The Feasibility of Percutaneous Externally Assembled Laparoscopic Nephrectomy: a New Surgical System

Laparoendoscopic single-site (LESS) nephrectomy provides excellent cosmetic outcomes, but is technically challenging due to loss of triangulation and increased instrument collision. A novel Percutaneous Externally Assembled Laparoscopic (PEAL) surgical system was developed to simplify minimally invasive surgery while providing a nearly scarless outcome. In this study, the feasibility of the PEAL system for nephrectomy was determined

Reproducibility of compartmental modelling of 18 F-FDG PET/CT to evaluate lung inflammation

Abstract: Introduction: Compartmental modelling is an established method of quantifying 18F-FDG uptake; however, only recently has it been applied to evaluate pulmonary inflammation. Implementation of compartmental models remains challenging in the lung, partly due to the low signal-to-noise ratio compared to other organs and the lack of standardisation. Good reproducibility is a key requirement of an imaging biomarker which has yet to be demonstrated in pulmonary compartmental models of 18F-FDG; in this paper, we address this unmet need. Methods: Retrospective subject data were obtained from the EVOLVE observational study: Ten COPD patients (age =66±9; 8M/2F), 10 α1ATD patients (age =63±8; 7M/3F) and 10 healthy volunteers (age =68±8; 9M/1F) never smokers. PET and CT images were co-registered, and whole lung regions were extracted from CT using an automated algorithm; the descending aorta was defined using a manually drawn region. Subsequent stages of the compartmental analysis were performed by two independent operators using (i) a MIAKATTM based pipeline and (ii) an in-house developed pipeline. We evaluated the metabolic rate constant of 18F-FDG (Kim) and the fractional blood volume (Vb); Bland-Altman plots were used to compare the results. Further, we adjusted the in-house pipeline to identify the salient features in the analysis which may help improve the standardisation of this technique in the lung. Results: The initial agreement on a subject level was poor: Bland-Altman coefficients of reproducibility for Kim and Vb were 0.0031 and 0.047 respectively. However, the effect size between the groups (i.e. COPD, α1ATD and healthy subjects) was similar using either pipeline. We identified the key drivers of this difference using an incremental approach: ROI methodology, modelling of the IDIF and time delay estimation. Adjustment of these factors led to improved Bland-Altman coefficients of reproducibility of 0.0015 and 0.027 for Kim and Vb respectively. Conclusions: Despite similar methodology, differences in implementation can lead to disparate results in the outcome parameters. When reporting the outcomes of lung compartmental modelling, we recommend the inclusion of the details of ROI methodology, input function fitting and time delay estimation to improve reproducibility

On the complexity of strongly connected components in directed hypergraphs

We study the complexity of some algorithmic problems on directed hypergraphs and their strongly connected components (SCCs). The main contribution is an almost linear time algorithm computing the terminal strongly connected components (i.e. SCCs which do not reach any components but themselves). "Almost linear" here means that the complexity of the algorithm is linear in the size of the hypergraph up to a factor alpha(n), where alpha is the inverse of Ackermann function, and n is the number of vertices. Our motivation to study this problem arises from a recent application of directed hypergraphs to computational tropical geometry. We also discuss the problem of computing all SCCs. We establish a superlinear lower bound on the size of the transitive reduction of the reachability relation in directed hypergraphs, showing that it is combinatorially more complex than in directed graphs. Besides, we prove a linear time reduction from the well-studied problem of finding all minimal sets among a given family to the problem of computing the SCCs. Only subquadratic time algorithms are known for the former problem. These results strongly suggest that the problem of computing the SCCs is harder in directed hypergraphs than in directed graphs.Comment: v1: 32 pages, 7 figures; v2: revised version, 34 pages, 7 figure

Diagnosis of patients with heart failure with preserved ejection fraction in primary care : Cohort study

Aims Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure (HF), but low awareness and diagnostic challenges hinder identification in primary care. Our aims were to evaluate the recruitment and diagnostic strategy in the Optimise HFpEF cohort and compare with recent recommendations for diagnosing HFpEF. Methods and results Patients were recruited from 30 primary care practices in two regions in England using an electronic screening algorithm and two secondary care sites. Baseline assessment collected clinical and patient-reported data and diagnosis by history, assessment, and trans-thoracic echocardiogram (TTE). A retrospective evaluation compared study diagnosis with H2FPEF score and HFA-PEFF diagnostic algorithm. A total of 152 patients (86% primary care, mean age 78.5, 40% female) were enrolled; 93 (61%) had HFpEF confirmed. Most participants had clinical features of HFpEF, but those with confirmed HFpEF were more likely female, obese, functionally impaired, and symptomatic. Some echocardiographic findings were diagnostic for HFpEF, but no difference in natriuretic peptide levels were observed. The H2FPEF and HFA-PEFF scores were not significantly different by group, although confirmed HFpEF cases were more likely to have scores indicating high probability of HFpEF. Conclusions Patients with HFpEF in primary care are difficult to identify, and greater awareness of the condition, with clear diagnostic pathways and specialist support, are needed. Use of diagnostic algorithms and scores can provide systematic approaches to diagnosis but may be challenging to apply in older multi-morbid patients. Where diagnostic uncertainty remains, pragmatic decisions are needed regarding the value of additional testing versus management of presumptive HFpEF

