A scalable phenotyping approach for female floral organ development and senescence in the absence of pollination in wheat.

In the absence of pollination, female reproductive organs senesce, leading to an irrevocable loss in the reproductive potential of the flower, which directly affects seed set. In self-pollinating crops like wheat (Triticum aestivum), the post-anthesis viability of unpollinated carpels has been overlooked, despite its importance for hybrid seed production systems. To advance our knowledge of carpel development in the absence of pollination, we created a high-throughput phenotyping approach to quantify stigma and ovary morphology. We demonstrate the suitability of the approach, which uses light-microscopy imaging and machine learning, for the analysis of floral organ traits in field-grown plants using fresh and fixed samples. We show that the unpollinated carpel undergoes a well-defined initial growth phase, followed by a peak phase in which stigma area reaches its maximum and the radial expansion of the ovary slows, and a final deterioration phase. These developmental dynamics were consistent across years and could be used to classify male-sterile cultivars. This phenotyping approach provides a new tool for examining carpel development, which we hope will advance research into female fertility of wheat.

A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma.

AIMS: GSK3511294 is a humanized anti-interleukin (IL)-5 monoclonal antibody (mAb) engineered for extended half-life and improved IL-5 affinity versus other anti-IL-5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts. METHODS: This was a double-blind, parallel-group, single-ascending-dose, multicenter, Phase 1 study (205 722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells µL-1 . Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary). RESULTS: Forty-eight patients received the study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo-treated and 81% of GSK3511294-treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection-site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post-dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at week 26). PK were linear and dose proportional over the dose range; terminal half-life was 38-53 days. CONCLUSIONS: GSK3511294 was well tolerated, with linear and dose proportional PK, extended half-life and blood eosinophil count reduction, supporting less frequent dosing versus other anti-IL-5 mAbs.

Surgical management of suspected gallbladder cancer: The role of intraoperative frozen section for diagnostic confirmation.

BACKGROUND: Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT). METHODS: MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes. RESULTS: A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p < 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically. CONCLUSIONS: The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time.

To transplant, or not to transplant? That is the question. A patient advocate evaluation of autologous stem cell transplant in neuroblastoma.

High-dose chemotherapy with autologous stem cell transplant (ASCT) has been a mainstay of high-risk neuroblastoma treatment for several decades, demonstrating improvements in event-free survival but with risks of serious or even life-threatening acute toxicities, severe long-term adverse health effects for survivors, and ongoing contention regarding overall survival benefit. The merits of ASCT in the modern era of immunotherapy are a source of debate among parents, advocates, and some physicians. Here we examine evidence for and against ASCT, explore parent attitudes and their turmoil over decision-making, and strongly encourage international research consortia to develop a coordinated strategy to accelerate progress toward a future that avoids the routine use of ASCT in high-risk neuroblastoma.

Evaluation of the utility of prognostic models for patients with resected hilar cholangiocarcinoma.

BACKGROUND: Several prognostic systems have been proposed to guide management strategies post-resection for patients with hilar cholangiocarcinoma. The objective of this study was to evaluate the efficacy of these conventional prognostic models, with respect to Overall Survival (OS), on patients in a modern single-centre resectional cohort. METHOD: Patients diagnosed with hilar cholangiocarcinoma, referred to a supra-regional tertiary referral centre between February 2009 and February 2016, were retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. RESULTS: Two-hundred and one patients were assessed for suitability for surgery. Eighty-three (41%) patients considered to have potentially resectable disease underwent surgical assessment of resectability. Fifty-six (68%) patients proceeded to resection. Multivariate analysis demonstrated that pre-operative Serum CA 19-9 (p = 0.007), Radiological Arterial Involvement (p = 0.005) and Amsterdam Medical Centre (AMC) prognostic model score (p = 0.032) retained significance in association with OS. Multivariate models developed from this cohort out-performed the conventional prognostic systems for OS. CONCLUSION: The cohort-derived multivariate models demonstrated significantly improved prognostic capability compared to conventional systems in explaining OS.

The wheat Phs-A1 pre-harvest sprouting resistance locus delays the rate of seed dormancy loss and maps 0.3 cM distal to the PM19 genes in UK germplasm.

