Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study.

OBJECTIVE: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. METHODS: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. RESULTS: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). CONCLUSION: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Prolonged vs Intermittent Infusions of ß-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis.

Importance: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged ß-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of ß-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of ß-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of ß-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged ß-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration: PROSPERO Identifier: CRD42023399434.

Continuous vs Intermittent ß-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial.

Importance: Whether ß-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a ß-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a ß-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of ß-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Comparative effectiveness of sotrovimab versus no treatment in non-hospitalised high-risk COVID-19 patients in north west London: a retrospective cohort study.

BACKGROUND: We assessed the effectiveness of sotrovimab vs no early COVID-19 treatment in highest-risk COVID-19 patients during Omicron predominance. METHODS: Retrospective cohort study using the Discover dataset in North West London. Included patients were non-hospitalised, aged ≥12 years and met ≥1 National Health Service highest-risk criterion for sotrovimab treatment. We used Cox proportional hazards models to compare HRs of 28-day COVID-19-related hospitalisation/death between highest-risk sotrovimab-treated and untreated patients. Age, renal disease and Omicron subvariant subgroup analyses were performed. RESULTS: We included 599 sotrovimab-treated patients and 5191 untreated patients. Compared with untreated patients, the risk of COVID-19 hospitalisation/death (HR 0.50, 95% CI 0.24, 1.06; p=0.07) and the risk of COVID-19 hospitalisation (HR 0.43, 95% CI 0.18, 1.00; p=0.051) were both lower in the sotrovimab-treated group; however, statistical significance was not reached. In the ≥65 years and renal disease subgroups, sotrovimab was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR 0.11, 95% CI 0.02, 0.82; p=0.03) and 82% (HR 0.18, 95% CI 0.05, 0.62; p=0.007), respectively. CONCLUSIONS: Risk of COVID-19 hospitalisation in sotrovimab-treated patients aged ≥65 years and with renal disease was significantly lower compared with untreated patients. Overall, risk of hospitalisation was also lower for sotrovimab-treated patients, but statistical significance was not reached.

UK clinicians' attitudes towards the application of molecular diagnostics to guide antibiotic use in ICU patients with pneumonias: a quantitative study.

BACKGROUND: Molecular diagnostic tests may improve antibiotic prescribing by enabling earlier tailoring of antimicrobial therapy. However, clinicians' trust and acceptance of these tests will determine their application in practice. OBJECTIVES: To examine ICU prescribers' views on the application of molecular diagnostics in patients with suspected hospital-acquired and ventilator-associated pneumonia (HAP/VAP). METHODS: Sixty-three ICU clinicians from five UK hospitals completed a cross-sectional questionnaire between May 2020 and July 2020 assessing attitudes towards using molecular diagnostics to inform initial agent choice and to help stop broad-spectrum antibiotics early. RESULTS: Attitudes towards using molecular diagnostics to inform initial treatment choices and to stop broad-spectrum antibiotics early were nuanced. Most (83%) were positive about molecular diagnostics, agreeing that using results to inform broad-spectrum antibiotic prescribing is good practice. However, many (58%) believed sick patients are often too unstable to risk stopping broad-spectrum antibiotics based on a negative result. CONCLUSIONS: Positive attitudes towards the application of molecular diagnostics to improve antibiotic stewardship were juxtapositioned against the perceived need to initiate and maintain broad-spectrum antibiotics to protect unstable patients.

Clinician and patient perspectives on the barriers and facilitators to physical rehabilitation in intensive care: a qualitative interview study.

OBJECTIVES: The objective of this study is to explore patient, relative/carer and clinician perceptions of barriers to early physical rehabilitation in intensive care units (ICUs) within an associated group of hospitals in the UK and how they can be overcome. DESIGN: Qualitative study using semi-structured interviews and thematic framework analysis. SETTING: Four ICUs over three hospital sites in London, UK. PARTICIPANTS: Former ICU patients or their relatives/carers with personal experience of ICU rehabilitation. ICU clinicians, including doctors, nurses, physiotherapists and occupational therapists, involved in the delivery of physical rehabilitation or decisions over its initiation. PRIMARY AND SECONDARY OUTCOMES MEASURES: Views and experiences on the barriers and facilitators to ICU physical rehabilitation. RESULTS: Interviews were carried out with 11 former patients, 3 family members and 16 clinicians. The themes generated related to: safety and physiological concerns, patient participation and engagement, clinician experience and knowledge, teamwork, equipment and environment and risks and benefits of rehabilitation in intensive care. The overarching theme for overcoming barriers was a change in working model from ICU clinicians having separate responsibilities (a multidisciplinary approach) to one where all parties have a shared aim of providing patient-centred ICU physical rehabilitation (an interdisciplinary approach). CONCLUSIONS: The results have revealed barriers that can be modified to improve rehabilitation delivery in an ICU. Interdisciplinary working could overcome many of these barriers to optimise recovery from critical illness.

