Practical Considerations for the Use of the Rapid AcuStar® ADAMTS13 Activity Assay in the Diagnosis of Acute Thrombotic Thrombocytopenic Purpura (TTP).

Introduction: Conventional practice in the management of acute TTP entails empirical treatment of suspected cases whilst awaiting confirmatory ADAMTS13 deficiency testing. Rapid ADAMTS13 assays offer increased accessibility and rapid diagnostics. The new automated HemosIL AcuStar® ADAMTS13 assay has seen increasing use among UK TTP Specialist Centres alongside the traditional ELISA method to confirm severe ADAMTS13 deficiency. Methods: A multi-centre retrospective case-control study was performed to review patients demonstrating discrepant ADAMTS13 activity results measured using rapid (AcuStar®) and ELISA assays in parallel from September 2019 to December 2021. Cases were compared with a cohort of suspected TTP patients exhibiting no difference in assay results and in relation to their presenting characteristics and pre-test probability of a diagnosis of TTP. Results: Where the clinical index of suspicion for TTP was high at presentation, acute TTP was confirmed using the AcuStar® assay < 0.2 IU/dL and subsequently < 10 IU/dL by ELISA with zero incidence of discrepancy. For patients with low clinical suspicion of acute TTP, a discrepancy between the AcuStar® and ELISA assay results was observed in 2% of cases; 5-10 IU/dL in AcuStar®, confirmed as >20 IU/dL by ELISA. A concurrent cancer diagnosis or sepsis was observed in 40% of discrepant cases. Conclusions: Where acute TTP is strongly suspected, there is a good correlation between the rapid AcuStar® ADAMTS13 assay and the conventional ELISA assay. Where the clinical suspicion of acute TTP is low, caution should be exercised in the interpretation of the ADAMTS13 activity using the AcuStar® assay. Accurate interpretation requires robust ADAMTS13 testing algorithms to be incorporated into diagnostic pathways.

Small lectin ligands as a basis for applications in glycoscience and glycomedicine.

Glycan recognition by lectins mediates important biological events. This Tutorial Review aims to introduce lectin-ligand interactions and show how these molecular recognition events inspire innovations such as: (i) glycomimetic ligands; (ii) multivalent ligand agonists/antagonists; (iii) ligands for precision delivery of therapies to cells, where therapies include vaccines, siRNA and LYTACs (iv) development of diagnostics. A small number of case studies are selected to demonstrate principles for development of new ligands for applications inspired by knowledge of natural glycan ligand structure and function.

INTRATHECAL BACLOFEN FOR NEUROFIBROMATOSIS RELATED SPINAL CORD INJURY WITH SPASTICITY - A CASE REPORT.

This case presents a 35-year-old male with spinal predominant neurofibromatosis-1 who developed an incomplete spinal cord injury (C3 Asia C) which did not improve despite urgent decompressive surgery for multiple cervical neurofibromas. This report outlines a novel indication for intrathecal baclofen. The patient suffered from lower limb weakness with severe spasticity and required assistance of at least two for all activities. The aim of rehabilitation was to improve overall tone while focusing on independence, mobility and quality of life. After a successful trial of intrathecal baclofen, he underwent implantation of an intrathecal baclofen pump. The dose was gradually increased while he received a progressive programme of stretching and functional rehabilitation therapy. After 6 weeks, his MAS had improved to 1-2/4 and he had progressed to independent transfers, independence for most activities of daily living and was able to discharge to his family home with minimal support.

Neurofibromatosis type 1 is a rare disorder causing various skin, skeletal, and neurological issues, including spinal cord injury due to tumours and severe scoliosis. Current treatment is supportive, with surgery sometimes needed for acute injuries. Spasticity, a common complication, leads to functional impairments and reliance on medications with side effects. Intrathecal baclofen pumps offer a targeted solution, delivering baclofen directly into the spine to reduce side effects. We present a case where a gentleman with neurofibromatosis-1-related spinal cord injury received intrathecal baclofen, coupled with intensive rehabilitation, to enhance comfort and daily independence. This case showcases the potential of intrathecal baclofen in managing spasticity in neurofibromatosis-1-related spinal cord disease.

Identifying Prevalence and Potential Predictors of Do-Not-Attempt-Resuscitation Orders to Facilitate Preoperative Discussions on Code Status.

