Clinical deployment environments: Five pillars of translational machine learning for health.

Machine Learning for Health (ML4H) has demonstrated efficacy in computer imaging and other self-contained digital workflows, but has failed to substantially impact routine clinical care. This is no longer because of poor adoption of Electronic Health Records Systems (EHRS), but because ML4H needs an infrastructure for development, deployment and evaluation within the healthcare institution. In this paper, we propose a design pattern called a Clinical Deployment Environment (CDE). We sketch the five pillars of the CDE: (1) real world development supported by live data where ML4H teams can iteratively build and test at the bedside (2) an ML-Ops platform that brings the rigour and standards of continuous deployment to ML4H (3) design and supervision by those with expertise in AI safety (4) the methods of implementation science that enable the algorithmic insights to influence the behaviour of clinicians and patients and (5) continuous evaluation that uses randomisation to avoid bias but in an agile manner. The CDE is intended to answer the same requirements that bio-medicine articulated in establishing the translational medicine domain. It envisions a transition from "real-world" data to "real-world" development.

Acquisition of sensorimotor fMRI under general anaesthesia: Assessment of feasibility, the BOLD response and clinical utility.

We evaluated whether task-related fMRI (functional magnetic resonance imaging) BOLD (blood oxygenation level dependent) activation could be acquired under conventional anaesthesia at a depth enabling neurosurgery in five patients with supratentorial gliomas. Within a 1.5 T MRI operating room immediately prior to neurosurgery, a passive finger flexion sensorimotor paradigm was performed on each hand with the patients awake, and then immediately after the induction and maintenance of combined sevoflurane and propofol general anaesthesia. The depth of surgical anaesthesia was measured and confirmed with an EEG-derived technique, the Bispectral Index (BIS). The magnitude of the task-related BOLD response and BOLD sensitivity under anaesthesia were determined. The fMRI data were assessed by three fMRI expert observers who rated each activation map for somatotopy and usefulness for radiological neurosurgical guidance. The mean magnitudes of the task-related BOLD response under a BIS measured depth of surgical general anaesthesia were 25% (tumour affected hemisphere) and 22% (tumour free hemisphere) of the respective awake values. BOLD sensitivity under anaesthesia ranged from 7% to 83% compared to the awake state. Despite these reductions, somatotopic BOLD activation was observed in the sensorimotor cortex in all ten data acquisitions surpassing statistical thresholds of at least p < 0.001uncorr. All ten fMRI activation datasets were scored to be useful for radiological neurosurgical guidance. Passive task-related sensorimotor fMRI acquired in neurosurgical patients under multi-pharmacological general anaesthesia is reproducible and yields clinically useful activation maps. These results demonstrate the feasibility of the technique and its potential value if applied intra-operatively. Additionally these methods may enable fMRI investigations in patients unable to perform or lie still for awake paradigms, such as young children, claustrophobic patients and those with movement disorders.

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study.

BACKGROUND: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. METHODS: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. FINDINGS: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0-20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1-5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27-10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29-0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53-0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60-0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07-0·43, p=0·0065; and 0·33, 0·14-0·51, p=0·00059, respectively). INTERPRETATION: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. FUNDING: The Stroke Association and the British Heart Foundation.

Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study.

PURPOSE: MRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment. METHODS: Twenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2-6 examinations per subject, interval range 0.1-3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age-matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied. RESULTS: In the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score. CONCLUSIONS: Using 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials.

The Spl Serine Proteases Modulate Staphylococcus aureus Protein Production and Virulence in a Rabbit Model of Pneumonia.

The Spl proteases are a group of six serine proteases that are encoded on the νSaß pathogenicity island and are unique to Staphylococcus aureus. Despite their interesting biochemistry, their biological substrates and functions in virulence have been difficult to elucidate. We found that an spl operon mutant of the community-associated methicillin-resistant S. aureus USA300 strain LAC induced localized lung damage in a rabbit model of pneumonia, characterized by bronchopneumonia observed histologically. Disease in the mutant-infected rabbits was restricted in distribution compared to that in wild-type USA300-infected rabbits. We also found that SplA is able to cleave the mucin 16 glycoprotein from the surface of the CalU-3 lung cell line, suggesting a possible mechanism for wild-type USA300 spreading pneumonia to both lungs. Investigation of the secreted and surface proteomes of wild-type USA300 and the spl mutant revealed multiple alterations in metabolic proteins and virulence factors. This study demonstrates that the Spls modulate S. aureus physiology and virulence, identifies a human target of SplA, and suggests potential S. aureus targets of the Spl proteases. IMPORTANCEStaphylococcus aureus is a versatile human pathogen that produces an array of virulence factors, including several proteases. Of these, six proteases called the Spls are the least characterized. Previous evidence suggests that the Spls are expressed during human infection; however, their function is unknown. Our study shows that the Spls are required for S. aureus to cause disseminated lung damage during pneumonia. Further, we present the first example of a human protein cut by an Spl protease. Although the Spls were predicted not to cut staphylococcal proteins, we also show that an spl mutant has altered abundance of both secreted and surface-associated proteins. This work provides novel insight into the function of Spls during infection and their potential ability to degrade both staphylococcal and human proteins.

