BackgroundCoagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive.Methodology/Principal FindingsImmunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by rt-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab–reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 5′ exons within the int22h-1 repeat responsible for intron 22 inversions in 40% of severe haemophiliacs. A reciprocal relationship between the presence of short isoforms and full-length FVIII transcript suggested potential splice-switching mechanisms.Conclusions/SignificanceThe pulmonary endothelium is confirmed as a site of FVIII secretion, with evidence of synthesis, cell surface expression, and coexpression with vWF. There is complex alternate transcription initiation from the FVIII gene. These findings provide a framework for future research on the regulation and perturbation of FVIII synthesis, and of potential relevance to haemophilia, thromboses, and pulmonary hypertensive states.

BackgroundPhysical activity (PA) brief interventions (BIs) involving screening and/or advice are recommended in primary care but frequency of delivery is unknown.AimTo examine the extent to which PA BIs are delivered in primary care, and explore factors associated with delivery, receipt, and patient receptivity.Design and settingA mixed-methods systematic review of studies conducted worldwide, with a narrative synthesis of results.MethodCINAHL, EMBASE, MEDLINE, and APA PsycINFO index databases were searched for qualitative and quantitative studies, dating from January 2012 to June 2020, that reported the level of delivery and/or receipt of PA BIs in primary care, and/or factors affecting delivery, receipt, and patient receptivity. Quality was assessed using the Mixed Methods Appraisal Tool. Attitudes towards and barriers to delivery were coded into the Theoretical Domains Framework and the Capability, Opportunity, and Motivation Behaviour model.ResultsAfter screening a total of 13 066 records, 66 articles were included in the review. The extent of PA screening and advice in primary care varied widely (2.4%–100% and 0.6%–100%, respectively). PA advice was delivered more often to patients with a higher body mass index, lower PA levels, and/or more comorbidities. Barriers — including a lack of time and training/guidelines — remain, despite recommendations from the World Health Organization and National Institute for Health and Care Excellence that PA advice should be provided in primary care. Few studies explored patients’ receptivity to advice.ConclusionPA BIs are not delivered frequently or consistently in primary care. Addressing barriers to delivery through system-level changes and training programmes could improve and increase the advice given. Understanding when patients are receptive to PA interventions could enhance health professionals’ confidence in their delivery.

Background. Signal detection theory (SDT) describes how respondents categorize ambiguous stimuli over repeated trials. It measures separately “discrimination” (ability to recognize a signal amid noise) and “criterion” (inclination to respond “signal” v. “noise”). This is important because respondents may produce the same accuracy rate for different reasons. We employed SDT to measure the referral decision making of general practitioners (GPs) in cases of possible lung cancer. Methods. We constructed 44 vignettes of patients for whom lung cancer could be considered and estimated their 1-year risk. Under UK risk-based guidelines, half of the vignettes required urgent referral. We recruited 216 GPs from practices across England. Practices differed in the positive predictive value (PPV) of their urgent referrals (chance of referrals identifying cancer) and the sensitivity (chance of cancer patients being picked up via urgent referral from their practice). Participants saw the vignettes online and indicated whether they would refer each patient urgently or not. We calculated each GP’s discrimination (d ′) and criterion (c) and regressed these on practice PPV and sensitivity, as well as on GP experience and gender. Results. Criterion was associated with practice PPV: as PPV increased, GPs’c also increased, indicating lower inclination to refer (b = 0.06 [0.02–0.09]; P = 0.001). Female GPs were more inclined to refer than male GPs (b = −0.20 [−0.40 to −0.001]; P = 0.049). Average discrimination was modest (d′ = 0.77), highly variable (range, −0.28 to 1.91), and not associated with practice referral performance. Conclusions. High referral PPV at the organizational level indicates GPs’ inclination to avoid false positives, not better discrimination. Rather than bluntly mandating increases in practice PPV via more referrals, it is necessary to increase discrimination by improving the evidence base for cancer referral decisions.

