Automated classification of cellular expression in multiplexed imaging data with Nimbus.

Multiplexed imaging offers a powerful approach to characterize the spatial topography of tissues in both health and disease. To analyze such data, the specific combination of markers that are present in each cell must be enumerated to enable accurate phenotyping, a process that often relies on unsupervised clustering. We constructed the Pan-Multiplex (Pan-M) dataset containing 197 million distinct annotations of marker expression across 15 different cell types. We used Pan-M to create Nimbus, a deep learning model to predict marker positivity from multiplexed image data. Nimbus is a pre-trained model that uses the underlying images to classify marker expression across distinct cell types, from different tissues, acquired using different microscope platforms, without requiring any retraining. We demonstrate that Nimbus predictions capture the underlying staining patterns of the full diversity of markers present in Pan-M. We then show how Nimbus predictions can be integrated with downstream clustering algorithms to robustly identify cell subtypes in image data. We have open-sourced Nimbus and Pan-M to enable community use at https://github.com/angelolab/Nimbus-Inference.

Insights and Opportunity Costs in Applying Spatial Biology to Study the Tumor Microenvironment.

SUMMARY: The recent development of high-dimensional spatial omics tools has revealed the functional importance of the tumor microenvironment in driving tumor progression. Here, we discuss practical factors to consider when designing a spatial biology cohort and offer perspectives on the future of spatial biology research.

Acute assessment services for patient flow assistance in hospital emergency departments.

BACKGROUND: Emergency departments (EDs) are facing serious and significant issues in the delivery of effective and efficient care to patients. Acute assessment services have been implemented at many hospitals internationally to assist in maintaining patient flow for identified groups of patients attending the ED. Identifying the risks and benefits, and optimal configurations of these services may be beneficial to those wishing to utilise an acute assessment service to improve patient flow. OBJECTIVES: To assess the effects of acute assessment services on patient flow following attendance at a hospital ED. SEARCH METHODS: We searched MEDLINE, CENTRAL, Embase and two trials registers on 24 September 2022 to identify studies. No restrictions were imposed on publication year, publication type, or publication language. SELECTION CRITERIA: Studies eligible for inclusion were randomised trials and cluster-randomised trials with at least two intervention and two control sites. Participants were adults (as defined by study authors) receiving care either in the ED or the acute assessment service, where both were based in the hospital setting. The comparison was hospital-based acute assessment services with usual, ED-only care. The outcomes of this review were mortality at time point closest to 30 days, length of stay in the service (in minutes), and waiting time to see a doctor (in minutes). DATA COLLECTION AND ANALYSIS: We followed the standard procedures of Cochrane Effective Practice and Organisation of Care for this review (https://epoc.cochrane.org/resources). MAIN RESULTS: We identified a total of 5754 records in the search. Following assessment of 3609 de-duplicated records, none were found to be eligible for inclusion in this review. AUTHORS' CONCLUSIONS: At present there are no randomised controlled trials exploring the effects of acute assessment services on patient flow in hospital-based emergency departments compared to usual, ED-only care.

Efficacy of acute care pathways for older patients: a systematic review and meta-analysis.

Meeting the needs of acute geriatric patients is often challenging, and although evidence shows that older patients need tailored care, it is still unclear which interventions are most appropriate. The objective of this study is to systematically evaluate the hospital-wide acute geriatric models compared with conventional pathways. The design of the study includes hospital-wide geriatric-specific models characterized by components including patient-centered care, frequent medical review, early rehabilitation, early discharge planning, prepared environment, and follow-up after discharge. Primary and secondary outcomes were considered, including functional decline, activities of daily living (ADL), length-of-stay (LoS), discharge destination, mortality, costs, and readmission. A systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A total of 20 studies reporting on 15 trials and acutely admitted patients with an average age of 79, complex conditions and comorbidities to acute geriatric-specific pathways (N = 13,595) were included. Geriatric-specific models were associated with lower costs (weighted mean difference, WMD = - $174.98, 95% CI = -$332.14 to - $17.82; P = 0.03), and shorter LoS (WMD = - 1.11, 95% CI = - 1.39 to - 0.83; P < 0.001). No differences were found in functional decline, ADL, mortality, case fatalities, discharge destination, or readmissions. Geriatric-specific models are valuable for improving patient and system-level outcomes. Although several interventions had positive results, further research is recommended to study hospital-wide geriatric-specific models. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00743-w.

Treatment of Impetigo with Antiseptics-Replacing Antibiotics (TIARA) trial: a single blind randomised controlled trial in school health clinics within socioeconomically disadvantaged communities in New Zealand.

