High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response.

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography-mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis.

An international RAND/UCLA expert panel to determine the optimal diagnosis and management of burn inhalation injury.

BACKGROUND: Burn inhalation injury (BII) is a major cause of burn-related mortality and morbidity. Despite published practice guidelines, no consensus exists for the best strategies regarding diagnosis and management of BII. A modified DELPHI study using the RAND/UCLA (University of California, Los Angeles) Appropriateness Method (RAM) systematically analysed the opinions of an expert panel. Expert opinion was combined with available evidence to determine what constitutes appropriate and inappropriate judgement in the diagnosis and management of BII. METHODS: A 15-person multidisciplinary panel comprised anaesthetists, intensivists and plastic surgeons involved in the clinical management of major burn patients adopted a modified Delphi approach using the RAM method. They rated the appropriateness of statements describing diagnostic and management options for BII on a Likert scale. A modified final survey comprising 140 statements was completed, subdivided into history and physical examination (20), investigations (39), airway management (5), systemic toxicity (23), invasive mechanical ventilation (29) and pharmacotherapy (24). Median appropriateness ratings and the disagreement index (DI) were calculated to classify statements as appropriate, uncertain, or inappropriate. RESULTS: Of 140 statements, 74 were rated as appropriate, 40 as uncertain and 26 as inappropriate. Initial intubation with ≥ 8.0 mm endotracheal tubes, lung protective ventilatory strategies, initial bronchoscopic lavage, serial bronchoscopic lavage for severe BII, nebulised heparin and salbutamol administration for moderate-severe BII and N-acetylcysteine for moderate BII were rated appropriate. Non-protective ventilatory strategies, high-frequency oscillatory ventilation, high-frequency percussive ventilation, prophylactic systemic antibiotics and corticosteroids were rated inappropriate. Experts disagreed (DI ≥ 1) on six statements, classified uncertain: the use of flexible fiberoptic bronchoscopy to guide fluid requirements (DI = 1.52), intubation with endotracheal tubes of internal diameter < 8.0 mm (DI = 1.19), use of airway pressure release ventilation modality (DI = 1.19) and nebulised 5000IU heparin, N-acetylcysteine and salbutamol for mild BII (DI = 1.52, 1.70, 1.36, respectively). CONCLUSIONS: Burns experts mostly agreed on appropriate and inappropriate diagnostic and management criteria of BII as in published guidance. Uncertainty exists as to the optimal diagnosis and management of differing grades of severity of BII. Future research should investigate the accuracy of bronchoscopic grading of BII, the value of bronchial lavage in differing severity groups and the effectiveness of nebulised therapies in different severities of BII.

Adult intensive care unit admissions with severe COVID-19 infection following emergency Caesarean section deliveries: A case series.

BACKGROUND: UK data suggest 6% of COVID-19 hospital admissions are either currently pregnant or immediately post-partum. However, the current literature suggests that if COVID-19 occurs in pregnancy, or post-partum, symptoms are mostly mild. METHODS: All COVID-19 admissions to one acute London National Health Service Foundation trust were reviewed since the beginning of the COVID-19 pandemic to 1 May 2020 to establish whether there were any pregnant or immediately post-partum admissions. Data were extracted from hospital electronic records and anonymised. Any patients admitted to adult intensive care unit had their case notes reviewed in detail and comparison made to a local risk-assessment guideline identifying patients at-risk of thromboembolic events or cytokine storms. Local hospital guidelines were followed. Patients admitted to adult intensive care unit gave written consent. RESULTS: A total of 24 pregnant or immediately post-partum patients with COVID-19 were admitted. Three patients required long adult intensive care unit admissions for severe single-organ respiratory failure after emergency C-sections. Two of these patients required proning (three times and eight times, respectively). All were considered medium risk for thromboembolic events but had rising D-dimers following adult intensive care unit admission, resulting in increased dosing of pharmacological thromboprophylaxis throughout their admission. All were considered low risk for a cytokine storm, and none had any significant cardiovascular or renal involvement. One patient developed a super-imposed fungal lung infection. All three patients developed delirium following cessation of sedation. CONCLUSION: Pregnant or immediately post-partum women can develop severe COVID-19 symptoms requiring prolonged adult intensive care unit admission. It is likely to be single-organ failure, but patients are at a high risk of a thromboembolic event and delirium.

