Emergency treatment of peri-operative anaphylaxis: Resuscitation Council UK algorithm for anaesthetists.

Peri-operative anaphylaxis is a rare but potentially catastrophic event which must be considered whenever unexpected and significant cardiovascular or respiratory compromise occurs during anaesthesia. The Resuscitation Council UK algorithm for peri-operative anaphylaxis highlights the importance of early intravenous adrenaline and fluid resuscitation and provides guidance on the treatment of refractory anaphylaxis and immediate follow-up. This algorithm is endorsed by the Royal College of Anaesthetists, Association of Anaesthetists, British Society of Allergy and Clinical Immunology and Clinical Immunology Professional Network of the British Society for Immunology. This document was produced by the Perioperative Allergy Network steering committee in collaboration with the Resuscitation Council UK.

Is the prefrontal cortex organized by supramodal or modality-specific sensory demands during adolescence?

Attention is inherently biased towards the visual modality during most multisensory scenarios in adults, but the developmental trajectory towards visual dominance has not been fully elucidated. More recent evidence in primates and adult humans suggests a modality-specific stratification of the prefrontal cortex. The current study therefore used functional magnetic resonance imaging (fMRI) to investigate the neuronal correlates of proactive (following cues) and reactive (following probes) cognitive control for simultaneous audio-visual stimulation in 67 healthy adolescents (13-18 years old). Behavioral results were only partially supportive of visual dominance in adolescents, with both reduced response times and accuracy during attend-visual relative to attend-auditory trials. Differential activation of medial and lateral prefrontal cortex for processing incongruent relative to congruent stimuli (reactive control) was also only observed during attend-visual trials. There was no evidence of modality-specific prefrontal cortex stratification during the active processing of multisensory stimuli or during separate functional connectivity analyses. Attention-related modulations were also greater within visual relative to auditory cortex, but were less robust than observed in previous adult studies. Collectively, current results suggest a continued transition towards visual dominance in adolescence, as well as limited modality-specific specialization of prefrontal cortex and attentional modulations of unisensory cortex.

A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy.

AIMS: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. MATERIALS AND METHODS: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. RESULTS: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). CONCLUSION: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

Do orthopaedic trauma patients develop higher rates of cardiac complications? An analysis of 56,000 patients.

PURPOSE: Less than 5 % of orthopaedic patients develop postoperative cardiac complications; however, there are little data suggesting which orthopaedic patients are at greatest risk. In an era where emerging reimbursement models place an emphasis on quality, reducing complications through perioperative planning will be of paramount importance for orthopaedic surgeons. The purpose of this study was to determine whether orthopaedic trauma patients are at greater risk for postoperative cardiac complications and to reveal which factors are most predictive of these complications. METHODS: All orthopaedic patients were identified in the 2006-2013 ACS-NSQIP database. Cardiac complications were defined as cardiac arrests or myocardial infarctions within 30 days following surgery. Chi squared analysis determined differences in cardiac complication rates between trauma and non-trauma patients. Bivariate analysis incorporating over 40 patient/surgical characteristics determined significant associations between patient characteristics and cardiac complications. These factors were incorporated into a multivariate regression model to identify predictive risk factors for cardiac complications. RESULTS: The presence of a traumatic injury resulted in greater odds of developing cardiac complications (OR: 1.645, p < 0.001). The cardiac complication rate in the trauma group was 1.3 % compared to 0.3 % in the non-trauma group (p < 0.001). For trauma patients, ventilator use (OR: 27.354, p = 0.004), recent transfusion (OR: 19.780, p = 0.001), and history of coma (OR: 17.922, p = 0.020) were most predictive of cardiac complications. CONCLUSION: Orthopaedic trauma patients are more likely to develop cardiac complications than non-trauma patients. To reduce cardiac complications, orthopaedic traumatologists should be aware of patient risk factors including ventilator use, blood transfusion, and history of coma.

Body mass index predicts perioperative complications following orthopaedic trauma surgery: an ACS-NSQIP analysis.