Corrigendum to "Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis" [Crit Care Resusc 23(3) (2021) 273-284].

[This corrects the article DOI: 10.51893/2021.3.oa4.].

"I'd rather wait and see what's around the corner": A multi-perspective qualitative study of treatment escalation planning in frailty.

INTRODUCTION: People living with frailty risk adverse outcomes following even minor illnesses. Admission to hospital or the intensive care unit is associated with potentially burdensome interventions and poor outcomes. Decision-making during an emergency is fraught with complexity and potential for conflict between patients, carers and clinicians. Advance care planning is a process of shared decision-making which aims to ensure patients are treated in line with their wishes. However, planning for future care is challenging and those living with frailty are rarely given the opportunity to discuss their preferences. The aim of the ProsPECT (Prospective Planning for Escalation of Care and Treatment) study was to explore perspectives on planning for treatment escalation in the context of frailty. We spoke to people living with frailty, their carers and clinicians across primary and secondary care. METHODS: In-depth online or telephone interviews and online focus groups. The topic guide explored frailty, acute decision-making and planning for the future. Data were thematically analysed using the Framework Method. Preliminary findings were presented to a sample of study participants for feedback in two online workshops. RESULTS: We spoke to 44 participants (9 patients, 11 carers and 24 clinicians). Four main themes were identified: frailty is absent from treatment escalation discussions, planning for an uncertain future, escalation in an acute crisis is 'the path of least resistance', and approaches to facilitating treatment escalation planning in frailty. CONCLUSION: Barriers to treatment escalation planning include a lack of shared understanding of frailty and uncertainty about the future. Emergency decision-making is focussed on survival or risk aversion and patient preferences are rarely considered. To improve planning discussions, we recommend frailty training for non-specialist clinicians, multi-disciplinary support, collaborative working between patients, carers and clinicians as well as broader public engagement.

Perspectives of healthcare professionals and older patients on shared decision-making for treatment escalation planning in the acute hospital setting: a systematic review and qualitative thematic synthesis.

Background: Shared Decision-Making (SDM) between patients and clinicians is increasingly considered important. Treament Escalation Plans (TEP) are individualised documents outlining life-saving interventions to be considered in the event of clinical deterioration. SDM can inform subjective goals of care in TEP but it remains unclear how much it is considered beneficial by patients and clinicians. We aimed to synthesise the existing knowledge of clinician and older patient (generally aged ≥65 years) perspectives on patient involvement in TEP in the acute setting. Methods: Systematic database search was performed in MEDLINE, EMBASE, PsycInfo and CINAHL databases as well as grey literature from database inception to June 8, 2023, using the Sample (older patients, clinicians, acute setting; studies relating to patients whose main diagnosis was cancer or single organ failure were excluded as these conditions may have specific TEP considerations), Phenomenon of Interest (Treatment Escalation Planning), Design (any including interview, observational, survey), Evaluation (Shared Decision-Making), Research type (qualitative, quantitative, mixed methods) tool. Primary data (published participant quotations, field notes, survey results) and descriptive author comments were extracted and qualitative thematic synthesis was performed to generate analytic themes. Quality assessment was made using the Critical Appraisal Skills Programme and Mixed Methods Appraisal Tools. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research) approach was used to assess overall confidence in each thematic finding according to methodology, coherence, adequacy and relevance of the contributing studies. The study protocol was registered on PROSPERO, CRD42022361593. Findings: Following duplicate exclusion there were 1916 studies screened and ultimately 13 studies were included, all from European and North American settings. Clinician-orientated themes were: treatment escalation is a medical decision (high confidence); clinicians want the best for their patients amidst uncertainty (high confidence); involving patients and families in decisions is not always meaningful and can involve conflict (high confidence); treatment escalation planning exists within the clinical environment, organisation and society (moderate confidence). Patient-orientated themes were: patients' relationships with Treatment Escalation Planning are complex (low confidence); interactions with doctors are important but communication is not always easy (moderate confidence); patients are highly aware of their families when considering TEP (moderate confidence). Interpretation: Based on current evidence, TEP decisions appear dominated by clinicians' perspectives, motivated by achieving the best for patients and challenged by complex decisions, communication and environmental factors; older patients' perspectives have seldom been explored, but their input on decisions may be modest. Presenting the context and challenge of SDM during professional education may allow reflection and a more nuanced approach. Future research should seek to understand what approach to TEP decision-making patients and clinicians consider to be optimum in the acute setting so that a mutually acceptable standard can be defined in policy. Funding: HCA International and the NIHR Imperial Biomedical Research Centre.