The precocious germination of cereal grains before harvest, also known as pre-harvest sprouting, is an important source of yield and quality loss in cereal production. Pre-harvest sprouting is a complex grain defect and is becoming an increasing challenge due to changing climate patterns. Resistance to sprouting is multi-genic, although a significant proportion of the sprouting variation in modern wheat cultivars is controlled by a few major quantitative trait loci, including Phs-A1 in chromosome arm 4AL. Despite its importance, little is known about the physiological basis and the gene(s) underlying this important locus. In this study, we characterized Phs-A1 and show that it confers resistance to sprouting damage by affecting the rate of dormancy loss during dry seed after-ripening. We show Phs-A1 to be effective even when seeds develop at low temperature (13 °C). Comparative analysis of syntenic Phs-A1 intervals in wheat and Brachypodium uncovered ten orthologous genes, including the Plasma Membrane 19 genes (PM19-A1 and PM19-A2) previously proposed as the main candidates for this locus. However, high-resolution fine-mapping in two bi-parental UK mapping populations delimited Phs-A1 to an interval 0.3 cM distal to the PM19 genes. This study suggests the possibility that more than one causal gene underlies this major pre-harvest sprouting locus. The information and resources reported in this study will help test this hypothesis across a wider set of germplasm and will be of importance for breeding more sprouting resilient wheat varieties.

RNA-Seq bulked segregant analysis enables the identification of high-resolution genetic markers for breeding in hexaploid wheat.

The identification of genetic markers linked to genes of agronomic importance is a major aim of crop research and breeding programmes. Here, we identify markers for Yr15, a major disease resistance gene for wheat yellow rust, using a segregating F2 population. After phenotyping, we implemented RNA sequencing (RNA-Seq) of bulked pools to identify single-nucleotide polymorphisms (SNP) associated with Yr15. Over 27 000 genes with SNPs were identified between the parents, and then classified based on the results from the sequenced bulks. We calculated the bulk frequency ratio (BFR) of SNPs between resistant and susceptible bulks, selecting those showing sixfold enrichment/depletion in the corresponding bulks (BFR > 6). Using additional filtering criteria, we reduced the number of genes with a putative SNP to 175. The 35 SNPs with the highest BFR values were converted into genome-specific KASP assays using an automated bioinformatics pipeline (PolyMarker) which circumvents the limitations associated with the polyploid wheat genome. Twenty-eight assays were polymorphic of which 22 (63%) mapped in the same linkage group as Yr15. Using these markers, we mapped Yr15 to a 0.77-cM interval. The three most closely linked SNPs were tested across varieties and breeding lines representing UK elite germplasm. Two flanking markers were diagnostic in over 99% of lines tested, thus providing a reliable haplotype for marker-assisted selection in these breeding programmes. Our results demonstrate that the proposed methodology can be applied in polyploid F2 populations to generate high-resolution genetic maps across target intervals.

Evaluation of non-polynomial equations for one-compartment correction of slope-intercept GFR: theoretical prediction and experimental measurement.

BACKGROUND: Polynomial equations for one-compartment correction of slope-intercept glomerular filtration rate (GFR) will underestimate values at high clearance rates. Non-polynomial correction equations that are independent of patient size and renal function would be advantageous and may have cross-species use. MATERIALS AND METHODS: The study explored the theoretical basis of firstly the Jodal and Brochner-Mortensen one-compartment correction equation, replacing plasma volume with extracellular fluid volume, and secondly an equation described by Peters. One-compartment correction factors (a which is related to plasma volume and v which is related to extracellular fluid volume) which avoided the need for scaling to body size were developed. Both factors were determined from the biexponential clearance curve of the markers iohexol and (51)Cr-EDTA in humans and iohexol in cats and dogs. Relationships between a and v and filtration function and body size were then determined using data from humans, cats and dogs to assess their validity and compare this with theoretical predictions. RESULTS: In all species, v was higher than a, as theoretically predicted. Both were significantly higher in humans than cats and dogs, ruling out cross-species use. Significant relationships were present between v and measures of filtration function in humans, but were weak with respect to a. Neither a nor v showed significant relationships with filtration function in animals or with body size in any species. CONCLUSIONS: a and v (which are factors independent of body size) can be used interchangeably for correcting slope-intercept clearance. However values of both for humans are higher compared to cats and dogs. Therefore a single cross-species factor cannot be used.