Objective Bayesian fMRI analysis-a pilot study in different clinical environments.

Functional MRI (fMRI) used for neurosurgical planning delineates functionally eloquent brain areas by time-series analysis of task-induced BOLD signal changes. Commonly used frequentist statistics protect against false positive results based on a p-value threshold. In surgical planning, false negative results are equally if not more harmful, potentially masking true brain activity leading to erroneous resection of eloquent regions. Bayesian statistics provides an alternative framework, categorizing areas as activated, deactivated, non-activated or with low statistical confidence. This approach has not yet found wide clinical application partly due to the lack of a method to objectively define an effect size threshold. We implemented a Bayesian analysis framework for neurosurgical planning fMRI. It entails an automated effect-size threshold selection method for posterior probability maps accounting for inter-individual BOLD response differences, which was calibrated based on the frequentist results maps thresholded by two clinical experts. We compared Bayesian and frequentist analysis of passive-motor fMRI data from 10 healthy volunteers measured on a pre-operative 3T and an intra-operative 1.5T MRI scanner. As a clinical case study, we tested passive motor task activation in a brain tumor patient at 3T under clinical conditions. With our novel effect size threshold method, the Bayesian analysis revealed regions of all four categories in the 3T data. Activated region foci and extent were consistent with the frequentist analysis results. In the lower signal-to-noise ratio 1.5T intra-operative scanner data, Bayesian analysis provided improved brain-activation detection sensitivity compared with the frequentist analysis, albeit the spatial extents of the activations were smaller than at 3T. Bayesian analysis of fMRI data using operator-independent effect size threshold selection may improve the sensitivity and certainty of information available to guide neurosurgery.

Functional MRI of music emotion processing in frontotemporal dementia.

Frontotemporal dementia is an important neurodegenerative disorder of younger life led by profound emotional and social dysfunction. Here we used fMRI to assess brain mechanisms of music emotion processing in a cohort of patients with frontotemporal dementia (n = 15) in relation to healthy age-matched individuals (n = 11). In a passive-listening paradigm, we manipulated levels of emotion processing in simple arpeggio chords (mode versus dissonance) and emotion modality (music versus human emotional vocalizations). A complex profile of disease-associated functional alterations was identified with separable signatures of musical mode, emotion level, and emotion modality within a common, distributed brain network, including posterior and anterior superior temporal and inferior frontal cortices and dorsal brainstem effector nuclei. Separable functional signatures were identified post-hoc in patients with and without abnormal craving for music (musicophilia): a model for specific abnormal emotional behaviors in frontotemporal dementia. Our findings indicate the potential of music to delineate neural mechanisms of altered emotion processing in dementias, with implications for future disease tracking and therapeutic strategies.

Design, operation, and safety of single-room interventional MRI suites: practical experience from two centers.

The design and operation of a facility in which a magnetic resonance imaging (MRI) scanner is incorporated into a room used for surgical or endovascular cardiac interventions presents several challenges. MR safety must be maintained in the presence of a much wider variety of equipment than is found in a diagnostic unit, and of staff unfamiliar with the MRI environment, without compromising the safety and practicality of the interventional procedure. Both the MR-guided cardiac interventional unit at Kings College London and the intraoperative imaging suite at the National Hospital for Neurology and Neurosurgery are single-room interventional facilities incorporating 1.5 T cylindrical-bore MRI scanners. The two units employ similar strategies to maintain MR safety, both in original design and day-to-day operational workflows, and between them over a decade of incident-free practice has been accumulated. This article outlines these strategies, highlighting both similarities and differences between the units, as well as some lessons learned and resulting procedural changes made in both units since installation.

Preventing visual field deficits from neurosurgery.