PURPOSE: The impact of obesity on outcomes has been documented extensively in the elective orthopaedic literature, but little is known about the impact of obesity on outcomes following orthopaedic trauma surgery. Utilizing the ACS-NSQIP database, we sought to investigate the relationship between BMI and perioperative complications in orthopaedic trauma patients. METHODS: 53,219 orthopaedic trauma patients were identified using a CPT code search between 2005 and 2013 in the NSQIP database. Patient demographics, and perioperative complications (including minor, major, and total) were collected. Multivariate regression analysis was performed to control for baseline demographics and comorbidities. RESULTS: Compared with patients of normal weight, underweight patients had significantly greater odds of minor [OR 1.12, 95 % CI (1.0, 1.26), p = 0.04], major [OR 1.20, 95 % CI (1.1, 1.3), p = 0.0009], and total complications [OR 1.18, 95 % CI (1.1, 1.3), p = 0.0003]. Morbidly obese patients had significantly greater odds of major [OR 1.22, 95 % CI (1.0, 1.5), p = 0.023] and total complications [OR 1.18, 95 % CI (1.0, 1.4), p = 0.023] compared to normal weight patients. When wound-related complications were examined independently, obesity was associated with increased odds of superficial [OR 1.67, 95 % CI (1.3, 2.1), p < 0.0001] and deep wound infection [OR 1.52, 95 % CI (1.075, 2.144), p = 0.018], and morbid obesity was associated with increased odds of wound dehiscence [OR 2.29, 95 % CI (1.1, 4.9), p = 0.034] and deep infection [OR 2.51, 95 % CI (1.6, 3.9), p < 0.0001]. CONCLUSIONS: Morbidly obese patients have significantly greater odds of wound dehiscence, deep wound infection, major complications, and total complications compared to patients of normal weight. Additionally, BMI under 18.5 is associated with increased odds of minor, major, and total perioperative complications. Interventions aimed at decreasing complication rates should be targeted at these high-risk patient populations on both ends of the BMI spectrum.

Predictors of 30-day mortality following hip/pelvis fractures.

INTRODUCTION: With the cost of healthcare in the United States reaching $2.9 trillion in 2013 and expected to increase with a growing geriatric population, the Center for Medicare and Medicaid Services (CMS) and Hospital Quality Alliance (HQA) began publicly reporting 30-day mortality rates so that hospitals and physicians may begin to confront clinical problems and promote high-quality and patient-centered care. Though the 30-day mortality is considered a highly effective tool in measuring hospital performance, little data actually exists that explores the rate and risk factors for trauma-related hip and pelvis fractures. Therefore, in this study, we sought to explore the risk factors associated with 30-day mortality in trauma-related hip and pelvic fractures. MATERIALS AND METHODS: Utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, 341,062 patients undergoing orthopaedic procedures from 2005 to 2013 were identified through a Current Procedural Terminology (CPT) code search. A second CPT code search identified 24,805 patients who sustained a hip/pelvis fracture. Patient demographics, preoperative comorbidities, operative characteristics and postoperative complications were collected and compared using Chi-squared test, Wilcoxon-Mann-Whitney test and multivariate logistic regression analysis. RESULTS: Preoperative and postoperative risk factors for 30-day mortality following a hip/pelvis fracture were found: ASA classification, ascites, disseminated cancer, dyspnea, functional status, history of congestive heart failure (CHF), history of chronic obstructive pulmonary disease (COPD), a recent blood transfusion, and the postoperative complications: pneumonia, myocardial infarction, stroke, and septic shock. DISCUSSION: Several preoperative patient risk factors and postoperative complications greatly increased the odds for patient mortality following 30-days after initial surgery. Orthopaedic surgeons can utilize these predictive risk factors to better improve patient care. LEVEL OF EVIDENCE: Retrospective study. Level IV.

Fatigue in people with localized colorectal cancer who do and do not receive chemotherapy: a longitudinal prospective study.

