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1.
Front Immunol ; 15: 1382638, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38715601

RESUMEN

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.


Asunto(s)
Linfocitos T CD4-Positivos , Ligando de CD40 , Pulmón , Células B de Memoria , Streptococcus pneumoniae , Animales , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Ratones , Streptococcus pneumoniae/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/microbiología , Linfocitos T CD4-Positivos/inmunología , Células B de Memoria/inmunología , Células B de Memoria/metabolismo , Infecciones Neumocócicas/inmunología , Ratones Endogámicos C57BL , Memoria Inmunológica , Quimiocina CXCL13/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Modelos Animales de Enfermedad , Transducción de Señal , Activación de Linfocitos/inmunología
2.
Occup Med (Lond) ; 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38717444

RESUMEN

BACKGROUND: To date, studies have been focused on sleep disturbances of nurses working during night shifts. There is a lack of understanding regarding the sleep quality of nurses working in the rapid rotation system for each type of shift work. AIMS: To determine the relationship between chronotype and sleep quality according to shift type (i.e. day, evening and night shifts) in nurses working 8-hour rotating shifts. METHODS: A cross-sectional, descriptive study was conducted from two tertiary hospitals in South Korea from December 2021 to September 2022, including nurses working 8-hour rotating shifts (N = 74). They completed questionnaires to measure general, occupational and sleep-related characteristics, chronotype, insomnia severity and daytime sleepiness. Additionally, sleep parameters were collected from actigraphy and sleep diaries for 7 days. RESULTS: A total of 64% of nurses had an evening chronotype and 37% of nurses had an intermediate chronotype. Nurses had significantly less total sleep time and worsened sleep latency and efficiency during the day shift compared to other shift types. Compared to nurses with an intermediate chronotype, those with an evening chronotype had poorer sleep quality during day shift work. CONCLUSIONS: Strategies to enhance nurses' sleep quality during day shifts should consider a two-level approach: individual approaches, such as improving sleep hygiene, and administrative approaches, such as establishing a chronotype-based shift system for scheduling.

3.
Nat Commun ; 15(1): 3990, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734685

RESUMEN

The path of tokamak fusion and International thermonuclear experimental reactor (ITER) is maintaining high-performance plasma to produce sufficient fusion power. This effort is hindered by the transient energy burst arising from the instabilities at the boundary of plasmas. Conventional 3D magnetic perturbations used to suppress these instabilities often degrade fusion performance and increase the risk of other instabilities. This study presents an innovative 3D field optimization approach that leverages machine learning and real-time adaptability to overcome these challenges. Implemented in the DIII-D and KSTAR tokamaks, this method has consistently achieved reactor-relevant core confinement and the highest fusion performance without triggering damaging bursts. This is enabled by advances in the physics understanding of self-organized transport in the plasma edge and machine learning techniques to optimize the 3D field spectrum. The success of automated, real-time adaptive control of such complex systems paves the way for maximizing fusion efficiency in ITER and beyond while minimizing damage to device components.

4.
Sci Rep ; 14(1): 10805, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734711

RESUMEN

The commissioning of multi-petawatt class laser facilities around the world is gathering pace. One of the primary motivations for these investments is the acceleration of high-quality, low-emittance electron bunches. Here we explore the interaction of a high-intensity femtosecond laser pulse with a mass-limited dense target to produce MeV attosecond electron bunches in transmission and confirm with three-dimensional simulation that such bunches have low emittance and nano-Coulomb charge. We then perform a large parameter scan from non-relativistic laser intensities to the laser-QED regime and from the critical plasma density to beyond solid density to demonstrate that the electron bunch energies and the laser pulse energy absorption into the plasma can be quantitatively described via the Zero Vector Potential mechanism. These results have wide-ranging implications for future particle accelerator science and associated technologies.