BACKGROUND: Do Not Attempt Resuscitation (DNAR) orders allow patients with life-threatening conditions to decline resuscitation efforts should the need arise. The American Society of Anesthesiologists (ASA) recommends discussions with patients on their code status to clarify and honor their goals of care perioperatively. This project sought to determine the prevalence of DNAR orders and to identify the demographics and potential clinical predictors of DNAR status at the beginning and end of admission, which would help anesthesiologists at our center facilitate these discussions. METHODS: Factors associated with DNAR status at beginning and at end of hospital stay were determined through univariate logistic regressions. For DNAR status at beginning and end of hospital admission, variables assessed were age at arrival, race, sex, palliative consult, use of palliative care service, length of stay in days, presence of surgery, presence of emergent surgery, care level, and medical service. RESULTS: Approximately 2.4 percent of the sample had an active DNAR order at the beginning of their hospital admission compared to 7.4 percent at the end of hospital admission. Factors significantly associated with DNAR status at the beginning of the hospital stay were consistent with prior literature (age, palliative care consult or service). However, factors significantly associated with DNAR status at the end of hospital stay that were notable included length of stay, undergoing emergent surgery, higher level of care, and being on the oncology service and medical respiratory intensive care unit. CONCLUSIONS: This retrospective study allows anesthesiologists at our institution to identify patients who may benefit from a more comprehensive perioperative discussion about code status based on certain clinical characteristics, which may improve quality of care by preventing unwanted resuscitative measures that do not align with a patient's goals of care.

Flow Chemistry for Synthesis of 2-(C-Glycosyl)acetates from Pyranoses via Tandem Wittig and Michael Reactions.

C-Glycosyl compounds (C-glycosides) are a class of saccharide derivatives with improved stability over their O-linked counterparts. This paper reports the synthesis of several trans-2-(C-glycosyl)acetates via a tandem Wittig-Michael reaction from pyranoses (cyclic hemiacetals) using continuous flow processing, which gave improvements compared to reactions conducted in round-bottom flasks. Products were isolated in yields of >60% from reactions of benzyl-protected xylopyranoses, glucopyranoses, and galactopyranoses at higher temperatures and pressures, which were superior to yields from batch procedures. A two-step procedure involving the Wittig reaction followed by Michael reaction (intramolecular oxa-Michael) of the unsaturated ester obtained in the presence of DBU was developed. Reactions of protected mannopyranose gave low yields in corresponding reactions in flow due to competing C-2 epimerization.

Application of Sublimation in the Synthesis and Crystal Growth of Organosulfones.

The solvent-free elimination of sulfinic acid and aromatization of 1,6-trans-substituted bis(arylsulfone) trienes is reported. It is shown that sublimation can be used as a 'green' method to combine the thermal transformation of six trienes and the crystal growth of the resulting 4-(phenylsulfonyl)biphenyls. When the sublimation conditions are carefully controlled, high quality single crystals of the 4-(phenylsulfonyl)biphenyls are obtained. Theoretical modelling of the reaction using the simplified triene Ph-(CH)6-SO2H showed that the cyclization is energetically feasible and that the complete conversion is possible during the timescale of the sublimation. At temperatures slightly higher than the optimum sublimation temperature two of the trienes transformed into 1,4-cyclohexadienes that did not eliminate phenylsulfinic acid. A reaction mechanism involving a 1,3-hydrogen shift induced by free PhS• radicals is proposed for the formation of the 1,4-cyclohexadienes.

A cross-disciplinary approach to learning medical physiology and behavioral skills involving drama students performing as simulated patients.

The early years of physiology education in medical curricula provide unique challenges. As well as inculcating concepts that are seen as difficult, modern curricula require that students learn in context in case-based learning courses. Additionally, regulating bodies stress that the soft skills of compassion, communication, and empathy are embedded throughout curricula. This has driven work in our organization involving drama and final-year medicine students during which they collaborate in realistic simulations of doctor/patient interactions. We adapted this transdisciplinary approach to second-year physiology tutorials. This emphasized the holistic importance of physiology to patient care, while also embedding "human factors" skills from the very earliest stages of the curriculum. After preparing by attending acting classes based on aspects of Konstantin Stanislavski's "System," the authors supervised tutorials in which drama students participated in a "physiology of hypofertility" session for second-year medical students, playing a 34-year-old woman with premature menopause (or their partner). Opinion (from all students) was evaluated by Likert questionnaires (which included open questions). A focus group of drama students was also interviewed, and the conversation was recorded for thematic analysis. Positive Likert scores were recorded for the authenticity of the tutorials, skills development, fostering empathy, and motivating students to improve. All participants evaluated the tutorial as highly enjoyable. These scores are reflected in positive open commentary on the questionnaires and in the focus group interviews. The results suggest that even basic science tutorials give opportunities for interdisciplinary study and enhancement of behavioral skills while gaining enthusiastic student acceptance.NEW & NOTEWORTHY This work details how physiology tutorials for early years medical students are transformed by taking the clinical case off the two-dimensional page and instead having the case scenario acted by drama students. This adds context and authenticity. The benefits are twofold: emphasizing the importance of physiology to the budding clinician and embedding empathy and compassion from the earliest points in a clinician's career.