Integration of patient and public involvement in a doctoral research study using the research cycle.

BACKGROUND: Patient and public involvement (PPI) in research is widely acknowledged as essential to achieving successful and impactful research. Despite this acknowledgement, there are limited reports on how to approach and apply meaningful PPI throughout the research cycle and how to address challenges for researchers such as doctoral students, particularly when undertaking research on sensitive topics. This paper provides insights and examples for researchers new to PPI, on the impact of active PPI and recommendations for building and developing a PPI group in a paediatric focused doctoral research study with bereaved parents and carers. METHODS: PPI was informed by the research cycle. The GRIPP2 short-form checklist was used to report PPI. The research was funded by the National Institute for Health and Care Research. RESULTS: PPI enhanced the research through input into the study design, recruitment, co-design of the study website and branding; and ethics amendments to increase participation in response to the COVID-19 pandemic. The literature review was extended to incorporate a PPI consultation phase and members contributed to data analysis. A flexible approach enabled involvement to develop iteratively throughout the research study, resulting in changes being made to enhance the study design and outcomes. CONCLUSION: This paper contributes to the limited knowledge base on embedding PPI into a doctoral research study and within the paediatric setting specifically working in partnership with bereaved parents and carers. Employing an adaptive approach to meet individual PPI needs, building a trusting and respectful partnership, creating shared ownership and investment in the research, are essential components to successful PPI.

Involving patients and the public in research provides the opportunity to develop meaningful outcomes that are relevant to the population being studied. Despite the benefits of patient and public involvement in research, guidelines that support researchers in doing so, lack detail on how to do this effectively. This is particularly important for those new to research such as doctoral students, who have so much to learn in developing a research study. Different approaches and applications to involvement are also likely to be needed depending on the population being studied. There are limited published papers on examples of how doctoral students have engaged and involved patients and the public in the context of their studies, and specifically within the children's setting, working in partnership with bereaved parents and carers, or those with seriously ill children. This paper offers examples and insights for those new to research in how to involve patients and the public throughout the research cycle. Specifically undertaking research in a sensitive subject of a particular childhood cancer which has poor outcomes and how to incorporate and evaluate successful patient and public involvement in their research activities such as study design and analysis of the results. Parent and carer reflections on their experiences of being involved are also reported and researcher recommendations for approaching and working with a patient and public group are described.

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

Long-term morbidity after surgery for perihilar cholangiocarcinoma: A cohort study.

BACKGROUND: Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival, but remains a formidable undertaking. Traditionally, 90-day post-operative complications and death are used to define operative risk. However, there is concern that this metric may not accurately capture long-term morbidity after such complex surgery. METHODS: A retrospective review of a prospective database of patients undergoing surgery for pCCA at a Western centre between January 2009-2020. RESULTS: Eighty-five patients underwent surgical resection for pCCA with a median overall survival of 36.3 months. Post-op (<90day) morbidity rates were high with 46% of patients developing a major complication (Clavien-Dindo grade 3-4). Post-op mortality rate was 13%. In total 38% (28/74) of patients experienced at least 1 episode of delayed morbidity (>90-days of surgery) resulting in 53 separate admissions with a median LOS of 7 days (IQR 2-15). These episodes were predominately secondary to biliary obstruction with the majority requiring radiological intervention (Clavien-Dindo grade 3). The development of long-term morbidity was associated with increased recurrence rates and correlated with poorer OS (27.6 months vs. 65.7 months HR 2.2 CI 1.63-2.77). CONCLUSIONS: Routinely cited 90-day morbidity and mortality does not accurately capture the patient morbidity experienced following surgery for pCCA. Surgery clearly offers a survival benefit and should be pursued in selected patients, but they must be fully counselled on the potential for long-term morbidity before embarking on this strategy.

New gender-specific formulae for estimating extracellular fluid volume from height and weight in adults.