BACKGROUND: Impetigo is a common and contagious bacterial skin infection, affecting children worldwide, but it is particularly prevalent in socioeconomically disadvantaged communities. In New Zealand, widespread prescribing of the topical antibiotic fusidic acid had led to an increase in antimicrobial resistance of Staphylococcus aureus. Alternative treatments are urgently being sought, and as impetigo is a superficial infection, it has been suggested that topical antiseptics such as hydrogen peroxide or simple wound care alone may treat impetigo while avoiding the risk of increased antimicrobial resistance. METHODS: This protocol for a non-inferiority, single-blind randomised controlled trial compares topical fusidic acid with topical hydrogen peroxide and with simple wound care in the treatment of childhood impetigo. Participants are randomised to one of the three treatments for 5 days. The primary outcome is clinical improvement assessed through paired photographs analysed by graders blinded to treatment arm. The trial is based in school health clinics in an urban centre in New Zealand. Comparison of antimicrobial resistance patterns pre- and post-treatment is also performed. DISCUSSION: Special note is made of the need to involve the communities most affected by impetigo in the design and implementation of the clinical trial to recruit the children most in need of safe and effective treatments. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) 12616000356460 . Registered on March 10, 2016  Protocol amendment number: 05 EB and AL contributed equally as senior authors.

Model averaging with the hybrid model: An asymptotic study and demonstration.

In this paper, we present a new model averaging technique that can be applied in medical research. The dataset is first partitioned by the values of its categorical explanatory variables. Then for each partition, a model average is determined by minimising some form of squared errors, which could be the leave-one-out cross-validation errors. From our asymptotic optimality study and the results of simulations, we demonstrate under several high-level assumptions and modelling conditions that this model averaging procedure may outperform jackknife model averaging, which is a well-established technique. We also present an example where a cross-validation procedure does not work (that is, a zero-valued cross-validation error is obtained) when determining the weights for model averaging.

Abusive head trauma in children: radiographs of the skull do not provide additional information in the diagnosis of skull fracture when multiplanar computed tomography with three-dimensional reconstructions is available.

BACKGROUND: Some data suggest that CT is more accurate than skull radiographs in diagnosing skull fractures in abusive head trauma. OBJECTIVES: We investigated whether multiplanar CT with three-dimensional (3-D) reconstructions alone is non-inferior to combination CT/skull radiography for the diagnosis of skull fracture in suspected physical abuse. MATERIALS AND METHODS: We identified children who had skull radiographs and concurrent multiplanar CT with 3-D reconstructions obtained during suspected physical abuse imaging between 2010 and 2019, and a fracture diagnosis in the formal report. We included all fracture cases and an equal number of randomly selected non-fracture controls in an anonymised dataset. This dataset was independently reviewed for skull fracture by two paediatric radiologists and one less-experienced trainee using either radiography alone, CT alone or CT/skull radiography. The primary outcome was discordance in diagnosis of skull fracture between CT alone and CT/skull radiography, with a result > 0.03 deemed to indicate inferiority of CT alone. The Fleiss kappa was used to assess interobserver agreement. RESULTS: We included 106 children, 53 with and 53 without skull fracture. A single case was discordant between CT alone and CT/skull radiography, resulting in discordance of 0.009, consistent with non-inferiority of CT alone. The sensitivity and specificity of CT alone and CT/skull radiography were 98% and 96-98%, respectively, whereas radiography alone was more inaccurate (81% sensitivity and 96% specificity). Interobserver agreement for all modalities was very high (kappa 0.86-0.95). CONCLUSION: Multiplanar CT with 3-D reconstructions alone is not inferior (and clinically equivalent) to CT/skull radiography for diagnosing skull fracture in suspected physical abuse imaging and was as accurate when reported by a less-experienced trainee. This suggests that skull radiography can be removed from suspected physical abuse imaging guidelines.

Impact of smoking on pain and function in rotator cuff repair: a prospective 5-year cohort follow-up of 1383 patients.