Randomised trial of the clinical and cost effectiveness of a supraglottic airway device compared with tracheal intubation for in-hospital cardiac arrest (AIRWAYS-3): Protocol, design and implementation.

Survival from in-hospital cardiac arrest is approximately 18%, but for patients who require advanced airway management survival is lower. Those who do survive are often left with significant disability. Traditionally, resuscitation of cardiac arrest patients has included tracheal intubation, however insertion of a supraglottic airway has gained popularity as an alternative approach to advanced airway management. Evidence from out-of-hospital cardiac arrest suggests no significant differences in mortality or morbidity between these two approaches, but there is no randomised evidence for airway management during in-hospital cardiac arrest. The aim of the AIRWAYS-3 randomised trial, described in this protocol paper, is to determine the clinical and cost effectiveness of a supraglottic airway versus tracheal intubation during in-hospital cardiac arrest. Patients will be allocated randomly to receive either a supraglottic airway or tracheal intubation as the initial advanced airway management. We will also estimate the relative cost-effectiveness of these two approaches. The primary outcome is functional status, measured using the modified Rankin Scale at hospital discharge or 30 days post-randomisation, whichever occurs first. AIRWAYS-3 presents ethical challenges regarding patient consent and data collection. These include the enrolment of unconscious patients without prior consent in a way that avoids methodological bias. Other complexities include the requirement to randomise patients efficiently during a time-critical cardiac arrest. Many of these challenges are encountered in other emergency care research; we discuss our approaches to addressing them. Trial registration: ISRCTN17720457. Prospectively registered on 29/07/2022.

The influence of personality on psychological safety, the presence of stress and chosen professional roles in the healthcare environment.

Healthcare teams are expected to deliver high quality and safe clinical care, a goal facilitated by an environment of psychological safety. We hypothesised that an individual's personality would influence psychological safety, perceived stressors in the clinical environment and confer a suitability for different professional roles. Staff members were recruited from the Emergency or Critical Care Departments of one National Health Service Trust. Qualitative interviews explored participants' experiences of personality, incorporating quantitative surveys to evaluate psychological safety and perceived stressors. The 16 Primary Factor Assessment provided a quantitative measure of personality. Participants demonstrated midrange scores for most personality traits, highlighting an ability to adapt to changing environments and requirements. There was a signal that different personality traits predominated between the two professional groups, and that certain traits were significantly associated with higher psychological safety and certain perceived stressors. Personality was described as having a strong influence on teamwork, the working environment and leadership ability. Our analysis highlights that personality can influence team dynamics and the suitability of individuals for certain clinical roles. Understanding the heterogeneity of personalities of team members and their likely responses to challenge may help leaders to support staff in times of challenge and improve team cohesiveness.

Escalation to intensive care for the older patient. An exploratory qualitative study of patients aged 65 years and older and their next of kin during the COVID-19 pandemic: the ESCALATE study.

BACKGROUND: older people comprise the majority of hospital medical inpatients so decision-making regarding admission of this cohort to the intensive care unit (ICU) is important. ICU can be perceived by clinicians as overly burdensome for patients and loved ones, and long-term impact on quality of life considered unacceptable, effecting potential bias against admitting older people to ICU. The COVID-19 pandemic highlighted the challenge of selecting those who could most benefit from ICU. OBJECTIVE: this qualitative study aimed to explore the views and recollections of escalation to ICU from older patients (aged ≥ 65 years) and next of kin (NoK) who experienced a COVID-19 ICU admission. SETTING: the main site was a large NHS Trust in London, which experienced a high burden of COVID-19 cases. SUBJECTS: 30 participants, comprising 12 patients, 7 NoK of survivor and 11 NoK of deceased. METHODS: semi-structured interviews with thematic analysis using a framework approach. RESULTS: there were five major themes: inevitability, disconnect, acceptance, implications for future decision-making and unique impact of the COVID-19 pandemic. Life was highly valued and ICU perceived to be the only option. Prior understanding of ICU and admission decision-making explanations were limited. Despite benefit of hindsight, having experienced an ICU admission and its consequences, most could not conceptualise thresholds for future acceptable treatment outcomes. CONCLUSIONS: in this study of patients ≥65 years and their NoK experiencing an acute ICU admission, survival was prioritised. Despite the ordeal of an ICU stay and its aftermath, the decision to admit and sequelae were considered acceptable.