BACKGROUND: Fatigue is associated with cancer and chemotherapy and may be sustained. Here, we describe a prospective longitudinal study evaluating fatigue and putative mechanisms in people with colorectal cancer (CRC). PATIENTS AND METHODS: People with localized CRC completed the Functional Assessment of Cancer Treatment-Fatigue (FACT-F) questionnaire at baseline (before chemotherapy, if given), 6, 12, and 24 months. Healthy controls (HCs) were assessed at the first three time points. Fatigue was defined by standardized FACT-F scores ≤68/100. Quality-of-life (QoL, assessed by the FACT-G questionnaire), affective, and cognitive symptoms were evaluated. Associations were sought between fatigue, baseline factors, and blood tests (including hemoglobin, cytokines, and sex hormones). Regression analyses, Fisher's exact tests, and Wilcoxon rank-sum tests assessed levels of fatigue at each time point and change in fatigue from baseline. A repeated-measures analysis investigated prognostic factors of fatigue across all time points. RESULTS: A total of 289 subjects with localized CRC (173 received chemotherapy) and 72 HCs were assessed. More CRC patients had fatigue than HCs at baseline (52% versus 26%, P < 0.001). Fatigue was increased in the chemotherapy (CTh) group at 6 months [CTh+ 70% versus CTh- 31% (P < 0.001), HCs 22%] and remained more common at 12 [CTh+ 44% versus CTh- 31% (P = 0.079)] and 24 months [CTh+ 39% versus CTh- 24% (P = 0.047)]. There was no significant difference between those not receiving chemotherapy and HCs at follow-up assessments. Fatigue was associated with poor QoL, affective and cognitive symptoms, but not consistently with cytokine levels. Predictors for sustained fatigue were baseline fatigue, treatment group, cognitive and affective symptoms, poorer QoL, and comorbidities. CONCLUSIONS: CRC patients have more fatigue than HCs at baseline. Fatigue peaks immediately after adjuvant chemotherapy, but remains common for 2 years in those who receive chemotherapy. Cognitive and affective symptoms, QoL, comorbidities, chemotherapy, and baseline fatigue predict for longer term fatigue.

Assessment of functional outcomes of surgically managed acetabular fractures: a systematic review.

UNLABELLED: We performed a systematic review of the literature pertaining to the functional outcomes of the surgical management of acetabular fractures. A total of 69 articles met our inclusion criteria, revealing that eight generic outcome instruments were used, along with five specific instruments. The majority of studies reported outcomes using a version of the d'Aubigne and Postel score, which has not been validated for use in acetabular fracture. Few validated outcome measures were reported. No psychometric testing of outcome instruments was performed. The current assessment of outcomes in surgery for acetabular fractures lacks scientific rigour, and does not give reliable outcome data for either scientific comparison or patient counselling. TAKE HOME MESSAGE: The use of non-validated functional outcome measures is a major limitation of the current literature pertaining to surgical management of acetabular fractures; future studies should use validated outcome measures to ensure the legitimacy of the reported results. Cite this article: Bone Joint J 2016;98-B:690-5.

The "Down the PC" view - A new tool to assess screw positioning in the posterior column of the acetabulum.

INTRODUCTION: Minimal-invasive placement of screws into the posterior column of the acetabulum (PC) is challenging. Due to the saddle-shaped curvature of the medial cortical border of the PC, the standard fluoroscopic views of the pelvis cannot provide the desired safety during screw insertion. The aim of this study was to define a view tangentially to the medial cortex of the PC and to evaluate its accuracy and inter-observer reproducibility. METHODS: Radio-dense markers on the medial cortex of the PC along the axis of a PC screw were brought in line and landmarks of the new "Down the PC" view were determined. Kirschner wires were placed into the PC of a pelvis composite model and five pelvic cadaver specimens in a total of 34 different correct and incorrect positions. Based on either only the "Down the PC" view, only the standard views, or a combination of both, three fellowship-trained orthopaedic surgeons had to decide if the inserted wires were in bone in the posterior column or had exited cortex, and if they penetrated the acetabulum. Sensitivity, specificity, and the intra-class correlation coefficient were calculated. RESULTS: A view using three radiographic landmarks (pelvic brim, medial cortical wall of the body of the ischium, ischial spine) was found. Sensitivity and specificity to detect perforation out of the bone were 1.00 and 0.97 for the "Down the PC" view, 0.46 and 0.97 if only the standard views were used, and 1.00 and 0.95 for a combination of both. Sensitivity and specificity to detect intra-articular wire placement were 1.00 and 0.96 for the "Down the PC" view, 0.72 and 0.95 if only the standard views were used, and 0.94 and 0.99 for a combination of both. Inter-observer agreement using only the "Down the PC" view was excellent with an ICC of 0.92 for perforation and ICC of 0.82 for intra-articular wire placement. CONCLUSIONS: The "Down the PC" view is a useful addendum in the orthopaedic trauma surgeon's tool box. Using simple landmarks, it is easily to reproduce and thereby shows excellent accuracy and inter-observer agreement in order to detect medial perforation or intra-articular implant position.

