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Background The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. Funding UK National Institute for Health and Care Research

In order to integrate genomic medicine into routine patient care and stratify personal risk, it is increasingly important to record family history (FH) information in general/family practice records. This is true for classic genetic disease as well as multifactorial conditions. Research suggests that FH recording is currently inadequate.To provide an up-to-date analysis of the frequency, quality, and accuracy of FH recording in UK general/family practice.An exploratory study, based at St Leonard's Practice, Exeter-a suburban UK general/family practice. Selected adult patients registered for over 1 year were contacted by post and asked to complete a written FH questionnaire. The reported information was compared with the patients' electronic medical record (EMR). Each EMR was assessed for its frequency (how often information was recorded), quality (the level of detail included), and accuracy (how closely the information matched the patient report) of FH recording.Two hundred and forty-one patients were approached, 65 (27.0%) responded and 62 (25.7%) were eligible to participate. Forty-three (69.4%) EMRs contained FH information. The most commonly recorded conditions were bowel cancer, breast cancer, diabetes, and heart disease. The mean quality score was 3.64 (out of 5). There was little negative recording. 83.2% of patient-reported FH information was inaccurately recorded or missing from the EMRs.FH information in general/family practice records should be better prepared for the genomic era. Whilst some conditions are well recorded, there is a need for more frequent, higher quality recording with greater accuracy, especially for multifactorial conditions.Taking a family history (FH) of disease can be a quick, cost-effective way of gathering genetic information. Genetic medicine is beginning to transform healthcare, so it is important to gather FH information. General practitioners, also known as family physicians, are in the best position to gather FH information as they regularly see multiple family members. Research suggests that FH recording in general/family practice is not yet good enough. This study aimed to find the areas for improvement by measuring the frequency, quality, and accuracy of FH recording. This study looked at 62 patients’ records in one UK general practice. Patients were asked to give up-to-date FH information in a questionnaire which was compared with their record. The study found that some conditions were often recorded. The most commonly recorded condition was heart disease. The conditions that are more likely to reflect the family environment, such as depression, were less frequently recorded. Recordings often included the side of the family the condition affected. Recordings rarely included the age that the relative was affected. The information was not very accurate, as most of the information from patient questionnaires was missing from the records. Research should now focus on how to improve recording.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed “remission” as the most appropriate descriptive term, and HbA1c

Purpose: Practice-based research networks (PBRNs) have developed dynamically across the world, paralleling the emergence of the primary care discipline. While this review focuses on the internal environment of PBRNs, the complete framework will be presented incrementally in future publications. Methods: We conducted a scoping review of the published and gray literature. Electronic databases, including MEDLINE (PubMed), OVID, CINAHL (EBSCOhost), Scopus, and SAGE Premier, were searched for publications between January 1, 1965 and December 31, 2020 for English-language articles. Rigorous inclusion/exclusion criteria were implemented to identify relevant publications, and inductive thematic analysis was applied to elucidate key elements, subthemes, and themes. Social network theory was used to synthesize findings. Results: A total of 229 publications described the establishment of 93 PBRNs in 15 countries that met the inclusion criteria. The overall framework yielded 3 main themes, 12 subthemes, and 57 key elements. Key PBRN activities included relationship building between academia and practitioners and development of a learning environment through multidirectional communication. Conclusions: PBRNs across many countries contributed significantly to shaping the landscape of primary health care and became an integral part of it. Many common features within the sphere of PBRNs can be identified that seem to promote their establishment across the world.

Background: Obesity poses significant challenges to healthcare globally, particularly through its bi-directional relationship with co-morbid metabolic conditions such as type 2 diabetes and hypertension. There is also emerging evidence of an association between obesity and chronic kidney disease (CKD) which is less well characterized. Methods: A literature search of electronic libraries was conducted to identify and present a narrative review of the interplay between obesity and CKD. Findings: Obesity may predispose to CKD directly as it is linked to the histopathological finding of obesity-related glomerulopathy and indirectly through its widely recognized complications such as atherosclerosis, hypertension, and type 2 diabetes. The biochemical and endocrine products of adipose tissue contribute to pathophysiological processes such as inflammation, oxidative stress, endothelial dysfunction, and proteinuria. The prevention and management of obesity may prove critical in counteracting both the development and advancement of CKD. Moreover, measures of abdominal adiposity such as waist circumference, are generally associated with worse morbidity and mortality in individuals receiving maintenance hemodialysis. Conclusion: Obesity is a risk factor for the onset and progression of CKD and should be recognized as a potential target for a preventative public health approach to reduce CKD rates within the general population. Future research should focus on the use of glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors in patients with CKD and obesity due to their multi-faceted actions on major outcomes.