AIMS: First, to derive gender-specific formulae for estimation of extracellular fluid volume (eECV) and second, compare eECV as a scaling metric for slope-intercept glomerular filtration rate (GFR) with estimated body surface area (eBSA), lean body mass (eLBM) and total body water (eTBW). METHODS: GFR and 'slope-only' GFR (GFR/ECV), both single compartment-corrected, were measured in a previously published multicentre database of healthy potential kidney transplant donors. Measured ECV (mECV) was obtained as ratio GFR-to-GFR/ECV. Formulae for eECV in men and women were derived from the relationship of mECV with height and weight and expressed as eECV = a.weight.height. In a population of prospective kidney transplant donors from a single centre, eECV was compared with mECV. GFR was scaled to eECV, eBSA, eLBM and eTBW, estimated from previously published formulae. RESULTS: In men and women, respectively, a was 0.0755 and 0.0399, x was 0.6185 and 0.6065 and y was 0.4982 and 0.6217. In the single centre, biases (±precisions) of eECV against mECV in men and women were 0.26 (±1.68) and 0.31 (±1.67) l. Mean GFR/eBSA was higher in men but mean GFR/eLBM and GFR/eTBW were higher in women. Mean GFR/ECV and mean GFR/eECV were very similar between the two genders. GFR/ECV and GFR/eECV showed correlations with each other that were almost identical between men and women. CONCLUSIONS: New formulae are described for estimating eECV. Scaling GFR to eECV is more physiological than scaling to eBSA and accounts for gender. eECV used for measuring GFR from a single blood sample should be gender-specific.

CamGFR v2: A New Model for Estimating the Glomerular Filtration Rate from Standardized or Non-standardized Creatinine in Patients with Cancer.

PURPOSE: Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS-standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods. EXPERIMENTAL DESIGN: GFR measurements, biometrics, and IDMS- or non-IDMS-standardized creatinine values were collected for adult patients from three cancer centers. Using statistical modeling, an IDMS and non-IDMS creatinine-compatible eGFR model (CamGFR v2) was developed. Its performance was compared with that of the existing models Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund-Malmö revised, and CamGFR v1, using statistics for bias, precision, accuracy, and clinical robustness. RESULTS: A total of 3,083 IDMS- and 4,612 non-IDMS-standardized creatinine measurements were obtained from 7,240 patients. IDMS-standardized creatinine values were lower than non-IDMS-standardized values in within-center comparisons (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in Manchester; P < 0.0001), and more consistent between centers. CamGFR v2 was the most accurate [root-mean-squared error for IDMS, 14.97 mL/minute (95% confidence interval, 13.84-16.13) and non-IDMS, 15.74 mL/minute (14.86-16.63)], most clinically robust [proportion with >20% error of calculated carboplatin dose for IDMS, 0.12 (0.09-0.14) and non-IDMS, 0.17 (0.15-0.2)], and least biased [median residual for IDMS, 0.73 mL/minute (-0.68 to 2.2) and non-IDMS, -0.43 mL/minute (-1.48 to 0.91)] eGFR model, particularly when eGFR was larger than 60 ml/minute. CONCLUSIONS: CamGFR v2 can utilize IDMS- and non-IDMS-standardized creatinine measurements and outperforms previous models. CamGFR v2 should be examined prospectively as a practice-changing standard of care for eGFR-based carboplatin dosing.

Estimated lean body mass is more appropriate than body surface area for scaling glomerular filtration rate and extracellular fluid volume.

BACKGROUND/AIMS: To compare body surface area (BSA) with lean body mass (LBM) for scaling extracellular fluid volume (ECV) and glomerular filtration rate (GFR). METHODS: Phase 1: Total body water (TBW), bromide space and LBM were measured with (3)H-water, (77)Br and dual X-ray absorptiometry, respectively, in 6 healthy adults. Phase 2: ECV and GFR were measured with (51)Cr-EDTA in 95 healthy adults and 56 children (0.5-13 years). ECV was calculated as GFR divided by GFR/ECV, both corrected for the one-compartment assumption. LBM was estimated (eLBM) in adults from height and weight and in children using a height/weight formula for estimating ECV and a constant derived from a separate adult population relating ECV to eLBM. RESULTS: Phase 1: LBM and BSA correlated closely with TBW and bromide space. With LBM, the regressions passed through the origin, but with BSA, the intercepts were significantly below zero. Phase 2: GFR/BSA and ECV/BSA were higher in men than women but no difference was recorded in GFR/eLBM, GFR/ECV or ECV/eLBM. ECV showed a linear relation with eLBM and a non-linear relation with BSA. GFR/BSA and ECV/BSA correlated significantly with BSA but neither GFR/eLBM nor ECV/eLBM correlated with eLBM. CONCLUSION: eLBM is preferable to BSA for scaling GFR and ECV.

