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What really makes the British royal family tick? It's a question that royal watchers have pondered for as long as there has been a royal family. And the answer? Well, surprisingly, it's not the royal family's devotion to duty, it's not their wealth or their status, it's not even their popularity (or notoriety!). No, what really makes the royal family tick is the huge body of servants and staff past and present who feed and clothe the royals, organise their days, polish their shoes, carry the deer and pheasants they shoot, and even put the toothpaste on their toothbrushes. If you want to find out who these servants are, what they do and why, in so many cases, they devote their whole lives to royal service, then this book is for you.

Mechanical chest compression devices have the potential to help maintain high-quality cardiopulmonary resuscitation (CPR), but despite their increasing use, little evidence exists for their effectiveness. We aimed to study whether the introduction of LUCAS-2 mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest. The pre-hospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial was a pragmatic, cluster-randomised open-label trial including adults with non-traumatic, out-of-hospital cardiac arrest from four UK Ambulance Services (West Midlands, North East England, Wales, South Central). 91 urban and semi-urban ambulance stations were selected for participation. Clusters were ambulance service vehicles, which were randomly assigned (1:2) to LUCAS-2 or manual CPR. Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene. The primary outcome was survival at 30 days following cardiac arrest and was analysed by intention to treat. Ambulance dispatch staff and those collecting the primary outcome were masked to treatment allocation. Masking of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. The study is registered with Current Controlled Trials, number ISRCTN08233942. We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 group, 2819 assigned to the control group) between April 15, 2010 and June 10, 2013. 985 (60%) patients in the LUCAS-2 group received mechanical chest compression, and 11 (<1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30 day survival was similar in the LUCAS-2 group (104 [6%] of 1652 patients) and in the manual CPR group (193 [7%] of 2819 patients; adjusted odds ratio [OR] 0·86, 95% CI 0·64–1·15). No serious adverse events were noted. Seven clinical adverse events were reported in the LUCAS-2 group (three patients with chest bruising, two with chest lacerations, and two with blood in mouth). 15 device incidents occurred during operational use. No adverse or serious adverse events were reported in the manual group. We noted no evidence of improvement in 30 day survival with LUCAS-2 compared with manual compressions. On the basis of ours and other recent randomised trials, widespread adoption of mechanical CPR devices for routine use does not improve survival. National Institute for Health Research HTA – 07/37/69.

The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs.

Objective To describe patterns of prehospital ECG (PHECG) use and determine its association with processes and outcomes of care in patients with ST-elevation myocardial infarction (STEMI) and non-STEMI. Methods Population-based linked cohort study of a national myocardial infarction registry. Results 288 990 patients were admitted to hospitals via emergency medical services (EMS) between 1 January 2005 and 31 December 2009. PHECG use increased overall (51% vs 64%, adjusted OR (aOR) 2.17, 95% CI 2.12 to 2.22), and in STEMI (64% vs 79%, aOR 2.34, 95% CI 2.25 to 2.44). Patients who received PHECG were younger (71 years vs 74 years, P<0.0001); and less likely to be female (33.1% vs 40.3%, OR 0.87, 95% CI 0.86 to 0.89), or to have comorbidities than those who did not. For STEMI, reperfusion was more frequent in those having PHECG (83.5% vs 74.4%, p<0.0001). PHECG was associated with more primary percutaneous coronary intervention patients achieving call-to-balloon time <90 min (27.9% vs 21.4%, aOR 1.38, 95% CI 1.24 to 1.54) and more patients who received fibrinolytic therapy achieving door-to-needle time <30 min (90.6% vs 83.7%, aOR 2.13, 95% CI 1.91 to 2.38). Patients with PHECG exhibited significantly lower 30-day mortality rates than those who did not (7.4% vs 8.2%, aOR 0.94, 95% CI 0.91 to 0.96). Conclusions Findings from this national MI registry demonstrate a survival advantage in STEMI and non-STEMI patients when PHECG was used.

Background Prehospital ambulance based research has unique ethical considerations due to urgency, time limitations and the locations involved. We sought to explore these issues through interviews with experts in this research field. Methods We undertook semi-structured interviews with expert informants, primarily based in the UK, seeking their views and experiences of ethics in ambulance based clinical research. Participants were questioned regarding their experiences of ambulance based research, their opinions on current regulations and guidelines, and views about their general ethical considerations. Participants were chosen because they were actively involved in, or in their expert capacity (e.g. law) expressed an interest in, ambulance based research. Results Fourteen participants were interviewed including principal investigators, researchers, ethicists and medical lawyers. Five major themes were identified: Capacity, Consent, Clinical Considerations, Consultation and Regulation. Questions regarding consent and capacity were foremost in the discussions as all participants highlighted these as areas for concern. The challenges and use of multiple consent models reflected the complexity of research in this environment. The clinical theme referred to the role of paramedics in research and how research involving ambulance services is increasingly informing improvements to patient care and outcomes and reducing the burden on hospital services. Most felt that, although current regulations were fit for purpose, more specific guidance on implementing these in the ambulance setting would be beneficial. This related closely to the theme of consultation, which examined the key role of ethics committees and other regulatory bodies, as well as public engagement. Conclusions By interviewing experts in research or ethics in this setting we were able to identify key concerns and highlight areas for future development such as improved guidance.