Development and implementation of a COVID-19 near real-time traffic light system in an acute hospital setting.

Common causes of death in COVID-19 due to SARS-CoV-2 include thromboembolic disease, cytokine storm and adult respiratory distress syndrome (ARDS). Our aim was to develop a system for early detection of disease pattern in the emergency department (ED) that would enhance opportunities for personalised accelerated care to prevent disease progression. A single Trust's COVID-19 response control command was established, and a reporting team with bioinformaticians was deployed to develop a real-time traffic light system to support clinical and operational teams. An attempt was made to identify predictive elements for thromboembolism, cytokine storm and ARDS based on physiological measurements and blood tests, and to communicate to clinicians managing the patient, initially via single consultants. The input variables were age, sex, and first recorded blood pressure, respiratory rate, temperature, heart rate, indices of oxygenation and C-reactive protein. Early admissions were used to refine the predictors used in the traffic lights. Of 923 consecutive patients who tested COVID-19 positive, 592 (64%) flagged at risk for thromboembolism, 241/923 (26%) for cytokine storm and 361/923 (39%) for ARDS. Thromboembolism and cytokine storm flags were met in the ED for 342 (37.1%) patients. Of the 318 (34.5%) patients receiving thromboembolism flags, 49 (5.3% of all patients) were for suspected thromboembolism, 103 (11.1%) were high-risk and 166 (18.0%) were medium-risk. Of the 89 (9.6%) who received a cytokine storm flag from the ED, 18 (2.0% of all patients) were for suspected cytokine storm, 13 (1.4%) were high-risk and 58 (6.3%) were medium-risk. Males were more likely to receive a specific traffic light flag. In conclusion, ED predictors were used to identify high proportions of COVID-19 admissions at risk of clinical deterioration due to severity of disease, enabling accelerated care targeted to those more likely to benefit. Larger prospective studies are encouraged.

Developing a case mix classification for child and adolescent mental health services: the influence of presenting problems, complexity factors and service providers on number of appointments.

Background: Case-mix classification is a focus of international attention in considering how best to manage and fund services, by providing a basis for fairer comparison of resource utilization. Yet there is little evidence of the best ways to establish case mix for child and adolescent mental health services (CAMHS).Aim: To develop a case mix classification for CAMHS that is clinically meaningful and predictive of number of appointments attended and to investigate the influence of presenting problems, context and complexity factors and provider variation.Method: We analysed 4573 completed episodes of outpatient care from 11 English CAMHS. Cluster analysis, regression trees and a conceptual classification based on clinical best practice guidelines were compared regarding their ability to predict number of appointments, using mixed effects negative binomial regression.Results: The conceptual classification is clinically meaningful and did as well as data-driven classifications in accounting for number of appointments. There was little evidence for effects of complexity or context factors, with the possible exception of school attendance problems. Substantial variation in resource provision between providers was not explained well by case mix.Conclusion: The conceptually-derived classification merits further testing and development in the context of collaborative decision making.

Immune therapy in sepsis: Are we ready to try again?

Immune therapy to ease the burden of sepsis has thus far failed to consistently improve patient outcomes. Advances in cancer immune therapy and awareness that prolonged immune-suppression in sepsis can leave patients vulnerable to secondary infection and death have driven resurgence in the field of sepsis immune-therapy investigation. As we develop and evaluate these novel therapies, we must learn from past experiences where single-mediator targeted immune therapies were blindly delivered to heterogeneous patient cohorts with complex and evolving immune responses. Advances in genomics, proteomics, metabolomics, and point-of-care technology, coupled with a better understanding of sepsis pathogenesis, have meant that personalised immune-therapy is on the horizon. Here, we review the complex immune pathogenesis in sepsis and the contemporary immune therapies that are being investigated to manipulate this response. An outline of the immune biomarkers that may be used to support this approach is also provided.

