Description: Objectives The primary aim was to investigate the impact of complaints on doctors’ psychological welfare and health. The secondary aim was to assess whether doctors report exposure to a complaints process is associated with defensive medical practise. Design This was a cross-sectional anonymous survey study. Participants were stratified into recent/current, past, no complaints. Each group completed tailored versions of the survey. Participants 95 636 doctors were invited to participate. A total of 10 930(11.4%) responded, 7926 (8.3%) completed the full survey and were included in the complete analysis. Main outcome measures Anxiety and depression were assessed using the standardised Generalised Anxiety Disorder scale and Physical Health Questionnaire. Defensive practise was evaluated using a new measure. Single-item questions measured stress-related illnesses, complaints-related experience, attitudes towards complaints and views on improving complaints processes. Results 16.9% of doctors with current/recent complaints reported moderate/severe depression (relative risk (RR) 1.77 (95% CI 1.48 to 2.13) compared to doctors with no complaints (9.5%)). Fifteen per cent reported moderate/severe anxiety (RR=2.08 (95% CI 1.61 to 2.68) compared to doctors with no complaints (7.3%)). Distress increased with complaint severity, with highest levels after General Medical Council (GMC) referral (26.3% depression, 22.3% anxiety). Doctors with current/recent complaints were 2.08 (95% CI 1.61 to 2.68) times more likely to report thoughts of self-harm or suicidal ideation. Most doctors reported defensive practise: 82–89% hedging and 46–50% avoidance. Twenty per cent felt victimised after whistleblowing, 38% felt bullied, 27% spent over 1 month off work. Over 80% felt processes would improve with transparency, managerial competence, capacity to claim lost earnings and action against vexatious complainants. Conclusions Doctors with recent/current complaints have significant risks of moderate/severe depression, anxiety and suicidal ideation. Morbidity was greatest in cases involving the GMC. Most doctors reported practising defensively, including avoidance of procedures and high-risk patients. Many felt victimised as whistleblowers or reported bullying. Suggestions to improve complaints processes included transparency and managerial competence.

Description: Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS - or BRAF -mutant non–small cell lung, ovarian, or pancreatic cancer. Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS -mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR .

Description: Purpose: To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models. Experimental Design: We established 12 PDXs from BRAF inhibitor–progressed melanoma patients. Following expansion, PDXs were analyzed using targeted sequencing and reverse-phase protein arrays. By using multi-arm preclinical trial designs, we identified efficacious precision medicine approaches. Results: We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDXs, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho-MAPK predominated, with parallel activation of PI3K in a subset. Second-line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib)/MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo . Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted in complete and sustained tumor regression in all animals. Conclusions: Genomic and proteomic data integration identifies dual-core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select personalized therapies of patients and avoid treatment failures. Clin Cancer Res; 22(7); 1592–602. ©2015 AACR . See related commentary by Hartsough and Aplin, p. 1550

Description: Objective The aim of this study was to validate a new generic patient-reported outcome measure, the Long-Term Conditions Questionnaire (LTCQ), among a diverse sample of health and social care users in England. Design Cross-sectional validation survey. Data were collected through postal surveys (February 2016–January 2017). The sample included a healthcare cohort of patients recruited through primary care practices, and a social care cohort recruited through local government bodies that provide social care services. Participants 1211 participants (24% confirmed social care recipients) took part in the study. Healthcare participants were recruited on the basis of having one of 11 specified long-term conditions (LTCs), and social care participants were recruited on the basis of receiving social care support for at least one LTC. The sample exhibited high multimorbidity, with 93% reporting two or more LTCs and 43% reporting a mental health condition. Outcome measures The LTCQ’s construct validity was tested with reference to the EQ-5D (5-level version), the Self-Efficacy for Managing Chronic Disease scale, an Activities of Daily Living scale and the Bayliss burden of morbidity scale. Results Low levels of missing data for each item indicate acceptability of the LTCQ across the sample. The LTCQ exhibits high internal consistency (Cronbach’s α=0.95) across the scale’s 20 items and excellent test–retest reliability (intraclass correlation coefficient=0.94, 95% CI 0.93 to 0.95). Associations between the LTCQ and all reference measures were moderate to strong and in the expected directions, indicating convergent construct validity. Conclusions This study provides evidence for the reliability and validity of the LTCQ, which has potential for use in both health and social care settings. The LTCQ could meet a need for holistic outcome measurement that goes beyond symptoms and physical function, complementing existing measures to capture fully what it means to live well with LTCs.