Background: EXS21546 (discovered in collaboration with Evotec) is a clinical stage A2AR selective antagonist with high potential in cancer immunotherapy as a combination agent. A completed healthy volunteer (HV) first-in-human (FIH) study is now being followed by the IGNITE Phase 1/2 trial in patients, which includes the retrospective study of an adenosine-specific patient enrichment biomarker strategy. Methods: A 3-part Phase 1 FIH study in 60 HV was completed (NCT04727138). Parts 1 and 2 were double-blind, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) studies investigating EXS21546 safety, tolerability, PK and PD. Part 3 was a 3-period, open label, randomized, sequential study evaluating bioavailability of oral EXS21546 as a granule in capsule vs reference powder suspension. The ongoing Phase 1/2 IGNITE trial will study EXS21546 in patients with immunotherapy relapsed or refractory RCC or NSCLC directly in combination with a PD-1 inhibitor. This combination aims to leverage the properties of A2AR antagonism in the tumor microenvironment, to drive the immune system through PD-1 inhibition. IGNITE will also provide clinical data to support the validation of our adenosine signature to identify patients with adenosine rich tumor microenvironments who may benefit from treatment (Alt et al, 2022). Data will be continually reassessed to determine the recommended Phase 2 dose. A dose escalation phase will be followed by an expansion phase. Results: PK/PD modeling of Phase 1 study results, along with the EXS21546 safety profile, allowed identification of a potential therapeutic starting dose. PK results aligned with design specifications, based upon predictive preclinical modeling, and support twice-daily (BID) dosing for continuous A2AR antagonism. EXS21546 induced dose-dependent inhibition of CREB phosphorylation in CD8-positive cells, with the PD profile mirroring plasma exposure. Inhibition of A2AR signaling was sustained over the BID dosing period, demonstrating a level of lasting target engagement. PoP PK/PD simulations informed the starting dose and dosing regimen for the Phase 1/2 trial. EXS21546 was well-tolerated with no CNS adverse events reported in the SAD at all doses and in the MAD at 150 mg BID. The majority of adverse events were considered mild and unrelated to EXS21546, with the exception of one Grade 3 Serious Adverse Event of elevated ALT/AST. Conclusions: Safety and tolerability of our A2AR antagonist EXS21546 were confirmed in a HV study, allowing selection of a starting dose for the ongoing IGNITE Phase 1/2 study. IGNITE trial design was based on extensive simulations to enable the most efficient continuous reassessment method settings, and will allow further verification of the patient enrichment biomarker strategy. Citation Format: Nieves Diaz, Holly Garratt, Aleksandra Zemla-Brown, Maria Dominguez, Eric Helmer, Isabella Alt, Robert Sehlke, Norbert Hieger, Thomas Winkler-Penz, Christophe Boudesco, Gregory Vladimer, Tom Wilde, Philip Evans, Antoine Italiano, Michael Krams. Data from first-in-human study of EXS21546, an A2A receptor antagonist, now progressing into phase 1 in RCC/NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT114.

The exceptional advances in genomic medicine in the last two decades, since the sequencing of the human genome, have already had a major impact on healthcare in the UK. Until recently this was predominantly in secondary and tertiary care, but we must now integrate ‘mainstream’ genomics in primary care. So far integration has of necessity been empirical, but must progress towards implementation research. We describe recent work undertaken by the RCGP and the NIHR CRN outlining areas where research is needed to fully integrate genomics into routine primary care and secure the future of these exciting developments.

