Safety-driven design of machine learning for sepsis treatment.

Machine learning (ML) has the potential to bring significant clinical benefits. However, there are patient safety challenges in introducing ML in complex healthcare settings and in assuring the technology to the satisfaction of the different regulators. The work presented in this paper tackles the urgent problem of proactively assuring ML in its clinical context as a step towards enabling the safe introduction of ML into clinical practice. In particular, the paper considers the use of deep Reinforcement Learning, a type of ML, for sepsis treatment. The methodology starts with the modelling of a clinical workflow that integrates the ML model for sepsis treatment recommendations. Then safety analysis is carried out based on the clinical workflow, identifying hazards and safety requirements for the ML model. In this paper the design of the ML model is enhanced to satisfy the safety requirements for mitigating a major clinical hazard: sudden change of vasopressor dose. A rigorous evaluation is conducted to show how these requirements are met. A safety case is presented, providing a basis for regulators to make a judgement on the acceptability of introducing the ML model into sepsis treatment in a healthcare setting. The overall argument is broad in considering the wider patient safety considerations, but the detailed rationale and supporting evidence presented relate to this specific hazard. Whilst there are no agreed regulatory approaches to introducing ML into healthcare, the work presented in this paper has shown a possible direction for overcoming this barrier and exploit the benefits of ML without compromising safety.

Novel phenolic inhibitors of the sarco/endoplasmic reticulum calcium ATPase: identification and characterization by quantitative structure-activity relationship modeling and virtual screening.

Inhibitors of the sarco/endoplasmic reticulum calcium ATPase (SERCA) are valuable research tools and hold promise as a new generation of anti-prostate cancer agents. Based on previously determined potencies of phenolic SERCA inhibitors, we created quantitative structure-activity relationship (QSAR) models using three independent development strategies. The obtained QSAR models facilitated virtual screens of several commercial compound collections for novel inhibitors. Sixteen compounds were subsequently evaluated in SERCA activity inhibition assays and 11 showed detectable potencies in the micro- to millimolar range. The experimental results were then incorporated into a comprehensive master QSAR model, whose physical interpretation by partial least squares analysis revealed that properly positioned substituents at the central phenyl ring capable of forming hydrogen bonds and of undergoing hydrophobic interactions were prerequisites for effective SERCA inhibition. The established SAR was in good agreement with findings from previous structural studies, even though it was obtained independently using standard QSAR methodologies.

Integrating palliative care and heart failure: a systematic realist synthesis (PalliatHeartSynthesis).

OBJECTIVES: (1) Develop a programme theory of why, for whom and in what contexts integrated palliative care (PC) and heart failure (HF) services work/do not work; (2) use the programme theory to co-produce with stakeholders, intervention strategies to inform best practice and future research. METHODS: A systematic review of all published articles and grey literature using a realist logic of analysis. The search strategy combined terms significant to the review questions: HF, PC and end of life. Documents were included if they were in English and provided data relevant to integration of PC and HF services. Searches were conducted in November 2021 in EMBASE, MEDLINE, PsycINFO, AMED, HMIC and CINAHL. Further relevant documents were identified via monthly alerts (up until April 2023) and the project stakeholder group (patient/carers, content experts and multidisciplinary practitioners). RESULTS: 130 documents were included (86 research, 22 literature reviews, 22 grey literature). The programme theory identified intervention strategies most likely to support integration of PC and HF services. These included protected time for evidence-based PC and HF education from undergraduate/postgraduate level and continuing professional practice; choice of educational setting (eg, online, face-to-face or hybrid); increased awareness and seeing benefits of PC for HF management; conveying the emotive and intellectual need for integrating PC and HF via credible champions; and prioritising PC and HF guidelines in practice. CONCLUSIONS: The review findings outline the required steps to take to increase the likelihood that all key players have the capacity, opportunity and motivation to integrate PC into HF management. PROSPERO REGISTRATION NUMBER: CRD42021240185.

Rethink reporting of evaluation results in AI.

Aggregate metrics and lack of access to results limit understanding.

Making cataract surgery possible in patients with ankylosing spondylitis: A new positioning technique.

