Aspiration thrombectomy versus stent retriever thrombectomy as first-line approach for large vessel occlusion (COMPASS): a multicentre, randomised, open label, blinded outcome, non-inferiority trial.

BACKGROUND: Stent retriever thrombectomy of large-vessel occlusion results in better outcomes than medical therapy alone. Alternative thrombectomy strategies, particularly a direct aspiration as first pass technique, while promising, have not been rigorously assessed for clinical efficacy in randomised trials. We designed COMPASS to assess whether patients treated with aspiration as first pass have non-inferior functional outcomes to those treated with a stent retriever as first line. METHODS: We did a multicentre, randomised, open label, blinded outcome, core lab adjudicated non-inferiority trial at 15 sites (ten hospitals and four specialty clinics in the USA and one hospital in Canada). Eligible participants were patients presenting with acute ischaemic stroke from anterior circulation large-vessel occlusion within 6 h of onset and an Alberta Stroke Program Early CT Score of greater than 6. We randomly assigned participants (1:1) via a central web-based system without stratification to either direct aspiration first pass or stent retriever first line thrombectomy. Those assessing primary outcomes via clinical examinations were masked to group assignment as they were not involved in the procedures. Physicians were allowed to use adjunctive technology as was consistent with their standard of care. The null hypothesis for this study was that patients treated with aspiration as first pass achieve inferior outcomes compared with those treated with a stent retriever first line approach. The primary outcome was non-inferiority of clinical functional outcome at 90 days as measured by the percentage of patients achieving a modified Rankin Scale score of 0-2, analysed by intent to treat; non-inferiority was established with a margin of 0·15. All randomly assigned patients were included in the safety analyses. This trial is registered at ClinicalTrials.gov, number: NCT02466893. FINDINGS: Between June 1, 2015, and July 5, 2017, we assigned 270 patients to treatment: 134 to aspiration first pass and 136 to stent retriever first line. A modified Rankin score of 0-2 at 90 days was achieved by 69 patients (52%; 95% CI 43·8-60·3) in the aspiration group and 67 patients (50%; 41·6-57·4) in the stent retriever group, showing that aspiration as first pass was non-inferior to stent retriever first line (pnon-inferiority=0·0014). Intracranial haemorrhage occurred in 48 (36%) of 134 in the aspiration first pass group, and 46 (34%) of 135 in the stent retriever first line group. All-cause mortality at 3 months occurred in 30 patients (22%) in both groups. INTERPRETATION: A direct aspiration as first pass thrombectomy conferred non-inferior functional outcome at 90 days compared with stent retriever first line thrombectomy. This study supports the use of direct aspiration as an alternative to stent retriever as first-line therapy for stroke thrombectomy. FUNDING: Penumbra.

Has the pandemic resulted in a renewed and improved focus on heath inequalities in England? A discourse analysis of the framing of health inequalities in national policy.

Objectives: The COVID-19 pandemic rapidly exacerbated health inequalities in England. Policy makers sought to ameliorate its impact. This paper aims to identify how health inequalities were framed in national policy documents published in England during the pandemic and how this impacts the framing of policy solutions. Study design: Discourse analysis of selected national policy documents. Methods: First, we identified relevant national policy documents through a broad search and eligibility criteria to identify illustrative policy documents. Second, we undertook a discourse analysis to understand the framing and constitution of health inequalities and consequent solutions within them. Third, we used existing health inequalities literature to critique the findings. Results: Based on analysis of six documents, we found evidence of the idea of lifestyle drift with a marked disjunction between the acknowledgement of the wider determinants of heath and the policy solutions advocated. The target population for interventions is predominantly the worst off, rather than the whole social gradient. Repeated appeals to behaviour change indicate an inherent individualist epistemology. Responsibility and accountability for health inequalities appears delegated locally without the power and resource required to deliver. Conclusion: Policy solutions are unlikely to address health inequalities. This could be done though through (i) shifting interventions towards structural factors and wider determinants of health, (ii) a positive vision of a health equitable society, (iii) a proportional universalism in approach and (iv) a delegation of power and resource alongside responsibility for delivering on health inequalities. These possibilities currently remain outside of the policy language of health inequalities.

The adjunct use of descending neurogenic-evoked potentials when transcranial motor-evoked potentials degrade into warning criteria in pediatric spinal deformity surgery: minimizing false-positive events.