Background: The safety, effectiveness and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, in patients in the community who are multiply-vaccinated and at increased risk of morbidity and mortality from COVID-19, has not been established. We aimed to determine whether molnupiravir added to usual care reduced hospital admissions/deaths among people at higher risk from COVID-19, and here report our preliminary analyses. Methods: Participants in this UK multicentre, open-label, adaptive, multi-arm, platform, randomised controlled trial were aged ≥50, or ≥18 years with comorbidities, and unwell ≤5 days with confirmed COVID-19 in the community, and were randomised to usual care or usual care plus molnupiravir (800mg twice daily for 5 days). The primary outcome measure was all-cause hospitalisation/death within 28 days, analysed using Bayesian models. The main secondary outcome measure was time to first self-reported recovery. A sub-set of participants in each group were assessed for the virology primary outcome measure of day seven SARS-CoV-2 viral load. Trial registration: ISRCTN30448031 Findings: Between December 8, 2021 and April 27, 2022, 25783 participants were randomised to molnupiravir plus usual care (n=12821) or usual care alone (n=12962). Mean (range) age of participants was 56·6 years (18 to 99), 58·6% were female, and 99% had at least one dose of a SARS-CoV-2 vaccine. The median duration of symptoms prior to randomisation was two days (IQR 1 – 3), the median number of days from symptom onset to starting to take the medication was three days (IQR 3 – 4), 87% (11109/11997) received their medication within five days of symptom onset, and 95·4% (n=11857) of participants randomised to molnupiravir reported taking molnupiravir for five days. Primary outcome measure data were available in 25000 (97%) participants and included in this analysis. 103/12516 (0·8%) hospitalisations/deaths occurred in the molnupiravir group versus 96/12484 (0·8%) in usual care alone with a posterior probability of superiority of 0·34 (adjusted odds ratio 1·061 (95% Bayesian credible interval [BCI]) 0·80 to 1·40). Estimates were similar for all subgroups. The observed median (IQR) time-to-first-recovery from randomisation was 9 (5–23) days in molnupiravir and 15 (7–not reached) days in usual care. There was an estimated benefit of 4·2 (95% BCI: 3·8 – 4·6) days in time-to-first-recovery (TTR) giving a posterior probability of superiority of >0·999 (estimated median TTR 10·3 [10·2 – 10·6] days vs 14·5 [14·2 – 14·9] days respectively; hazard ratio [95% BCI], 1·36 [1·3–1·4] days), which met the pre-specified superiority threshold. On day 7, SARS-CoV-2 virus was below detection levels in 7/34 (21%) of the molnupiravir group, versus 1/39 (3%) in the usual care group (p=0.039), and mean viral load was lower in the molnupiravir group compared with those receiving usual care [(SD) of log10(viral load) 3·82 (1·40) in the molnupiravir group and 4.93 (1·38) in the usual care group, (P Interpretation: In this preliminary analysis, we found that molnupiravir did not reduce already low hospitalisations/deaths among higher risk, vaccinated adults with COVID-19 in the community, but resulted in faster time to recovery, and reduced viral detection and load. Funding: This project is funded by the NIHR (NIHR135366). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

ObjectivesColchicine has been proposed as a COVID-19 treatment, but its effect on time to recovery is unknown. We aimed to determine whether colchicine is effective at reducing time to recovery and COVID-19 related hospitalisations/deaths among people in the community.DesignProspective, multicentre, open-label, multi-arm, adaptive Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE).SettingNational trial run remotely from a central trial site and at multiple primary care centres across the United Kingdom.ParticipantsAdults aged ≥65, or ≥18 years with comorbidities or shortness of breath, and unwell ≤14 days with suspected COVID-19 in the community.InterventionsParticipants were randomised to usual care, usual care plus colchicine (500µg daily for 14 days), or usual care plus other interventions.Main outcome measuresThe co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm).ResultsThe trial opened on April 2, 2020, with randomisation to colchicine starting on March 04, 2021 and stopping on May 26, 2021, because the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.919 [95% credible interval 0.72 to 1.16] and an estimated increase of 1.14 days [−1.86 to 5.21] in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 [0.28 to 1.89] and an estimated difference of −0.4% [−2.7% to 2.4]. One serious adverse event occurred in the colchicine group and one in usual care.ConclusionsColchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.Trial registrationISRCTN86534580.

I read with interest the proposed mechanisms that link relational continuity to outcomes.1 The discussion is comprehensive and the proposed theories plausible. It is important to note, though, that most trial evidence supporting continuity and outcomes examines longitudinal, rather than relational, continuity. These two forms of continuity are obviously related and often conflated, but they are different. Despite this, and the lack of trial evidence supporting causation, …

Background Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes. Methods We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580. Findings The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI −0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference −0·5% [95% BCI −2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group. Interpretation In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19. Funding UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research.