OBJECTIVE: We assessed whether display of optic radiation tractography during anterior temporal lobe resection (ATLR) for refractory temporal lobe epilepsy (TLE) can reduce the severity of postoperative visual field deficits (VFD) and increase the proportion of patients who can drive and whether correction for brain shift using intraoperative MRI (iMRI) is beneficial. METHODS: A cohort of 21 patients underwent ATLR in an iMRI suite. Preoperative tractography of the optic radiation was displayed on the navigation and operating microscope displays either without (9 patients) or with (12 patients) correction for brain shift. VFD were quantified using Goldmann perimetry and eligibility to drive was assessed by binocular Esterman perimetry 3 months after surgery. Secondary outcomes included seizure freedom and extent of hippocampal resection. The comparator was a cohort of 44 patients who underwent ATLR without iMRI. RESULTS: The VFD in the contralateral superior quadrant were significantly less (p = 0.043) with iMRI guidance (0%-49.2%, median 14.5%) than without (0%-90.9%, median 24.0%). No patient in the iMRI cohort developed a VFD that precluded driving whereas 13% of the non-iMRI cohort failed to meet UK driving criteria. Outcome did not differ between iMRI guidance with and without brain shift correction. Seizure outcome and degree of hippocampal resection were unchanged. CONCLUSIONS: Display of the optic radiation with image guidance reduces the severity of VFD and did not affect seizure outcome or hippocampal resection. Correction for brain shift is possible but did not further improve outcome. Future work to incorporate tractography into conventional neuronavigation systems will make the work more widely applicable.

Phosphatidylinositol-specific phospholipase C contributes to survival of Staphylococcus aureus USA300 in human blood and neutrophils.

Staphylococcus aureus is an important human pathogen that employs a large repertoire of secreted virulence factors to promote disease pathogenesis. Many strains of S. aureus possess a plc gene that encodes a phosphatidylinositol (PI)-specific phospholipase C (PI-PLC) capable of hydrolyzing PI and cleaving glycosyl-PI (GPI)-linked proteins from cell surfaces. Despite being secreted by virulent staphylococci, the contribution of PI-PLC to the capacity of S. aureus to cause disease remains undefined. Our goal in these studies was to understand PI-PLC in the context of S. aureus biology. Among a collection of genetically diverse clinical isolates of S. aureus, community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 secreted the most PI-PLC. Screening a collection of two-component system (TCS) mutants of S. aureus, we identified both the agr quorum-sensing system and the SrrAB TCS to be positive regulators of plc gene expression. Real-time PCR and PI-PLC enzyme assays of the TCS mutants, coupled with SrrA promoter binding studies, demonstrated that SrrAB was the predominant transcriptional activator of plc. Furthermore, plc regulation was linked to oxidative stress both in vitro and in vivo in a SrrAB-dependent manner. A Δplc mutant in a CA-MRSA USA300 background exhibited a survival defect in human whole blood and in isolated neutrophils. However, the same mutant strain displayed no survival defect in murine models of infection or murine whole blood. Overall, these data identify potential links between bacterial responses to the host innate immune system and to oxidative stress and suggest how PI-PLC could contribute to the pathogenesis of S. aureus infections.

MprA and DosR coregulate a Mycobacterium tuberculosis virulence operon encoding Rv1813c and Rv1812c.

Mycobacterium tuberculosis remains a significant global pathogen, causing extensive morbidity and mortality worldwide. This bacterium persists within granulomatous lesions in a poorly characterized, nonreplicating state. The two-component signal transduction systems MprAB and DosRS-DosT (DevRS-Rv2027c) are responsive to conditions likely to be present within granulomatous lesions and mediate aspects of M. tuberculosis persistence in vitro and in vivo. Here, we describe a previously uncharacterized locus, Rv1813c-Rv1812c, that is coregulated by both MprA and DosR. We demonstrate that MprA and DosR bind to adjacent and overlapping sequences within the promoter region of Rv1813c and direct transcription from an initiation site located several hundred base pairs upstream of the Rv1813 translation start site. We further show that Rv1813c and Rv1812c are cotranscribed, and that the genomic organization of this operon is specific to M. tuberculosis and Mycobacterium bovis. Although Rv1813c is not required for survival of M. tuberculosis in vitro, including under conditions in which MprAB and DosRST signaling are activated, an M. tuberculosis ΔRv1813c mutant is attenuated in the low-dose aerosol model of murine tuberculosis, where it exhibits a lower bacterial burden, delayed time to death, and decreased ability to stimulate proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-12. Interestingly, overcomplementation of these phenotypes is observed in the M. tuberculosis ΔRv1813c mutant expressing both Rv1813c and Rv1812c, but not Rv1813c alone, in trans. Therefore, Rv1813c and Rv1812c may represent general stress-responsive elements that are necessary for aspects of M. tuberculosis virulence and the host immune response to infection.

