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This randomized trial of adjuvant chemotherapy in women with axillary lymph node–positive or high-risk, lymph node–negative breast cancer showed that weekly paclitaxel improved disease-free and overall survival as compared with docetaxel, when either was given after standard adjuvant chemotherapy. In women with axillary lymph node–positive or high-risk, lymph node–negative breast cancer, weekly paclitaxel improved disease-free and overall survival as compared with docetaxel, when either was given after standard adjuvant chemotherapy. Adjuvant chemotherapy substantially reduces the risk of recurrence and death among women with operable breast cancer. 1 The addition of a taxane to an anthracycline-containing regimen, whether after or concurrently with anthracycline treatment, further reduces the risk of relapse. Two studies in which patients received four cycles of paclitaxel every 3 weeks after receiving four cycles of doxorubicin and cyclophosphamide every 3 weeks 2 , 3 established a new standard of care for operable breast cancer and led to regulatory approval of paclitaxel for axillary lymph node–positive breast cancer. Another study demonstrating that concurrent administration of docetaxel with doxorubicin and cyclophosphamide was more . . .

The diets of laboratory rats were isotopically and nutritionally manipulated using purifiedC3 and/or C4 macronutrients to investigate the routing of dietary carbonto bone collagen biosynthesis. Diets were formulated with purified proteins, carbohydrates andlipids of defined composition and natural abundance stable isotope ratios. Bulk protein and constituent amino acid δ13C values determined for whole diet and bone collagen provided the basis for assessing isotopic fractionation and estimating the degree of routing versus synthesis de novo of essential, non-essential and conditionally indispensable amino acids. Essential and conditionally indispensable amino acids were shown to be routed from diet to collagen with little isotopic fractionation whereas non-essential amino acids differed by up to 20‰. Mathematical modelling of the relationships between macronutrient and tissue δ13C values provided qualitative and quantitative insights into the metabolic and energetic controls on bone collagen biosynthesis. Essential amino acids comprise 21·7% of the carbon in collagen, defining the minimum amount of dietary carbon routing. Estimates of 42 and 28% routing were shown for the non-essential amino acids, glycine and aspartate, respectively. In total, the routing of non-essential and conditionally indispensable amino acids was estimated to equal 29·6% of the carbon in collagen. When the contribution of carbon from the essential amino acids is also considered, we arrive at an overall minimum estimate of 51·3% routing of dietary amino acid carbon into bone collagen.

Previous investigations have shown that women undergoing chemotherapy for breast cancer experience both disturbed sleep and fatigue. However, most of the previous research examined women either during or after chemotherapy. This study examined sleep, fatigue, and circadian rhythms in women with breast cancer before the start of chemotherapy. Eighty five women with Stages I-IIIA breast cancer who were scheduled to begin adjuvant or neoadjuvant anthracycline-based chemotherapy participated. Each had sleep/wake activity recorded with actigraphy for 72 consecutive hours and filled out questionnaires on sleep, fatigue, depression, and functional outcome. On average, the women slept for about 6 h a night and napped for over an hour during the day. Sleep was reported to be disturbed and fatigue levels were high. Circadian rhythms were robust, but women who were more phase-delayed reported more daily dysfunction (p<0.01). The data from the current study suggest that the women with breast cancer likely experience both disturbed sleep and fatigue before the beginning of chemotherapy. Although their circadian rhythms are robust, breast cancer patients with more delayed rhythms experience more daily dysfunction secondary to fatigue. These data suggest that strategies to improve disturbed sleep and to phase-advance circadian rhythms prior to initiation of chemotherapy may be beneficial in improving daily function in breast cancer patients.

The endoplasmic reticulum (ER) is the largest intracellular membranous organelle. Functions of the ER are many and diverse, which include various biosynthetic, transport and signalling roles, central to cellular physiology, such as the biosynthesis of membrane and secretory proteins and the regulation of intracellular calcium. Its continuous lumen also serves as a highway for the distribution of proteins and ions to different regions of the cell, independent of the cytosol. The ER is an excitable organelle, capable of generating a regenerative wave of calcium release, which can propagate along the endomembrane throughout the entire cell, serving as a system of intracelluar communication in polarised cells. Nowhere is this feature of ER function more crucial than in neurones. The extremely polarised nature of nerve cells presents a unique challenge for the global co-ordination of localised physiological events such as growth cone guidance and synaptic plasticity. Clearly, the physical continuity of the neuronal ER lumen is central to its functionality as a conduit for communication. To further probe the continuity of ER in neurones and glia, we developed LV-PA-pIN-KDEL, a photoactivatable analogue of our recently described vector LV-pIN-KDEL, a lentivirally delivered ER-targeting soluble GFP. We demonstrate the ability of this vector to transduce astrocytes and neurones in culture and in cortical explants. Furthermore, we exploit the photoactivatable attributes of the vector together with a focal laser photoactivation protocol to reveal the continuous nature of the ER lumen in these cell types, presenting the first direct evidence of an astrocytic ER luminal continuum and providing more data to support the existence of a single ER lumen in neurones.

IntroductionCONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC).MethodsThe treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic (‘COVID’ cohort, 16/03/2020-10/05/2020), with 12-month follow-up.ResultsAmong 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8–4.1) vs. 4.4 (IQR 3.6–5.2) months, p = 0.093).ConclusionPathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.

AimTo compare the palatability of oral non-soluble and oral soluble prednisolone tablets in paediatric patients admitted to the general paediatric wards in an acute London Trust.MethodAs part of ongoing quality improvement initiatives, the Paediatric and Pharmacy departments compared tolerability of soluble versus non-soluble prednisolone in a group of 27 patients. Using a modified 5 point hedonic scale with ‘smiley’ faces we measured palatability and tolerance (swallowed versus refusal or vomiting) over two three week periods: the first period whilst soluble prednisolone was dispensed (n=17) and the second period after the switch to non-soluble prednisolone had been made (n=10). All data were collected by doctors and nurses on the two paediatrics wards.ResultsWe found acceptance of prednisolone to be similar before and after formulations were switched: 2 non-tolerated doses before (n=17) versus 3 non-tolerated doses after the switch (n=10).We found that ‘disguising’ the taste of the non-soluble prednisolone within a portion of sugar free jam, or mixed with 5 ml of sugar-free blackcurrant cordial, helped with acceptance, although both soluble and non-soluble formulations were frequently reported to be “Yuk”!ConclusionsThe Trust has since made the switch to non-soluble prednisolone for all paediatric inpatients and for take home medications. An information leaflet has been developed for parents or carers to understand how to crush the prednisolone tablets. We have not had any parent or carer reported difficulty in preparing or administering the medication.Children under 15 account for 37.8% (20,510 of 54,300) of annual hospital admissions for acute asthma.1 A minimum course of 3 days' oral steroids are recommended in the BTS/SIGN 2014 guideline on the management of asthma.2 This acute Trust covers a population of over 300,000 in deprived boroughs of London.A typical three-day course of soluble prednisolone (at 2 mg/kg as per guidance, or approximately 20 mg) costs £20.88, compared to £2.48 for the equivalent dose of non-soluble prednisolone dispensed with a tablet crusher. Several hospital trusts have switched to using non-soluble prednisolone in order to achieve cost savings, but there have been anecdotal reports of poor palatability, raising concerns about compliance with taking medication once discharged.The switch from a soluble to a non-soluble formulation of prednisolone represents an annual saving of more than £44,000 for this hospital alone and, at scale, could realise substantial potential savings to the NHS, without compromising patients' clinical care.

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most.

Background/ObjectivesObesity in pregnancy has been associated with increased childhood cardiometabolic risk and reduced life expectancy. The UK UPBEAT multicentre randomised control trial was a lifestyle intervention of diet and physical activity in pregnant women with obesity. We hypothesised that the 3-year-old children of women with obesity would have heightened cardiovascular risk compared to children of normal BMI women, and that the UPBEAT intervention would mitigate this risk.Subjects/MethodsChildren were recruited from one UPBEAT trial centre. Cardiovascular measures included blood pressure, echocardiographic assessment of cardiac function and dimensions, carotid intima-media thickness and heart rate variability (HRV) by electrocardiogram.ResultsCompared to offspring of normal BMI women (n = 51), children of women with obesity from the trial standard care arm (n = 39) had evidence of cardiac remodelling including increased interventricular septum (IVS; mean difference 0.04 cm; 95% CI: 0.018 to 0.067), posterior wall (PW; 0.03 cm; 0.006 to 0.062) and relative wall thicknesses (RWT; 0.03 cm; 0.01 to 0.05) following adjustment. Randomisation of women with obesity to the intervention arm (n = 31) prevented this cardiac remodelling (intervention effect; mean difference IVS −0.03 cm (−0.05 to −0.008); PW −0.03 cm (−0.05 to −0.01); RWT −0.02 cm (−0.04 to −0.005)). Children of women with obesity (standard care arm) compared to women of normal BMI also had elevated minimum heart rate (7 bpm; 1.41 to 13.34) evidence of early diastolic dysfunction (e prime) and increased sympathetic nerve activity index by HRV analysis.ConclusionsMaternal obesity was associated with left ventricular concentric remodelling in 3-year-old offspring. Absence of remodelling following the maternal intervention infers in utero origins of cardiac remodelling.Clinical trial registry name and registration numberThe UPBEAT trial is registered with Current Controlled Trials, ISRCTN89971375.