IntroductionThere is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications.Methods and analysisThe Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50–64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 ‘hot hubs’ and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes.Ethics and disseminationEthical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals.Trial registration numberISRCTN86534580.

The benefits associated with continuity of GP care for patients, for GPs, and for the health system have become progressively stronger.1 However, the routine measurement of this continuity in clinical practice has not kept pace with the increasing evidence base. …

Hundreds of studies from various countries and health systems have linked increased continuity to positive outcomes; some show no link and only a few an association with adverse effects.1 To the best of our current knowledge, and on the balance of probabilities, continuity is likely to be beneficial. On this basis it is now important to consider what possible mechanisms can explain the continuity effects.

For the past ten years, the UK Government has attempted ‘to improve the health and wealth of the nation through research’. Investment into the NIHR and its CRNs has helped make the healthcare system safer, more effective and cost-efficient, as well as improve the research agenda. However, due to commissioning and the service contract tendering process, changes in contract provider (specifically to non-NHS organisations) can hamper ongoing clinical research, affecting both organisations and patients. This paper explores the issues and discusses next steps in the continuity of research activity.

The objectives of this study were to characterise the particle size distribution of aerosols generated by standard dental aerosol generating procedures (AGPs) and to assess the impact of aerosol management interventions on ‘fallow time’. Aerosol management interventions included combinations of high-volume intra-oral suction (HVS(IO)), high volume extra-oral suction (HVS(EO)) and an air cleaning system (ACS). A sequence of six AGPs were performed in succession on a phantom head. Real-time aerosol measurements (size range 0.0062 – 9.6 µm) were taken using a high-resolution particle sizer acquiring air samples from six locations within a typical dental treatment room (35 m3). The majority (>99%) of AGP particles were < 0.3 µm diameter and remained at significant levels around the dental team during the AGPs. This emphasises the importance of personal protection equipment, particularly, the use of properly fitted respiratory protection to the appropriate (FFP3) standard. In the absence of active aerosol management interventions, AGP particles were estimated to remain above the baseline range for around 25-31 minutes from the end of the sequence of procedures. It was found that HVS(IO), either alone or in combination with the ACS, reduced particle concentrations to baseline levels on completion of AGPs. These data indicated that there is scope to reduce fallow time to 0 minutes.

Introduction: Were we to be aware at thoracoscopy which patients would benefit from a tunnelled indwelling pleural catheter (TIPC), we could perform both procedures simultaneously thus simplifying the treatment pathway for the patient and potentially relieving breathlessness earlier. Aim: To evaluate the frequency of post-thoracoscopy TIPC insertion and describe this cohort of patients. Method: Data was collected regarding the diagnosis, duration of TIPCs and complications for patients who underwent thoracoscopy and TIPC insertion at the Royal Gwent Hospital from October 2010 to November 2019. Results: 349 patients had thoracoscopy during the time period whilst 151 patients had TIPCs inserted, of which 51 (34%) were inserted post thoracoscopy and 4 at thoracoscopy. The mean time between thoracoscopy and TIPC insertion was 65 days. 36% of all thoracoscopy patients with mesothelioma had a TIPC, compared to 16% of patients with other malignancies. 21 TIPCs were inserted within 30 days of thoracoscopy; of these, 13 had mesothelioma, 9 had talc at thoracoscopy, and 10 had visible non-expandable lung (NEL) at thoracoscopy. 20 patients had their TIPC removed due to pleurodesis, and 4 due to localised infection. The average duration of a non-infected TIPC was 105 days. 26 (47%) patients died with a TIPC in situ with an average time from insertion to death of 109 days. Conclusion: The 21 patients who had a TIPC inserted within 30 days of thoracoscopy would have benefitted most from having simultaneous procedures. We could consider inserting a TIPC at thoracoscopy when there is a high index of suspicion for both mesothelioma and NEL. The availability of pleural manometry may aid this decision.

