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BACKGROUND Palliative care remains suboptimal in end-stage liver disease. AIM To inform a definitive study, we assessed palliative long-term abdominal drains in end-stage liver disease to determine recruitment, attrition, safety/potential effectiveness, questionnaires/interview uptake/completion and make a preliminary cost comparison. METHODS A 12-week feasibility nonblinded randomised controlled trial comparing large-volume paracentesis vs long-term abdominal drains in refractory ascites due to end-stage liver disease with fortnightly home visits for clinical/questionnaire-based assessments. Study success criteria were attrition not >50%

Presence of teratoma in the orchiectomy and residual retroperitoneal mass size are known predictors of finding teratoma during postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). We sought to determine if the percentage of teratoma in the orchiectomy specimen could better stratify the risk of teratoma in the retroperitoneum.The Indiana University Testis Cancer Database was reviewed to identify patients who underwent PC-RPLND for nonseminomatous germ cell tumors from 2010 to 2018. A logistic regression model was fit to predict the presence of retroperitoneal teratoma using teratoma and yolk sac tumor in the orchiectomy, residual mass size and log transformed values of prechemotherapy alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin. The study cohort was split into 60% training and 40% validation sets using 200 bootstraps. A predictive nomogram was developed for predicting teratoma in the retroperitoneum.A total of 422 men were included. Presence of teratoma in the orchiectomy (OR 1.02, p0.001), residual mass size (OR 1.16, p0.001) and log transformed prechemotherapy AFP (OR 1.12, p=0.002) were predictive factors for having teratoma in the retroperitoneum. The C-statistic using this model demonstrated a predictive ability of 0.77. Training set C-statistic was 0.78 compared to 0.75 for the validation set. A nomogram was developed to aid in clinical utility.The model better predicts patients at higher risk for teratoma in the retroperitoneum following chemotherapy, which can aid in a more informed referral for surgical resection.

Although scholars have often claimed that the Council of Trent called for the elimination of secular elements in church music, the official decree issued by that body in 1562 actually called only f...

OBJECTIVE To compare the effects of (a) tibolone, (b) continuous combined oestrogen plus progestogen and (c) placebo on plasma lipid and lipoprotein markers of cardiovascular risk in healthy postmenopausal women. STUDY DESIGN Randomized, single-centre, placebo-controlled, double-blind study. PATIENTS One hundred and one postmenopausal women were randomized (1:1:1) into one of three groups taking daily 2.5 mg tibolone, continuous oral oestradiol-17β 2 mg plus norethisterone acetate 1 mg daily (E2 /NETA) or placebo. MAIN OUTCOME MEASURES Fasting serum lipid, lipoprotein and apolipoprotein concentrations measured at baseline and after 6, 12 and 24 months of treatment. RESULTS Both tibolone and E2 /NETA lowered plasma total cholesterol concentrations relative to placebo. With tibolone, high-density lipoprotein cholesterol (HDL-C) was reduced (-27% at 24 months, P

Introduction The REDUCe study is a multicentre feasibility randomised controlled trial (RCT) comparing palliative long term abdominal drains (LTAD) with standard care, recurrent large volume paracentesis (LVP), in advanced cirrhosis and refractory ascites (RA), where ineligible for liver transplant (LT). Limited data exist on symptom burden in this group. Clinical, patient/carer reported, qualitative and health economic (HE) assessments were performed to resolve uncertainties and inform the design of a definitive RCT of LTAD as a palliative strategy in RA. Here we report on patient/carer reported outcomes. Methods Patients randomised 1:1 (LVP or LTAD). The LTAD group had community nurse home visits for ascites drainage. The LVP arm received standard care attending hospital. Follow up was 12 weeks with home visits every two weeks for clinical and questionnaire-based assessments: palliative care needs/symptom burden (IPOS); quality of life (QoL) (SF-LDQOL) and EQ-5D-5L; carer burden (ZBI-12) and service use. Results Thirty-six patients were randomised; 19 LVP and 17 LTAD. Uptake of questionnaires was high (>85%). Only 47% of the participants had carers who could complete ZBI-12 (9 LTAD vs 8 LVP). Symptom burden score (IPOS) was comparable in both groups at baseline and 12 weeks follow up. Compared to baseline, the EQ-5D-5L Health index worsened in LTAD but remained stable in LVP group, the reverse being true for the EQ-5D-5L visual analogue scale. SF-LDQoL: baseline domains were higher in the LTAD group, during follow up scores became similar in both groups (data not shown) except in the following domains where LTAD group had lower scores: memory, distress, loneliness and hopelessness. Baseline carer burden (ZBI-12) in LTAD was higher, but remained stable; however, in LVP carer burden was higher at 12 week follow up (table 1). Conclusions Preliminary data from REDUCe confirms and extends findings of significant symptom and carer burden in advanced cirrhosis and RA. LTAD may help mitigate carer burden, which was higher in the LVP group. Results of other PROM (SF-LDQOL and EQ-5D-5L) were variable. This may reflect the timing of questionnaire completion in relation to ascites drainage and large sampling variability. Finally the presence of the LTAD may have been a constant reminder of the palliative nature of the illness. Our results need further validation. Results will inform appropriate QoL assessment tools for definitive RCT design.

Introduction Ascites develops in about 90% with advanced cirrhosis; when refractory to medical therapy, standard of care is repeated large volume paracentesis (LVP) with albumin support. Refractory ascites (RA) confers a median life expectancy of six months without liver transplantation (LT). LVP is not an optimal palliative strategy. One alternative is long-term abdominal drains (LTAD), used in advanced malignant ascites, also enabling community management. Our ultimate aim is to improve end of life care (EoLC) in advanced cirrhosis and RA. This feasibility randomised controlled trial (RCT) aimed to resolve uncertainties in designing a definitive RCT. Methods Multicentre feasibility RCT with 1:1 randomisation between standard of care (LVP) vs. LTAD (Rocket Medical) in adults with RA, ineligible for LT. Both arms received prophylactic antibiotics. LTAD were inserted under ultrasound guidance. Community nurses undertook home visits to drain ascites dependent on symptoms; (maximum 6L/week), without albumin support. Follow up was 12 weeks with home visits every two weeks for the following assessments: clinical, questionnaire based to include quality of life, palliative care needs, carer burden and health economics (HE). Here we report clinical and HE outcomes. Results Thirty six patients were randomised; 19 LVP (two withdrew, wanting LTAD) and 17 LTAD (one withdrew - insufficient ascites). Mean age (years) LTAD vs. LVP 66 ± 10.4 vs. 68 ± 12; predominately male (76% vs. 74%). Participants were well matched at baseline in liver tests and prognostic scores: LTAD vs. LVP (serum bilirubin (μmol/L) 26 ± 15.8 vs. 16 ±10, serum albumin (g/L) 33 ± 4.2 vs. 31 ± 3.3, serum creatinine (mmol/L) 113 ± 46.7 vs.118 ± 53.1; MELD 14 ± 4.6 vs. 16 ± 7.2). One LTAD participant required hospitalisation for repeated LVP. Serum albumin (g/L) in the LTAD arm declined to 29 ± 3.3 at week two, subsequently remaining stable LTAD vs. LVP (29 ± 5.6 vs. 31 ± 5.5). Serum creatinine remained stable in both arms. There were no LTAD related serious adverse reactions. LTAD related adverse reactions included mild cellulitis (n=4) and small volume leakage around LTAD insertion site (n=3), all resolving rapidly. Peritonitis was rare, LTAD (possible) n=1 and LVP n=2. Overall mortality was 36% (12/33). Mortality and median survival (days in those who died) were 7/16 (44%) vs. 5/17 (29%), 53 days (IQR 43) vs. 61 days (IQR 35) in LTAD vs. LVP respectively. All but one death was liver related. Those in LTAD arm spent ≈20% less time in hospital. All nine alive in the LTAD arm at end of study elected to keep LTAD in. Detailed clinical and HE analysis is underway. Conclusions Preliminary data from the REDUCe study supports the safety and efficacy of palliative LTAD in RA due to advanced cirrhosis. LTAD allows successful management in the community with reduction in health resource utilisation. Proceeding to a definitive RCT is justified.