Description: Objective How adverse outcomes and complaints are managed may significantly impact on physician well-being and practice. We aimed to investigate how depression, anxiety and defensive medical practice are associated with doctors actual and perceived support, behaviour of colleagues and process issues regarding how complaints investigations are carried out. Design A survey study. Respondents were classified into three groups: no complaint, recent/current complaint (within 6 months) or past complaint. Each group completed specific surveys. Setting British Medical Association (BMA) members were invited to complete an online survey. Participants 95 636 members of the BMA were asked to participate. 7926 (8.3%) completed the survey, of whom 1780 (22.5%) had no complaint, 3889 (49.1%) had a past complaint and 2257 (28.5%) had a recent/current complaint. We excluded those with no complaints leaving 6144 in the final sample. Primary outcomes measures We measured anxiety and depression using the Generalised Anxiety Disorder Scale 7 and Physical Health Questionnaire 9. Defensive practice was assessed using a new measure for avoidance and hedging. Results Most felt supported by colleagues (61%), only 31% felt supported by management. Not following process (56%), protracted timescales (78%), vexatious complaints (49%), feeling bullied (39%) or victimised for whistleblowing (20%), and using complaints to undermine (31%) were reported. Perceived support by management (relative risk (RR) depression: 0.77, 95% CI 0.71 to 0.83; RR anxiety: 0.80, 95% CI 0.74 to 0.87), speaking to colleagues (RR depression: 0.64, 95% CI 0.48 to 0.84 and RR anxiety: 0.69, 95% CI 0.51 to 0.94, respectively), fair/accurate documentation (RR depression: 0.80, 95% CI 0.75 to 0.86; RR anxiety: 0.81, 95% CI 0.75 to 0.87), and being informed about rights (RR depression 0.96 (0.89 to 1.03) and anxiety 0.94 (0.87 to 1.02), correlated positively with well-being and reduced defensive practice. Doctors worried most about professional humiliation following a complaint investigation (80%). Conclusion Poor process, prolonged timescales and vexatious use of complaints systems are associated with decreased psychological welfare and increased defensive practice. In contrast, perceived support from colleagues and management is associated with a reduction in these effects.

Description: Introduction Optimal targets for systemic oxygenation in paediatric critical illness are unknown. Observational data indicate that high levels of arterial oxygenation are associated with poor outcomes in resuscitation of the newborn and in adult critical illness. Within paediatric intensive care units (PICUs), staff prevent severe hypoxia wherever possible, but beyond this there is no consensus. Practice varies widely with age, diagnosis, treating doctor and local or national guidelines followed, though peripheral blood oxygen saturations (SpO 2 ) of 〉95% are often targeted. The overall aim of this pilot study is to determine the feasibility of performing a randomised trial in critically ill children comparing current practice of liberal SpO 2 targets with a more conservative target. Methods and analysis Oxy-PICU is a pragmatic, open, pilot randomised controlled trial in infants and children requiring mechanical ventilation and receiving supplemental oxygen for abnormal gas exchange accepted for emergency admission to one of three participating UK PICUs. The study groups will be either a conservative SpO 2 target of 88%–92% (inclusive) or a liberal SpO 2 target of 〉94%. Infants and children who fulfil all inclusion criteria and none of the exclusion criteria will be randomised 1:1 by a secure web-based system to one of the two groups. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support. Discharge outcomes will also be recorded. In addition to observational data, blood and urine samples will be taken to identify biochemical markers of oxidative stress. Outcomes are targeted at assessing study feasibility with a primary outcome of adequate study recruitment (target: 120 participants). Ethics and dissemination The trial received Health Research Authority approval on 1 June 2017 (16/SC/0617). Study findings will be disseminated in national and international conferences and peer-reviewed journals. Trial registration number NCT03040570.

Description: Introduction Over 18 000 children are admitted annually to UK paediatric intensive care units (PICUs), of whom nearly 75% receive respiratory support (invasive and/or non-invasive). Continuous positive airway pressure (CPAP) has traditionally been used to provide first-line non-invasive respiratory support (NRS) in PICUs; however, high-flow nasal cannula therapy (HFNC), a novel mode of NRS, has recently gained popularity despite the lack of high-quality trial evidence to support its effectiveness. This feasibility study aims to inform the design and conduct of a future definitive randomised clinical trial (RCT) comparing the two modes of respiratory support. Methods and analysis We will conduct a three-centre randomised feasibility study over 12 months. Patients admitted to participating PICUs who satisfy eligibility criteria will be recruited to either group A (primary respiratory failure) or group B (postextubation). Consent will be obtained from parents/guardians prior to randomisation in ‘planned’ group B, and deferred in emergency situations (group A and ‘rescue’ group B). Participants will be randomised (1:1) to either CPAP or HFNC using sealed, opaque envelopes, from a computer-generated randomisation sequence with variable block sizes. The study protocol specifies algorithms for the initiation, maintenance and weaning of HFNC and CPAP. The primary outcomes are related to feasibility, including the number of eligible patients in each group, feasibility of randomising 〉50% of eligible patients and measures of adherence to the treatment protocols. Data will also be collected on patient outcomes (eg, mortality and length of PICU stay) to inform the selection of an appropriate outcome measure in a future RCT. We aim to recruit 120 patients to the study. Ethics and dissemination Ethical approval was granted by the National Research Ethics Service Committee North East—Tyne&Wear South (15/NE/0296). Study findings will be disseminated through peer-reviewed journals, national and international conferences. Trials registration number NCT02612415; pre-results.