Radiomics allows additional information to be extracted from medical images, which cannot be seen with the naked eye. By calculating features based on the voxel intensities and spatial relationships, we can gain further knowledge of the underlying structure of cancer tumours. These radiomic features (RFs) can be utilised to predict cancer patient outcome. However, when patients are imaged there are a variety of settings and scanner manufacturers available, which can have a significant impact on RFs. Due to the findings in the literature there is much discussion on the reliability of RFs. This work addresses two key radiomics questions. The first is whether consistent RF values can be obtained from a consistent experimental setup. The second is looking at CT image reconstruction parameters and how these effect RFs. A phantom, containing 10 different materials, designed for radiomic research, was CT scanned 5 times on the same scanner, with a 10-minute rest period between scans. The phantom was then scanned 10 times in quick succession, using the same setup. This tested the effects of the x-ray detectors heating up on the RF values. For the second research question, one CT image was reconstructed using a range of reconstruction parameters, such as kernel sharpness and denoise level, to assess their impact on RFs. RF stability was evaluated using a second order coefficient of variation. X-ray detector heat was found to have a minimal impact on RF stability, with both sets of scans having 96% of RFs being stable. Across all the reconstruction parameters the RF stability was poor, with 69% of RFs being unstable. Reconstruction parameters, such as high kernel sharpness and denoising level were found to have a large impact on the RFs. These results help to determine which aspects of CT imaging need to be standardised to obtain reliable measurements in radiomic studies.

We offer new evidence on the risk versus mispricing explanations for the R&D anomaly. Return covariance with a characteristic-based factor captures the cross-sectional return variation on R&D portfolios not explained by asset pricing models. This is consistent with both covariance risk and mispricing. Under the framework of the ICAPM, we find little economic justification that an R&D factor is a proxy for innovations to a state variable. The characteristic subsumes the factor loading in direct tests, providing support to the mispricing hypothesis. Investigating the mispricing explanation further, we reject the assertion that the R&D anomaly arises from the correction of stocks mispriced by investor sentiment. A natural experiment exploiting the pilot program under Regulation SHO shows no evidence that the anomaly persists due to limits to arbitrage in the form of short sale constraints.

Background Research is fundamental to high-quality care, but concerns have been raised about whether health research is conducted in the populations most affected by high disease prevalence. Geographical distribution of research activity is important for many reasons. Recruitment is a major barrier to research delivery, and undertaking recruitment in areas of high prevalence could be more efficient. Regional variability exists in risk factors and outcomes, so research done in healthier populations may not generalise. Much applied health research evaluates interventions, and their impact may vary by context (including geography). Finally, fairness dictates that publically funded research should be accessible to all, so that benefits of participating can be fairly distributed. We explored whether recruitment of patients to health research is aligned with disease prevalence in England. Methods We measured disease prevalence using the Quality and Outcomes Framework in England (total long-term conditions, mental health and diabetes). We measured research activity using data from the NIHR Clinical Research Network. We presented descriptive data on geographical variation in recruitment rates. We explored associations between the recruitment rate and disease prevalence rate. We calculated the share of patient recruitment that would need to be redistributed to align recruitment with prevalence. We assessed whether associations between recruitment rate and disease prevalence varied between conditions, and over time. Results There was significant geographical variation in recruitment rates. When areas were ranked by disease prevalence, recruitment was not aligned with prevalence, with disproportionately low recruitment in areas with higher prevalence of total long-term and mental health conditions. At the level of 15 local networks, analyses suggested that around 12% of current recruitment activity would need to be redistributed to align with disease prevalence. Overall, alignment showed little change over time, but there was variation in the trends over time in individual conditions. Conclusions Geographical variations in recruitment do not reflect the suitability of the population for research. Indicators should be developed to assess the fit between research and need, and to allow assessment of interventions among funders, researchers and patients to encourage closer alignment between research activity and burden.