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Quantitative analysis of dynamic 18F-FDG PET/CT for measurement of lung inflammation

$\textbf{Background:}$ An inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, is present in some patients with chronic obstructive pulmonary disease (COPD). Thoracic fluorodeoxyglucose $^{18}$F-FDG) positron emission tomography (PET) has been proposed as a promising imaging biomarker to assess this inflammation. We sought to introduce a fully quantitative analysis method and compare this with previously published studies based on the Patlak approach using a dataset comprising $^{18}$F-FDG PET scans from COPD subjects with elevated circulating inflammatory markers (fibrinogen) and matched healthy volunteers (HV). Dynamic $^{18}$F-FDG PET scans were obtained for high-fibrinogen (>2.8 g/l) COPD subjects (N = 10) and never smoking HV (N = 10). Lungs were segmented using co-registered computed tomography images and subregions (upper, middle and lower) were semi-automatically defined. A quantitative analysis approach was developed, which corrects for the presence of air and blood in the lung (qABL method), enabling direct estimation of the metabolic rate of FDG in lung tissue. A normalised Patlak analysis approach was also performed to enable comparison with previously published results. Effect sizes (Hedge's g) were used to compare HV and COPD groups. $\textbf{Results:}$ The qABL method detected no difference (Hedge's g = 0.15 [-0.76 1.04]) in the tissue metabolic rate of FDG in the whole lung between HV (μ = 6.0 ± 1.9 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$) and COPD (μ = 5.7 ± 1.7 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$). However, analysis with the normalised Patlak approach detected a significant difference (Hedge's g = -1.59 [-2.57 -0.48]) in whole lung between HV (μ = 2.9 ± 0.5 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$) and COPD (μ = 3.9 ± 0.7 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$). The normalised Patlak endpoint was shown to be a composite measure influenced by air volume, blood volume and actual uptake of $^{18}$F-FDG in lung tissue. $\textbf{Conclusions:}$ We have introduced a quantitative analysis method that provides a direct estimate of the metabolic rate of FDG in lung tissue. This work provides further understanding of the underlying origin of the $^{18}$F-FDG signal in the lung in disease groups and helps interpreting changes following standard or novel therapies.JC and IBW acknowledge the funding support from the Cambridge Comprehensive Biomedical Research Centre. MIP’s contribution to this work was funded by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College who part fund his salary. EVOLUTION and EVOLVE studies were funded by Innovate UK under the ERICA consortium grant with in kind contributions from GSK

Microeconomic institutions and personnel economics for health care delivery: a formal exploration of what matters to health workers in Rwanda

Background: Most developing countries face important challenges regarding the quality of health care and there is a growing consensus that health workers play a key role in this process. Our understanding as to what are the key institutional challenges in human resources, and their underlying driving forces, is more limited. A conceptual framework that structures existing insights and provides concrete directions for policy making is also missing. Methods: To gain a bottom up perspective we gather qualitative data through semi-structured interviews with different levels of health workers and users of health services in rural and urban Rwanda. We conducted discussions with 48 health workers and 25 users of health services in nine different groups in 2005. We maximized within-group heterogeneity by selecting participants using specific criteria that affect health worker performance and career choice. The discussion were analysed electronically, to identify key themes and insights, and are documented with a descriptive quantitative analysis relating to the associations between quotations. The findings from this research are then revisited ten years later making use of detailed follow up studies that have been carried out since then. Findings: The original discussions identified both key challenges in human resources for health, and driving forces of these challenges, as well as possible solutions. Two sets of issues were highlighted: those related to the size and distribution of the workforce, and those related to health workers’ on-the-job performance. Among the latter, four categories were identified: health workers’ poor attitudes towards patients, absenteeism, corruption and embezzlement, and lack of medical skills among some categories of health workers. The discussion suggest that four components constitute the deeper causal factors, which are, ranked in order of ease of malleability: incentives, monitoring arrangements, professional and workplace norms and intrinsic motivation. Three institutional innovations are identified that aim at improving performance: performance pay, community health workers and increased attention to training of health workers. Revisiting the findings from this primary research making use of later in depth studies, the analysis demonstrates their continued relevance and usefulness. We discuss how the different factors affect the quality of care by impacting on health worker performance and labour market choices, making use of insights from economics and development studies on the role of institutions. Conclusion: The study results indicates that health care quality to an important degree depends on four institutional factors at the micro level that strongly impact on health workers performance and career choice, and which deserve more attention in applied research and policy reform. The analysis also helps to identify ways forwards, which fit well with the Ministry’s most recent strategic plan

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers.

BACKGROUND: Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo. METHODS: Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers. RESULTS: Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (-8.33 ± 0.172 logM vs -8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003). CONCLUSIONS: GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov.This work was supported by GSK [SEH114068] and Innovate UK (ERICA Consortium 10037625), the Wellcome Trust grant numbers 100780/Z/12/Z, and WT103782AIA awarded to LY, and DEN respectively; the Raymond and Beverley Sackler fellowship awarded to LY; National Institute for Health Research funding awarded to IBW, and JC in the Cambridge Comprehensive Biomedical Research, and the British Heart Foundation grant numbers CH/0 9/002, and RG66885 RCZA/008 awarded to DEN, and IBW. JLG and ZA are funded by the Medical Research Council (Medical Research Council Lipid Profiling and Signalling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 130 30)