PURPOSE: This studies objective was to evaluate the utility of descending neurogenic-evoked potentials (DNEPs) in the setting of transcranial motor-evoked potentials (TCeMEPs) degradation into warning criteria during pediatric spinal deformity surgery. METHODS: An institutional spinal cord monitoring database was queried to identify all primary and revision pediatric spinal deformity cases, < / = 21 years of age performed from 1/2006 to 12/2021, in which TCeMEPs were the primary motor tract assessment modality which degraded into warning criteria, with subsequent initiation of adjunct DNEPs. RESULTS: Fourteen surgical cases (0.42%; 3351 total cases) in fourteen patients met inclusion criteria. Mean age was 13.2 years (7.5-21.3). DIAGNOSES: syndromic (n = 7), kyphosis (n = 3), congenital (n = 2), and idiopathic (n = 2). Three-column osteotomies (3CO)were done in eight patients. TCeMEPs degraded into warning criteria during screw placement (n = 7), 3CO performance/closure (n = 4), or deformity correction (n = 3). DNEPs were present in all cases of warning-criteria TCeMEPs and one case had degradation of DNEPs. Intraoperative Stagnara wake-up tests were performed in only 2/14 cases, with one transient new neurologic deficit (NND). In this specific scenario, DNEPs sensitivity was 50%, specificity 100%, positive predictive value 100%, and negative predictive value 92% to detect aNND. CONCLUSION: DNEPs were useful in assessing spinal cord function in the setting of TCeMEP data degradation in complex pediatric deformity surgeries. DNEPs demonstrated a higher specificity and positive predictive value in this clinical setting than TCeMEPs when assessing long-term neurologic function after surgery. Based on this small cohort, DNEPs appear to be a useful adjunct modality to TCeMEPs, in this challenging clinical scenario.

Impact of Spinal Deformity Characteristics on Patient-reported Outcome Measurement Information System Scores in Patients With Idiopathic Scoliosis Undergoing Posterior Spinal Fusion.

INTRODUCTION: The impact of posterior spinal fusion (PSF) on physical function and pain and mental health in pediatric patients as quantified by the Patient-Reported Outcomes Measurement Information System (PROMIS), developed by the National Institute of Health, is largely unknown. The purpose of this study is to report the changes of PROMIS scores for upper extremity (UE), pain interference (PI), mobility (MOB), and peer relationships (PR) after PSF in patients with idiopathic scoliosis (IS), compare postoperative changes in PROMIS PI and Scoliosis Research Society-30 pain scores, and evaluate associations between curve characteristics and PROMIS scores. METHODS: A retrospective cohort of 122 patients (<18 years old) who underwent PSF for IS was identified through electronic medical record search. PROMIS scores were obtained preoperatively and 6 weeks, 6 months, 1 years, 2 years, and 3 years postoperatively. RESULTS: The mean age of the cohort was 14.2 ± 1.6 years, and the mean Cobb angle was 62.9 ± 13.8° at surgery. Eighty patients had preoperative PROMIS data. UE and MOB scores were statistically lower at 6 weeks and 6 months postoperatively and returned to baseline with a longer follow-up. PI scores were significantly lower at 1 and 2 years postoperatively. PR was unchanged up to 2 years postoperatively and then showed significant improvement. There was a statistically significant negative relationships between lowest instrumented vertebra and PROMIS UE and MOB scores at 6 weeks and 1 year postoperatively, but not at a longer follow-up. There were no significant differences noted in PI and PR PROMIS scores and lowest instrumented vertebra. PROMIS scores were not statistically associated with the Lenke Classification, number of vertebral levels fused, or percentage coronal correction. DISCUSSION: Changes in PROMIS functional domains (UE and MOB) postoperatively normalize at longer follow-ups. Changes in PI and PR demonstrated improvements over preoperative values at 1 to 2 years postoperatively. Preoperative coronal and sagittal measures, and the percentage correction did not correlate with any PROMIS scores.

Outcome Prediction from Behaviour Change Intervention Evaluations using a Combination of Node and Word Embedding.