Towards an EKG for SBO: A Neural Network for Detection and Characterization of Bowel Obstruction on CT.

A neural network was developed to detect and characterize bowel obstruction, a common cause of acute abdominal pain. In this retrospective study, 202 CT scans of 165 patients with bowel obstruction from March to June 2022 were included and partitioned into training and test data sets. A multi-channel neural network was trained to segment the gastrointestinal tract, and to predict the diameter and the longitudinal position ("longitude") along the gastrointestinal tract using a novel embedding. Its performance was compared to manual segmentations using the Dice score, and to manual measurements of the diameter and longitude using intraclass correlation coefficients (ICC). ROC curves as well as sensitivity and specificity were calculated for diameters above a clinical threshold for obstruction, and for longitudes corresponding to small bowel. In the test data set, Dice score for segmentation of the gastrointestinal tract was 78 ± 8%. ICC between measured and predicted diameters was 0.72, indicating moderate agreement. ICC between measured and predicted longitude was 0.85, indicating good agreement. AUROC was 0.90 for detection of dilated bowel, and was 0.95 and 0.90 for differentiation of the proximal and distal gastrointestinal tract respectively. Overall sensitivity and specificity for dilated small bowel were 0.83 and 0.90. Since obstruction is diagnosed based on the diameter and longitude of the bowel, this neural network and embedding may enable detection and characterization of this important disease on CT.

Neonatal epidermolysis bullosa: a clinical practice guideline.

DEBRA International is undertaking a long-term initiative to develop clinical practice guidelines (CPGs) for epidermolysis bullosa (EB), to -improve the clinical care of people living with EB. Current neonatal care is based on evidence, clinical expertise and trial and error, with collaboration between the EB specialist team, parent or carer and patient, and is dependent on the neonate's individual presentation and type of EB. Early intervention based on research and clinical practice is needed to establish a foundation of knowledge to guide international practitioners to create and improve standards of care and to be able to work effectively with those newly diagnosed with EB. This CPG was created by an international panel with expertise working with persons with EB. The CPG focuses on neonatal care using a systematic review methodology covering four key areas: (i) diagnosis and parental psychosocial support; (ii) hospital management: medical monitoring, wound care and pain; (iii) feeding and nutrition; and (iv) discharge planning and EB education. These four areas highlight the importance of a multidisciplinary team approach, to provide a patient-specific holistic care model that incorporates the needs and wishes of the parents and carers. The Hospital Implementation Tool included promotes transfer of theory to clinical practice.

Untapped resource: the simulation-based healthcare environment as a means to study human stress.

The effects of 'stress' within the healthcare professions are wide-reaching, not least of all within the field of simulation-based healthcare education. Whilst this popular method of experiential learning offers a 'safe space' for participants to develop their skillset, it also has a more surreptitious action; namely, the incubation of simulation-related stress. Currently, research concerning the complex relationship between stress, learning, and performance is ambiguous, leaving fertile ground for simulationists to debate what level of stress is appropriate for an optimised educational experience. In this narrative review, we examine the human response to stress and outline the various methods that have been used by researchers to measure stress in a quantifiable and standardised way. We then provide a brief overview of simulation-based healthcare education before describing why stress responses have been of interest to healthcare educationalists for some time. Finally, we outline how simulation education environments might provide an ideal environment for studying the human response to stress generally, with ramifications extending beyond the field of medical education.

Training simulated participants for role portrayal and feedback practices in communication skills training: A BEME scoping review: BEME Guide No. 86.