5.
J Physiol Pharmacol ; 75(2): 195-203, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38736266

RESUMEN

Asthma is a common airway disease associated with allergic inflammation. Environmental factors, such as pollens, pollution, insect-borne antigens, or commercial chemicals, cause this disease. The common symptoms of this airway allergic reaction are increasing mucus, narrowing of the airway wall, coughing, and chest tightness. Medications, such as steroids, alleviate the disease but with severe side effects. Several studies have reported the anti-inflammatory effects of tree-based essential oil components, particularly 3-carene. Therefore, this study used 3-carene to determine if it alleviates asthmatic symptoms in the murine model. First, BALB/c mice were sensitized to an ovalbumin and aluminium hydroxide mixture on day 7th and 14th. From days 21st to 23rd, the mice were challenged with 3-carene and budesonide. The lung trachea, plasma, and bronchiolar lavage fluid (BAL fluid) were collected on day 24. The 3-carene treatment suppressed the cytokine gene expression, such as interleukin-4 (IL-4), IL-5, and IL-13, reducing the lung epithelial cell thickness in the asthmatic model. These results suggest that essential oil 3-carene has an anti-asthmatic effect.


Asunto(s)
Asma , Monoterpenos Bicíclicos , Interleucina-13 , Interleucina-4 , Interleucina-5 , Animales , Femenino , Ratones , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones Endogámicos BALB C , Ovalbúmina , Monoterpenos Bicíclicos/farmacología
6.
Nat Commun ; 15(1): 3152, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38605064

RESUMEN

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fluorodesoxiglucosa F18 , Radiofármacos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Estudios Retrospectivos
7.
Gait Posture ; 110: 129-137, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38581933

RESUMEN

OBJECTIVE: To examine whether immersive virtual reality (VR) can improve balance, gait, mobility and fear of falling in older people. DATA SOURCES: MEDLINE, EMBASE, CINAHL, PsycINFO, ProQuest Central (Engineering and Computer Science) and reference lists of included articles. STUDY SELECTION: Randomised controlled trials that administered immersive VR training and assessed balance, gait and mobility outcomes in older adults without neurological disorders (mean age ≥ 65). Primary outcomes were standing balance (e.g. postural sway), multi-item balance scales (e.g. Berg Balance Scale), gait (e.g. gait speed) and mobility (e.g. Timed Up and Go test). Secondary outcomes comprised measures of enjoyment, fear of falling, adherence (e.g. dropout rate), feasibility/usability and adverse effects (e.g. motion sickness). RESULTS: Meta-analyses showed that immersive VR training significantly improved standing balance (SMD: 0.51, 95% CI: .15, 0.86, p = 0.005, I2 = 28% - 3 studies, n = 79) and performance on the Berg Balance Scale (MD: 2.36, 95% CI: 1.17, 3.56, p=0.0001, I2=0% - 4 studies, n = 190). No significant improvement in gait, mobility or fear of falling was found. Subgroup analyses revealed higher training doses (≥4.5 total hours) and VR interventions using non-head mounted displays were more likely to improve standing balance. No meta-analyses were conducted for enjoyment, adherence, feasibility/usability and adverse events. CONCLUSIONS: The findings indicate immersive VR has beneficial effects on balance, but not gait, mobility or fear of falling. Further research is required to examine these outcomes in trials that also include quantitative measurements of enjoyment, adherence, clinical feasibility, usability and adverse effects.


Asunto(s)
Accidentes por Caídas , Marcha , Equilibrio Postural , Humanos , Equilibrio Postural/fisiología , Anciano , Marcha/fisiología , Accidentes por Caídas/prevención & control , Terapia de Exposición Mediante Realidad Virtual/métodos , Realidad Virtual
8.
Int J Clin Health Psychol ; 24(2): 100458, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38623146

