Royal Surrey NHS Foundation Trust

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Importance: In the last decade, new biomarkers for acute kidney injury (AKI) have been identified and studied in clinical trials. Guidance is needed regarding how best to incorporate them into clinical practice. Objective: To develop recommendations on AKI biomarkers based on existing data and expert consensus for practicing clinicians and researchers. Evidence Review: At the 23rd Acute Disease Quality Initiative meeting, a meeting of 23 international experts in critical care, nephrology, and related specialties, the panel focused on 4 broad areas, as follows: (1) AKI risk assessment; (2) AKI prediction and prevention; (3) AKI diagnosis, etiology, and management; and (4) AKI progression and kidney recovery. A literature search revealed more than 65 000 articles published between 1965 and May 2019. In a modified Delphi process, recommendations and consensus statements were developed based on existing data, with 90% agreement among panel members required for final adoption. Recommendations were graded using the Grading of Recommendations, Assessment, Development and Evaluations system. Findings: The panel developed 11 consensus statements for biomarker use and 14 research recommendations. The key suggestions were that a combination of damage and functional biomarkers, along with clinical information, be used to identify high-risk patient groups, improve the diagnostic accuracy of AKI, improve processes of care, and assist the management of AKI. Conclusions and Relevance: Current evidence from clinical studies supports the use of new biomarkers in prevention and management of AKI. Substantial gaps in knowledge remain, and more research is necessary.

BACKGROUND: Goal achievement has been considered to be an important measure of outcome by clinicians working with patients in physical and neurological rehabilitation settings. This systematic review was undertaken to examine the reliability, validity and sensitivity of goal setting and goal attainment scaling approaches when used with working age and older people. AIMS AND OBJECTIVES: To review the reliability, validity and sensitivity of both goal setting and goal attainment scaling when employed as an outcome measure within a physical and neurological working age and older person rehabilitation environment, by examining the research literature covering the 36 years since goal-setting theory was proposed. METHODS: Data sources included a computer-aided literature search of published studies examining the reliability, validity and sensitivity of goal setting/goal attainment scaling, with further references sourced from articles obtained through this process. MAIN FINDINGS: There is strong evidence for the reliability, validity and sensitivity of goal attainment scaling. Empirical support was found for the validity of goal setting but research demonstrating its reliability and sensitivity is limited. CONCLUSIONS: Goal attainment scaling appears to be a sound measure for use in physical rehabilitation settings with working age and older people. Further work needs to be carried out with goal setting to establish its reliability and sensitivity as a measurement tool.

