Protein associated with SMAD1 (PAWS1/FAM83G) is a substrate for type I bone morphogenetic protein receptors and modulates bone morphogenetic protein signalling

Bone morphogenetic proteins (BMPs) control multiple cellular processes in embryos and adult tissues. BMPs signal through the activation of type I BMP receptor kinases, which then phosphorylate SMADs 1/5/8. In the canonical pathway, this triggers the association of these SMADs with SMAD4 and their translocation to the nucleus, where they regulate gene expression. BMPs can also signal independently of SMAD4, but this pathway is poorly understood. Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. We also demonstrate that PAWS1 regulates the expression of several non-BMP target genes, suggesting roles for PAWS1 beyond the BMP pathway

Why are fish oil supplements apparently failing to reproduce fish consumption epidemiology in RCT for cardiovascular disease?

Abstract of a presentation

It is important that the process goes quickly, isn't it?” A qualitative multi-country study of colorectal or lung cancer patients’ narratives of the timeliness of diagnosis and quality of care

Purpose: The emphasis on early diagnosis to improve cancer survival has been a key factor in the development of cancer pathways across Europe. The aim of this analysis was to explore how the emphasis on early diagnosis and timely treatment is reflected in patient's accounts of care, from the first suspicion of colorectal or lung cancer to their treatment in Denmark, England and Sweden. Method: We recruited 155 patients in Denmark, England and Sweden who were within six months of being diagnosed with lung or colorectal cancer. Data were collected via semi-structured narrative interviews and analysed using a thematic approach. Results: Participants’ accounts of quality of care were closely related to how quickly (or not) diagnosis, treatment and/or healthcare processes went. Kinetic metaphors as a description of care (such as treadmill) could be interpreted positively as participants were willing to forgo some degree of control and accept disruption to their lives to ensure more timely care. Drawing on wider cultural expectations of the benefits of diagnosing and treating cancer quickly, some participants were concerned that the waiting times between interventions might allow time for the cancer to grow. Conclusions: Initiatives emphasising the timeliness of diagnosis and treatment are reflected in the ways some patients experience their care. However, these accounts were open to further contextualisation about what speed of healthcare processes meant for evaluating the quality of their care. Healthcare professionals could therefore be an important patient resource in providing reassurance and support about the timeliness of diagnosis or treatment

USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis

Influenza epidemiology, vaccine coverage and vaccine effectiveness in children admitted to sentinel Australian hospitals in 2014: The influenza complications alert network (FluCAN)

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance programme operating in all states and territories in Australia. We summarise the epidemiology of children hospitalised with laboratory-confirmed influenza in 2014 and reports on the effectiveness of inactivated trivalent inactivated vaccine (TIV) in children. In this observational study, cases were defined as children admitted with acute respiratory illness (ARI) with influenza confirmed by PCR. Controls were hospitalised children with ARI testing negative for influenza. Vaccine effectiveness (VE) was estimated as 1 minus the odds ratio of vaccination in influenza positive cases compared with test-negative controls using conditional logistic regression models. From April until October 2014, 402 children were admitted with PCR-confirmed influenza. Of these, 28% were aged < 1 year, 16% were Indigenous, and 39% had underlying conditions predisposing to severe influenza. Influenza A was detected in 90% of cases of influenza; influenza A(H1N1)pdm09 was the most frequent subtype (109/141 of subtyped cases) followed by A(H3N2) (32/141). Only 15% of children with influenza received antiviral therapy. The adjusted VE of one or more doses of TIV for preventing hospitalised influenza was estimated at 55.5% (95% confidence intervals (CI): 11.6–77.6%). Effectiveness against influenza A(H1N1)pdm09 was high (91.6%, 95% CI: 36.0–98.9%) yet appeared poor against H3N2. In summary, the 2014 southern hemisphere TIV was moderately effective against severe influenza in children. Significant VE was observed against influenza A(H1N1)pdm0

Patients' initial steps to cancer diagnosis in Denmark, England and Sweden: what can a qualitative, cross-country comparison of narrative interviews tell us about potentially modifiable factors?

