Project description:Sproutys (Sprys) are downstream targets and negative feedback regulators of the FGF-Ras-ERK signaling pathway. Our previous studies have shown that Spry1 and Spry2, through negative modulation of FGF-ERK signaling, allow lens vesicle separation from the overlying ectoderm and regulate corneal epithelial proliferation. Here we show that Spry1 and Spry2 are necessary for eyelid closure. Murine palpebral conjunctival epithelial cells that differentiate as inner eyelids and adjacent mesenchymal cells express Spry1 and Spry2 prior to eyelid closure. Conditional deletion of both Spry1 and Spry2, but not either one alone, in the ocular surface epithelial cells result in the "EOB" (eyes open at birth) phenotype suggesting redundant roles for these proteins during eyelid closure. Spry mutant eyelids show increased proliferation of conjunctival epithelial cells with concomitant induction of FGF targets, Erm, Pea3 and Dusp6 and elevated ERK phosphorylation. Peridermal cells at the leading edge of Spry-mutant eyelids showed reduced c-Jun, but not ERK, phosphorylation, reduced F-actin polymerization and reduced motility in vitro. Spry mutant eyelids also showed disruptions in epithelial mesenchymal interactions reflected in the enhanced mesenchymal Spry1 and Spry4 expression, disaggregation of BMP4-positive mesenchymal cells and loss of Shh in the eyelid epithelium. Spry mutant eyelids also showed increased Wnt signaling and reduced expression of Foxc1 and Foxc2, two transcription factors previously shown to be necessary for eyelid closure. Collectively, our results show that conjunctival epithelial Spry1 and Spry2 redundantly promote eyelid closure by (a) stimulating ERK-independent, c-Jun-mediated peridermal migration, (b) suppressing conjunctival epithelial proliferation through FGF-ERK signaling, (c) mediating conjunctival epithelial-mesenchymal interactions and (d) maintaining expression of Foxc1 and Foxc2.
Project description:Neural tube closure is a fundamental process during vertebrate embryogenesis, which leads to the formation of the central nervous system. Defective neural tube closure leads to neural tube defects which are some of the most common human birth defects. While the intrinsic morphogenetic events shaping the neuroepithelium have been studied extensively, how tissues mechanically coupled with the neural plate influence neural tube closure remains poorly understood. Here, using Xenopus laevis embryos, live imaging in combination with loss of function experiments and morphometric analysis of fixed samples we explore the reciprocal mechanical communication between the neural plate and the somitic mesoderm and its impact on tissue morphogenesis. We show that although somitic mesoderm convergent extension occurs independently from neural plate morphogenesis neural tube closure depends on somitic mesoderm morphogenesis. Specifically, impaired somitic mesoderm remodelling results in defective apical constriction within the neuroepithelium and failure of neural tube closure. Last, our data reveal that mild abnormalities in somitic mesoderm and neural plate morphogenesis have a synergistic effect during neurulation, leading to severe neural tube closure defects. Overall, our data reveal that defective morphogenesis of tissues mechanically coupled with the neural plate can not only drastically exacerbate mild neural tube defects that may arise from abnormalities within the neural tissue but can also elicit neural tube defects even when the neural plate is itself free of inherent defects.
Project description:Psychiatry liaison services provide the interface between mental and physical health in the acute medical hospital, however there can be logistical and operational difficulties to overcome. This quality improvement project aimed to improve the timeliness of referrals to a liaison service from an acute hospital through simple interventions of a newsletter, email to staff, and a pilot including attending post-take ward rounds on the Medical Assessment Unit (MAU) of the hospital. This resulted in a faster referral process to liaison as well as improved staff satisfaction with the liaison service, both of which will have a positive benefit on the clinical management of patients and the patients experience in hospital. There was a significant improvement in overall staff satisfaction with the referral pathway, appropriateness of referrals and working hours of the Mental Health Liaison Team - increasing from 14% at baseline to 100% at the end of the study. Referral outcomes also showed a considerable improvement, with the percentage of junior doctors successfully able to locate the referral form increasing from 60% at baseline to 100%.
Project description:ObjectivesMissed hospital appointments pose a major challenge for healthcare systems. There is a lack of information about drivers of missed hospital appointments in non-Western countries and extent of variability between different types of clinics. The aim was to evaluate the rate and predictors of missed hospital appointments and variability in drivers between multiple outpatient clinics.SettingOutpatient clinics in the Royal hospital (tertiary referral hospital in Oman) between 2014 and 2018.ParticipantsAll patients with a scheduled outpatient clinic appointment (N=7 69 118).Study designRetrospective cross-sectional analysis.Primary and secondary outcome measuresA missed appointment was defined as a patient who did not show up for the scheduled hospital appointment without notifying or asking for the appointment to be cancelled or rescheduled. The outcomes were the rate and predictors of missed hospital appointments overall and variations by clinic. Conditional logistic regression compared patients who attended and those who missed their appointment.ResultsThe overall rate of missed hospital appointments was 22.3%, which varied between clinics (14.0% for Oncology and 30.3% for Urology). Important predictors were age, sex, service costs, patient's residence distance from hospital, waiting time and appointment day and season. Substantive variability between clinics in ORs for a missed appointment was present for predictors such as service costs and waiting time. Patients aged 81-90 in the Diabetes and Endocrine clinic had an adjusted OR of 0.53 for missed appointments (95% CI 0.37 to 0.74) while those in Obstetrics and Gynaecology had OR of 1.70 (95% CI 1.11 to 2.59). Adjusted ORs for longer waiting times (>120 days) were 2.22 (95% CI 2.10 to 2.34) in Urology but 1.26 (95% CI 1.18 to 1.36) in Oncology.ConclusionPredictors of a missed appointment varied between clinics in their effects. Interventions to reduce the rate of missed appointments should consider these factors and be tailored to clinic.