Cave men: stone tools, Victorian science, and the 'primitive mind' of deep time.

Palaeoanthropology, the study of the evolution of humanity, arose in the nineteenth century. Excavations in Europe uncovered a series of archaeological sediments which provided proof that the antiquity of human life on Earth was far longer than the biblical six thousand years, and by the 1880s authors had constructed a basic paradigm of what 'primitive' human life was like. Here we examine the development of Victorian palaeoanthropology for what it reveals of the development of notions of cognitive evolution. It seems that Victorian specialists rarely addressed cognitive evolution explicitly, although several assumptions were generally made that arose from preconceptions derived from contemporary 'primitive' peoples. We identify three main phases of development of notions of the primitive mind in the period.

The HtrA-like serine protease PepD interacts with and modulates the Mycobacterium tuberculosis 35-kDa antigen outer envelope protein.

Mycobacterium tuberculosis remains a significant global health concern largely due to its ability to persist for extended periods within the granuloma of the host. While residing within the granuloma, the tubercle bacilli are likely to be exposed to stress that can result in formation of aberrant proteins with altered structures. Bacteria encode stress responsive determinants such as proteases and chaperones to deal with misfolded or unfolded proteins. pepD encodes an HtrA-like serine protease and is thought to process proteins altered following exposure of M. tuberculosis to extra-cytoplasmic stress. PepD functions both as a protease and chaperone in vitro, and is required for aspects of M. tuberculosis virulence in vivo. pepD is directly regulated by the stress-responsive two-component signal transduction system MprAB and indirectly by extracytoplasmic function (ECF) sigma factor SigE. Loss of PepD also impacts expression of other stress-responsive determinants in M. tuberculosis. To further understand the role of PepD in stress adaptation by M. tuberculosis, a proteomics approach was taken to identify binding proteins and possible substrates of this protein. Using subcellular fractionation, the cellular localization of wild-type and PepD variants was determined. Purified fractions as well as whole cell lysates from Mycobacterium smegmatis or M. tuberculosis strains expressing a catalytically compromised PepD variant were immunoprecipitated for PepD and subjected to LC-MS/MS analyses. Using this strategy, the 35-kDa antigen encoding a homolog of the PspA phage shock protein was identified as a predominant binding partner and substrate of PepD. We postulate that proteolytic cleavage of the 35-kDa antigen by PepD helps maintain cell wall homeostasis in Mycobacterium and regulates specific stress response pathways during periods of extracytoplasmic stress.

PepD participates in the mycobacterial stress response mediated through MprAB and SigE.

Currently, one-third of the world's population is believed to be latently infected with Mycobacterium tuberculosis. The mechanisms by which M. tuberculosis establishes latent infection remain largely undefined. mprAB encodes a two-component signal transduction system required by M. tuberculosis for aspects of persistent infection. MprAB regulates a large and diverse group of genetic determinants in response to membrane stress, including the extracytoplasmic function (ECF) sigma factor sigE and the HtrA-like serine protease pepD. Recent studies have demonstrated that PepD functions as both a protease and chaperone in vitro. In addition, inactivation of pepD alters the virulence of M. tuberculosis in a mouse model system of infection. Here, we demonstrate that PepD plays an important role in the stress response network of Mycobacterium mediated through MprAB and SigE. In particular, we demonstrate that the protease activity of PepD requires the PDZ domain, in addition to the catalytic serine at position 317. pepD expression initiates from at least three promoters in M. tuberculosis, including one that is regulated by SigE and is located upstream of the mprA coding sequence. Deletion of pepD or mprAB in Mycobacterium smegmatis and M. tuberculosis alters the stress response phenotypes of these strains, including increasing sensitivity to SDS and cell wall antibiotics and upregulating the expression of stress-responsive determinants, including sigE. Taking these data together, we hypothesize that PepD utilizes its PDZ domain to recognize and process misfolded proteins at the cell membrane, leading to activation of the MprAB and SigE signaling pathways and subsequent establishment of a positive feedback loop that facilitates bacterial adaptation.