Variability in Surgical Treatment of Spondylolisthesis Among Spine Surgeons

Background There are a multitude of treatments for low-grade lumbar spondylolisthesis. There are no clear guidelines for the optimal approach. Objective To identify the surgical treatment patterns for spondylolisthesis among United States spine surgeons. Methods 445 spine surgeons in the United States completed a survey of clinical/radiographic case scenarios on patients with lumbar spondylolisthesis with neurogenic claudication with (S+BP) or without (S−BP) associated mechanical back pain. Treatment options included decompression, laminectomy with posterolateral fusion, posterior lumbar interbody fusion, or none of the above. The primary outcome measure was the probability of 2 randomly chosen surgeons disagreeing on the treatment method. Results There was 64% disagreement (36% agreement) among surgeons for treatment of spondylolisthesis with mechanical back pain (S+BP) and 71% disagreement (29% agreement) for spondylolisthesis without mechanical back pain (S−BP). For S+BP, disagreement was 52% for those practicing 5 to 10 years versus 70% among those practicing more than 20 years. Orthopedic surgeons had greater disagreement than did neurosurgeons (76% vs. 56%) for S+BP. Greater clinical equipoise was seen for S−BP than for S+BP regardless of surgeon characteristics. For spondylolisthesis without mechanical back pain, neurosurgeons were significantly more likely to select decompression-only than were orthopedic surgeons, who more commonly selected fusion. Conclusions Clinical equipoise exists for the treatment of spondylolisthesis. Differences are greater when the patient presents without associated back pain. Surgeon case volume, practice duration, and specialty training influence operative decisions for a given pathologic condition. Recognizing this practice variation will hopefully lead to better evidence and practice guidelines for the optimal and most cost-effective treatment paradigms

Biomarkers of severity and threshold of allergic reactions during oral peanut challenges

Background: oral food challenge (OFC) is the criterion standard to assess peanut allergy (PA), but it involves a risk of allergic reactions of unpredictable severity.Objective: our aim was to identify biomarkers for risk of severe reactions or low dose threshold during OFC to peanut.Methods: we assessed Learning Early about Peanut Allergy study, Persistance of Oral Tolerance to Peanut study, and Peanut Allergy Sensitization study participants by administering the basophil activation test (BAT) and the skin prick test (SPT) and measuring the levels of peanut-specific IgE, Arachis hypogaea 2–specific IgE, and peanut-specific IgG4, and we analyzed the utility of the different biomarkers in relation to PA status, severity, and threshold dose of allergic reactions to peanut during OFC.Results: when a previously defined optimal cutoff was used, the BAT diagnosed PA with 98% specificity and 75% sensitivity. The BAT identified severe reactions with 97% specificity and 100% sensitivity. The SPT, level of Arachis hypogaea 2–specific IgE, level of peanut-specific IgE, and IgG4/IgE ratio also had 100% sensitivity but slightly lower specificity (92%, 93%, 90%, and 88%, respectively) to predict severity. Participants with lower thresholds of reactivity had higher basophil activation to peanut in vitro. The SPT and the BAT were the best individual predictors of threshold. Multivariate models were superior to individual biomarkers and were used to generate nomograms to calculate the probability of serious adverse events during OFC for individual patients.Conclusions: the BAT diagnosed PA with high specificity and identified severe reactors and low threshold with high specificity and high sensitivity. The BAT was the best biomarker for severity, surpassed only by the SPT in predicting threshold. Nomograms can help estimate the likelihood of severe reactions and reactions to a low dose of allergen in individual patients with PA

Physical activity coaching for adults with mobility limitations: protocol for the ComeBACK pragmatic hybrid effectiveness-implementation type 1 randomised controlled trial