Background UK deaths due to chronic liver diseases such as cirrhosis have quadrupled over the last 40 years, making this condition now the third most common cause of premature death. Most patients with advanced cirrhosis (end-stage liver disease [ESLD]) develop ascites. This is often managed with diuretics, but if refractory, then the fluid is drained from the peritoneal cavity every 10–14 days by large volume paracentesis (LVP), a procedure requiring hospital admissions. As the life expectancy of patients with ESLD and refractory ascites (if ineligible for liver transplantation) is on average ≤ 6 months, frequent hospital visits are inappropriate from a palliative perspective. One alternative is long-term abdominal drains (LTADs), used successfully in patients whose ascites is due to malignancy. Although inserted in hospital, these drains allow ascites management outside of a hospital setting. LTADs have not been formally evaluated in patients with refractory ascites due to ESLD. Methods/design Due to uncertainty about appropriate outcome measures and whether patients with ESLD would wish or be able to participate in a study, a feasibility randomised controlled trial (RCT) was designed. Patients were consulted on trial design. We plan to recruit 48 patients with refractory ascites and randomise them (1:1) to either (1) LTAD or (2) current standard of care (LVP) for 12 weeks. Outcomes of interest include acceptability of the LTAD to patients, carers and healthcare professionals as well as recruitment and retention rates. The Integrated Palliative care Outcome Scale, the Short Form Liver Disease Quality of Life questionnaire, the EuroQol 5 dimensions instrument and carer-reported (Zarit Burden Interview) outcomes will also be assessed. Preliminary data on cost-effectiveness will be collected, and patients and healthcare professionals will be interviewed about their experience of the trial with a view to identifying barriers to recruitment. Discussion LTADs could potentially improve end-of-life care in patients with refractory ascites due to ESLD by improving symptom control, reducing hospital visits and enabling some self-management. Our trial is designed to see if such patients can be recruited, as well as to inform the design of a subsequent definitive trial. Trial registration ISRCTN, ISRCTN30697116. Registered on 7 October 2015. Electronic supplementary material The online version of this article (10.1186/s13063-018-2779-0) contains supplementary material, which is available to authorized users.

Background UK deaths due to chronic liver diseases such as cirrhosis have quadrupled over the last 40 years, making this condition now the third most common cause of premature death. Most patients with advanced cirrhosis (end-stage liver disease [ESLD]) develop ascites. This is often managed with diuretics, but if refractory, then the fluid is drained from the peritoneal cavity every 10–14 days by large volume paracentesis (LVP), a procedure requiring hospital admissions. As the life expectancy of patients with ESLD and refractory ascites (if ineligible for liver transplantation) is on average ≤ 6 months, frequent hospital visits are inappropriate from a palliative perspective. One alternative is long-term abdominal drains (LTADs), used successfully in patients whose ascites is due to malignancy. Although inserted in hospital, these drains allow ascites management outside of a hospital setting. LTADs have not been formally evaluated in patients with refractory ascites due to ESLD. Methods/design Due to uncertai/nty about appropriate outcome measures and whether patients with ESLD would wish or be able to participate in a study, a feasibility randomised controlled trial (RCT) was designed. Patients were consulted on trial design. We plan to recruit 48 patients with refractory ascites and randomise them (1:1) to either (1) LTAD or (2) current standard of care (LVP) for 12 weeks. Outcomes of interest include acceptability of the LTAD to patients, carers and healthcare professionals as well as recruitment and retention rates. The Integrated Palliative care Outcome Scale, the Short Form Liver Disease Quality of Life questionnaire, the EuroQol 5 dimensions instrument and carer-reported (Zarit Burden Interview) outcomes will also be assessed. Preliminary data on cost-effectiveness will be collected, and patients and healthcare professionals will be interviewed about their experience of the trial with a view to identifying barriers to recruitment. Discussion LTADs could potentially improve end-of-life care in patients with refractory ascites due to ESLD by improving symptom control, reducing hospital visits and enabling some self-management. Our trial is designed to see if such patients can be recruited, as well as to inform the design of a subsequent definitive trial. Trial registration ISRCTN, ISRCTN30697116. Registered on 7 October 2015.