BACKGROUND: This multicentre cohort study investigates the effect of smoking on the outcome of rotator cuff repair (RCR), with attention to age at presentation for surgery, pre-operative and post-operative pain and function and intra-operative findings. METHODS: Patient information was collected pre-operatively, including Flex Shoulder Function (Flex SF) and visual analogue scale pain, then at 6 months, 1, 2 and 5 years post-operatively. Intra-operative technical data were collected by the operating surgeon. Current smokers were classified by daily cigarette consumption. RESULTS: A total of 1383 RCRs in as many patients were included with an 84% 5-year follow-up. Smokers were on average 6.7 years younger than non-smokers (51.8 vs. 58.5, P < 0.001). There was no difference in intra-operatively assessed tear size both in anteroposterior dimension (P = 0.5) and retraction (P = 0.9). Pre-operative Flex SF score in smokers was below that of non-smokers (23.0 vs. 24.5, P = 0.002) and at 6 months (P = 0.02) but no different at 5 years (P = 0.7). Pain scores were higher in smokers than non-smokers both pre-operatively (5.34 vs. 4.67, P < 0.001) and up to 2 years (P < 0.001) but not at 5 years (P = 0.073). CONCLUSION: Smokers undergoing RCR were younger than non-smokers, and had worse pre-operative pain scores and shoulder function. Poorer post-operative function persisted to 6 months, and with higher reported pain to 2 years in smokers. However, at 5-year follow-up, patient-reported outcomes were not affected by smoking status.

A Biomechanical Comparison of Locked Unicortical with Non-Locking Bicortical Screws for Metacarpal Shaft Fractures in a Randomized Human Cadaveric Model.

Background: Locking plate fixation is widely used in large long bone fixation and is now available for small "long" bones in the hand. Potential advantages of unicortical locked fixation are reduced risk of over-drilling and therefore reduced risk of damage to surrounding structures and reduced risk of irritation from proud screws. Furthermore, unicortical fixation may be used where bicortical fixation is technically impossible. Our aim was to compare fixation strength of unicortical locked plate fixation with bicortical non-locked fixation in a human cadaveric model, by assessing strength under cyclical loading conditions and load to failure (LTF). Methods: 16 matched pairs of embalmed and refrigerated human cadaveric metacarpals were randomly allocated to either unicortical locked or bicortical non-locked plate and screw fixation. A transverse osteotomy was made. Fractures were stabilized with 2.0 mm self-tapping locking or cortical screws. Each metacarpal was then loaded with a 3-point cantilever testing using a 100 N cell on an Instron materials testing device, cyclically loading them at 1,000 repetitions of 30 N and 50 N. If there was no visible failure of the fixation from cyclical loading they were then loaded to failure with a 1 kN cell. Results: There was a significant difference of average LTF between the bicortical non-locking and unicortical locking of 38.07-59.95 N (p < 0.01). However, both groups showed no statistically significant difference when comparing their performance under cyclical loading. Conclusions: The authors regard unicortical locked fixation as a useful adjunct to standard plating technique.

Case study of the prediction of elective surgery durations in a New Zealand teaching hospital.

We present an elective surgery redesign project involving several New Zealand hospitals that is primarily data-driven. One of the project objectives is to improve the predictions of surgery durations. We address this task by considering two approaches: (a) linear regression modelling, and (b) improvement of the data quality. For (a) we evaluate the accuracy of predictions using two performance measures. These predictions are compared to the surgeons' estimates that may subsequently be adjusted. We demonstrate using the historical surgical lists that the estimates from our prediction techniques improve the scheduling of elective surgeries by minimising the occurrences of list under- and over-runs. For (b), we discuss how the surgical data motivates a review of the surgery procedure classification which takes into account the design of the electronic booking form. The proposed hierarchical classification streamlines the specification of surgery types and therefore retains the potential for improved predictions.

An interprofessional perspective on job satisfaction in the operating room: a review of the literature.

Maintaining job satisfaction across the team in the operating room (OR) is essential for reducing staff turnover, stress, burnout, medical errors and increasing patient satisfaction. This literature review explores factors impacting on job satisfaction for OR team members, with a specific focus on nurses, anaesthetists and surgeons. A literature search from January 1997 to November 2017 was conducted using databases CINHAL, psychINFO, Medline and ABI/inform. Surgeon, anaesthetist, OR nurse and OR team job satisfaction studies were included. The search yielded 48 studies. Dominant contributing factors for all three disciplines included: work conditions, support and acknowledgement from management, and fulfilment from the clinical role. Career prospects, research opportunities, autonomy, utilising the full extent of one's skills, team dynamics/communication, pressure from management, and social support systems were also identified as significant for specific disciplines within the team. This review highlights the importance of addressing factors relating to job satisfaction from an 'OR team' perspective and considering the inter-relationship between roles. Further research into 'team satisfaction' in the OR, its measurement and its relationship with retention and productivity would be of benefit.

Exploring trade-offs between staffing levels and turnaround time in a pathology laboratory using discrete event simulation.