The aim of this contribution is to present the design as well as findings of a survey targeted assessing the needs of stakeholders in the transportation domain with respect to climate change driven damages. This ‘User needs survey’ is one of the major objectives of multifarious collaborations investigating anticipatory asset protection strategies under accelerated climate change. The viability of these efforts is guaranteed by pairing up the scientific community (CIT, University of Vienna, BOKU, TU Vienna) with notable stakeholders (F&L, WMO, BMNT).The ‘User needs’ survey, was carried out in cooperation between the Climate Impact Team (CIT) the European Transport, Freight and Logistics Leaders Forum (F&L) and the World Meteorological Organization (WMO). The aim of the survey is to identify services that stakeholders in the realm of transportation themselves consider significant and beneficial. Therefore, findings should be of vital importance for -- (i) setting up meaningful climate services; (ii) selecting sustainable protection measures strengthening transportation system resilience in the face of future climate change; (iii) compiling the chapter on 'Land Transport' in WMO’s new Service Delivery Guide -- as they ensure the expediency of the services described.Presented results encompass: (i) an assessment of extreme events in terms of their damaging impacts on transport, freight and logistics by stakeholders; (ii) an assessment of the vulnerability of assets in transport, freight and logistics by stakeholders; (iii) an illustration of the extent of impacts climate-change (through shifts in extremes and associated threats) has had on transport, freight and logistics over the past decades; (iv) the stakeholders' expectations regarding future developments towards advancing climate-change and (v) an evaluation of time horizons (short, medium and long term) at which stakeholders need services. A summary completes this contribution.

Background The use of Patient Reported Outcome Measures (PROMS) in clinical practice has the potential to promote patient-centred care and improve patients’ quality of life. Individualized PROMs may be particularly helpful in identifying, prioritizing and monitoring health problems of patients with multimorbidity. We aimed to develop an intervention centred around PROMs feedback as part of Primary Care annual reviews for patients with multimorbidity and evaluate its feasibility and acceptability. Methods We developed a nurse-oriented intervention including (a) training of nurses on PROMs; (b) administration to patients with multimorbidity of individualized and standardized PROMS; and (c) feedback to both patients and nurses of PROMs scores and interpretation guidance. We then tailored the intervention to patients with two or more highly prevalent conditions (asthma, COPD, diabetes, heart failure, depression, and hip/knee osteoarthritis) and designed a non-controlled feasibility and acceptability evaluation in a convenience sample of primary care practices (5). PROMs were administered and scores fed back immediately ahead of scheduled annual reviews with nurses. Patients and nurses rated the acceptability of the intervention using with a brief survey including optional free comments. Thematic analysis of qualitative interviews with a sample of participating patients (10) and nurses (4) and of survey free comments was conducted for further in-depth evaluation of acceptability. Feasibility was estimated based on rates of participation and completion. Results Out of 68 recruited patients (mean age 70; 47% female), 68 completed the PROMs (100%), received feedback (100%) and confirmed nurse awareness of their scores (100%). Most patients (83%) “agreed”/”strongly agreed” that the PROMs feedback had been useful, a view supported by nurses in 89% of reviews. Thematic analysis of rich qualitative data on PROMS administration, feedback and role in annual reviews indicated that both patients and nurses perceived the intervention as acceptable and promising, emphasizing its comprehensiveness and patient-centredness. Conclusions We have developed and tested an intervention focusing on routine PROM assessment of patients with multimorbidity in Primary Care. Preliminary findings support its feasibility and a high degree of acceptability from both patients and nurses. The next step is to conduct a full-scale trial for evaluating the effectiveness of the proposed intervention.

We show evidence that female board representation is associated with greater innovative success, and thus enhances firm performance in innovation-intensive industries. Firms with female directors tend to invest more in innovation and obtain more patents and citations for given R&D expenditures. An increase of 10 percentage points in the tenure-weighted fraction of female directors is associated with approximately 6% more patents and 7% more citations. Investigating the underlying mechanisms, the positive association between female board representation and corporate innovation is stronger when product market competition is lower and when managers are more entrenched, consistent with increased monitoring by female directors improving managers’ incentives to innovate. Furthermore, we find that female board representation is positively associated with performance only for firms for which innovation and creativity play a particularly important role.