Background and aims: Ascites develops in about 90% with advanced cirrhosis; when refractory to medical therapy, standard of care is repeated large volume paracentesis (LVP) with albumin support. Refractory ascites (RA) confers a median life expectancy of six months without liver transplantation (LT). LVP is not an optimal palliative strategy. One alternative is long-term abdominal drains (LTAD), used in advanced malignant ascites, also enabling community management. Our ultimate aim is to improve end of life care (EoLC) in advanced cirrhosis and RA. This feasibility randomised controlled trial (RCT) aimed to resolve uncertainties in designing a definitive RCT. Method: Multicentre feasibility RCT with 1:1 randomisation between standard of care (LVP) vs. LTAD (Rocket Medical) in adults with RA, ineligible for LT. Both arms received prophylactic antibiotics. LTAD were inserted under ultrasound guidance. Community nurses undertook home visits to drain ascites dependent on symptoms; (maximum 6L/week), without albumin support. Follow-up was 12 weeks with home visits every two weeks for the following assessments: clinical, questionnaire based to include quality of life, palliative care needs, carer burden and health economics (HE). Here we report clinical and HE outcomes. Results: Thirty six patients were randomised; 19 LVP (two withdrew, wanting LTAD) and 17 LTAD (one withdrew-insufficient ascites). Mean age (years) LTAD vs. LVP 66 + 10.4 vs. 68 ± 12; predominately male (76% vs. 74%). Participants were well matched at baseline in liver tests and prognostic scores: LTAD vs. LVP (serum bilirubin (μmol/L) 26 ± 15.8 vs. 16 ±10, serum albumin (g/L) 33 ± 4.2 vs. 31 ± 3.3, serum creatinine (mmol/L) 113 ± 46.7 vs.118 ± 53.1; MELD 14 ± 4.6 vs. 16 ± 7.2). One LTAD participant required hospitalisation for repeated LVP. Serum albumin (g/L) in the LTAD arm declined to 29 ± 3.3 at week two, subsequently remaining stable LTAD vs. LVP (29 ± 5.6 vs. 31 ± 5.5). Serum creatinine remained stable in both arms. There were no LTAD related serious adverse reactions. LTAD related adverse reactions included mild cellulitis (n = 4) and small volume leakage around LTAD insertion site (n = 3), all resolving rapidly. Peritonitis was rare, LTAD (possible) n = 1 and LVP n = 2. Overall mortality was 36% (12/33). Mortality and median survival (days in those who died) were 7/16 (44%) vs. 5/17 (29%), 53 days (IQR 43) vs. 61 days (IQR 35) in LTAD vs. LVP respectively. All but one death was liver related. Those in LTAD arm spent ≈20% less time in hospital. All nine alive in the LTAD arm at end of study elected to keep LTAD in. Detailed clinical and HE analysis is underway. Conclusion: Preliminary data from the REDUCe study supports the safety and efficacy of palliative LTAD in RA due to advanced cirrhosis. LTAD allows successful management in the community with reduction in health resource utilisation. Proceeding to a definitive RCT is justified.

Since its discovery in 1975 dobutamine has been used off-label for treating hemodynamic insufficiency in newborns and children. We present a structured literature review of pharmacokinetic and pharmacodynamic data for dobutamine in the pediatric population. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria. Where possible, results for the pharmacodynamic and pharmacokinetic effect of dobutamine were reported as pooled data. Forty-six papers met the inclusion criteria. With regard to pharmacodynamic data a number of studies reported significant increases in a number of clinical parameters such as heart rate, blood pressure, cardiac output across a wide range of pediatric populations. With regard to pharmacokinetic data studies reported that the infusion rate was positively correlated to plasma dobutamine concentration. There was great variability with regard to dobutamine clearance between individuals and as to whether it followed first- or zero-order elimination kinetics. While the pharmacodynamic effects of dobutamine appear to reflect the pharmacological profile of the drug, the pharmacokinetic data are difficult to interpret due to inhomogeneity between study populations ages, comorbidities, dobutamine dosages and methodologies. High-quality prospective pharmacokinetic and pharmacodynamic data especially in newborns are urgently required prior to a large randomized study.

Thomas of Sibthorpe, a Nottinghamshire clergyman and chancery clerk, prospered under the regime of Edward II and his favourite Hugh Despenser the younger, and again under Edward III, when he also became a clerk of parliament and a justice of assize and of the peace. In 1326 he established at Sibthorpe a college of chantry priests to pray for his soul and those of others; it was twice expanded and more lavishly endowed, in 1335 and 1343. He appointed a keeper or warden to take charge of the college, and used all available legal means to ensure that the endowment was firmly appropriated to the warden, who was obliged periodically to render him accounts. In 1351 the third warden, Robert of Kneeton, aided by others, allegedly murdered him in order to avoid rendering such an account. They were tried at a Nottingham gaol delivery, convicted of seditious killing and sentenced to be drawn and hanged, the punishment reserved for traitors, because the victim was a royal clerk and justice. The circumstances of Sibthorpe's death may have had a significant effect on the terms of the first Great Statute of Treasons, adopted by parliament only a few months later, and presumably incorporating the views of the most senior judges in England.

What made a motet appropriate for performance on a particular occasion in the sixteenth century? Previous studies have demonstrated that motets performed on a given day generally drew their texts from the liturgy of that day. Yet many of the eighty-five motets assigned to the Sundays and major feasts of the year in Johannes Rühling's Tabulaturbuch (1583) do not. What mattered to this Lutheran organist was not a motet text's previous liturgical association but its ability to gloss—sometimes in surprising ways—the Gospel or Epistle lesson of the day. His approach has strong parallels in a tradition of Lutheran preaching grounded in exegesis of the assigned lessons. The same exegetical approach figures, moreover, in Catholic use of the motet, exemplified both in musical sources, such as Andreas Pevernage's Cantiones sacrae (1578 and 1602), and in performances recorded in the diaries of the Sistine Chapel.