Findings from randomized controlled trials (RCTs) of behaviour change interventions encode much of our knowledge on intervention efficacy under defined conditions. Predicting outcomes of novel interventions in novel conditions can be challenging, as can predicting differences in outcomes between different interventions or different conditions. To predict outcomes from RCTs, we propose a generic framework of combining the information from two sources - i) the instances (comprised of surrounding text and their numeric values) of relevant attributes, namely the intervention, setting and population characteristics of a study, and ii) abstract representation of the categories of these attributes themselves. We demonstrate that this way of encoding both the information about an attribute and its value when used as an embedding layer within a standard deep sequence modeling setup improves the outcome prediction effectiveness.

BT7480, a novel fully synthetic Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™) induces tumor localized CD137 agonism.

BACKGROUND: CD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide (Bicycle®) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™). METHODS: Nectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action. RESULTS: Transcriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists. CONCLUSION: BT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.

Attitudes to Palliative Care in Patients With Neck-of-Femur Fracture-A Multicenter Survey.

INTRODUCTION: The mortality of patients with neck-of-femur (NOF) fractures remains high, with increasing recognition of a subgroup of patients with predictable mortality. The role of palliative care in this group is poorly understood and underdeveloped. This research aims to investigate current clinician attitudes toward palliative care for patients with NOF fracture, and explore processes in place for early identification for patients nearing the end of life. MATERIALS AND METHODS: An online survey was constructed with reference to National Institute for Health and Clinical Excellence end-of-life guidelines (CG13) and distributed to multidisciplinary teams involved in the care of NOF fracture patients in 4 hospitals of contrasting size and location in the United Kingdom. RESULTS: Forty health-care professionals with a broad range of seniority and roles responded. The palliative care team was felt to have several potential roles in the care of NOF fracture patients, but there was difference of opinion between specialties about what these were. A number of barriers to palliative referral were identified, including stigma and active surgical management. The majority (75%) felt that all NOF fracture patients should have a discussion about ceiling of care, with difference of opinion about who should do so, and when. DISCUSSION: As the elderly population has grown, so too has the volume of NOF fracture patients. It is increasingly important to identify and escalate patients who have poor prognosis following hip fracture and ensure they benefit from palliative care where appropriate. This survey demonstrates a barrier to addressing the care of these patients and a lack of consensus on identification and referral to appropriate palliative care planning. CONCLUSIONS: There should be close communication between specialties with regard to requirements for palliative care in NOF fracture patients, with ongoing education and clear local and national guidance to ensure they receive the right care at the right time.

Establishing a causal link between social relationships and health using the Bradford Hill Guidelines.

An abundance of evidence suggests that the size and quality of our social relationships improves humans' physical and mental health while increasing lifespan. However most of this evidence comes from observational rather than experimental (randomised trial) evidence, leaving open the possibility that the connection between social relationships and health could be associational rather than causal. However there are examples, including the link between smoking and lung cancer, where a cause was established without experimental evidence. This was sometimes achieved by looking at the totality of evidence, using the 'Bradford Hill Guidelines', which considers factors including the strength of association, reversibility, and evidence of a plausible mechanism. In this paper we apply the Bradford Hill Guidelines to the link between social relationships and health. We conclude that having strong and supportive social relationships causes better health and longer life. Beyond establishing that social relationships are a causal factor for health, the method we used here can be applied to other areas where randomised trials are unethical or not feasible.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

Phenomenology of neurophysiologic changes during surgical treatment of carotid stenosis using signal analysis.

OBJECTIVE: To describe the changes in the shape and topology of the somatosensory evoked potential (SSEP) during carotid endarterectomy, with particular reference to the time of clamping. METHODS: Routine intraoperative monitoring was performed on 30 patients undergoing carotid endarterectomy (15) or undergoing stenting (15) using median nerve SSEPs. Post-operatively the first and second derivatives of the potential were examined. Separate analysis of the SSEP using wavelets was also performed. RESULTS: In no instances did changes in the SSEP reach clinical significance. The first derivative showed significant changes that were temporally related to the clamp period. After clamping the 'velocity' was higher than baseline. There were changes in the wavelets related to the clamp period with more marked spectral edges at the conclusion of the procedure than baseline. In all instances the patient had a good clinical outcome. CONCLUSIONS: Wavelet and derivative analysis of evoked potentials show changes that are not apparent with measures of amplitude and latency. The clinical relevance of these changes remains uncertain and await larger studies. SIGNIFICANCE: Increased velocity and spectral edges may be markers of increased cerebral blood flow, at least in the setting of pre-existing carotid stenosis.