BackgroundLung cancer is a good example of the potential benefit of symptom-based diagnosis, as it is the commonest cancer worldwide, with the highest mortality from late diagnosis and poor symptom recognition. The diagnosis and risk assessment tools currently available have been shown to require further validation. In this study, we determine the symptoms associated with lung cancer prior to diagnosis and demonstrate that by separating prior risk based on factors such as smoking history and age, from presenting symptoms and combining them at the individual patient level, we can make greater use of this knowledge to create a practical framework for the symptomatic diagnosis of individual patients presenting in primary care.AimTo provide an evidence-based analysis of symptoms observed in lung cancer patients prior to diagnosis.Design and settingSystematic review and meta-analysis of primary and secondary care data.MethodSeven databases were searched (MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Health Management Information Consortium, Web of Science, British Nursing Index and Cochrane Library). Thirteen studies were selected based on predetermined eligibility and quality criteria for diagnostic assessment to establish the value of symptom-based diagnosis using diagnosistic odds ratio (DOR) and summary receiver operating characteristic (SROC) curve. In addition, routinely collated real-time data from primary care electronic health records (EHR), TransHis, was analysed to compare with our findings.ResultsHaemoptysis was found to have the greatest diagnostic value for lung cancer, diagnostic odds ratio (DOR) 6.39 (3.32–12.28), followed by dyspnoea 2.73 (1.54–4.85) then cough 2.64 (1.24–5.64) and lastly chest pain 2.02 (0.88–4.60). The use of symptom-based diagnosis to accurately diagnose lung cancer cases from non-cases was determined using the summary receiver operating characteristic (SROC) curve, the area under the curve (AUC) was consistently above 0.6 for each of the symptoms described, indicating reasonable discriminatory power. The positive predictive value (PPV) of diagnostic symptoms depends on an individual’s prior risk of lung cancer, as well as their presenting symptom pattern. For at risk individuals we calculated prior risk using validated epidemiological models for risk factors such as age and smoking history, then combined with the calculated likelihood ratios for each symptom to establish posterior risk or positive predictive value (PPV).ConclusionOur findings show that there is diagnostic value in the clinical symptoms associated with lung cancer and the potential benefit of characterising these symptoms using routine data studies to identify high-risk patients.

BackgroundUncoded chronic kidney disease (CKD) is associated with poorer quality of care.AimTo ascertain the proportion and determinants of CKD, which have not been formally recorded (Read coded), and identify differences in management and quality-of-care measures for patients with coded and uncoded CKD.Design and settingCross-sectional survey undertaken in an ethnically diverse adult population using primary care electronic health records (EHRs) from GP clinics in Lambeth, South London, UK.MethodMultivariable logistic regression analysis examined the association of demographic factors, selected comorbidities, deprivation, and cardiovascular disease risk management in CKD, with coding status as outcome.ResultsIn total, the survey involved 286 162 adults, of whom 9325 (3.3%) were identified with CKD stage 3–5 (assigned as CKD based on estimated glomerular filtration rate [eGFR] values). Of those identified with CKD, 4239 (45.5%) were Read coded, and 5086 (54.5%) were uncoded. Of those identified with CKD stage 3–5, individuals aged ≥50 years were more likely to be coded for CKD, compared with those aged <50 years. Lower levels of coding were independently associated with deprivation and black Caribbean, black African, South Asian, and non-stated ethnicities, compared with white ethnicity. Prescribed statin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker medications were associated with increased odds of coded CKD.ConclusionThis study found that >50% of CKD was uncoded and, for those patients, quality of care was lower compared with those with coded CKD. Future research and practices should focus on areas of greater deprivation and targeted initiatives for those aged <50 years and of black African, black Caribbean, South Asian, or non-stated ethnic groups. Possible areas for improvement include diagnostic coding support, automated CKD recording, and clinical decision support (based on adjusted eGFR results) in the GP clinical records.