Project description:BackgroundThe optimal time to deliver adjuvant chemotherapy has not been defined.MethodsA retrospective study of consecutive patients receiving adjuvant anthracycline and/or taxane 1993-2010. Primary endpoint included 5-year disease-free survival (DFS) in patients commencing chemotherapy <31 versus ≥31 days after surgery. Secondary endpoints included 5-year overall survival (OS) and sub-group analysis by receptor status.ResultsWe identified 2003 eligible patients: 1102 commenced chemotherapy <31 days and 901 ≥31 days after surgery. After a median follow-up of 115 months, there was no difference in 5-year DFS rate with chemotherapy <31 compared to ≥31 days after surgery in the overall population (81 versus 82% hazard ratio (HR) 1.15, 95% confidence interval (95% CI) 0.92-1.43, p = 0.230). The 5-year OS rate was similar in patients who received chemotherapy <31 or ≥31 days after surgery (90 versus 91%, (HR 1.21, 95% CI 0.89-1.64, p = 0.228). For 250 patients with triple-negative breast cancer OS was significantly worse in patients who received chemotherapy ≥31 versus <31 days (HR = 2.18, 95% CI 1.11-4.30, p = 0.02).DiscussionAlthough adjuvant chemotherapy ≥31 days after surgery did not affect DFS or OS in the whole study population, in TN patients, chemotherapy ≥31 days after surgery significantly reduced 5-year OS; therefore, delays beyond 30 days in this sub-group should be avoided.
Project description:The cytoskeleton is widely considered essential for neurulation, yet the mouse spinal neural tube can close despite genetic and non-genetic disruption of the cytoskeleton. To investigate this apparent contradiction, we applied cytoskeletal inhibitors to mouse embryos in culture. Preventing actomyosin cross-linking, F-actin assembly or myosin II contractile activity did not disrupt spinal closure. In contrast, inhibiting Rho kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) or blocking F-actin disassembly prevented closure, with apical F-actin accumulation and adherens junction disturbance in the neuroepithelium. Cofilin-1-null embryos yielded a similar phenotype, supporting the hypothesis that there is a key role for actin turnover. Co-exposure to Blebbistatin rescued the neurulation defects caused by RhoA inhibition, whereas an inhibitor of myosin light chain kinase, ML-7, had no such effect. We conclude that regulation of RhoA, Rho kinase, LIM kinase and cofilin signalling is necessary for spinal neural tube closure through precise control of neuroepithelial actin turnover and actomyosin disassembly. In contrast, actomyosin assembly and myosin ATPase activity are not limiting for closure.
Project description:Cancer patients are frequently admitted to hospital due to acute conditions or refractory symptoms. This occurs through the emergency departments and requires medical oncologists to take an active role. The use of acute-care hospital increases in the last months of life.We aimed to describe the admissions to a medical oncology inpatient service within a 16-month period with respect to patients and tumor characteristics, and the outcome of the hospital stay.672 admissions of 454 patients were analysed. The majority of admissions were urgent (74.1%), and were due to uncontrolled symptoms (79.6%). Among the chief complaints, dyspnoea occurred in 15.7%, pain in 15.2%, and neurological symptoms in 14.5%. The majority of the hospitalizations resulted in discharge to home (60.6%); in 26.5% the patient died and in 11.0% was transferred to a hospice. Admissions due to symptoms correlated with a longer hospital stay and a higher incidence of in-hospital death.We suggest that hospital use is not necessarily a sign of inappropriately aggressive care: inpatient care is probably an unavoidable step in the cancer trajectory. Optimization of inpatient supportive procedures should be a specific task of modern medical oncology.
Project description:Mounting evidence has suggested the clinical significance of body composition abnormalities in the context of cirrhosis. Herein, we aimed to investigate the association between visceral adiposity and malnutrition risk in 176 hospitalized patients with cirrhosis. The adiposity parameters were obtained by computed tomography (CT) as follows: total adipose tissue index (TATI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue area ratio (VSR). Malnutrition risk was screened using Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT). Visceral adiposity was determined given a higher VSR based on our previously established cutoffs. Multivariate analysis implicated that male gender (OR = 2.884, 95% CI: 1.360-6.115, p = 0.006), BMI (OR = 0.879, 95% CI: 0.812-0.951, P = 0.001), albumin (OR = 0.934, 95% CI: 0.882-0.989, P = 0.019), and visceral adiposity (OR = 3.413, 95% CI: 1.344-8.670, P = 0.010) were independent risk factors of malnutrition risk. No significant difference was observed regarding TATI, SATI, and VATI among patients with low or moderate and high risk of malnutrition. In contrast, the proportion of male patients embracing visceral adiposity was higher in high malnutrition risk group compared with that in low or moderate group (47.27 vs. 17.86%, p = 0.009). Moreover, this disparity was of borderline statistical significance in women (19.05 vs. 5.88%, p = 0.061). Assessing adipose tissue distribution might potentiate the estimation of malnutrition risk in cirrhotics. It is pivotal to recognize visceral adiposity and develop targeted therapeutic strategies.