Many health delivery services have required performance targets. Typically, these targets are presented as percentiles of patients to be seen within specified timeframes. These targets present hospital administrators with a resourcing problem complicated by conflicting objectives: How to minimize costs while maximizing throughput to achieve the performance targets? In this paper, we describe the use of a simulation model to evaluate the effect of changes to staff levels in a cytology department, investigating the trade-off between staff levels and turnaround times in light of performance targets specified by government. Standard practice for determining staffing levels in a cytology department uses average workload estimates and does not take into account target performance measures, task variability, and the interruptive nature of the workload of pathologists. We develop a simulation model for pathologist workload within a cytology department in New Zealand. We describe the model construction process that follows the hierarchical control conceptual modeling (HCCM) framework. We use the resulting simulation model to examine the trade-offs between staffing levels (and associated rosters) and task turnaround time. The results indicate that consideration of variation in task arrivals is important when considering the effect of staffing levels on turnaround time. Furthermore, as the cytology department is required to meet performance targets that involve maximum service times for a percentile of patients, such an approach is necessary in order to estimate the performance level of a staffing roster.

Role of Extracellular Matrix in Development and Cancer Progression.

The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly dynamic as it is constantly deposited, remodelled, and degraded during development until maturity to maintain tissue homeostasis. The ECM's composition and organization are spatiotemporally regulated to control cell behaviour and differentiation, but dysregulation of ECM dynamics leads to the development of diseases such as cancer. The chemical cues presented by the ECM have been appreciated as key drivers for both development and cancer progression. However, the mechanical forces present due to the ECM have been largely ignored but recently recognized to play critical roles in disease progression and malignant cell behaviour. Here, we review the ways in which biophysical forces of the microenvironment influence biochemical regulation and cell phenotype during key stages of human development and cancer progression.

Optimal plate fixation of distal femoral fractures in the presence of a well fixed cemented hip arthroplasty femoral stem.

INTRODUCTION: The requirement for lateral plate fixation in the presence of a hip arthroplasty stem is increasing, yet the optimal plate construct necessary to reduce inter-prosthetic strain and prevent subsequent fractures is unknown. Therefore, the purpose of this study was to determine the optimal position of a lateral femoral plate in relation to a femoral stem. METHODS: We used 4th Generation Composite Sawbones®, a collarless polished cemented femoral stem and a broad Peri-loc™ plate with varying overlap of the stem. Each construct was subjected to torsion, axial compression and 3-point lateral bending, with the strain measured at the tip of the femoral stem and the force-to-failure recorded. RESULTS: In all three loading directions a plate, which extended at least two shaft diameters proximal to the tip of the stem, experienced the lowest strain ( p < 0.001). Constructs with no overlap, and particularly those with a small gap between the tip of the stem and the proximal extent of the plate experienced the highest strain ( p < 0.001). This high strain resulted in lower forces required to cause fracture in the clinically significant scenarios of femoral torsion and lateral bending. CONCLUSIONS: Optimal plate fixation is achieved by extending a lateral femoral plate at least two shaft diameters proximal to the tip of the stem and using a spread of proximal screws. Distal fixation increases the strain experienced at the tip of the stem and higher strains are noted the smaller the gap between the proximal extent of the femoral plate and the tip of stem.

Achilles tenotomy as an office procedure and current practising trends among New Zealand orthopaedic surgeons.

BACKGROUND: Percutaneous Achilles tenotomy (PAT) is performed during the final phase of casting with Ponseti method. Several settings have been proposed as venues for this procedure, however it is increasingly being performed in theatre under a general anaesthetic (GA). General anaesthesia, however, is expensive and not without risks. The purpose of the present study was to compare results of outpatient releases to theatre releases, and assess current practising trends among orthopaedic surgeons. METHODS: Retrospective comparison of patients with idiopathic clubfoot managed by Ponseti method who had Achilles tenotomy performed in outpatient clinic and in theatre. Surveys were sent to all POSNZ members to determine current practising trends in New Zealand. Parental satisfaction surveys were performed. Comparative cost analysis was performed using hospital billing information. RESULTS: The current study includes 64 idiopathic congenital clubfeet (19 bilateral cases). PAT was performed on 26 clubfeet under local anaesthetic in an outpatient setting, and 33 clubfeet under GA in a theatre setting. There was no significant difference for post-operative complications, or recurrence (p=0.67). Those in theatre group were exposed to a greater number of general anaesthetics before the age of four. Among practising New Zealand paediatric orthopaedic surgeons, 77.78% perform this in theatre under general anaesthesia, while only 22.22% perform PAT in outpatient clinic. The main barriers included concerns regarding pain control, concerns regarding incomplete release, concerns regarding distress to family and concerns regarding sterility. Parental satisfaction surveys found pain management to be excellent. Financial data was analysed and indicative costs were $6,061 NZD per procedure in theatre, compared to $378 NZD per procedure in clinic. CONCLUSION: PAT performed in a clinic setting is both safe and efficacious with results comparative to that performed in theatre. There was no difference in post-operative complications or recurrence. Parental satisfaction to this procedure is excellent. There are significant financial advantages. Based on this data, our institution now performs all releases in an outpatient setting.