Description: Objective Reconfiguration of trauma services, with direct transport of patients with traumatic brain injury (TBI) to specialist neuroscience centres (SNCs)—bypassing non-specialist acute hospitals (NSAHs), could improve outcomes. However, delays in stabilisation of airway, breathing and circulation (ABC) may worsen outcomes when compared with selective secondary transfer from nearest NSAH to SNC. We conducted a pilot cluster randomised controlled trial to determine the feasibility and plausibility of bypassing suspected patients with TBI —directly into SNCs—producing a measurable effect. Setting Two English Ambulance Services. Participants 74 clusters (ambulance stations) were randomised within pairs after matching for important characteristics. Clusters enrolled head-injured adults—injured nearest to an NSAH—with internationally accepted TBI risk factors and stable ABC. We excluded participants attended by Helicopter Emergency Medical Services or who were injured more than 1 hour by road from nearest SNC. Interventions Intervention cluster participants were transported directly to an SNC bypassing nearest NSAH; control cluster participants were transported to nearest NSAH with selective secondary transfer to SNC. Outcomes Trial recruitment rate (target n=700 per annum) and percentage with TBI on CT scan (target 80%) were the primary feasibility outcomes. 30-day mortality, 6-month Extended Glasgow Outcome Scale and quality of life were secondary outcomes. Results 56 ambulance station clusters recruited 293 patients in 12 months. The trial arms were similar in terms of age, conscious level and injury severity. Less than 25% of recruited patients had TBI on CT (n=70) with 7% (n=20) requiring neurosurgery. Complete case analysis showed similar 30-day mortality in the two trial arms (control=8.8 (2.7–14.0)% vs intervention=9.4(2.3–14.0)%). Conclusion Bypassing patients with suspected TBI to SNCs gives an overtriage (false positive) ratio of 13:1 for neurosurgical intervention and 4:1 for TBI. A measurable effect from a full trial of early neuroscience care following bypass is therefore unlikely. Trial registration number ISRCTN68087745.

Description: Objectives Overuse of asthma relievers, particularly without anti-inflammatory preventers, increases asthma risks. This study aimed to identify how many reliever-only users have urgent healthcare, explore their attitudes and beliefs about asthma and its treatment, and investigate whether purchasing over-the-counter relievers was associated with worse asthma outcomes than by prescription. Design and setting Cross-sectional population-based Internet survey in Australia. Participants Of 2686 participants ≥16 years with current asthma randomly drawn from a web-based panel, 1038 (50.7% male) used only reliever medication. Main outcome measures Urgent asthma-related healthcare; Asthma Control Test (ACT); patient attitudes about asthma and medications; reliever purchase (with/without prescription). Results Of 1038 reliever-only participants, 23.3% had required urgent healthcare for asthma in the previous year, and only 36.0% had a non-urgent asthma review. Those needing urgent healthcare were more likely than those without such events to be male (56.5% vs 49.0%, p=0.003) and current smokers (29.4% vs 23.3%, p=0.009). Only 30.6% had well-controlled asthma (ACT ≥20) compared with 71.0% of those with no urgent healthcare (p〈0.0001), and 20.8% used relievers regularly to prevent asthma symptoms (vs 5.5% of those without urgent healthcare). Those with urgent healthcare were more frustrated by their asthma and less happy with how they managed it, and they were less confident about their ability to manage worsening asthma, but just as likely as those without urgent healthcare to manage worsening asthma themselves rather than visit a doctor. Reliever-only users purchasing over-the-counter relievers were no more likely than those purchasing relievers by prescription to have uncontrolled asthma (35.9% vs 40.6%, p=0.23) but were less likely to have had a non-urgent asthma review. Conclusions One-quarter of the reliever-only population had needed urgent asthma healthcare in the previous year, demonstrating the importance of identifying such patients. Their attitudes and beliefs suggest opportunities for targeting this population in the community.

Description: Objectives To explore the views of a range of stakeholders regarding whether patient-reported outcome measures (PROMs) can be developed to measure key attributes of long-term conditions (LTCs) care in England, and the potential value of a single generic measure. Design Qualitative semistructured interview study, analysed using a framework approach. Participants and setting Interviews with 31 stakeholders from primary care, secondary care, social care, policy and patient-focused voluntary organisations in England. Results There was broad support for a single PROM that could be used to measure outcomes for patients with any LTCs in any health or social care setting. Interviewees identified three desired uses for a PROM: to improve the quality of individual care; to increase people's engagement in their own care; and to monitor the performance of services. Interviewees felt that a PROM for LTCs should incorporate a mixture of traditional and non-traditional domains, such as functioning, empowerment and social participation, and be codesigned with patients and professional end-users. Stakeholders emphasised the need for a PROM to be feasible for practical implementation at the individual clinical level as a first priority. A number of concerns and potential problems were identified in relation to the application and interpretation of an LTC PROM. Conclusions This study has demonstrated support for a single self-report outcome measure that reflects the priorities of people with LTCs, if such a measure can be shown to be meaningful and useful at the individual level. People with LTCs and professional end-users in health and social care should be involved in the development and evaluation of such a measure.