MEN1 Surveillance Guidelines:Time to (re)Think?

Clinical practice guidelines for patients with multiple endocrine neoplasia type 1 (MEN1) recommend a variety of surveillance options. Given progress over the past decade in this area, it is timely to evaluate their ongoing utility. MEN1 is characterized by the development of synchronous or asynchronous tumors affecting a multitude of endocrine and nonendocrine tissues, resulting in premature morbidity and mortality, such that the rationale for undertaking surveillance screening in at-risk individuals appears robust. Current guidelines recommend an intensive regimen of clinical, biochemical, and radiological surveillance commencing in early childhood for those with a clinical or genetic diagnosis of MEN1, with the aim of early tumor detection and treatment. Although it is tempting to assume that such screening results in patient benefits and improved outcomes, the lack of a strong evidence base for several aspects of MEN1 care, and the potential for iatrogenic harms related to screening tests or interventions of unproven benefit, make such assumptions potentially unsound. Furthermore, the psychological as well as economic burdens of intensive screening remain largely unstudied. Although screening undoubtedly constitutes an important component of MEN1 patient care, this perspective aims to highlight some of the current uncertainties and challenges related to existing MEN1 guidelines with a particular focus on the role of screening for presymptomatic tumors. Looking forward, a screening approach that acknowledges these limitations and uncertainties and places the patient at the heart of the decision-making process is advocated

Physical soil quality indicators for monitoring British soils

The condition or quality of soils determines its ability to deliver a range of functions that support ecosystem services, human health and wellbeing. The increasing policy imperative to implement successful soil monitoring programmes has resulted in the demand for reliable soil quality indicators (SQIs) for physical, biological and chemical soil properties. The selection of these indicators needs to ensure that they are sensitive and responsive to pressure and change e.g. they change across space and time in relation to natural perturbations and land management practices. Using a logical sieve approach based on key policy-related soil functions, this research assessed whether physical soil properties can be used to indicate the quality of British soils in terms of its capacity to deliver ecosystem goods and services. The resultant prioritised list of physical SQIs were tested for robustness, spatial and temporal variability and expected rate of change using statistical analysis and modelling. Six SQIs were prioritised; packing density, soil water retention characteristics, aggregate stability, rate of erosion, depth of soil and soil sealing. These all have direct relevance to current and likely future soil and environmental policy and are appropriate for implementation in soil monitoring programs

Permanent grasslands in Europe : Land use change and intensification decrease their multifunctionality

Acknowledgments We acknowledge the financial support of this work by European Union Horizon 2020 research and innovation programme, under grant agreement 774124, project SUPER-G (Developing Sustainable Permanent Grassland Systems and Policies).Peer reviewedPublisher PD

Characterization of patients in the International Severe Asthma Registry with high steroid exposure who did or did not initiate biologic therapy

Peer reviewedPostprin

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Qualitative Impact Assessment of Land Management Interventions on Ecosystem Services (“QEIA”). Report-1: Executive Summary: QEIA Evidence Review & Integrated Assessment

The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten teams involving 45 experts drawn from the independent research community in a consistent series of Evidence Reviews covering the broad topics of: • Air quality • Greenhouse gas emissions • Soils • Water management • Biodiversity: croplands • Biodiversity: improved grassland • Biodiversity: semi-natural habitats • Biodiversity: integrated systems-based actions • Carbon sequestration • Cultural services (including recreation, geodiversity and regulatory services). It should be noted that this piece of work is just one element of the wider underpinning work Defra has commissioned to support the development of the ELM schemes

Qualitative impact assessment of land management interventions on Ecosystem Services (‘QEIA’). Report-2: Integrated Assessment

The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten expert teams drawn from the independent research community in a consistent series of ten Evidence Reviews covering the broad topics of; • Air quality • Greenhouse gas emissions • Soils • Water management • Biodiversity: croplands • Biodiversity: improved grassland • Biodiversity: semi-natural habitats • Biodiversity: integrated systems-based actions • Carbon sequestration • Cultural services (including recreation, geodiversity and regulatory services) These reviews were undertaken rapidly at Defra’s request by ten teams involving 45 experts who together captured more than 2,400 individual sources of evidence. This was followed by the Integrated Assessment (IA) reported here to provide a more accessible summary of these evidence reviews with a focus on capturing the actions with the greatest potential magnitude of change for the intended ES, and their potential co-benefits and trade-offs for the other ES