OBJECTIVES: To illuminate patterns observed in International Cancer Benchmarking Programme studies by extending understanding of the various influences on presentation and referral with cancer symptoms. DESIGN: Cross-country comparison of Denmark, England and Sweden with qualitative analysis of in-depth interview accounts of the prediagnostic process in lung or bowel cancer. PARTICIPANTS: 155 women and men, aged between 35 and 86 years old, diagnosed with lung or bowel cancer in 6 months before interview. SETTING: Participants recruited through primary and secondary care, social media and word of mouth. Interviews collected by social scientists or nurse researchers during 2015, mainly in participants' homes. RESULTS: Participants reported difficulties in interpreting diffuse bodily sensations and symptoms and deciding when to consult. There were examples of swift referrals by primary care professionals in all three countries. In all countries, participants described difficulty deciding if and when to consult, highlighting concerns about access to general practitioner appointments and overstretched primary care services, although this appears less prominent in the Swedish data. It was not unusual for there to be more than one consultation before referral and we noted two distinct patterns of repeated consultation: (1) situations where the participant left the primary care consultation with a plan of action about what should happen next; (2) participants were unclear about under which conditions to return to the doctors. This second pattern sometimes extended over many weeks during which patients described uncertainty, and sometimes frustration, about if and when they should return and whether there were any other feasible investigations. The latter pattern appeared more evident in the interviews in England and Denmark than Sweden. CONCLUSION: We suggest that if clear action plans, as part of safety netting, were routinely used in primary care consultations then uncertainty, false reassurance and the inefficiency and distress of multiple consultations could be reduced

Addressing inequitable access to hospice care

The ‘Lancet Commission on the Value of Death’ proposes radical change and challenges the very core of hospice service provision. Without action, inequalities in access to hospice care will continue to be amplified. The COVID pandemic brought increased needs and demands in the community setting but also provided opportunities for new palliative partnerships and ways of working. Returning to the status quo should not be an option. Rather moving towards a shared vision and purpose, which has the person and their community network at its centre, enables hospices to have a pivotal role and bring about more equitable palliative care

An early warning risk prediction tool (RECAP-V1) for patients diagnosed with COVID-19: the protocol for a statistical analysis plan

Background: Since the start of the Covid-19 pandemic efforts have been made to develop early warning risk scores to help clinicians decide which patient is likely to deteriorate and require hospitalisation. The RECAP (Remote COVID Assessment in Primary Care) study investigates the predictive risk of hospitalisation, deterioration, and death of patients with confirmed COVID-19, based on a set of parameters chosen through a Delphi process done by clinicians. The study aims to use rich data collected remotely through the use of electronic data templates integrated in the electronic health systems of a number of general practices across the UK to construct accurate predictive models that will use pre-existing conditions and monitoring data of a patient’s clinical parameters such as blood oxygen saturation to make reliable predictions as to the patient’s risk of hospital admission, deterioration, and death. Objective: We outline the statistical methods to build the prediction model to be used in the prioritisation of patients in the primary care setting. The statistical analysis plan for the RECAP study includes as primary outcome the development and validation of the RECAP-V1 prediction model. Such prediction model will be adapted as a three-category risk score split into red (high risk), amber (medium risk), and green (low risk) for any patient with suspected covid-19. The model will predict risk of deterioration, hospitalisation, and death. Methods: After the data has been collected, we will assess the degree of missingness and use a combination of traditional data imputation using multiple imputation by chained equations, as well as more novel machine learning approaches to impute the missing data for the final analysis. For predictive model development we will use multiple logistic regressions to construct the model on a training dataset, as well as validating the model on an independent dataset. The model will also be applied for multiple different datasets to assess both its performance in different patient groups, and applicability for different methods of data collection. Results: As of 5th of May 2021 we have recruited 2280 patients for the main dataset for model development, as well as a further 1741 patients for the validation dataset. Final analysis will commence as soon as data for 2880 are collected. Conclusions: We believe that the methodology for the development of the RECAP V1 prediction model as well as the risk score will provide clinicians with a statistically robust tool to help prioritise Covid-19 patients. Clinical Trial: Trial registration number: NCT0443504

Intelligence Studies, Universities and Security

This article offers a critical assessment of academic intelligence studies in higher education. It argues that universities (and academics) should value this subject far more highly than they currently do. Doing so will enhance better public understanding of an increasingly important and unique device in modern governance. It will also improve the quality of intelligence activity by raising awareness of both good and bad practice, encourage lawfulness by means of public understanding and so defending a vital public service from ill-informed attacks in today’s conflicted world. This, rather than training potential officers, should be the primary purpose of intelligence studies