BACKGROUND: Providing feedback is a key aspect of simulated participants' (SPs) educational work. In teaching contexts, the ability to provide feedback to learners is central to their role. Suboptimal feedback practices may deny learners the valuable feedback they need to learn and improve. This scoping review systematically maps the evidence related to SPs' role as educators and identifies how SPs prepare for their role and feedback practices. METHODS: The authors conducted a scoping review and included a group of international stakeholders with experience and expertise in SP methodology. Five online databases were systematically searched and ERIC, MedEdPortal and MedEdPublish were hand searched to identify relevant studies. Inclusion/exclusion criteria were developed. Data screening and subsequently data charting were performed in pairs. The results of data charting were thematically analysed including categories relating to the Association of SP Educators (ASPE) Standards of Best Practice (SOBP). RESULTS: From 8179 articles identified for the title and abstract screening, 98 studies were included. Studies reported the benefit of SPs' authentic role portrayal and feedback interactions for learners and on the reported learning outcomes. Data was heterogeneous with a notable lack of consistency in the detail regarding the scenario formats for communication skills training interventions, SP characteristics, and approaches to training for feedback and role portrayal. CONCLUSIONS: The published literature has considerable heterogeneity in reporting how SPs are prepared for role portrayal and feedback interactions. Additionally, our work has identified gaps in the implementation of the ASPE SOBP, which promotes effective SP-learner feedback interactions. Further research is required to identify effective applications of SP methodology to prepare SPs for their role as educators.

Stimulus characteristics of a novel air-based multiple stimulus aesthesiometer.

PURPOSE: To identify the stimulus airflow characteristics and confirm the consistency of a novel air jet-based aesthesiometer capable of producing and applying multiple stimuli separated either by time and/or by space. METHODS: A novel aesthesiometer (Dolphin Aesthesiometer) was designed around a micro-blower under software management. Two nozzle attachments assisted in airflow control (flexible tube 1.6 mm diameter; brass tube 0.5 mm diameter). Four studies that tested the characteristics of the airflow and stimulus consistency were completed: (i) airflow pattern/trajectory, (ii) airflow surface dispersion, (iii) force of airflow across a range of stimulus strengths and (iv) thermal effects on the ocular surface. RESULTS: Stimulus characteristic studies revealed: (i) airflow is coherent within the expected test distance range for the instrument, and spread rate is constant irrespective of stimulus strength; (ii) airflow dispersion occurs upon encountering a surface and dispersion increases with increasing airflow rate; (iii) a consistent and small force (10-4 N) is applied by the airflow and (iv) repeatable thermal effects occur in relation to the airflow, and the mode of stimulation of the Dolphin aesthesiometer is predominantly thermal in nature. CONCLUSIONS: These studies confirm the repeatability and consistency of the novel instrument. The device is suitable for measuring corneal sensitivity. The availability of additional air jets allows the application of multiple stimuli to facilitate corneal summation investigations.

Investigating the effectiveness of oral ketamine on pain, mood and quality of life in treatment resistant chronic pain.

Introduction: Chronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic. Methods: This study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale. Results: 73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine. Discussion: This work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key message: This real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions.

Unlocking the learning potential of simulation-based education.

Simulation is ubiquitous in the training of hospital-based doctors worldwide, often focusing on an individual level in traditional 'skills and drills'-based training. However, there has been an expansion in the use of simulation in healthcare practice and training. Simulation is being adopted into many disciplines that traditionally have not used this form of experiential learning. Moreover, simulation is increasingly being harnessed to enhance team and organisational learning in hospital-based practice. This article shares some insights into simulation-based education and makes the 'familiar unfamiliar' about this important method of learning. The aim is to broaden readers' outlook about what simulation has to offer beyond the classic notion of skills and drills-based training.

Consensus-based guidelines for the provision of palliative and end-of-life care for people living with epidermolysis bullosa.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a cluster of rare, genetic skin and mucosal fragility disorders with multi-system and secondary effects, in which blistering and erosions occur in response to friction/mechanical trauma. Considering the incurable and potentially life-limiting nature of the condition and the challenges posed by its symptoms, a palliative approach to EB-related care is necessary. However, knowledge and experience related to the provision of EB palliative care is minimal. Evidence-based, best care guidelines are needed to establish a base of knowledge for practitioners to prevent or ease suffering while improving comfort at all stages of the illness, not just the end of life. METHODS: This consensus guideline (CG) was begun at the request of DEBRA International, an international organization dedicated to improvement of care, research, and dissemination of knowledge for EB patients, and represents the work of an international panel of medical experts in palliative care and EB, people living with EB, and people who provide care for individuals living with EB. Following a rigorous, evidence-based guideline development process, the author panel identified six clinical outcomes based on the results of a survey of people living with EB, carers, and medical experts in the field, as well as an exhaustive and systematic evaluation of literature. Recommendations for the best clinical provision of palliative care for people living with EB for each of the outcomes were reached through panel consensus of the available literature. RESULTS: This article presents evidence-based recommendations for the provision of palliative healthcare services that establishes a base of knowledge and practice for an interdisciplinary team approach to ease suffering and improve the quality of life for all people living with EB. Any specific differences in the provision of care between EB subtypes are noted. CONCLUSIONS: Because there is yet no cure for EB, this evidence-based CG is a means of optimizing and standardizing the IDT care needed to reduce suffering while improving comfort and overall quality of life for people living with this rare and often devastating condition.