RESUMEN

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

10.
Epidemiol Psychiatr Sci ; 33: e22, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38602075

RESUMEN

AIMS: In the United States, lesbian, gay, bisexual, transgender, queer, intersex, asexual and other sexually minoritized and gender expansive (LGBTQ+) young adults are at increased risk for experiencing mental health inequities, including anxiety, depression and psychological distress-related challenges associated with their sexual and gender identities. LGBTQ+ young adults may have unique experiences of sexual and gender minority-related vulnerability because of LGBTQ+-related minority stress and stressors, such as heterosexism, family rejection, identity concealment and internalized homophobia. Identifying and understanding specific LGBTQ+-related minority stress experiences and their complex roles in contributing to mental health burden among LGBTQ+ young adults could inform public health efforts to eliminate mental health inequities experienced by LGBTQ+ young adults. Therefore, this study sought to form empirically based risk profiles (i.e., latent classes) of LGBTQ+ young adults based on their experiences with familial heterosexist experiences, LGBTQ+-related family rejection, internalized LGBTQ+-phobia and LGBTQ+ identity concealment, and then identify associations of derived classes with psychological distress. METHODS: We recruited and enrolled participants using nonprobability, cross-sectional online survey data collected between May and August 2020 (N = 482). We used a three-step latent class analysis (LCA) approach to identify unique classes of response patterns to LGBTQ+-related minority stressor subscale items (i.e., familial heterosexist experiences, LGBTQ+-related family rejection, internalized LGBTQ+-phobia and LGBTQ+ identity concealment), and multinomial logistic regression to characterize the associations between the derived classes and psychological distress. RESULTS: Five distinct latent classes emerged from the LCA: (1) low minority stress, (2) LGBTQ+ identity concealment, (3) family rejection, (4) moderate minority stress and (5) high minority stress. Participants who were classified in the high and moderate minority stress classes were more likely to suffer from moderate and severe psychological distress compared to those classified in the low minority stress class. Additionally, relative to those in the low minority stress class, participants who were classified in the LGBTQ+ identity concealment group were more likely to suffer from severe psychological distress. CONCLUSION: Familial heterosexist experiences, LGBTQ+-related family rejection, internalized LGBTQ+-phobia and LGBTQ+ identity concealment are four constructs that have been extensively examined as predictors for mental health outcomes among LGBTQ+ persons, and our study is among the first to reveal nuanced gradients of these stressors. Additionally, we found that more severe endorsement of minority stress was associated with greater psychological distress. Given our study results and the previously established negative mental health impacts of minority stressors among LGBTQ+ young adults, findings from our study can inform research, practice, and policy reform and development that could prevent and reduce mental health inequities among LGBTQ+ young adults.


Asunto(s)
Salud Mental , Minorías Sexuales y de Género , Femenino , Humanos , Adulto Joven , Estados Unidos , Estudios Transversales , Análisis de Clases Latentes , Estrés Psicológico/epidemiología , Estrés Psicológico/psicología , Identidad de Género
11.
Clin Radiol ; 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38622045

RESUMEN

AIM: The aim of this study was to identify preoperative magnetic resonance imaging (MRI) findings that can predict the shunt responsiveness in idiopathic normal-pressure hydrocephalus (iNPH) patients and to investigate postoperative outcome and complications. MATERIALS AND METHODS: A total of 192 patients with iNPH who underwent shunt at our hospital between 2000 and 2021 were included to investigate complications. Of these, after exclusion, 127 (1-month postoperative follow-up) and 77 (1-year postoperative follow-up) patients were evaluated. The preoperative MRI features (the presence of tightness of the high-convexity subarachnoid space, Sylvian fissure enlargement, Evans' index, and callosal angle) of the shunt-response and nonresponse groups were compared, and a systematic review was conducted to evaluate whether preoperative MRI findings could predict shunt response. RESULTS: Postoperative complications within one month after surgery were observed in 6.8% (13/192), and the most common complication was hemorrhage. Changes in corpus callosum were observed in 4.2% (8/192). The shunt-response rates were 83.5% (106/127) in the 1-month follow-up group and 70.1% (54/77) in 1-year follow-up group. In the logistic regression analysis, only Evans' index measuring >0.4 had a significant negative relationship with shunt response at 1-month follow-up; however, no significant relationship was observed at 1-year follow-up. According to our systematic review, it is still controversial whether preoperative MRI findings could predict shunt response. CONCLUSION: Evans' index measure of >0.4 had a significant relationship with the shunt response in the 1-month follow-up group. In systematic reviews, there is ongoing debate about whether preoperative MRI findings can accurately predict responses to shunt surgery. Postoperative corpus callosal change was observed in 4.2% of iNPH patients.

