BACKGROUND: Both vedolizumab and ustekinumab are approved for the management of Crohn's disease [CD]. Data on which one would be the most beneficial option when anti-tumour necrosis factor [anti-TNF] agents fail are limited. AIMS: To compare the durability, effectiveness, and safety of vedolizumab and ustekinumab after anti-TNF failure or intolerance in CD. METHODS: CD patients from the ENEIDA registry who received vedolizumab or ustekinumab after anti-TNF failure or intolerance were included. Durability and effectiveness were evaluated in both the short and the long term. Effectiveness was defined according to the Harvey-Bradshaw index [HBI]. The safety profile was compared between the two treatments. The propensity score was calculated by the inverse probability weighting method to balance confounder factors. RESULTS: A total of 835 patients from 30 centres were included, 207 treated with vedolizumab and 628 with ustekinumab. Dose intensification was performed in 295 patients. Vedolizumab [vs ustekinumab] was associated with a higher risk of treatment discontinuation (hazard ratio [HR] 2.55, 95% confidence interval [CI]: 2.02-3.21), adjusted by corticosteroids at baseline [HR 1.27; 95% CI: 1.00-1.62], moderate-severe activity in HBI [HR 1.79; 95% CI: 1.20-2.48], and high levels of C-reactive protein at baseline [HR 1.06; 95% CI: 1.02-1.10]. The inverse probability weighting method confirmed these results. Clinical response, remission, and corticosteroid-free clinical remission were higher with ustekinumab than with vedolizumab. Both drugs had a low risk of adverse events with no differences between them. CONCLUSION: In CD patients who have failed anti-TNF agents, ustekinumab seems to be superior to vedolizumab in terms of durability and effectiveness in clinical practice. The safety profile is good and similar for both treatments.

[Challenges and strategies to recover and dynamize primary care: SWOT-CAME analysis in a Health Department]. / Retos y estrategias para recuperar y dinamizar la atención primaria. Metodología DAFO (Debilidades, Amenazas, Fortalezas y Oportunidades)-CAME (Corregir, Afrontar, Mantener y Explotar) en un departamento de salud.

OBJECTIVE: To identify strengths, obstacles, changes in the environment, and capabilities of primary care teams and support units, with the aim of providing high-quality care in an integrated healthcare area. DESIGN: Mixed methods study based on the SWOT matrix and CAME analysis. LOCATION: Primary care, Valencian community. PARTICIPANTS: A total of 271 professionals from different collectives and patient association representatives participated. 99 in the idea generation phase, 154 in the SWOT matrix development phase, and 18 in the CAME analysis development phase. INTERVENTIONS: A SWOT-CAME analysis was conducted, from which action lines were established. Information capture was carried out through nominal groups, and the consensus phase involved integrating all professionals through Delphi and consensus conference techniques. MAIN MEASUREMENTS: Prioritization of proposals to maintain strengths, address threats, exploit opportunities, and correct weaknesses within the framework of an integrated healthcare area action plan. RESULTS: A total of 82 different ideas were proposed (20 strengths; 40 weaknesses; 4 threats; 12 opportunities; 6 threats-opportunities), which, once prioritized, were translated into 7 lines and 33 prioritized actions/interventions (CAME analysis). CONCLUSIONS: Integrated care, seeking collaborative approaches between care levels, redefining roles, digital solutions, staff training, and improvements in equipment and support processes, along with measures to address the aging population and the needs of socio-sanitary centers, constitute the challenges to be addressed.

Asymmetrical nucleosomal DNA signatures regulate transcriptional directionality.

Despite the symmetrical structure of nucleosomes, in vitro studies have shown that transcription proceeds with different efficiency depending on the orientation of the DNA sequence around them. However, it is unclear whether this functional asymmetry is present in vivo and whether it could regulate transcriptional directionality. Here, we report that the proximal and distal halves of nucleosomal DNA contribute differentially to nucleosome stability in the genome. In +1 nucleosomes, this asymmetry facilitates or hinders transcription depending on the orientation of its underlying DNA, and this difference is associated with an asymmetrical interaction between DNA and histones. These properties are encoded in the DNA signature of +1 nucleosomes, since its incorporation in the two orientations into downstream nucleosomes renders them asymmetrically accessible to MNase and inverts the balance between sense and antisense transcription. Altogether, our results show that nucleosomal DNA endows nucleosomes with asymmetrical properties that modulate the directionality of transcription.