Slope-only glomerular filtration rate and single-sample glomerular filtration rate as measurements of the ratio of glomerular filtration rate to extracellular fluid volume.

AIMS: The Jacobsson single-sample equation for measuring glomerular filtration rate (GFR) after bolus injection is based on two factors of questionable theoretical validity for correcting the single-compartment assumption. The aims were to redevelop a more transparent equation, show its fundamental similarity with 'slope-only' GFR and compare it with the original equation and with slope-only GFR. METHODOLOGY: The modified Jacobsson equation is k = (1/t).ln[V(t)/V(0)], where k is the rate constant of the terminal exponential and V(0) and V(t) are distribution volumes at times 0 and t. V(0) exceeds extracellular fluid volume (ECV): that is k' = (1/t).ln[V(t)/ECV], where k' > k. Moreover, [GFR/ECV] >k (= k + [15.4.k(2)]). The ratio k/k' was determined in 476 patients to calculate single-sample k (3 or 4 h post-injection). Slope-only and single-sample GFR/ECV were measured using Cr-51-EDTA in 105 further studies, multiplied by ECV (estimated from weight), scaled to 1.73 m(2) and compared with GFR/1.73 m(2) from the original Jacobsson equation against reference multi-sample GFR/1.73 m(2) simultaneously and independently measured with iohexol. RESULTS: The relation between k and k' was linear. k/k' was 0.827 at 3 h and 0.864 at 4 h. There was no difference in bias or precision between the original Jacobsson and modified equations. In both, precision was better than slope-only GFR/BSA. When GFR remained scaled to ECV, slope-only GFR showed marginally better precision against reference GFR/ECV. CONCLUSIONS: Single-sample and slope-only techniques give GFR as k. Although the theory of the modified Jacobsson equation is more transparent than the original equation, it gives the same result. It is, however, easier to use.

Comparison of GFR measurements assessed from single versus multiple samples.

BACKGROUND: Many previous studies have evaluated single-sample glomerular filtration rate (GFR) against multisample GFR, of which the single sample was a member, but none have compared single and multisample GFRs against an independent reference method. We therefore performed this comparison by using simultaneous independent multisample GFR measured with a different indicator. SETTING & PARTICIPANTS: University hospital: patients and healthy volunteers (95 studies in 60 patients and 20 healthy participants). Healthy volunteers were studied fasting and after food; 10 of them had a repeated fasting study. STUDY DESIGN: Diagnostic test study. INDEX TEST: Single-sample GFR. REFERENCE TEST: Multisample GFR with a different indicator. MEASUREMENTS: GFR was measured by using chromium-51 ((51)Cr)-EDTA and iohexol, injected into opposite arms and scaled to 1.73 m(2). Blood samples, obtained bilaterally 20, 40, 60, 120, 180, and 240 minutes after injection, were assayed for indicator injected contralaterally. Single-sample GFR (Jacobsson method) was calculated from indicator concentrations at 3 and 4 hours. Single-sample GFR from 1 indicator was compared with multisample GFR from the other and vice versa, as well as from the same indicator. Differences were expressed as limits of agreement between paired measurements in Bland-Altman plots. Precision was expressed as the SD of the mean difference between paired measurements. RESULTS: Limits of agreement between multisample GFRs measured by using (51)Cr-EDTA and iohexol (-12 to 20 mL/min) were similar to the corresponding limits for single-sample GFR at 3 (-16 to 17 mL/min) and 4 hours (-11 to 17 mL/min). The precision of single-sample GFR at 4 hours by using (51)Cr-EDTA for predicting iohexol multisample GFR (6.9 mL/min) was better than that of multisample GFR with (51)Cr-EDTA (7.9 mL/min). When analysis was limited to patients with GFR less than 60 mL/min, single-sample GFR was slightly inferior to multisample GFR. In healthy participants, single-sample GFR with (51)Cr-EDTA at 3 and 4 hours showed repeatability (SD of change, 9.4 and 9.3 mL/min) similar to multisample GFR with (51)Cr-EDTA (10.7 mL/min). Single-sample GFR at 4 hours by using (51)Cr-EDTA detected a food-induced increase in GFR (4.4 +/- 5.9 mL/min; P < 0.001) with more confidence than multisample GFR by using (51)Cr-EDTA (4.6 +/- 7.5 mL/min; P < 0.01). LIMITATIONS: No separate gold standard (eg, inulin) to facilitate interpretation of observed differences between 2 markers. CONCLUSIONS: Single-sample GFR is as reliable as multisample GFR for measuring GFR, especially when GFR is greater than 60 mL/min.