Apnoeic oxygenation in morbid obesity: a randomised controlled trial comparing facemask and high-flow nasal oxygen delivery.

BACKGROUND: Obesity is a risk factor for airway-related incidents during anaesthesia. High-flow nasal oxygen has been advocated to improve safety in high-risk groups, but its effectiveness in the obese population is uncertain. This study compared the effect of high-flow nasal oxygen and low-flow facemask oxygen delivery on duration of apnoea in morbidly obese patients. METHODS: Morbidly obese patients undergoing bariatric surgery were randomly allocated to receive either high-flow nasal (70 L min-1) or facemask (15 L min-1) oxygen. After induction of anaesthesia, the patients were apnoeic for 18 min or until peripheral oxygen saturation decreased to 92%. RESULTS: Eighty patients were studied (41 High-Flow Nasal Oxygen, 39 Facemask). The median apnoea time was 18 min in both the High-Flow Nasal Oxygen (IQR 18-18 min) and the Facemask (inter-quartile range [IQR], 4.1-18 min) groups. Five patients in the High-Flow Nasal Oxygen group and 14 patients in the Facemask group desaturated to 92% within 18 min. The risk of desaturation was significantly lower in the High-Flow Nasal Oxygen group (hazard ratio=0.27; 95% confidence interval [CI], 0.11-0.65; P=0.007). CONCLUSIONS: In experienced hands, apnoeic oxygenation is possible in morbidly obese patients, and oxygen desaturation did not occur for 18 min in the majority of patients, whether oxygen delivery was high-flow nasal or low-flow facemask. High-flow nasal oxygen may reduce desaturation risk compared with facemask oxygen. Desaturation risk is a more clinically relevant outcome than duration of apnoea. Individual physiological factors are likely to be the primary determinant of risk rather than method of oxygen delivery. CLINICAL TRIAL REGISTRATION: NCT03428256.

Breaking bad news in the era of artificial intelligence and algorithmic medicine: an exploration of disclosure and its ethical justification using the hedonic calculus.

An appropriate ethical framework around the use of Artificial Intelligence (AI) in healthcare has become a key desirable with the increasingly widespread deployment of this technology. Advances in AI hold the promise of improving the precision of outcome prediction at the level of the individual. However, the addition of these technologies to patient-clinician interactions, as with any complex human interaction, has potential pitfalls. While physicians have always had to carefully consider the ethical background and implications of their actions, detailed deliberations around fast-moving technological progress may not have kept up. We use a common but key challenge in healthcare interactions, the disclosure of bad news (likely imminent death), to illustrate how the philosophical framework of the 'Felicific Calculus' developed in the eighteenth century by Jeremy Bentham, may have a timely quasi-quantitative application in the age of AI. We show how this ethical algorithm can be used to assess, across seven mutually exclusive and exhaustive domains, whether an AI-supported action can be morally justified.

Exploring the working environment of Hospital Managers: a mixed methods study investigating stress, stereotypes, psychological safety and individual resilience.