12.
PLoS One ; 19(4): e0300285, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38564604

RESUMEN

Previous research on stabilization methods for microbiome investigations has largely focused on human fecal samples. There are a few studies using feces from other species, but no published studies investigating preservation of samples collected from cattle. Given that microbial taxa are differentially impacted during storage it is warranted to study impacts of preservation methods on microbial communities found in samples outside of human fecal samples. Here we tested methods of preserving bovine fecal respiratory specimens for up to 2 weeks at four temperatures (room temperature, 4°C, -20°C, and -80°C) by comparing microbial diversity and community composition to samples extracted immediately after collection. Importantly, fecal specimens preserved and analyzed were technical replicates, providing a look at the effects of preservation method in the absence of biological variation. We found that preservation with the OMNIgene®â€¢GUT kit resulted in community structure most like that of fresh samples extracted immediately, even when stored at room temperature (~20°C). Samples that were flash-frozen without added preservation solution were the next most representative of original communities, while samples preserved with ethanol were the least representative. These results contradict previous reports that ethanol is effective in preserving fecal communities and suggest for studies investigating cattle either flash-freezing of samples without preservative or preservation with OMNIgene®â€¢GUT will yield more representative microbial communities.


Asunto(s)
ADN , Manejo de Especímenes , Bovinos , Humanos , Animales , Manejo de Especímenes/métodos , Heces/química , ADN/análisis , Etanol/análisis , Sistema Respiratorio , Genómica , ARN Ribosómico 16S/genética
13.
Psychiatr Serv ; : appips20230211, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38566561

RESUMEN

OBJECTIVE: The authors measured implementation of Zero Suicide (ZS) clinical practices that support identification of suicide risk and risk mitigation, including screening, risk assessment, and lethal means counseling, across mental health specialty and primary care settings. METHODS: Six health care systems in California, Colorado, Michigan, Oregon, and Washington participated. The sample included members ages ≥13 years from 2010 to 2019 (N=7,820,524 patients). The proportions of patients with suicidal ideation screening, suicide risk assessment, and lethal means counseling were estimated. RESULTS: In 2019, patients were screened for suicidal ideation in 27.1% (range 5.0%-85.0%) of mental health visits and 2.5% (range 0.1%-35.0%) of primary care visits among a racially and ethnically diverse sample (44.9% White, 27.2% Hispanic, 13.4% Asian, and 7.7% Black). More patients screened positive for suicidal ideation in the mental health setting (10.2%) than in the primary care setting (3.8%). Of the patients screening positive for suicidal ideation in the mental health setting, 76.8% received a risk assessment, and 82.4% of those identified as being at high risk received lethal means counseling, compared with 43.2% and 82.4%, respectively, in primary care. CONCLUSIONS: Six health systems that implemented ZS showed a high level of variation in the proportions of patients receiving suicide screening and risk assessment and lethal means counseling. Two opportunities emerged for further study to increase frequency of these practices: expanding screening beyond patients with regular health care visits and implementing risk assessment with lethal means counseling in the primary care setting directly after a positive suicidal ideation screening.

14.
Niger J Clin Pract ; 27(4): 541-544, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38679780

RESUMEN

ABSTRACT: Myotonic dystrophy (DM) is an autosomal dominant genetic disorder characterized by progressively worsening loss of muscle mass and weakness. Anesthesiologists face challenges in managing these patients due to risks such as prolonged intubation and delayed recovery associated with anesthesia in such conditions. We report a case of a 40-year-old male patient undergoing open total gastrectomy under general anesthesia. After the surgery, we administered sugammadex to reverse neuromuscular blockade and confirmed the patient's spontaneous breathing. We then proceeded to extubate the patient. However, the patient experienced complications such as apnea, desaturation, and mental changes. The patient was re-intubated and transferred to the intensive care unit for ventilator support. He was diagnosed with DM by genetic test later. Poor preoperative assessment or undiagnosed DM in surgical patients can lead to severe complications. Thus, it is important to carefully check preoperative laboratory results, patient history, and physical findings.


Asunto(s)
Anestesia General , Distrofia Miotónica , Humanos , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/complicaciones , Masculino , Adulto , Anestesia General/métodos , Gastrectomía/métodos , Sugammadex , Bloqueo Neuromuscular/métodos
15.
Front Oncol ; 14: 1324057, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38590653