IMPORTANCE: Patients with Ankylosing Spondylitis frequently have fixed kyphosis of their spine together with pain. This makes achieving acceptable head position for ocular surgery difficult. The proposal of new methods that result in successful intraocular surgery will reduce morbidity and sight loss in this group of patients. OBJECTIVE: To describe a novel technique using a vacuum bean bag positioner which enabled cataract surgery to be performed successfully under local anaesthesia. To allow prospects of technique development to standardise cataract surgery positioning in this cohort. RESULTS: A 42 year-old male patient underwent phacoemulsification under Sub-Tenon's local anaesthetic with intra-ocular lens implant in the inverted position with no immediate post-operative complications. CONCLUSIONS AND RELEVANCE: Standard operating theatre equipment combined with a vacuum bean bag positioner, soft supports and securing straps can attain a position that is feasible for awake ocular surgery in patients with gross anatomical changes affecting the neck.

Integrating palliative care and heart failure: a protocol for a realist synthesis (PalliatHeartSynthesis).

INTRODUCTION: Heart failure affects over 26 million people worldwide with prevalence expected to grow due to an ageing global population. Palliative care can address the holistic needs of patients with heart failure, and integrated palliative care in heart failure management has been indicated to improve outcomes for patients. Despite known benefits for integrated palliative care in heart failure management, implementation is poor across the majority of global health services. Recent systematic reviews have identified the benefits of integrating palliative care into heart failure management and highlighted barriers to implementation. However, there was heterogeneity in terms of countries, healthcare settings, delivery by differing staff across multidisciplinary teams, modes of delivery and different intervention components. METHODS AND ANALYSIS: The aim of this study is to identify how integrated palliative care and heart failure interventions produce desired outcomes, in which contexts, and for which patients. We will undertake a realist synthesis to identify this, using Pawson's five iterative steps. We will recruit an international stakeholder group comprised of healthcare providers and patients with heart failure to advise and provide feedback throughout the review. Our initial realist programme theory sets out the necessary steps needed to accomplish the final intended outcome(s) from the implementation of integrated palliative care and heart failure. This initial programme theory will be shaped through an iterative process of testing and refinement. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. With our stakeholder group, we will coproduce a user guide that outlines practical advice to optimise, tailor and implement interventions designed to integrate palliative care and heart failure, taking into consideration local context, alongside user-friendly summaries of the synthesis findings using short animations to convey complex findings. We will draw on the expertise within the stakeholder group to identify key stakeholders for disseminating to relevant audiences, ensuring outputs are tailored for their respective needs. PROSPERO REGISTRATION NUMBER: CRD42021240185.

System performance evaluation of the cobas t 711 and cobas t 511 coagulation analyzers in routine laboratory settings.

: Utility of coagulation analyzers in real-world settings depends on characteristics that are often not studied comprehensively. This study aimed to investigate the analytical performance, system functionality, practicability, consistency and throughput of two new automated coagulation analyzers in routine laboratory practice. Real-world settings were simulated in three major European hemostasis laboratories and multiple assays were performed in anonymized plasma samples in parallel with routine clinical practice on the cobas t 711 (high-throughput) and cobas t 511 (mid-throughput) analyzers using activated partial thromboplastin time (aPTT), aPTT Lupus, aPTT Screen, Antithrombin (AT), D-Dimer, Fibrinogen, Prothrombin Time (PT)-derived Fibrinogen, PT Owren, PT Rec (recombinant human thromboplastin reagent) and Thrombin Time assays. Precision was tested in a 21-day experiment and accuracy was compared with reference methods of the same laboratory. A number of experiments simulated challenging real-life situations. Pearson's correlation coefficient was more than 0.98 in all assays. Across assays, coefficients of variation ranged from 0.0 to 1.5% for intermediate precision; 0.2 to 3.0% for repeatability and 0.4 to 3.7% for total precision. Good between-run comparability was seen when testing samples under random conditions. Calculated maximum throughput was 197 and 387-402 tests/h for the cobas t 511 and 711 analyzers, respectively. Practicability met or exceeded user expectations in 98% of cases. In a simulated real-life setting of three major laboratories, the new cobas t 511 and cobas t 711 coagulation analyzers demonstrated a good functionality, practicability and performance and the throughput was high.

Research priorities in advanced heart failure: James Lind alliance priority setting partnership.