The Observed Structured Clinical Examination (OSCE) is a well validated as a tool for assessing medical trainee performance, and has been identified by the Accreditation Council for Graduate Medical Education (ACGME) as a method for assessing the core competencies of interpersonal skills, communication and professionalism. Recently, the use of OSCEs in gastroenterology fellowship training has been shown to be a useful method for evaluating fellows' skills of these competencies relating to IBD education. Here, we report a pilot study of implementing a longitudinal OSCE experience to assess fellow's competency in IBD management.MethodsFour GI fellows from 2 programs participated in an identical 4-station OSCE for 2 consecutive years. The first case (“UC Flare”) evaluated communication between the GI fellow and an Emergency Department physician pertaining to initial triage and management of a patient with an ulcerative colitis flare. The second case (“Shared Decision Making”) focused on shared decision making in a patient with Crohn's disease who was deemed to benefit from combination therapy. The third case (“Transition of Care”) evaluated the GI fellow's ability to communicate with a young patient transitioning from pediatric to adult IBD care. The final case (“Geriatrics”) addressed discharge planning and education for a geriatric patient being discharged from the hospital after an IBD flare. Each station was observed by an attending gastroenterologist in addition to the standardized patient/physician (SP). Previously validated checklists utilizing 3 and 5-point Likert scales were scored across multiple domains by SPs, who each provided feedback after each case. After the completion of all cases, the fellows attended a debriefing session to review key IBD teaching points and communication skills, and completed a survey assessing the educational value of the experience.ResultsFour fellows participated in the longitudinal OSCE experience, representing 33% of the total participants each year. Notable improvement was observed in the domain of Communication (average score 3.6 versus 4.3 in 2014 and 2015, respectively), with 4/4 fellows improving in this domain. More modest improvements were observed in the domains of Relationship Development (average score 2.6 versus 2.8 in 2014 and 2015, respectively), with 4/4 fellows improving in this domain, and in the domain of Information Gathering (average score 2.7 versus 2.8 in 2014 and 2015, respectively) with 3/4 fellows showing improvement in score. No change in score was observed in the domain of Patient Education (average score 2.7 in 2014 and 2015), with only 2/4 fellows improving their score. There was net improvement in scores in the UC Flare and Geriatrics cases, and a net decrease in scores in the Transition of Care case. On post-OSCE survey, 50% of the fellows rated the repeat experience as useful.ConclusionsTo our knowledge, this is the first use of an OSCE to evaluate longitudinal development of skills in IBD management for gastroenterology fellows. This pilot study identified both areas of improvement and decline in fellow performance, and could be useful in development of targeted educational interventions for areas of weakness in the form of continuing medical education (CME) activities after fellowship completion.

Background All obese pregnant women are considered at equal high risk with respect to complications in pregnancy and birth, and are commonly managed through resource-intensive care pathways. However, the identification of maternal characteristics associated with normal pregnancy outcomes could assist in the management of these pregnancies. The present study aims to identify the factors associated with uncomplicated pregnancy and birth in obese women, and to assess their predictive performance. Methods Data form obese women (BMI ≥ 30 kg/m 2 ) with singleton pregnancies included in the UPBEAT trial were used in this analysis. Multivariable logistic regression was used to identify sociodemographic, clinical and biochemical factors at 15 +0 to 18 +6 weeks’ gestation associated with uncomplicated pregnancy and birth, defined as delivery of a term live-born infant without antenatal or labour complications. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC). Internal validation and calibration were also performed. Women were divided into fifths of risk and pregnancy outcomes were compared between groups. Sensitivity, specificity, and positive and negative predictive values were calculated using the upper fifth as the positive screening group. Results Amongst 1409 participants (BMI 36.4, SD 4.8 kg/m 2 ), the prevalence of uncomplicated pregnancy and birth was 36% (505/1409). Multiparity and increased plasma adiponectin, maternal age, systolic blood pressure and HbA1c were independently associated with uncomplicated pregnancy and birth. These factors achieved an AUROC of 0.72 (0.68–0.76) and the model was well calibrated. Prevalence of gestational diabetes, preeclampsia and other hypertensive disorders, preterm birth, and postpartum haemorrhage decreased whereas spontaneous vaginal delivery increased across the fifths of increasing predicted risk of uncomplicated pregnancy and birth. Sensitivity, specificity, and positive and negative predictive values were 38%, 89%, 63% and 74%, respectively. A simpler model including clinical factors only (no biomarkers) achieved an AUROC of 0.68 (0.65–0.71), with sensitivity, specificity, and positive and negative predictive values of 31%, 86%, 56% and 69%, respectively. Conclusion Clinical factors and biomarkers can be used to help stratify pregnancy and delivery risk amongst obese pregnant women. Further studies are needed to explore alternative pathways of care for obese women demonstrating different risk profiles for uncomplicated pregnancy and birth.