BACKGROUND: Hospital managers are responsible for the delivery of organisational strategy, development of clinical services and maintaining quality standards. There is limited research on hospital managers, in particular how stress manifests and impacts managers and the presence of individual resilience. Managers must work closely with clinical colleagues, however these relationships can be hindered by the perception of stereotyping and differing priorities. This study aimed to explore the working environment of hospital managers, focusing upon the unique stresses faced, psychological safety and the presence of resilience. METHODS: This study utilised mixed methodology using an embedded approach. Participants were purposively recruited from all levels of hospital management within one National Health Service Trust in London, United Kingdom. An exploration of managers experiences was undertaken using semi-structured qualitative interviews. Psychological safety and individual resilience were additionally assessed using validated surveys. Qualitative data were analysed iteratively using inductive thematic analysis, and triangulated with quantitative data. Kruskal-Wallis statistical analysis was performed to evaluate differences in resilience and psychological safety according to seniority and background experience. RESULTS: Twenty-two managers were recruited and interviewed, with 20 returning completed surveys. Key findings from the thematic analysis included the importance of good working relationships with clinical colleagues, the persistence of some stereotyping, and feeling unsupported in times of challenge. Stresses described included the bureaucracy involved when delivering change, conflict with colleagues and target driven expectations. Participants described their own psychological safety as lower than desired, supported by quantitative data; but recognised its importance and strived to create it within their own teams. Sixteen participants had 'normal' scores for resilience, with senior managers more likely to have higher scores than those more junior (p=0.011). CONCLUSION: Positive working relationships, high psychological safety and individual resilience are important for organisational safety and individual wellbeing. Our data illustrate unique stressors faced by hospital managers, provide detail on sometimes challenging working relationships, and demonstrate scope to improve both the psychological safety and resilience of those in managerial positions. A map for senior healthcare leaders was constructed, facilitating the identification of modifiable areas within their organisation to promote good working relationships and improve the working environment of hospital managers.

Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure.

Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. An analysis of large K. pneumoniae genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine-to-thymine transition at position 25 (25c > t) in ompK36. We show that the 25c > t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates K. pneumoniae in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c > t transition tips the balance toward treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c > t transition mediates an intramolecular messenger RNA (mRNA) interaction between a uracil encoded by 25t and the first adenine within the Shine-Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure.

Clinical and survival differences during separate COVID-19 surges: Investigating the impact of the Sars-CoV-2 alpha variant in critical care patients.

A number of studies have highlighted physiological data from the first surge in critically unwell Covid-19 patients but there is a paucity of data describing emerging variants of SARS-CoV-2, such as B.1.1.7. We compared ventilatory parameters, biochemical and physiological data and mortality between the first and second COVID-19 surges in the United Kingdom, where distinct variants of SARS-CoV-2 were the dominant stain. We performed a retrospective cohort study investigating critically unwell patients admitted with COVID-19 across three tertiary regional ICUs in London, UK. Of 1782 adult ICU patients screened, 330 intubated and ventilated patients diagnosed with COVID-19 were included. In the second wave where B.1.1.7 variant was the dominant strain, patients were had increased severity of ARDS whilst compliance was greater (p<0.05) and d-dimer lower. The 28-day mortality was not statistically significant (1st wave: 42.2% vs 2nd wave: 39.8%). However, when adjusted for key covariates, the hazard ratio for 28-day mortality in those patients with B.1.1.7 was 3.79 (CI 1.04-13.8; p = 0.043) compared to the original strain. During the second surge in the UK, where the COVID-19 variant B.1.1.7 was most prevalent, significantly more patients presented to critical care with severe ARDS. Furthermore, mortality risk was significantly greater in our ICU population during the second wave of the pandemic in those patients with B.1.1.7. As ICUs are experiencing further waves (particularly by the delta (B.1.617.2) variant), we highlight the urgent need for prospective studies describing immunological and pathophysiological differences across novel emerging variants.

Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae.

Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both an in vitro and in vivo competitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.

Highlighting uncertainty in clinical risk prediction using a model of emergency laparotomy mortality risk.

Clinical prediction models typically make point estimates of risk. However, values of key variables are often missing during model development or at prediction time, meaning that the point estimates mask significant uncertainty and can lead to over-confident decision making. We present a model of mortality risk in emergency laparotomy which instead presents a distribution of predicted risks, highlighting the uncertainty over the risk of death with an intuitive visualisation. We developed and validated our model using data from 127134 emergency laparotomies from patients in England and Wales during 2013-2019. We captured the uncertainty arising from missing data using multiple imputation, allowing prospective, patient-specific imputation for variables that were frequently missing. Prospective imputation allows early prognostication in patients where these variables are not yet measured, accounting for the additional uncertainty this induces. Our model showed good discrimination and calibration (95% confidence intervals: Brier score 0.071-0.078, C statistic 0.859-0.873, calibration error 0.031-0.059) on unseen data from 37 hospitals, consistently improving upon the current gold-standard model. The dispersion of the predicted risks varied significantly between patients and increased where prospective imputation occurred. We present a case study that illustrates the potential impact of uncertainty quantification on clinical decision making. Our model improves mortality risk prediction in emergency laparotomy and has the potential to inform decision-makers and assist discussions with patients and their families. Our analysis code was robustly developed and is publicly available for easy replication of our study and adaptation to predicting other outcomes.