Creating a Structurally Realistic Finite Element Geometric Model of a Cardiomyocyte to Study the Role of Cellular Architecture in Cardiomyocyte Systems Biology.

With the advent of three-dimensional (3D) imaging technologies such as electron tomography, serial-block-face scanning electron microscopy and confocal microscopy, the scientific community has unprecedented access to large datasets at sub-micrometer resolution that characterize the architectural remodeling that accompanies changes in cardiomyocyte function in health and disease. However, these datasets have been under-utilized for investigating the role of cellular architecture remodeling in cardiomyocyte function. The purpose of this protocol is to outline how to create an accurate finite element model of a cardiomyocyte using high resolution electron microscopy and confocal microscopy images. A detailed and accurate model of cellular architecture has significant potential to provide new insights into cardiomyocyte biology, more than experiments alone can garner. The power of this method lies in its ability to computationally fuse information from two disparate imaging modalities of cardiomyocyte ultrastructure to develop one unified and detailed model of the cardiomyocyte. This protocol outlines steps to integrate electron tomography and confocal microscopy images of adult male Wistar (name for a specific breed of albino rat) rat cardiomyocytes to develop a half-sarcomere finite element model of the cardiomyocyte. The procedure generates a 3D finite element model that contains an accurate, high-resolution depiction (on the order of ~35 nm) of the distribution of mitochondria, myofibrils and ryanodine receptor clusters that release the necessary calcium for cardiomyocyte contraction from the sarcoplasmic reticular network (SR) into the myofibril and cytosolic compartment. The model generated here as an illustration does not incorporate details of the transverse-tubule architecture or the sarcoplasmic reticular network and is therefore a minimal model of the cardiomyocyte. Nevertheless, the model can already be applied in simulation-based investigations into the role of cell structure in calcium signaling and mitochondrial bioenergetics, which is illustrated and discussed using two case studies that are presented following the detailed protocol.

Cortical Neuroprosthesis Merges Visible and Invisible Light Without Impairing Native Sensory Function.

Adult rats equipped with a sensory prosthesis, which transduced infrared (IR) signals into electrical signals delivered to somatosensory cortex (S1), took approximately 4 d to learn a four-choice IR discrimination task. Here, we show that when such IR signals are projected to the primary visual cortex (V1), rats that are pretrained in a visual-discrimination task typically learn the same IR discrimination task on their first day of training. However, without prior training on a visual discrimination task, the learning rates for S1- and V1-implanted animals converged, suggesting there is no intrinsic difference in learning rate between the two areas. We also discovered that animals were able to integrate IR information into the ongoing visual processing stream in V1, performing a visual-IR integration task in which they had to combine IR and visual information. Furthermore, when the IR prosthesis was implanted in S1, rats showed no impairment in their ability to use their whiskers to perform a tactile discrimination task. Instead, in some rats, this ability was actually enhanced. Cumulatively, these findings suggest that cortical sensory neuroprostheses can rapidly augment the representational scope of primary sensory areas, integrating novel sources of information into ongoing processing while incurring minimal loss of native function.

Perioperative Breast Analgesia: A Qualitative Review of Anatomy and Regional Techniques.

Breast surgery is exceedingly common and may result in significant acute as well as chronic pain. Numerous options exist for the control of perioperative breast pain, including several newly described regional anesthesia techniques, but anesthesiologists have an insufficient understanding of the anatomy of the breast, the anatomic structures disrupted by the various breast surgeries, and the theoretical and experimental evidence supporting the use of the various analgesic options. In this article, we review the anatomy of the breast, common breast surgeries and their potential anatomic sources of pain, and analgesic techniques for managing perioperative pain. We performed a systematic review of the evidence for these analgesic techniques, including intercostal block, epidural administration, paravertebral block, brachial plexus block, and novel peripheral nerve blocks.