Effect of extracellular fluid volume on single-sample measurement of glomerular filtration rate.

UNLABELLED: Objective. The objective of our study was to evaluate the effect of extracellular fluid volume (ECV) on the accuracy of measurement of glomerular filtration rate from a single sample (GFR1). METHODS: Multi-sample GFR (GFR6) and ECV (per 1.73 m(2)) were measured with both Cr-51-EDTA and iohexol, injected into opposite arms (110 studies in 80 subjects). Six plasma samples were obtained bilaterally 20- 240 min post-injection to measure GFR6/1.73 m(2). GFR1/1.73 m(2) was calculated from 2-, 3- and 4-h samples using Jacobsson's formula for iohexol and the Christensen and Groth formula for Cr-51-EDTA. The quotient, GFR1/GFR6, was taken to indicate the accuracy of GFR1. RESULTS: When GFR6 was <60 ml/min/1.73 m(2), GFR1/ GFR6 correlated positively with ECV at all single-sample times. When GFR6 was 60-90 ml/min/1.73 m(2) or >90 ml/min/1.73 m(2), GFR1/GFR6 correlated positively with ECV at 2 h, but negatively at 4 h, indicating that at some time between 2 and 4 h, GFR1/GFR6 was transiently independent of ECV. A plot of the regression gradient of GFR1/GFR6 on ECV against sample time indicated that the time of transient independence, at which time GFR1 depends exclusively on GFR6, was 3.2-3.9 h (depending on indicator combination used) when GFR6 was 60-90 ml/min/1.73 m(2) and 2.4-2.9 h when GFR was >90 ml/min/1.73 m(2). Transient independence when GFR6 was <60 ml/min/1.73 m(2) was not reached by 4 h and estimated to be 5-7 h. CONCLUSION: The accuracy of GFR1 depends on ECV, overestimation or underestimation respectively depending on sample time and GFR. The time at which GFR1 is independent of ECV increases with decreasing GFR. If sampling time is too early, GFR1 overestimates GFR, but the reverse occurs when sampling is too late, even if GFR is abnormally low.

Evaluation of the Modification of Diet in Renal Disease equation (eGFR) against simultaneous, dual-marker multi-sample measurements of glomerular filtration rate.

BACKGROUND: Estimation of glomerular filtration rate (GFR) using plasma creatinine remains controversial, especially when GFR approaches normal values. The aim was to re-examine estimated GFR (eGFR) using dual-reference GFR measurements. METHODS: eGFR (simplified modified Modification of Diet in Renal Disease equation) was compared with GFR measured with iohexol for predicting GFR measured with (51)Cr-ethylenediaminetetraacetic acid (EDTA). Dual six-sample GFR (20-240 min postinjection) was measured in 60 patients and 20 normal volunteers with (51)Cr-EDTA (GFR(EDTA)) and iohexol (GFR(iohexol)) injected into separate arms and sampled contralaterally. This was repeated in the normal volunteers under fasting conditions (twice in nine). Percentage bias, imprecision (SD of bias) and disagreement (sign-less difference) between eGFR and GFR(EDTA) were compared with those between GFR(iohexol) and GFR(EDTA). RESULTS: Changes between fasting and postprandial eGFR correlated significantly with corresponding changes in GFR(iohexol) and GFR(EDTA). eGFR predicted GFR(EDTA) less precisely (SD 19.9%) than GFR(iohexol) (10.5%; P < 0.01). Although eGFR showed a poorer correlation with GFR(EDTA) when GFR(EDTA) > 80 mL/min/1.73 m(2) compared with <80 mL/min/1.73 m(2), there was no significant difference with respect to imprecision or disagreement of >20 or 30%. However, eGFR was closer than GFR(iohexol) to GFR(EDTA) in a higher fraction of studies when GFR(EDTA) > 80 mL/min/1.73 m(2) (28/60) than when it was <80 mL/min/1.73 m(2) (9/37; P < 0.05). CONCLUSION: eGFR is inferior to GFR(iohexol) for predicting GFR(EDTA). The disagreement between GFR(iohexol) and GFR(EDTA) illustrates the extent to which uncertainty in GFR(EDTA) contributes to the performance of eGFR. eGFR performs no better at lower, compared with higher levels of GFR.