Development of a framework for prospective payment for child mental health services.

OBJECTIVES: There is a need to develop a payment system for services for children with mental health problems that allows more targeted commissioning based on fairness and need. This is currently constrained by lack of clinical consensus on the best way forward, wide variation in practice, and lack of data about activity and outcomes. In the context of a national initiative in England our aim was to develop a basis for an improved payment system. METHODS: Three inter-related studies: a qualitative consultation with child and adolescent mental health services (CAMHS) stakeholders on what the key principles for establishing a payment system should be, via online survey (n = 180) and two participatory workshops (n = 91); review of relevant national clinical guidelines (n = 15); and a quantitative study of the relationship between disorders and resource use (n = 1774 children from 23 teams). RESULTS: CAMHS stakeholders stressed the need for a broader definition of need than only diagnosis, including the measurement of indirect service activities and appropriate outcome measurement. National clinical guidance suggested key aspects of best practice for care packages but did not include consideration of contextual factors such as complexity. Modelling data on cases found that problem type and degree of impairment independently predicted resource use, alongside evidence for substantial service variation in the allocation of resources for similar problems. CONCLUSIONS: A framework for an episode-based payment system for CAMHS should include consideration of: complexity and indirect service activities; evidence-based care packages; different needs in terms of impairment and symptoms; and outcome measurement as a core component.

Tumour lysis syndrome in a patient with intravascular spread from a recurrent epithelial ovarian cancer.

Tumour lysis syndrome is a potentially life-threatening oncological emergency most commonly encountered in patients with rapidly proliferating, treatment-responsive haematological malignancies. It is rarely observed in solid tumours and, to our knowledge, this is the first time that it has been reported in a cancer with an intravascular tumour extension. In this report, we describe a case of a woman who presented with recurrent ovarian cancer and was found to have tumour invading into her vasculature. The patient subsequently developed tumour lysis syndrome after receiving chemotherapy. The case highlights the importance of considering tumour lysis syndrome prophylaxis when treating patients with intravascular involvement from a solid malignancy even if, as in this case, it is a recurrent tumour. Included is a brief review of the literature. We propose that 'intravascular tumour invasion is recognised as an important risk factor for the development of tumour lysis syndrome.

Systematic variation of the stellar initial mass function in early-type galaxies.

Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars, which depends on the present number of each type of star in the galaxy. The present number depends on the stellar initial mass function (IMF), which describes the distribution of stellar masses when the population formed, and knowledge of it is critical to almost every aspect of galaxy evolution. More than 50 years after the first IMF determination, no consensus has emerged on whether it is universal among different types of galaxies. Previous studies indicated that the IMF and the dark matter fraction in galaxy centres cannot both be universal, but they could not convincingly discriminate between the two possibilities. Only recently were indications found that massive elliptical galaxies may not have the same IMF as the Milky Way. Here we report a study of the two-dimensional stellar kinematics for the large representative ATLAS(3D) sample of nearby early-type galaxies spanning two orders of magnitude in stellar mass, using detailed dynamical models. We find a strong systematic variation in IMF in early-type galaxies as a function of their stellar mass-to-light ratios, producing differences of a factor of up to three in galactic stellar mass. This implies that a galaxy's IMF depends intimately on the galaxy's formation history.

Spinal arteriovenous malformation presenting as spastic monoplegic cerebral palsy in a child.