Primary care-based models of care for osteoarthritis; a scoping review.

OBJECTIVE: To identify and describe the extent, nature, characteristics, and impact of primary care-based models of care (MoCs) for osteoarthritis (OA) that have been developed and/or evaluated. DESIGN: Six electronic databases were searched from 2010 to May 2022. Relevant data were extracted and collated for narrative synthesis. RESULTS: Sixty-three studies pertaining to 37 discrete MoCs from 13 countries were included, of which 23 (62%) could be classified as OA management programmes (OAMPs) comprising a self-management intervention to be delivered as a discrete package. Four models (11%) focussed on enhancing the initial consultation between a patient presenting with OA at the first point of contact into a local health system and the clinician. Emphasis was placed on educational training for general practitioners (GPs) and allied healthcare professionals delivering this initial consultation. The remaining 10 MoCs (27%) detailed integrated care pathways of onward referral to specialist secondary orthopaedic and rheumatology care within local healthcare systems. The majority (35/37; 95%) were developed in high-income countries and 32/37 (87%) targeted hip/and or knee OA. Frequently identified model components included GP-led care, referral to primary care services and multidisciplinary care. The models were predominantly 'one-size fits all' and lacked individualised care approaches. A minority of MoCs, 5/37 (14%) were developed using underlying frameworks, three (8%) of which incorporated behaviour change theories, while 13/37 (35%) incorporated provider training. Thirty-four of the 37 models (92%) were evaluated. Outcome domains most frequently reported included clinical outcomes, followed by system- and provider-level outcomes. While there was evidence of improved quality of OA care associated with the models, effects on clinical outcomes were mixed. CONCLUSION: There are emerging efforts internationally to develop evidence-based models focused on non-surgical primary care OA management. Notwithstanding variations in healthcare systems and resources, future research should focus on model development alignment with implementation science frameworks and theories, key stakeholder involvement including patient and public representation, provision of training and education for providers, treatment individualisation, integration and coordination of services across the care continuum and incorporation of behaviour change strategies to foster long-term adherence and self-management.

Visual Image Annotation for Bowel Obstruction: Repeatability and Agreement with Manual Annotation and Neural Networks.

Bowel obstruction is a common cause of acute abdominal pain. The development of algorithms for automated detection and characterization of bowel obstruction on CT has been limited by the effort required for manual annotation. Visual image annotation with an eye tracking device may mitigate that limitation. The purpose of this study is to assess the agreement between visual and manual annotations for bowel segmentation and diameter measurement, and to assess agreement with convolutional neural networks (CNNs) trained using that data. Sixty CT scans of 50 patients with bowel obstruction from March to June 2022 were retrospectively included and partitioned into training and test data sets. An eye tracking device was used to record 3-dimensional coordinates within the scans, while a radiologist cast their gaze at the centerline of the bowel, and adjusted the size of a superimposed ROI to approximate the diameter of the bowel. For each scan, 59.4 ± 15.1 segments, 847.9 ± 228.1 gaze locations, and 5.8 ± 1.2 m of bowel were recorded. 2d and 3d CNNs were trained using this data to predict bowel segmentation and diameter maps from the CT scans. For comparisons between two repetitions of visual annotation, CNN predictions, and manual annotations, Dice scores for bowel segmentation ranged from 0.69 ± 0.17 to 0.81 ± 0.04 and intraclass correlations [95% CI] for diameter measurement ranged from 0.672 [0.490-0.782] to 0.940 [0.933-0.947]. Thus, visual image annotation is a promising technique for training CNNs to perform bowel segmentation and diameter measurement in CT scans of patients with bowel obstruction.

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response.

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production.