A Case Series and Discussion on Surgical Treatment Strategy for Atypical Proximal Femoral Fractures Associated with Bisphosphonate Use.

The aim of this study was to determine the incidence of atypical femoral fractures in our local population, study their current outcomes and present a novel surgical strategy based on these data. Patients who received surgical fixation of an atypical pattern proximal femoral fracture over a four-year period were identified and followed up in the clinic until union, revision surgery or death. The local incidence of atypical femoral fractures is 1.1 per 1000 per annum amongst patients receiving bisphosphonates. Twelve fixation procedures were carried out in 10 patients. Intra-operative reduction and nailing led to an average deformity of 8.5° varus and 13° apex anterior. Five cases required revision surgery. Fifty percent of primary procedures resulted in radiographic union within two years. We suggest that the lateral side of the fracture should be considered a primary nonunion. We advocate undertaking a wedge excision to correct the bone to a valgus morphology and stabilising with an intramedullary nail and a lateral tension plate. Multicentre studies are needed to demonstrate the efficacy of any particular approach.

In vivo bioassay-guided fractionation of marine sediment extracts from the Southern California Bight, USA, for estrogenic activity.

The exposure and uptake of environmental estrogenic compounds have been reported in previous studies of demersal flatfish species in the central Southern California Bight (SCB), USA. The objective of this study was to evaluate the estrogenic or feminizing activity of marine sediments from the SCB by using in vivo vitellogenin (VTG) assays in male or juvenile fish. In 2003, sediments were collected near wastewater outfalls serving the counties of Los Angeles (LACSD) and Orange (OCSD), and the city of San Diego (SD), California, USA. Cultured male California halibut (CH; Paralichthys californicus) were either directly exposed to sediments for 7 d or treated with two intraperitoneal injections of sediment extract over 7 d. The 17beta-estradiol (E2) equivalent values ranged from 1 to 90 microg/kg with LACSD > SD > OCSD. Measurable concentrations of E2 were observed in all sediment extracts and ranged from 0.16 to 0.45 ng/g. Estrone (El) was only observed in sediments near the LACSD outfall (0.6 ng/g). Alkylphenols and alkylphenol ethoxylates were observed in all sediment samples, but were highest near the OCSD outfall, where concentrations of nonylphenol were 3,200 ng/g. Fractionation studies of the LACSD sediment extract collected in 2004 failed to demonstrate relationships between VTG expression and 62 analytes, including E2, which was observed in the whole extract (2.9 ng/g). Oxybenzone (1.6 ng/g) was identified in bioactive fractions as well as unknown compounds of relatively high polarity. These results indicate that estrogen receptor-based assays may underestimate environmental estrogenic activity and estrogenic compounds other than classic natural and xenoestrogens may contribute to estrogenic activity of sediments from the SCB.

A correlation between a proteomic evaluation and conventional measurements in the assessment of renal proximal tubular toxicity.

4-Aminophenol (4-AP), D-serine, and cisplatin are established rodent nephrotoxins that damage proximal tubules within the renal cortex. Using high throughput 2D gel proteomics to profile protein changes in the plasma of compound-treated animals, we identified several markers of kidney toxicity. Male F344 and Alpk rats were treated with increasing doses of 4-AP, D-serine, or cisplatin, and plasma samples were collected over time. Control groups received saline or nontoxic isomers, L-serine, and transplatin. Plasma proteins that displayed dose- and temporal-dependent regulation in each study were further characterized by mass spectrometry to elucidate the protein identity. Several isoforms of the rat-specific T-kininogen protein were identified in each study. T-kininogen was elevated in the plasma of 4-AP-, D-serine-, and cisplatin-treated animals at early time points, returning to baseline levels 3 weeks after treatment. The protein was not elevated in the plasma of control animals or those treated with nontoxic compounds. We propose that T-kininogen may be required to counteract apoptosis in proximal tubular cells in order to minimize tissue damage following a toxic insult. In addition, T-kininogen may be required to stimulate localized inflammation to aid tissue repair. We also identified several isoforms of the inter-alpha inhibitor H4P heavy chain in the 4-AP and D-serine studies. In each case, the protein expression levels in the blood samples paralleled the extent of kidney toxicity, highlighting the correlation between protein alterations and clinical chemistry endpoints. A further set of proteins correlating with kidney damage was found to be a component of the complement cascade and other blood clotting factors, indicating a contribution of the immune system to the observed toxicity. These observations underscore the value of proteomics in identifying new biomarkers and in the elucidation of mechanisms of toxicity.