A 54-year-old woman was admitted to hospital with a presumed allergic reaction to a single dose of amoxicillin given for a suspected upper respiratory tract infection. She complained of chest tightness although there was no wheeze or stridor. On examination, she was pyrexial, tachycardic, hypertensive and had a diffuse mottled rash on her lower limbs. Her initial investigations showed raised inflammatory markers. She was treated in the intensive care for a presumed anaphylactic reaction with an underlying sepsis. Further investigations including CT head and CSF examination were unremarkable; however, a CT abdomen showed a 10 cm heterogeneous right adrenal mass. Based on review by the endocrine team, a diagnosis of pheochromocytoma crisis was made, which was subsequently confirmed on 24-h urinary metanephrine measurement. An emergency adrenalectomy was considered although she was deemed unfit for surgery. Despite intensive medical management, her conditioned deteriorated and she died secondary to multi-organ failure induced by pheochromocytoma crisis. Learning points: Pheochromocytoma have relatively higher prevalence in autopsy series (0.05–1%) suggestive of a diagnosis, which is often missed. Pheochromocytoma crisis is an endocrine emergency characterized by hemodynamic instability induced by surge of catecholamines often precipitated by trauma and medications (β blockers, general anesthetic agents, ephedrine and steroids). Pheochromocytoma crisis can mimic acute coronary syndrome, cardiogenic or septic shock. Livedo reticularis can be a rare although significant cutaneous marker of underlying pheochromocytoma crisis. Background Pheochromocytoma crisis (PMC) is characterized by hemodynamic instability induced by a surge of catecholamines, which can often be precipitated by medications (steroids, dopamine receptor antagonists, anticholinergics, general anesthetic agents etc.) or trauma (1). It can mimic other medical emergencies such as acute coronary syndrome, cardiogenic or septic shock. Livedo reticularis may be a rare although significant cutaneous clue to an underlying diagnosis of PMC. Management of PMC involves early use of α-adrenergic blockers (prior to β-adrenergic blockers) in addition to close monitoring and hemodynamic supportive measures. The timing of adrenalectomy in such patients is debatable although based on our experience and a recently published European case series, an emergency adrenalectomy should be considered in patients presenting with life-threatening PMC.

Background Skin tears are common in older adults and those taking steroids and warfarin. They are traumatic, often blunt injuries caused by oblique knocks to the extremities. The epidermis may separate from the dermis or both layers from underlying tissues leaving a skin flap or total loss of tissue, which is painful and prone to infection. ‘Dermatuff™’ knee-length socks containing Kevlar fibres (used in stab-proof vests and motorcyclists’ clothing) aim to prevent skin tears. The acceptability of the socks and the feasibility of a randomised controlled trial (RCT) had not been explored. Methods In this pilot parallel group RCT, 90 people at risk of skin-tear injury from Devon care homes and primary care were randomised to receive the socks or treatment as usual (TAU). The pilot aimed to estimate parameters to inform the design of a substantive trial and record professionals’ views and participants’ acceptability of the intervention and of study participation. Results Participants were randomised from July 2013 and followed up until February 2015. Community participants were easier to recruit than care homes residents but were 10 years younger on average and more active. To recruit 90 participants, 395 had to be approached overall as 77% were excluded or declined. Seventy-nine participants (88%) completed the trial and 27/44 (61%) wore the socks for 16 weeks. There were 31 skin tear injuries affecting 18 (20%) of the 90 participants. The TAU group received more injuries, more repeated episodes, and larger tears with greater severity. Common daily diary reasons for not wearing the socks included perceived warmth in hot weather or not being available (holiday, in hospital, bed rest). Resource use data were obtainable and indicated that sock wearing gave a reduction in treatment costs whilst well-completed questionnaires showed improvements in secondary outcomes. Conclusions This pilot trial has successfully informed the design and conduct of a future definitive cost-effectiveness RCT. It would need to be conducted in primary care with 880 active at-risk, elderly patients (440 per arm). Skin tear incidence and quality of life (from EQ5D5L) over a 4-month period would be the primary and secondary outcomes respectively. Trial registration ISRCTN, ISRCTN96565376 .

General practice computer systems are remarkably sophisticated but their potential is underused. In contrast many private sector businesses use IT meticulously to measure performance. For example, many retail stores know exactly how sales change according to how they position goods in the shop or even how they alter the lighting. Following Drucker,1 the father of management theory, ‘If you don’t measure it, you can’t manage it.’ Drawing on research and data collection performed at a practice over 30 years, we suggest that there are eight core management statistics that are easily available to every general practice. These make it possible for GPs to understand exactly what is happening in the practice. The core data are: the number, the age/sex structure and the duration of registration of the registered patients, the annual consultation rate, the average duration of face-to-face GP consultations, level of continuity of care, and measures of routine appointment provision and availability. All GPs already understand the importance of knowing the number of patients registered with the practice and this figure is commonly used when describing a general practice. This is available for the population nationally, regionally, and for individual practices. It is particularly helpful to know the proportion of older patients, since they have many more health problems, which helps planning. This is freely available to all practices on the Public Health England Practice Profiles …