RESUMEN

Accurate diagnoses are crucial in determining the most effective treatment across different cancers. In challenging cases, morphology-based traditional pathology methods have important limitations, while molecular profiling can provide valuable information to guide clinical decisions. We present a 35-year female with lung cancer with choriocarcinoma features. Her disease involved the right lower lung, brain, and thoracic lymph nodes. The pathology from brain metastasis was reported as "metastatic choriocarcinoma" (a germ cell tumor) by local pathologists. She initiated carboplatin and etoposide, a regimen for choriocarcinoma. Subsequently, her case was assessed by pathologists from an academic cancer center, who gave the diagnosis of "adenocarcinoma with aberrant expression of ß-hCG" and finally pathologists at our hospital, who gave the diagnosis of "poorly differentiated carcinoma with choriocarcinoma features". Genomic profiling detected a KRAS G13R mutation and transcriptomics profiling was suggestive of lung origin. The patient was treated with carboplatin/paclitaxel/ipilimumab/nivolumab followed by consolidation radiation therapy. She had no evidence of progression to date, 16 months after the initial presentation. The molecular profiling could facilitate diagnosing of challenging cancer cases. In addition, chemoimmunotherapy and local consolidation radiation therapy may provide promising therapeutic options for patients with lung cancer exhibiting choriocarcinoma features.

16.
Women Birth ; : 101589, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38580584

RESUMEN

BACKGROUND: Work-related stress is high in midwifery with negative implications for midwives' health and performance. This systematic review therefore examined which stress management interventions (SMIs) are most effective at reducing occupational stress and improving midwives' health and well-being, performance, and job satisfaction. METHODS: A systematic review included studies if they were: investigating midwives or student midwives; examining an individual- or organisation-level intervention; reporting the intervention effects on at least one outcome (e.g., job performance); peer-reviewed; and published in English. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was conducted and data were presented by SMI level (i.e., individual vs. organisation) and modality type (e.g., mindfulness, care model). Sum codes were used to compare the effects of individual- and organisation-level SMIs on outcomes. FINDINGS: From 2605 studies identified, 30 were eligible (18 individual- and 12 organisation-level SMIs). Eight studies were deemed low quality. While individual- and organisation-level SMIs were equally effective in improving job satisfaction and performance, there was a trend for organisation-level SMIs more effectively reducing work stress and improving health and well-being. Specific individual- (i.e., mindfulness, simulation training) and organisation-level (i.e., reflective groups, midwifery care models) SMIs were most beneficial. CONCLUSION: It is recommended that health practitioners and policy makers implement interventions that target both individual- and organisation-levels to optimally support midwives' work stress, health, well-being, and performance. Notwithstanding these findings and implications, some studies had poor methodological quality; thus, future research should better follow intervention reporting guidelines.

17.
Cell Rep ; 43(4): 114114, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38625791

RESUMEN

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders.


Asunto(s)
Células Endoteliales , Mutación con Ganancia de Función , Pulmón , Proteínas de la Membrana , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ratones , Pulmón/patología , Pulmón/metabolismo , Linfocitos/metabolismo , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/metabolismo , Ratones Endogámicos C57BL , Humanos
19.
Cancers (Basel) ; 16(5)2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38473297

RESUMEN

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.

20.
Cells ; 13(5)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38474337

RESUMEN

Inflammatory bowel disease (IBD) is marked by a state of chronic energy deficiency that limits gut tissue wound healing. This energy shortfall is partially due to microbiota dysbiosis, resulting in the loss of microbiota-derived metabolites, which the epithelium relies on for energy procurement. The role of microbiota-sourced purines, such as hypoxanthine, as substrates salvaged by the colonic epithelium for nucleotide biogenesis and energy balance, has recently been appreciated for homeostasis and wound healing. Allopurinol, a synthetic hypoxanthine isomer commonly prescribed to treat excess uric acid in the blood, inhibits the degradation of hypoxanthine by xanthine oxidase, but also inhibits purine salvage. Although the use of allopurinol is common, studies regarding how allopurinol influences the gastrointestinal tract during colitis are largely nonexistent. In this work, a series of in vitro and in vivo experiments were performed to dissect the relationship between allopurinol, allopurinol metabolites, and colonic epithelial metabolism and function in health and during disease. Of particular significance, the in vivo investigation identified that a therapeutically relevant allopurinol dose shifts adenylate and creatine metabolism, leading to AMPK dysregulation and disrupted proliferation to attenuate wound healing and increased tissue damage in murine experimental colitis. Collectively, these findings underscore the importance of purine salvage on cellular metabolism and gut health in the context of IBD and provide insight regarding the use of allopurinol in patients with IBD.


Asunto(s)
Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Ratones , Animales , Alopurinol , Purinas/metabolismo , Hipoxantina/metabolismo , Colitis/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico
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