Weather system scale variation in radon-222 concentration of indoor air.

Radon-222 concentration measurements using the charcoal adsorption technique were made continuously over periods of up to 2 years in three houses, two rural and one urban. The measurement records for all houses show a variation in radon concentration on a seasonal scale on which is superimposed shorter periods of relatively large magnitude fluctuations on a scale longer than the typically 4-5-day measurement duration. Regression analysis using meteorological data from a weather station remote from the houses shows that much of the variation in both monthly and 3-day mean radon concentration can be explained by regional scale external temperature variation. Wind speed, rainfall and barometric pressure apparently influence the 3-day values to a much smaller degree. Differences in the radon levels between the houses reflect the different geological radon potential of the two areas, with notably higher levels over limestone than glacial till and sandstone. Other differences within and between houses reflect house construction and occupancy factors.

Study design and rationale of a dose-ranging trial of LX4211, a dual inhibitor of SGLT1 and SGLT2, in type 2 diabetes inadequately controlled on metformin monotherapy.

Sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) are the major cellular transporters responsible for gastrointestinal (GI) glucose absorption and renal glucose reabsorption, respectively. LX4211, a dual inhibitor of SGLT1 and SGLT2, reduces glucose absorption from the GI tract and enhances urinary glucose excretion. Although several SGLT2-selective inhibitors have been tested in large phase 2 studies, dual inhibition of SGLT1 and SGLT2 is novel at this stage of drug development, and it has implications for clinical-trial design. In this article, we describe the design and rationale of a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of LX4211 in subjects with type 2 diabetes mellitus who have inadequate glycemic control on metformin monotherapy. The primary endpoint is the change in glycated hemoglobin A1c from baseline to week 12. Secondary endpoints include the proportion of subjects achieving a glycated hemoglobin A1c value of <7%, change from baseline in fasting plasma glucose and postprandial glucose (as part of an oral glucose tolerance test), body weight, and blood pressure. Safety is evaluated with particular focus on hypoglycemia, GI symptoms, and incidence of genitourinary tract infections.

Who cares............For the carers?

This paper is about carers; a family member or members who provide unpaid care to a loved one with a chronic condition. Caring for someone who is chronically ill permeates every aspect of life. Dreams may be shattered, plans for the future may have to be radically altered or shelved permanently. Psychological stress is common, but many carers find it difficult to access services. Resources are there to support the person diagnosed, or, on treatment. What resources are directed to the care and support of carers? Drawing on relevant literature and my own clinical experience I give examples of the demands, often unrelenting, and difficulties carers face. I suggest some interventions that can support and facilitate carers, enabling them to continue their role in a healthy, life giving manner.

Prevalence of cognitive impairment in patients attending pre-dialysis clinic.

Approximately 20-30% of patients on renal replacement therapy (RRT) have cognitive impairment. Less is known about the prevalence of cognitive impairment in patients with advanced kidney disease awaiting the initiation of dialysis. Routine cognitive assessment was implemented in the pre-dialysis clinic, which enabled the Nephrologist and Pre-dialysis Nurse to identify those patients with impaired cognitive function and utilise this information to assess the suitability for self-care treatments, such as peritoneal dialysis, as well as to adapt information to meet their needs. Subsequently, a cross-sectional single-centre audit was undertaken to identify the prevalence of cognitive impairment in 132 consecutive new referrals to the pre-dialysis clinic using the Mini-mental State Examination (MMSE). Twenty percent (95% CI = 0.13, 0.27) were classified as cognitively impaired. Those with cognitive impairment were significantly older, and had lower eGFR and higher serum creatinine. It can be concluded that approximately 1 in 5 patients attending the pre-dialysis clinic has cognitive impairment, which may not be apparent on a routine clinical history. Cognitive function assessment is recommended for all, but particularly to the older patient, before advising on choice of dialysis modality or opting for conservative treatment.