INTRODUCTION: Mobility limitation is common and often results from neurological and musculoskeletal health conditions, ageing and/or physical inactivity. In consultation with consumers, clinicians and policymakers, we have developed two affordable and scalable intervention packages designed to enhance physical activity for adults with self-reported mobility limitations. Both are based on behaviour change theories and involve tailored advice from physiotherapists. METHODS AND ANALYSIS: This pragmatic hybrid effectiveness-implementation type 1 randomised control trial (n=600) will be undertaken among adults with self-reported mobility limitations. It aims to estimate the effects on physical activity of: (1) an enhanced 6-month intervention package (one face-to-face physiotherapy assessment, tailored physical activity plan, physical activity phone coaching from a physiotherapist, informational/motivational resources and activity monitors) compared with a less intensive 6-month intervention package (single session of tailored phone advice from a physiotherapist, tailored physical activity plan, unidirectional text messages, informational/motivational resources); (2) the enhanced intervention package compared with no intervention (6-month waiting list control group); and (3) the less intensive intervention package compared with no intervention (waiting list control group). The primary outcome will be average steps per day, measured with the StepWatch Activity Monitor over a 1-week period, 6 months after randomisation. Secondary outcomes include other physical activity measures, measures of health and functioning, individualised mobility goal attainment, mental well-being, quality of life, rate of falls, health utilisation and intervention evaluation. The hybrid effectiveness-implementation design (type 1) will be used to enable the collection of secondary implementation outcomes at the same time as the primary effectiveness outcome. An economic analysis will estimate the cost-effectiveness and cost-utility of the interventions compared with no intervention and to each other. ETHICS AND DISSEMINATION: Ethical approval has been obtained by Sydney Local Health District, Royal Prince Alfred Zone. Dissemination will be via publications, conferences, newsletters, talks and meetings with health managers. TRIAL REGISTRATION NUMBER: ACTRN12618001983291

Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy

OBJECTIVE: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. DESIGN: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival 23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. RESULTS: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. CONCLUSIONS: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings

Amyloid Precursor Protein and Proinflammatory Changes Are Regulated in Brain and Adipose Tissue in a Murine Model of High Fat Diet-Induced Obesity

Background: Middle age obesity is recognized as a risk factor for Alzheimer’s disease (AD) although a mechanistic linkage remains unclear. Based upon the fact that obese adipose tissue and AD brains are both areas of proinflammatory change, a possible common event is chronic inflammation. Since an autosomal dominant form of AD is associated with mutations in the gene coding for the ubiquitously expressed transmembrane protein, amyloid precursor protein (APP) and recent evidence demonstrates increased APP levels in adipose tissue during obesity it is feasible that APP serves some function in both disease conditions. Methodology/Principal Findings: To determine whether diet-induced obesity produced proinflammatory changes and altered APP expression in brain versus adipose tissue, 6 week old C57BL6/J mice were maintained on a control or high fat diet for 22 weeks. Protein levels and cell-specific APP expression along with markers of inflammation and immune cell activation were compared between hippocampus, abdominal subcutaneous fat and visceral pericardial fat. APP stimulation-dependent changes in macrophage and adipocyte culture phenotype were examined for comparison to the in vivo changes. Conclusions/Significance: Adipose tissue and brain from high fat diet fed animals demonstrated increased TNF-a and microglial and macrophage activation. Both brains and adipose tissue also had elevated APP levels localizing to neurons and macrophage/adipocytes, respectively. APP agonist antibody stimulation of macrophage cultures increased specific cytokin

Multiple Signals Converge on a Differentiation MAPK Pathway

An important emerging question in the area of signal transduction is how information from different pathways becomes integrated into a highly coordinated response. In budding yeast, multiple pathways regulate filamentous growth, a complex differentiation response that occurs under specific environmental conditions. To identify new aspects of filamentous growth regulation, we used a novel screening approach (called secretion profiling) that measures release of the extracellular domain of Msb2p, the signaling mucin which functions at the head of the filamentous growth (FG) MAPK pathway. Secretion profiling of complementary genomic collections showed that many of the pathways that regulate filamentous growth (RAS, RIM101, OPI1, and RTG) were also required for FG pathway activation. This regulation sensitized the FG pathway to multiple stimuli and synchronized it to the global signaling network. Several of the regulators were required for MSB2 expression, which identifies the MSB2 promoter as a target “hub” where multiple signals converge. Accessibility to the MSB2 promoter was further regulated by the histone deacetylase (HDAC) Rpd3p(L), which positively regulated FG pathway activity and filamentous growth. Our findings provide the first glimpse of a global regulatory hierarchy among the pathways that control filamentous growth. Systems-level integration of signaling circuitry is likely to coordinate other regulatory networks that control complex behaviors

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial