RESUMEN
Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics.
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Proteína Huntingtina/genética , Enfermedad de Huntington/patología , Animales , Peso Corporal , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Sistemas CRISPR-Cas/genética , Corteza Cerebral/patología , Corteza Cerebral/ultraestructura , Cuerpo Estriado/patología , Cuerpo Estriado/ultraestructura , Modelos Animales de Enfermedad , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/mortalidad , Imagen por Resonancia Magnética , Neuronas/metabolismo , Neuronas/patología , Técnicas de Transferencia Nuclear , Tasa de Supervivencia , Porcinos , Repeticiones de TrinucleótidosRESUMEN
BACKGROUND: Breast cancer (BC) incidence rates for First Nations (FN) women in Canada have been steadily increasing and are often diagnosed at a later stage. Despite efforts to expand the reach of BC screening programs for FN populations in Alberta (AB), gaps in screening and outcomes exist. METHODS: Existing population-based administrative databases including the AB BC Screening Program, the AB Cancer Registry, and an AB-specific FN registry data were linked to evaluate BC screening participation, detection, and timeliness of outcomes in this retrospective study. Tests of proportions and trends compared the findings between FN and non-FN women, aged 50-74 years, beginning in 2008. Incorporation of FN principles of ownership, control, access, and possession (OCAP®) managed respectful sharing and utilization of FN data and findings. RESULTS: The average age-standardized participation (2013-8) and retention rates (2015-6) for FN women compared to non-FN women in AB were 23.8% (P < .0001) and 10.3% (P = .059) lower per year, respectively. FN women were diagnosed with an invasive cancer more often in Stage II (P-value = .02). Following 90% completion of diagnostic assessments, it took 2-4 weeks longer for FN women to receive their first diagnosis as well as definitive diagnoses than non-FN women. CONCLUSION: Collectively, these findings suggest that access to and provision of screening services for FN women may not be equitable and may contribute to higher BC incidence and mortality rates. Collaborations between FN groups and screening programs are needed to eliminate these inequities to prevent more cancers in FN women.
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Neoplasias de la Mama , Detección Precoz del Cáncer , Indígena Canadiense , Femenino , Humanos , Alberta/epidemiología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Tamizaje Masivo , Estudios RetrospectivosRESUMEN
A meta-analysis was conducted to comprehensively evaluate the impact of wound drainage on postoperative wound infection and healing in patients undergoing spinal surgery. Computer searches were performed, from database inception to October 2023, in EMBASE, Google Scholar, Cochrane Library, PubMed, Wanfang and China National Knowledge Infrastructure databases for studies related to the application of wound drainage in spinal surgery. Two researchers independently screened the literature, extracted data and conducted quality assessments. Stata 17.0 software was employed for data analysis. Overall, 11 articles involving 2102 spinal surgery patients were included. The analysis showed that, compared to other treatment methods, the use of wound drainage in spinal surgery patients significantly shortened the wound healing time (standardized mean difference [SMD]: -1.35, 95% confidence intervals [CI]: -1.91 to -0.79, p < 0.001). However, there was no statistical difference in the incidence of wound infection (odds ratio: 1.35, 95% CI: 0.83-2.19, p = 0.226). This study indicates that wound drainage in patients undergoing spinal surgery is effective, can accelerate wound healing and is worth promoting in clinical practice.
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Procedimientos Neuroquirúrgicos , Infección de la Herida Quirúrgica , Humanos , Infección de la Herida Quirúrgica/epidemiología , Cicatrización de Heridas , Factores de Tiempo , Drenaje/métodosRESUMEN
In knee osteoarthritis surgery, managing postoperative wound healing and minimizing scar formation are pivotal for patient recovery and satisfaction. These aspects are particularly challenging due to the nature of the surgical procedure and patient demographics. Physiotherapy interventions are increasingly recognized for their role in improving these postoperative outcomes. This meta-analysis sought to evaluate the efficacy of physiotherapy in enhancing wound healing, as measured by REEDA scores, and reducing scar formation, as indicated by Manchester Scar Scale (MSS) scores, following knee osteoarthritis surgery. Analysing data from eight studies, we found that physiotherapy significantly improved wound healing, evidenced by lower REEDA scores (SMD = -19.58, 95% CI: [-22.49, -16.66], p < 0.01), and reduced scar formation, reflected in lower MSS scores (SMD = -24.79, 95% CI: [-30.03, -19.55], p < 0.01). These findings highlight the crucial role of physiotherapy in postoperative care for knee osteoarthritis patients, emphasizing its impact on enhancing recovery and improving surgical outcomes.
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Osteoartritis de la Rodilla , Humanos , Osteoartritis de la Rodilla/cirugía , Cicatriz , Modalidades de Fisioterapia , Cicatrización de Heridas , Cuidados PosoperatoriosRESUMEN
Complex fractures present significant challenges in orthopaedic surgery, particularly in terms of postoperative wound healing. Nutritional status plays a crucial role in the recovery process, with early nutritional support potentially influencing wound healing outcomes. This meta-analysis aimed to assess the impact of early nutritional interventions on postoperative wound healing and scar formation in patients with complex fractures. From an initial pool of 1742 articles, 7 studies were selected for analysis. The results revealed that preoperative nutritional support significantly improved early wound healing, as indicated by lower REEDA scores (SMD = -14.06, 95% CI: [-16.79, -11.32], p < 0.01) 1 week post-surgery. Furthermore, there was a notable reduction in scar formation, as demonstrated by lower Manchester Scar Scale scores (SMD = -25.03, 95% CI: [-30.32, -19.74], p < 0.01) 3 months post-surgery. These findings highlight the importance of incorporating nutritional strategies into the management of complex fractures to optimize postoperative recovery.
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Fracturas Óseas , Procedimientos Ortopédicos , Humanos , Cicatriz , Cicatrización de Heridas , Fracturas Óseas/cirugía , Apoyo NutricionalRESUMEN
Opportunistic pathogens frequently cause volatile infections in hosts with compromised immune systems or a disrupted normal microbiota. The commensalism of diverse microorganisms contributes to colonization resistance, which prevents the expansion of opportunistic pathogens. Following microbiota disruption, pathogens promptly adapt to altered niches and obtain growth advantages. Nevertheless, whether and how resident bacteria modulate the growth dynamics of invasive pathogens and the eventual outcome of such infections are still unclear. Here, we utilized birds as a model animal and observed a resident bacterium exacerbating the invasion of Avibacterium paragallinarum (previously Haemophilus paragallinarum) in the respiratory tract. We first found that negligibly abundant Staphylococcus chromogenes, rather than Staphylococcus aureus, played a dominant role in Av. paragallinarum-associated infectious coryza in poultry based on epidemic investigations and in vitro analyses. Furthermore, we determined that S. chromogenes not only directly provides the necessary nutrition factor nicotinamide adenine dinucleotide (NAD+) but also accelerates its biosynthesis and release from host cells to promote the survival and growth of Av. paragallinarum. Last, we successfully intervened in Av. paragallinarum-associated infections in animal models using antibiotics that specifically target S. chromogenes. Our findings show that opportunistic pathogens can hijack commensal bacteria to initiate infection and expansion and suggest a new paradigm to ameliorate opportunistic infections by modulating the dynamics of resident bacteria.
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Infecciones Oportunistas/microbiología , Enfermedades de las Aves de Corral/microbiología , Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/veterinaria , Animales , Antiinfecciosos/farmacología , Pollos , Infecciones por Haemophilus/microbiología , Haemophilus paragallinarum/efectos de los fármacos , Haemophilus paragallinarum/patogenicidad , Microbiota , Infecciones del Sistema Respiratorio/microbiología , Staphylococcus/efectos de los fármacosRESUMEN
AIMS: FAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to have a crucial role in the pathological mechanisms of diverse human ailments. However, the role of FAM134B-mediated ER-phagy in ototoxicity, particularly in cisplatin-induced ototoxicity, remains unclear. The present study endeavors to investigate whether FAM134B is expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) and C57BL/6 murine cochlear hair cells (HCs), and to explore its potential function in cisplatin-mediated ototoxicity, with the aim of discovering new insights that can mitigate or forestall the irreversible adverse effect of cisplatin. METHODS: Immunofluorescence (IF) staining was used to test the expression pattern of FAM134B, levels of C/EBP-homologous protein (CHOP), autophagy, and co-localization ratio of lysosomes and ER. Western blotting was employed to measure changes in expression levels of FAM134B, LC3B, ER stress-related proteins, LAMP1 and apoptotic mediators. Cell apoptosis was examined using transferase dUTP nick end labeling (TUNEL) assay and flow cytometry. RESULTS: In the present investigation, it was observed that FAM134B exhibited a diffuse expression pattern in the cytoplasm and nuclei of control HEI-OC1 cells. Following cisplatin administration, FAM134B was found to accumulate and form distinct dots around the nuclei, concomitant with increased levels of ER-phagy, ER stress, unfolded protein response (UPR), and cell apoptosis. Additionally, knockdown of FAM134B resulted in reduced ER-phagy, mitigated ER stress and UPR, and decreased apoptotic activity in HEI-OC1 cells following cisplatin exposure. CONCLUSIONS: Collectively, the findings of this study demonstrate that FAM134B-mediated ER-phagy enhances the susceptibility of HCs to ER stress and apoptosis in response to cisplatin-induced stress. This suggests a sequential progression of ER-phagy, ER stress and apoptosis following cisplatin stimulus, and implies the potential therapeutic benefit of inhibiting of FAM134B-mediated ER-phagy in the prevention of cisplatin-related ototoxicity.
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Cisplatino , Ototoxicidad , Ratones , Humanos , Animales , Cisplatino/toxicidad , Ototoxicidad/metabolismo , Estrés del Retículo Endoplásmico , Células Ciliadas Auditivas/metabolismo , Autofagia , Retículo Endoplásmico/metabolismo , ApoptosisRESUMEN
Lung-on-chips have showed great promise as a tool to recapitulate the respiratory system for investigation of lung diseases in the past decade. However, the commonly applied artificial elastic membrane (e.g., polydimethylsiloxane, PDMS) in the chip failed to mimic the alveolar basal membrane in the composition and mechanical properties. Here we replaced the PDMS film by a thin, biocompatible, soft, and stretchable membrane based on F127-DA hydrogel that well approached to the composition and stiffness of extracellular matrix in human alveoli for construction of lung-on-a-chip. This chip well reconstructed the mechanical microenvironments in alveoli so that the epithelial/endothelial functions were highly expressed with a well established alveolar-capillary barrier. In opposite to the unexpectedly accelerated fibrotic process on the PDMS-based lung-on-a-chip, HPAEpiCs on hydrogel-based chip only presented fibrosis under nonphysiologically high strain, well reflecting the features of pulmonary fibrosis in vivo. This physiologically relevant lung-on-a-chip would be an ideal model in investigation of lung diseases and for development of antifibrosis drugs.
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Enfermedades Pulmonares , Técnicas Analíticas Microfluídicas , Humanos , Microfluídica , Hidrogeles , Biomimética , Pulmón , Membranas Artificiales , Dispositivos Laboratorio en un ChipRESUMEN
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) gene encodes rate-limiting enzyme in cholesterol biosynthesis, which is related to cell proliferation and mitochondrial function. The present study was designed to explore the expression of HMGCR in murine cochlear hair cells and HEI-OC1 cells and the possible mechanisms underpinning the actions of HMGCR in cisplatin-induced ototoxicity, with special attention given to p38 mitogen-activated protein kinase (MAPK) activities in vitro. The expressions of HMGCR, p-p38, cleaved caspase-3 and LC3B was measured by immunofluorescence and western blot. JC-1 staining and MitoSOX Red were used to detect mitochondria membrane potential (MMP) and reactive oxygen species (ROS) levels respectively. The apoptosis of auditory cells was assessed by TUNEL staining and flow cytometry. Protein levels of bcl2/bax and beclin1 were examined by western blot. We found that HMGCR was widely expressed in the auditory cells, of both neonatal mice and 2-month-old mice, in cytoplasm, nucleus and stereocilia. Moreover, 30 µM cisplatin elicited the formation of ROS, which, in turn, led to HMGCR reduction, activating p38 kinase-related apoptosis and autophagy in auditory cells. Meanwhile, co-treatment with ROS scavenger at a concentration of 2 mM, N-acetyl-L-cysteine (NAC), could alleviate the aforementioned changes. In addition, HMGCR silencing resulted in higher p38 MAPK-mediated apoptosis and autophagy under cisplatin injury. Taken together, we demonstrate that, for the first time, that HMGCR is expressed in the cochlear. Furthermore, HMGCR exerts protective benefit on auditory cells against cisplatin-mediated injury stimulated by ROS, culminating in regulation of p38 MAPK-dependent apoptosis and autophagy.
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Ototoxicidad , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ratones , Cisplatino/toxicidad , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Especies Reactivas de Oxígeno , Transducción de Señal , Células Ciliadas AuditivasRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a leading cause of death in Canada and early detection can prevent deaths through screening. However, CRC screening in Alberta, Canada remains suboptimal and varies by sociodemographic and health system characteristics, as well as geographic location. This study aimed to further the understanding of these participant and health system characteristics associated with CRC screening in Alberta and identify clusters of regions with higher rates of overdue or unscreened individuals. METHODS: We included Albertans aged 52 to 74 as of December 31, 2019 (index date) and we used data from administrative health data sources and linked to the Alberta Colorectal Cancer Screening Program database to determine colorectal cancer screening rates. We used multivariable multinomial logistic regression analysis to investigate the relationship between sociodemographic, health system characteristics and participation in CRC screening. We used optimized Getis-Ord Gi* hot-spot analysis to identify hot and cold-spots in overdue for and no record of CRC screening. RESULTS: We included 919,939 Albertans, of which 65% were currently up to date on their CRC screening, 21% were overdue, and 14% had no record of CRC screening. Compared to Albertans who were currently up to date, those who were in older age groups, those without a usual provider of care, those who were health system non-users, and those living in more deprived areas were more likely to have no record of screening. Areas with high number of Albertans with no record of screening were concentrated in the North and Central zones. CONCLUSIONS: Our study showed important variation in colorectal cancer screening participation across sociodemographic, health system and geographical characteristics and identified areas with higher proportions of individuals who have no record of screening or are under-screened in Alberta, Canada.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Anciano , Alberta/epidemiología , Estudios Transversales , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/prevención & control , Tamizaje MasivoRESUMEN
Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse huntingtin gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.
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Enfermedad de Huntington/genética , ARN/genética , Animales , Modelos Animales de Enfermedad , Femenino , Técnicas de Sustitución del Gen , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Biosíntesis de Proteínas , ARN/metabolismo , Expansión de Repetición de Trinucleótido , Repeticiones de TrinucleótidosRESUMEN
Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.
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Cuerpo Estriado/patología , Enfermedad de Huntington/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , Optogenética , Animales , Cuerpo Estriado/metabolismo , Dependovirus , Regulación de la Expresión Génica , Enfermedad de Huntington/genética , Rayos Láser , Luz , Ratones , Red Nerviosa , Proteínas del Tejido Nervioso/genéticaRESUMEN
Inequities in cancer screening were identified in Calgary, AB, by correlating low screening participation with higher material deprivation. This initiative sought to understand awareness of and barriers to breast, cervical and colorectal cancer screening to inform the co-design and implementation of an outreach strategy to increase screening awareness. Online focus groups with community members (n = 69) identified five themes, and interviews with community health workers (n = 21) identified four themes. The engagement phase led to a multi-component outreach strategy including a multilingual video series, a media campaign leveraging partner channels and a health worker information package with resources to assist with hosting community-based education sessions.
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Equidad en Salud , Neoplasias , Humanos , Detección Precoz del Cáncer , Educación en Salud , Grupos FocalesRESUMEN
OBJECTIVES: Human papillomavirus (HPV) testing can be incorporated into the post-treatment pathway of cervical intraepithelial neoplasia (CIN) to confirm disease-free status. To inform a post-treatment strategy based on risk of recurrence, we modelled disease and economic outcomes. METHODS: The current Alberta, Canada, post-treatment care pathway-cytology testing with colposcopy assessment-was compared with 6 other scenarios incorporating cytology, HPV testing, or both tests at different time points in a modelling study based on a microsimulation program. Input parameter values for the screening participation, screening age groups, and follow-up options and test compliance for HPV, cytology, and colposcopy were varied, based on Alberta cervical cancer screening program data. Health outcomes over the short- and long-term were projected, which incorporated the increasing population-level coverage of HPV vaccination. Lifetime incremental cost-effectiveness ratios (ICERs) were used to evaluate economic outcomes and descriptive statistics compared with numbers of tests, visits, and procedures as well as changes in incidence and mortality rates between the scenarios. RESULTS: At 5 years after implementation of the "HPV testing alone at 6 and 18 months" post-treatment pathway, the number of colposcopies dropped by 36% and the number of pre-cancer treatments, by 6%. Lifetime ICERs were CAD $6170 versus $248,495 per quality-adjusted life-year compared with the status quo pathway. Cervical cancer incidence and mortality rates decreased significantly and similarly in all scenarios. CONCLUSION: Strategies that involve HPV testing in CIN post-treatment follow-up care are expected to be more cost effective with improved clinical outcomes than traditional cytology and colposcopy-based follow-up.
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Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Alberta/epidemiología , Colposcopía , Vías Clínicas , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Tamizaje Masivo/métodos , Papillomaviridae , Infecciones por Papillomavirus/diagnóstico , Embarazo , Neoplasias del Cuello Uterino/prevención & control , Frotis Vaginal , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/epidemiologíaRESUMEN
Regular screening mammography reduces breast cancer mortality. However, in women with dense breasts, the performance of screening mammography is reduced, which is reflected in higher interval cancer rates (ICR). In Canada, population-based screening mammography programs generally screen women biennially; however, some provinces and territories offer annual mammography for women with dense breast tissue routinely and/or on recommendation of the radiologist. This study compared the ICRs in those breast screening programs with a policy of annual vs. those with biennial screening for women with dense breasts. Among 148,575 women with dense breasts screened between 2008 to 2010, there were 288 invasive interval breast cancers; screening programs with policies offering annual screening for women with dense breasts had fewer interval cancers 63/70,814 (ICR 0.89/1000, 95% CI: 0.67-1.11) compared with those with policies of usual biennial screening 225/77,761 (ICR 1.45 /1000 (annualized), 95% CI: 1.19-1.72) i.e. 63% higher (p = 0.0016). In screening programs where radiologists' screening recommendations were able to be analyzed, a total of 76,103 women were screened, with 87 interval cancers; the ICR was lower for recommended annual (65/69,650, ICR 0.93/1000, 95% CI: 0.71, 1.16) versus recommended biennial screening (22/6,453, ICR 1.70/1000 (annualized), 95%CI: 0.70, 2.71)(p = 0.0605). Screening program policies of annual as compared with biennial screening in women with dense breasts had the greatest impact on reducing interval cancer rates. We review our results in the context of current dense breast notification in Canada.
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Densidad de la Mama , Neoplasias de la Mama/diagnóstico por imagen , Diagnóstico Tardío/prevención & control , Detección Precoz del Cáncer/métodos , Mamografía/métodos , Anciano , Canadá , Femenino , Humanos , Persona de Mediana Edad , Medición de RiesgoRESUMEN
The present study incorporated a moderated mediation model to explore the role of attitude towards condom use in mediating the link between sexual sensation seeking (SSS) and condom use and whether this indirect link was modified by HIV-related knowledge among Chinese YMSM. Survey data were collected from a cross-sectional study conducted in Wuhan, China and 373 YMSM were recruited. The mediation and moderated mediation modelling analyses were performed with the software SPSS PROCESS macro. Mediation analysis indicated that attitude towards condom use partly mediated the link between SSS and condom use (indict effect = -0.158, P < 0.001). Moderation analysis found HIV-related knowledge acted as a moderator in the relationship between SSS and attitude towards condom use (interact effect = 0.089, P = 0.001). Final moderated mediation analysis demonstrated that the indirect effect from SSS to condom use through attitude towards condom use was moderated by HIV-related knowledge, that is the interaction between HIV-related knowledge and SSS was positively associated with attitude towards condom use (ß = 0.101, P < 0.001). Therefore, increased YMSM-specific HIV-related knowledge education programs need to be conducted. Further longitudinal research is required to verify the findings of this study.
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Infecciones por VIH , Minorías Sexuales y de Género , China , Condones , Estudios Transversales , Homosexualidad Masculina , Humanos , Masculino , Sensación , Conducta SexualRESUMEN
Continued reports of infections with infectious bronchitis virus (IBV) variants have occurred since its first isolation in the 1930s. Currently, QX-like IBVs are the predominant circulating genotype around the world. Here, the pathogenicity of QX-like IBV strain SD was characterized in chickens at different ages of exposure to the virus, and the protection efficacy of available vaccine combinations against IBV was evaluated. The results revealed that QX-like IBV strain SD was severely pathogenic in chickens, causing respiratory, urinary and reproductive infections, irrespective of age, based on clinical observations, viral distribution in tissues and a ciliostasis study. Severe respiratory signs, tracheal cilia injury, nephritis and abnormal development of the oviduct and ovarian follicles were evident throughout the experiment. A challenge experiment demonstrated that the homologous QX vaccine showed superior protection efficacy compared with other available vaccines, confirming the importance of IBV vaccine seed homology against the circulating IBV strains. Our findings aid an understanding of the pathogenicity of QX-like IBVs that may help to further control the infection.
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Pollos , Infecciones por Coronavirus/veterinaria , Virus de la Bronquitis Infecciosa/inmunología , Enfermedades de las Aves de Corral/prevención & control , Factores de Edad , Animales , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/virología , Enfermedades de las Aves de Corral/virología , Organismos Libres de Patógenos Específicos , Vacunación/veterinaria , Vacunas Virales/inmunologíaRESUMEN
BACKGROUND: No studies, particularly quantitative analyses, have been conducted regarding the workload of village doctors in the National Essential Public Health Services (NEPHS) program and differences in service delivery by village doctors, according to region and services. In this study, we developed a quantitative analysis approach to measure the workload of NEPHS provided by village doctors in six provinces of China in 2016. We aimed to identify areas and services of the NEPHS needing improvement, so as to implement targeted measures to ensure adequate delivery of NEPHSs in rural remote underserved areas. METHODS: Based on survey data from 300 town hospital centers (THCs) located in 60 counties in the six selected provinces, we calculated village doctors' share of workload under the NEPHS using the equivalent value (EV) model. To define the workload and corresponding EV of each NEPHS, a series of five meetings was held with THC managers, public health workers, family physicians, nurses and village doctors. Field observations were conducted to verify the workload and EV of each service. RESULTS: Village doctors' share of the workload under the NEPHS program was 43.71% across the 300 sampled THCs in six provinces. The village doctors' workload shares for different NEPHS ranged from 17.14 to 57.00%. The percentage workload undertaken by village doctors under the NEPHS program varied across different provinces, with the highest proportion 63.4% and the lowest 28.5%. CONCLUSIONS: The total NEPHS workload assigned to village doctors by THCs in the six sampled provinces exceeded the Chinese government's requirement of 40%, but the workload proportion in some provinces was less than 40%. In addition, the percentage workload for some NEPHS undertaken by village doctors was lower than others. We suggest conducting district-level analysis of the workload among village doctors under the NEPHS program using the EV method, to identify areas and services needing improvement, to implement targeted measures to expand and promote health service provision in China's rural underserved areas.
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Médicos , Servicios de Salud Rural , China , Humanos , Encuestas y Cuestionarios , Carga de TrabajoRESUMEN
The objective of this study was to elucidate whether paeoniflorin (PF) exerted an effect on cisplatin-induced spiral ganglion neuron (SGN) damage, with special attention given to the role of PINK1/BAD pathway in this process. Middle cochlear turn culture and C57BL/6 mice were utilized to identify the character of PF in vitro and in vivo. We found that cisplatin treatment led to SGN damage, in which reactive oxygen species (ROS) generation increased, PINK1 expression decreased, BAD accumulation on mitochondria raised and mitochondrial apoptotic pathway activated. Conversely, we demonstrated that PF pre-treatment obviously mitigated cisplatin-induced SGN damage. Mechanistic studies showed that PF could reduce ROS levels, increase PINK1 expression, decrease the BAD accumulation on mitochondria and, thus, alleviate the activated mitochondrial apoptosis in SGNs caused by cisplatin. Overall, the findings from this work reveal the important role of PF and provide another strategy against cisplatin-induced ototoxicity.
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Cóclea/efectos de los fármacos , Glucósidos/farmacología , Monoterpenos/farmacología , Proteínas Quinasas/genética , Ganglio Espiral de la Cóclea/metabolismo , Proteína Letal Asociada a bcl/genética , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cisplatino/efectos adversos , Cisplatino/farmacología , Cóclea/metabolismo , Cóclea/patología , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Neuronas/efectos de los fármacos , Neuronas/patología , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patologíaRESUMEN
Intensive vaccination strategies against Newcastle disease (ND) have been implemented in many countries for a long time, but ND outbreaks still occur frequently, with most isolates belonging to genotype VII of Newcastle disease virus (NDV). Many researchers have revealed that vaccines closely matched to epidemic viruses provide better protection. Therefore, using a previously established reverse genetics system, we generated a recombinant NDV vaccine strain (rLa Sota-HN) based on the La Sota vaccine strain expressing the haemagglutinin-neuraminidase (HN) protein of genotype VII NDV. The pathogenicity of the recombinant virus was confirmed by the mean death time in 9-day-old specific-pathogen-free embryonated chicken eggs and the intracerebral pathogenicity index in 1-day-old specific-pathogen-free chickens. Subsequently, 1-day-old chickens were immunized with commercial vaccine La Sota and recombinant virus rLa Sota-HN and then challenged with virulent genotype VII NDV strain. The results indicated that recombinant virus rLa Sota-HN provided increased protection of vaccinated chickens from morbidity and mortality, and inhibited the shedding of virulent virus after challenging with genotype VII virus, compared with the conventional vaccine La Sota. Our findings indicated that rLa Sota-HN is a promising vaccine candidate to improve the protection efficiency against ND in chickens, thereby preventing frequent outbreaks of this disease.