Background In this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity. Methods Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF). Results One hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p  = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p  = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p  = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex. Conclusion Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered. Trial registration The trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Pulmonary-resident memory T cells (T ) and B cells (B ) orchestrate protective immunity to reinfection with respiratory pathogens. Developing methods for the detection of these populations would benefit both research and clinical settings. To address this need, we developed a novel immunolabelling approach combined with clinic-ready fibre-based optical endomicroscopy (OEM) to detect canonical markers of lymphocyte tissue residency in human lungs undergoing lung ventilation (EVLV). Initially, cells from human lung digests (confirmed to contain T /B populations using flow cytometry) were stained with CD69 and CD103/CD20 fluorescent antibodies and imaged using KronoScan, demonstrating it's ability to detect antibody labelled cells. We next instilled these pre-labelled cells into human lungs undergoing EVLV and confirmed they could still be visualised using both fluorescence intensity and lifetime imaging against background lung architecture. Finally, we instilled fluorescent CD69 and CD103/CD20 antibodies directly into the lung and were able to detect T /B following labelling within seconds of direct delivery of microdoses of fluorescently labelled antibodies. , no wash, immunolabelling with OEM imaging is a novel methodology with the potential to expand the experimental utility of EVLV and pre-clinical models.

Bronchiectasis is a chronic lung disease with permanently damaged airways predisposing to recurrent respiratory tract infections. There is an increasing prevalence of bronchiectasis in the elderly, affecting approximately 10 patients per 1,000 population. Studies have shown that older, frailer patients tend to have a more severe and symptomatic disease, with those aged 80 and above with worse quality of life, increased hospitalization and increased mortality. These patients will be encountered by clinicians working in all aspects of elderly care. This review covers the various investigations and aspects of treatment for bronchiectasis and how they may be utilized in a more older and generally frailer population.

Background Out-of-hospital cardiac arrest (OHCA) is a common reason for calls for intervention by emergency medical teams (EMTs) in Poland. Regardless of the mechanism, OHCA is a state in which the chance of survival is dependent on rapid action from bystanders and responding health professionals in emergency medical services (EMS). We aimed to identify factors associated with return of spontaneous circulation (ROSC). Methods The medical records of 2137 EMS responses to OHCA in the city of Wroclaw, Poland between July 2017 and June 2018 were analyzed. Results The OHCA incidence rate for the year studied was 102 cases per 100,000 inhabitants. EMS were called to 2317 OHCA events of which 1167 (50.4%) did not have resuscitation attempted on EMS arrival. The difference between the number of successful and failed cardiopulmonary resuscitations (CPRs) was statistically significant ( p  < 0.001). Of 1150 patients in whom resuscitation was attempted, ROSC was achieved in 250 (27.8%). Rate of ROSC was significantly higher when CPR was initiated by bystanders ( p  < 0.001). Patients presenting with asystole or pulseless electrical activity (PEA) had a higher risk of CPR failure (86%) than those with ventricular fibrillation/ventricular tachycardia (VF/VT). Patients with VF/VT had a higher chance of ROSC (OR 2.68, 1.86–3.85) than those with asystole ( p  < 0.001). The chance of ROSC was 1.78 times higher when the event occurred in a public place ( p  < 0.001). Conclusions The factors associated with ROSC were occurrence in a public place, CPR initiation by witnesses, and presence of a shockable rhythm. Gender, age, and the type of EMT did not influence ROSC. Low bystander CPR rates reinforce the need for further efforts to train the public in CPR.

Background Paramedics make important and increasingly complex decisions at scene about patient care. Patient safety implications of influences on decision making in the pre-hospital setting were previously under-researched. Cutting edge perspectives advocate exploring the whole system rather than individual influences on patient safety. Ethnography (the study of people and cultures) has been acknowledged as a suitable method for identifying health care issues as they occur within the natural context. In this paper we compare multiple methods used in a multi-site, qualitative study that aimed to identify system influences on decision making. Methods The study was conducted in three NHS Ambulance Trusts in England and involved researchers from each Trust working alongside academic researchers. Exploratory interviews with key informants e.g. managers ( n  = 16) and document review provided contextual information. Between October 2012 and July 2013 researchers observed 34 paramedic shifts and ten paramedics provided additional accounts via audio-recorded ‘digital diaries’ (155 events). Three staff focus groups (total n  = 21) and three service user focus groups (total n  = 23) explored a range of experiences and perceptions. Data collection and analysis was carried out by academic and ambulance service researchers as well as service users. Workshops were held at each site to elicit feedback on the findings and facilitate prioritisation of issues identified. Results The use of a multi-method qualitative approach allowed cross-validation of important issues for ambulance service staff and service users. A key factor in successful implementation of the study was establishing good working relationships with academic and ambulance service teams. Enrolling at least one research lead at each site facilitated the recruitment process as well as study progress. Active involvement with the study allowed ambulance service researchers and service users to gain a better understanding of the research process. Feedback workshops allowed stakeholders to discuss and prioritise findings as well as identify new research areas. Conclusion Combining multiple qualitative methods with a collaborative research approach can facilitate exploration of system influences on patient safety in under-researched settings. The paper highlights empirical issues, strengths and limitations for this approach. Feedback workshops were effective for verifying findings and prioritising areas for future intervention and research.