OBJECTIVE: To determine research priorities in advanced heart failure (HF) for patients, carers and healthcare professionals. METHODS: Priority setting partnership using the systematic James Lind Alliance method for ranking and setting research priorities. An initial open survey of patients, carers and healthcare professionals identified respondents' questions, which were categorised to produce a list of summary research questions; questions already answered in existing literature were removed. In a second survey of patients, carers and healthcare professionals, respondents ranked the summary research questions in order of priority. The top 25 unanswered research priorities were then considered at a face-to-face workshop using nominal group technique to agree on a 'top 10'. RESULTS: 192 respondents submitted 489 responses each containing one or more research uncertainty. Out-of-scope questions (35) were removed, and collating the responses produced 80 summary questions. Questions already answered in the literature (15) were removed. In the second survey, 65 questions were ranked by 128 respondents. The top 10 priorities were developed at a consensus meeting of stakeholders and included a focus on quality of life, psychological support, the impact on carers, role of the charity sector and managing prognostic uncertainty. Ranked priorities by physicians and patients were remarkably divergent. CONCLUSIONS: Engaging stakeholders in setting research priorities led to a novel set of research questions that might not have otherwise been considered. These priorities can be used by researchers and funders to direct future research towards the areas which matter most to people living with advanced HF.

Automated urinalysis combining physicochemical analysis, on-board centrifugation, and digital imaging in one system: A multicenter performance evaluation of the cobas 6500 urine work area.

BACKGROUND: We evaluated the analytical performance of the fully automated cobas® 6500 urine work area and its automated components-cobas u 601 and cobas u 701. DESIGN AND METHODS: The study was conducted at three European centers using un-centrifuged surplus routine urine samples; all measurements were performed within 2 h of sample collection. Precision, sample carry-over, and method comparisons were evaluated per Clinical and Laboratory Standards Institute guidelines. Method comparisons: cobas u 601 versus Urisys 2400 and cobas u 411 urine test strips; and cobas u 701 versus KOVA® visual microscopy and iQ200 analyzer. Operability and functionality were assessed using questionnaires. RESULTS: Precision of the entire cobas 6500 system was within predefined acceptance limits and no significant carry-over was observed. Erythrocytes, leukocytes, nitrites, and protein were in good agreement (≥93%) with cobas u 411 reflectometry. High correlation was shown between the cobas u 701 analyzer and KOVA visual microscopy for red blood cells (RBC; slope, 0.89; Pearson's r, 0.95) and white blood cells (WBC; slope, 0.96; Pearson's r, 0.96), demonstrating equivalence of test results. The 97.5% percentile reference values on the cobas u 701 analyzer were 5.3 cells/µL (RBC) and 6.2 cells/µL (WBC). The cobas 6500 system showed good sensitivity for small bacteria (>1 µm) and pathological casts, and the user interface, maintenance wizards, and system design were highly rated by operators. CONCLUSIONS: The fully automated workflow, high precision, and high throughput of the cobas 6500 system have the potential to facilitate standardization of urine screening.

The diagnostic significance of serum IgG4 levels in patients with autoimmune pancreatitis: a UK study.

BACKGROUND: Autoimmune pancreatitis (AIP) is recognised as an end organ manifestation of the systemic condition known as IgG4-sclerosing disease. One major characteristic of this disease, regardless of its location in the body, is the presence of high levels of circulating serum IgG, in particular IgG4 antibody. In the case of AIP, differential diagnosis from other conditions of the pancreas and biliary system, particularly cancers, can be difficult, but could result in avoiding invasive procedures and surgery. Earlier studies have evaluated the use of checking IgG4 levels in AIP diagnosis; these have produced variable results. OBJECTIVE: To further assess the diagnostic significance of serum IgG4 levels in AIP and investigate its value in differentiating from cancer of the gastroenterological system. METHODS: A retrospective study of 196 IgG4-requested samples from a 24-month period was examined. Samples were sorted into confirmed AIP, cancer or other pancreatic conditions including primary sclerosing cholangitis. RESULTS: Patients with AIP possessed a mean serum IgG level that was significantly higher compared with all other groups (mean serum IgG level=19.0 g/l+/-2.5, P<0.001). The mean serum IgG4 level of AIP patients was also significantly higher compared with all other conditions including cancer patients (mean IgG4 level=3.7 g/l+/-0.5, P<0.001). CONCLUSION: This data lends support to circulating IgG4 levels only being used as an accompanying diagnostic marker to imaging, histology and clinical presentation. In particular, this may help in differentiating between AIP and pancreatic carcinoma.

Synthesis and biological activities of YkFA analogues: effects of position 4 substitutions and altered ring size on in vitro opioid activity.

Substitution in position 4 of the potent opioid peptide YkFA with aliphatic hydrophobic residues resulted in compounds that retained low nanomolar activities at both mu and delta opioid receptors, while ring contraction by incorporation of diaminobutyric acid in position 2 resulted in a more pronounced decrease in potency at both receptors for the psi[CH(2)NH] pseudopeptide as compared to the all amide parent.