Role of a pre-operative radiological scoring system in determining resectability for potentially resectable hilar cholangiocarcinoma.

AIMS: Cholangiocarcinoma is a rare cancer arising from the biliary tree. Case series indicate that 25-40% of all borderline resectable primary tumours are potentially resectable. The Memorial Sloane Kettering System (MSKCC) stratifies patients for resectability by longitudinal and radial extension of the hilar tumour. The Bismuth-Corlette system describes the longitudinal extension of the tumour within the biliary duct system. We sought to validate and, if possible, augment these two scores within an independent validation cohort. METHODS: Patients diagnosed with hilar cholangiocarcinoma between January 2009 and December 2016 were analysed from a prospectively held database. Patients with distal cholangiocarcinoma, peripheral cholangiocarcinoma and gallbladder cancer were excluded. Comparison of surgical findings to pre-operative radiological imaging was undertaken at the time of surgery. RESULTS: The validation cohort was formed of 198 patients, of which, 55 (27.8%) patients underwent resection. Logistic regression analyses identified that BC score, MSKCC score, age at diagnosis and left artery involvement were all significant independent predictor's univariately. BC score explained 28% of the variability in resectability compared to 26% explained by MSKCC. In combination, the model consisting of BC score, age at diagnosis and left artery involvement explained 39% of variability in resectability compared to the 34% explained same model including MSKCC score instead of BC score. CONCLUSION: In this cohort an augmented BC score, incorporating left hepatic artery involvement, is more discriminative in predicting resectability than the current MSKCC system.

A systematic review of 3251 emergency department thoracotomies: is it time for a national database?

PURPOSE: Emergency department thoracotomy (EDT) is a potentially life-saving procedure, performed on patients suffering traumatic cardiac arrest. Multiple indications have been reported, but overall survival remains unclear for each indication. The objective of this systematic review is to determine overall survival, survival stratified by indication, and survival stratified by geographical location for patients undergoing EDT across the world. METHODS: Articles published between 2000 and 2016 were identified which detailed outcomes from EDT. All articles referring to pre-hospital, delayed, or operating room thoracotomy were excluded. Pooled odds ratios (OR) were calculated comparing differing indications. RESULTS: Thirty-seven articles, containing 3251 patients who underwent EDT, were identified. There were 277 (8.5%) survivors. OR demonstrate improved survival for; penetrating vs blunt trauma (OR 2.10; p 0.0028); stab vs gun-shot (OR 5.45; p < 0.0001); signs of life (SOL) on admission vs no SOL (OR 5.36; p < 0.0001); and SOL in the field vs no SOL (OR 19.39; p < 0.0001). Equivalence of survival was demonstrated between cardiothoracic vs non-cardiothoracic injury (OR 1.038; p 1.000). Survival was worse for USA vs non-USA cohorts (OR 1.59; p 0.0012). CONCLUSIONS: Penetrating injury remains a robust indication for EDT. Non-cardiothoracic cause of cardiac arrest should not preclude EDT. In the absence of on scene SOL, survival following EDT is extremely unlikely. Survival is significantly higher in the non-USA publications; reasons for this are highly complex. A UK multicentre prospective study which collects standardised data on all EDTs could provide robust evidence for better patient stratification.