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy. Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability.1 CD can affect individuals of any age, from children to the elderly,2,3 and may cause significant morbidity and impact on quality of life [QoL]. The precise aetiology of CD remains unknown and a curative therapy is not yet available. Contemporary therapy therefore is focused on control of inflammation, using medications along with timely surgical interventions to alleviate the symptoms of bowel damage. The European Crohn’s and Colitis Organisation [ECCO] produces several guidelines aimed at providing evidence-based guidance on critical aspects of IBD care. In 2020, ECCO published new guidelines on the management of CD in two manuscripts focused on the medical and surgical management of disease.4,5 For the 2020 CD guidelines, ECCO adopted the Grading of Recommendations Assessment, Development, and Evaluation [GRADE] approach, a systematic process for developing guidelines that addresses how to frame the health care questions, summarise the evidence, formulate the recommendations, and grade their strength and quality of associated evidence.6 The present manuscript represents an update to the 2020 guidelines and is focused specifically on medical management of CD, and a companion manuscript developed as part of the same process addresses optimal surgical management.5 We take a drug-by-drug approach to review the evidence for various medical and dietary strategies used in the management of CD. For this iteration of the guidelines, we have introduced several new, clinically relevant questions as chosen by members of the guidelines group, a systematic approach to reviewing and updating previous topics to incorporate any new evidence, and a reappraisal of all evidence in the context of contemporary practice. We have also introduced several ‘practice points’ to summarise evidence, and expert recommendations in certain key areas of practice where the evidence base is limited but where clinicians and patients need to make decisions nonetheless. Here, where application of the GRADE methodology might be impractical, we have used an approach based on systematic literature review, expert discussion, and voting to form consensus recommendations outside the formal GRADE process. It is important to remember that achieving optimal outcomes in CD relies not just on knowledge of the appropriate use of current medical and surgical therapies but also on careful attention to wider aspects of management, including early diagnosis, prompt initial management,7 close monitoring of treatment response, and psychological and dietary support.8 The development of these guidelines followed the GRADE workflow, as adopted in previous ECCO guidelines.9 A panel of 46 experts were selected from an open call according to criteria based on IBD expertise, scientific background, knowledge of GRADE methodology, and prior contribution to ECCO projects. Additionally, six patients with CD selected by the European Federation of Crohn’s and Colitis Associations [EFFCA] were invited to participate in discussions. The group was supported in their work by a team of professional methodologists and librarians. The panellists first agreed on a list of questions using the Population, Intervention, Comparator, Outcomes [PICO] format. PICO questions addressed as part of the 2020 ECCO CD guidelines were reviewed and considered for retention with regards to ongoing relevance, and new PICO questions were formulated, discussed, and added to the list. The relevant outcomes for all PICO questions were graded according to importance using a Delphi consensus process. Note that for PICO questions retained from 2020, the importance of the outcomes was nonetheless revised according to the results of this new consensus. The professional librarians next performed a comprehensive literature search on EMBASE, PubMed/Medline, and Cochrane Central databases, using specific search strings developed for each PICO question [Supplementary files available as Supplementary data at ECCO-JCC online]. For PICO questions retained from the 2020 guidelines, the same search string was used as during the prior literature search, and the start date of database queries set to the same as the end search date for the previous guidelines 1 April 2018. For all new PICO questions, the search start date was unlimited. Two independent consensus group members assessed the relevance of each abstract to the PICO and included or excluded all the relevant papers for the final data extraction and analysis. Subsequently, group members systematically reviewed and summarised the evidence on every outcome voted as ‘important’ or ‘critical’, to compile a Summary of Findings [SoF] table for each question, or updated the prior SoF tables from 2020 [including revision according to any changes to outcomes deemed critical or important]. We adopted a standard hierarchical approach, searching for recent, high-quality systematic reviews and meta-analyses of clinical trials to use in preference to individual randomised clinical trials [RCTs] or observational studies. Results of individual studies were pooled using random-effects meta-analysis as appropriate and when needed. The quality of evidence was then classified and used to inform draft recommendations according to the GRADE methodology.6 GRADE evidence levels for safety data tended to be low, due to downgrading for sparsity of events, reflecting the overall relative safety of the interventions under consideration. Therefore, whereas the evidence for all ‘important’ and ‘critical’ outcomes was considered in the drafting of a recommendation, we decided to base the overall assessment of evidence quality used to inform the strength of each recommendation upon the lowest quality of evidence obtained for the clinical or endoscopic outcomes for each PICO question. Where evidence was not available for an outcome of critical importance, this was reflected in the overall assessment of the quality of the evidence. The assessment of evidence for all individual outcomes was available to all panel members and is presented in the Supplementary materials. During initial discussions and based on feedback from previous ECCO guidelines, we recognised that in certain areas of CD management there are limited high-quality sources of evidence available, but that clinicians and patients must make decisions nonetheless. There are also broad, overarching themes relating to approaches to care that cannot be readily formulated into a PICO question. Use of the GRADE approach in these areas can be resource intensive and lead to recommendations of limited clinical utility. We therefore decided to frame a separate series of ‘practice points’ for such common areas of importance. For these, the systematic literature review and data extraction exercise were followed and the findings used to inform drafting of an expert recommendation. We recognise that the resulting practice points are based upon a different level of evidence compared with the GRADE recommendations, but hope that they will be of practical use to readers nonetheless. These are clearly delineated in the text as distinct from GRADE recommendations. 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The group that started the Enhanced Recovery After Surgery (ERAS) Society in 2010 introduced their first consensus guideline already in 2005 to improve the care of patients undergoing major colorectal surgery. When properly implemented, care pathways based on these guidelines have been shown to reduce morbidity rates, improve recovery, shorten length of stay (LOS), and reduce costs after major colorectal surgery.1 Since the publication of the first ERAS colorectal guideline, a total of 3 subsequent sets of guidelines have been published.

. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.

. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition.

Abstract B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS) 1,2 . Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive 1,2 . Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma 3 . We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Abstract Rationale Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy. Objectives To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS. Methods We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours. Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13–58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction). Conclusions The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02338843).

Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose-lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients' long-term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient- and physician-related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. The present review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification.

BACKGROUND: Emergency laparotomies in the U.K., U.S.A. and Denmark are known to have a high risk of death, with accompanying evidence of suboptimal care. The emergency laparotomy pathway quality improvement care (ELPQuiC) bundle is an evidence-based care bundle for patients undergoing emergency laparotomy, consisting of: initial assessment with early warning scores, early antibiotics, interval between decision and operation less than 6 h, goal-directed fluid therapy and postoperative intensive care. METHODS: The ELPQuiC bundle was implemented in four hospitals, using locally identified strategies to assess the impact on risk-adjusted mortality. Comparison of case mix-adjusted 30-day mortality rates before and after care-bundle implementation was made using risk-adjusted cumulative sum (CUSUM) plots and a logistic regression model. RESULTS: Risk-adjusted CUSUM plots showed an increase in the numbers of lives saved per 100 patients treated in all hospitals, from 6.47 in the baseline interval (299 patients included) to 12.44 after implementation (427 patients included) (P < 0.001). The overall case mix-adjusted risk of death decreased from 15.6 to 9.6 per cent (risk ratio 0.614, 95 per cent c.i. 0.451 to 0.836; P = 0.002). There was an increase in the uptake of the ELPQuiC processes but no significant difference in the patient case-mix profile as determined by the mean Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity risk (0.197 and 0.223 before and after implementation respectively; P = 0.395). CONCLUSION: Use of the ELPQuiC bundle was associated with a significant reduction in the risk of death following emergency laparotomy.

Abstract Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy 1 . Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study 2,3 . Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

UNLABELLED: There is a wide choice of fecal occult blood tests (FOBTs) for colorectal cancer screening. GOAL: To highlight the issues applicable when choosing a FOBT, in particular which FOBT is best suited to the range of screening scenarios. Four scenarios characterize the constraints and expectations of screening programs: (1) limited colonoscopy resource with a need to constrain test positivity rate; (2) a priority for maximum colorectal neoplasia detection with little need to constrain colonoscopy workload; (3) an "adequate" endoscopy resource that allows balancing the benefits of detection with the burden of service provision; and (4) a need to maximize participation in screening. Guaiac-based FOBTs (gFOBTs) have significant deficiencies, and fecal immunochemical tests (FITs) for hemoglobin have emerged as better tests. gFOBTs are not sensitive to small bleeds, specificity can be affected by diet or drugs, participant acceptance can be low, laboratory quality control opportunities are limited, and they have a fixed hemoglobin concentration cutoff determining positivity. FITs are analytically more specific, capable of quantitation and hence provide flexibility to adjust cutoff concentration for positivity and the balance between sensitivity and specificity. FITs are clinically more sensitive for cancers and advanced adenomas, and because they are easier to use, acceptance rates are high. CONCLUSIONS: FOBT must be chosen carefully to meet the needs of the applicable screening scenario. Quantitative FIT can be adjusted to suit Scenarios 1, 2 and 3, and for each, they are the test of choice. FITs are superior to gFOBT for Scenario 4 and gFOBT is only suitable for Scenario 1.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

Abstract Rationale Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy. Objectives To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate. Methods This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2. We defined the “alactic base excess,” as the sum of lactate and standard base excess. Measurements and Main Results Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine &amp;gt;2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance. Conclusions Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.

INTRODUCTION: Pancreatic exocrine insufficiency is a finding in many conditions, predominantly affecting those with chronic pancreatitis, pancreatic cancer and acute necrotising pancreatitis. Patients with pancreatic exocrine insufficiency can experience gastrointestinal symptoms, maldigestion, malnutrition and adverse effects on quality of life and even survival.There is a need for readily accessible, pragmatic advice for healthcare professionals on the management of pancreatic exocrine insufficiency. METHODS AND ANALYSIS: A review of the literature was conducted by a multidisciplinary panel of experts in pancreatology, and recommendations for clinical practice were produced and the strength of the evidence graded. Consensus voting by 48 pancreatic specialists from across the UK took place at the 2019 Annual Meeting of the Pancreatic Society of Great Britain and Ireland annual scientific meeting. RESULTS: Recommendations for clinical practice in the diagnosis, initial management, patient education and long term follow up were developed. All recommendations achieved over 85% consensus and are included within these comprehensive guidelines.

This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO Guidelines.