A case of spinal arterio-venous malformation (AVM) initially diagnosed as unilateral cerebral palsy (CP) is reported. The presentation was of a long-standing spastic monoparesis of the left leg, with initial response to Botulinum toxin injections to the calf and tibialis posterior muscles. This was followed by progressive deterioration occurring over a 3-month period before further investigation and definitive diagnosis at 7 years. Imaging demonstrated a large extra-medullary spinal AVM compressing the mid-thoracic cord. This was successfully managed by embolisation with a non-adhesive polymer: ethylene-vinyl alcohol copolymer injected into the dominant feeding vessel. This case highlights the need to consider alternative diagnoses when a child with a diagnosis of CP presents with atypical clinical features such as monoparesis and has worsening or altered clinical signs. Moreover, a normal magnetic resonance imaging brain scan and the absence of ipsilateral upper limb neurological signs or functional impairment should raise suspicion even in the context of static lower limb signs. A literature review was performed on the management of spinal AVM in children and this will be is discussed.

Percutaneous transluminal angioplasty in recurrent necrotizing enterocolitis--a case report.

A 35-week gestation male neonate had 3 episodes of necrotizing enterocolitis (NEC), the first of which was managed surgically. Two further episodes of NEC were treated by medical management. Angiography then identified a stricture at the origin of the superior mesenteric artery. Percutaneous transluminal angioplasty successfully dilated the stenosis, and no further episodes of NEC occurred. Eight years later, the child exhibits a mild spastic diplegia and is thriving with no gastrointestinal disturbances. Angioplasty is technically feasible in the neonate and may be a treatment option in recurrent NEC associated with visceral arterial stenosis.

Angioplasty for renovascular hypertension in children: 20-year experience.

OBJECTIVE: Our aim was to evaluate the clinical outcomes, safety, and efficacy of percutaneous transluminal angioplasty for renovascular hypertension in children. METHODS: A retrospective review of data for all children with renovascular hypertension who underwent percutaneous transluminal angioplasty at a single center between 1984 and 2003 was performed. Patients with renal transplants and inflammatory multisystem diseases were excluded. RESULTS: Thirty-three children, 1.9 to 17.9 years of age (median: 10.3 years), underwent renal angioplasty and/or stenting. Underlying syndromes were present in 10. On angiograms, 16 had bilateral renal artery stenosis, 15 intrarenal disease, 8 aortic stenosis, and 7 cerebrovascular disease. Forty-eight percutaneous transluminal angioplasty procedures were performed, including 15 stenting procedures. There was a high rate of restenosis after stenting (7 of 19 cases, compared with 2 of 27 cases after balloon dilation). Outcomes were cured (ie, blood pressure normal without treatment) for 9 patients, improved blood pressure with same or reduced treatment for 7, blood pressure maintained in >95th percentile because of cerebrovascular disease for 2, no change in blood pressure despite technical success for 10, and technical failure for 5. Blood pressure control improved in 11 of 13 children who had main renal artery disease alone and in 6 of 20 with associated intrarenal disease or stenoses in other vascular beds. There was 1 procedure-related death and 5 minor complications. CONCLUSIONS: Angioplasty produced clinically worthwhile improvement for approximately 50% of patients. High incidence rates of extrarenal involvement and intrarenal disease and a high restenosis rate after stenting accounted for poor blood pressure control in the rest.

Intravascular ultrasound guidance for transjugular intrahepatic portosystemic shunt procedure in a swine model.

A new method is described for guiding hepato-portal venous puncture using a longitudinal side-view intravascular ultrasound (L-IVUS) transducer to assist in the performance of transjugular intrahepatic portosystemic shunt (TIPS) in three Australian swine. Simultaneous L-IVUS with an AcuNav 5-10 MHz 10 Fr transducer (Acuson Corporation, Mountain View, CA, USA) and fluoroscopy guidance was used to image and monitor the hepatic to portal venous puncture, dilatation of the tract, and deployment of the TIPS stent. Flow through the shunt could be demonstrated with both L-IVUS and angiography. TIPS was successful in all swine. The time for portal vein puncture once the target portal vein was identified was reduced at each attempt. The number of portal vein puncture attempts was 2, 1, and 1. No post-procedural complication was evident. L-IVUS-guided TIPS is practical and has the potential to improve safety by permitting simultaneous ultrasound and fluoroscopic imaging of the needle and target vascular structures. This technique allows for a more streamlined approach to TIPS, decreasing the fluoroscopic time (hence, decreasing the radiation exposure to the staff and patient) and anesthetic time. In addition, there are improved safety benefits obviating the need for wedged portography, facilitating avoidance of bile duct and hepatic arterial puncture, and minimizing hepatic injury by decreasing liver capsular puncture and the attendant risks.

MDCT of acute lower gastrointestinal bleeding.

OBJECTIVE: We evaluated the use of MDCT in the diagnosis and management of lower gastrointestinal bleeding (hematochezia). CONCLUSION: MDCT is proposed as an alternative first-line investigation to locate lower gastrointestinal bleeding before placing the patient under observation or performing embolization or surgery.

A case of primary cerebral neuroblastoma in adolescence.

Primary cerebral neuroblastoma is one of a group of highly malignant undifferentiated primitive neuroectodermal tumours arising from germinal matrix cells of the embryonic neural tube. They occur primarily in young children and are extremely rare in adults. They may be multicentric and have often spread throughout the central nervous system at the time of diagnosis. A case of a 16-year-old man is described, and the recent literature is reviewed.

Renal angiography in children with polyarteritis nodosa.

This study describes the angiographic findings in children with polyarteritis nodosa (PAN). Visceral angiograms of 25 children with PAN were reviewed retrospectively by two independent radiologists. In the PAN group, 40% of children had aneurysms demonstrated on selective renal angiography. Most aneurysms affected small and medium-sized arteries. There was agreement between radiologists regarding medium and large aneurysms ( K=0.81), but less so for smaller aneurysms. Overall, the presence of medium or large aneurysms was significantly associated with the presence of renal impairment and hypertension. Non-aneurysmal changes were detected more commonly on renal angiography than aneurysms in the PAN group. The most reliable non-aneurysmal signs were perfusion defects, the presence of collateral arteries, lack of crossing of peripheral renal arteries, and delayed emptying of small renal arteries. The sensitivity and specificity of renal angiographic diagnosis of PAN using aneurysms alone was 43% (SE 10%) and 69% (SE 14%) respectively. The sensitivity increased to 80%, and specificity fell to 50% for angiogram positivity defined as the presence of at least one of the most reliable non-aneurysmal signs irrespective of the presence of aneurysms. Aneurysms were also demonstrated on hepatic and mesenteric angiography, and non-aneurysmal signs were found on hepatic, mesenteric, and splenic angiography, although interobserver agreement for angiographic findings in these vascular beds was lower. It is important to consider both aneurysmal and non-aneurysmal angiographic signs, and to include examinations of several vascular beds when utilising angiography for diagnostic purposes in children with PAN.

Introducing problem-based learning to special needs dentistry--a case study.

INTRODUCTION: In order to promote training and education in special-needs dentistry an attempt was made to introduce problem-based learning (PBL) as a method of postgraduate dental education. The aim of this paper was to review the principles of PBL and report on a case study using this methodology. METHOD: The case study was of a PBL session, on the subject of 'problems of obtaining appropriate dental care for people with epilepsy', undertaken at a national conference. Delegates were asked to complete a pre- and post-session questionnaire on PBL and their attitudes to the session. RESULTS: The session received a mixed response. Only 33 (35%) thought the session was valuable and only 20 (31%) thought it was better than conventional teaching methods and yet over half (55%) said they would like to attend more PBL in special-needs dentistry. Professionals complementary to dentistry were more likely to find the PBL session of value and to prefer the method to a more conventional format than dentists were (chi-square = 5.5, df = 1, p < 0.05 and chi-square = 5.9, df = 1, p < 0.05 respectively). CONCLUSION: Valuable feedback was received from delegates. This will enable improvements to be made in future courses so that the effectiveness of PBL can be optimised.