Feasibility and acceptability of web-based enhanced relapse prevention for bipolar disorder (ERPonline): trial protocol.

BACKGROUND: Relapse prevention interventions for Bipolar Disorder are effective but implementation in routine clinical services is poor. Web-based approaches offer a way to offer easily accessible access to evidence based interventions at low cost, and have been shown to be effective for other mood disorders. METHODS/DESIGN: This protocol describes the development and feasibility testing of the ERPonline web-based intervention using a single blind randomised controlled trial. Data will include the extent to which the site was used, detailed feedback from users about their experiences of the site, reported benefits and costs to mental health and wellbeing of users, and costs and savings to health services. We will gain an estimate of the likely effect size of ERPonline on a range of important outcomes including mood, functioning, quality of life and recovery. We will explore potential mechanisms of change, giving us a greater understanding of the underlying processes of change, and consequently how the site could be made more effective. We will be able to determine rates of recruitment and retention, and identify what factors could improve these rates. DISCUSSION: The findings will be used to improve the site in accordance with user needs, and inform the design of a large scale evaluation of the clinical and cost effectiveness of ERPonline. They will further contribute to the growing evidence base for web-based interventions designed to support people with mental health problems.

Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis.

OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.

Cognitive function and fatigue after diagnosis of colorectal cancer.

BACKGROUND: Cognitive impairment and fatigue have been associated with cancer and its treatment. We present baseline data from a large longitudinal study that evaluates cognitive function, fatigue, and potential underlying mechanisms following diagnosis of colorectal cancer (CRC). PATIENTS AND METHODS: We evaluated CRC patients with stage I-III disease before or after surgery, participants with limited metastatic disease and healthy controls (HC). Neuropsychological evaluation included clinical and computerised tests. Participants completed questionnaires for fatigue and quality of life (QOL)-(FACT-F), anxiety/depression, and cognitive symptoms (FACT-Cog). Ten cytokines, clotting factors, sex hormones, carcinoembryonic antigen (CEA), and apolipoprotein E genotype were evaluated. Primary end points were cognitive function on clinical tests evaluated by a Global Deficit score (GDS) and fatigue. Associations between test results, demographic, and disease related factors were explored. RESULTS: We assessed 291 participants with early-stage disease [median age 59 (23-75) years, 63% men], 72 with metastatic disease, and 72 HC. Using GDS, 45% (126/281) of participants with early-stage CRC had cognitive impairment versus 15% (11/72) of HC (odds ratio 4.51, 95% confidence interval 2.28-8.93; P < 0.001), with complex processing speed, attention/working memory, and verbal learning efficiency being most affected. Women with early-stage CRC had greater cognitive impairment than men [55/105 (52%) versus 71/176 (40%), P < 0.050]. Cognitive symptoms were self-reported by 21% (59/286) of early-stage patients versus 17% (12/72) of HC; fatigue by 52% (149/287) of early-stage patients and 26% (19/72) of HC (P < 0.0001). Women reported more fatigue than men (P = 0.003). Fatigue, QOL, anxiety/depression, and cognitive symptoms were associated with each other (r = 0.43-0.71), but not with neuropsychological performance. Most cytokines were elevated in cancer patients. Cognitive function was not associated with cytokines, sex hormones, clotting factors, CEA, or apolipoprotein E genotype. CONCLUSIONS: The incidence of cognitive impairment was three to five times higher in CRC patients than HC, with women having higher impairment rates than men. The cognitive impairment profile suggests dysfunction primarily in fronto-subcortical brain systems. TRIAL REGISTRATION: NCT00188331.

The effect of serum matrix and gender on cortisol measurement by commonly used immunoassays.

BACKGROUND: Considerable intermethod bias has been observed between cortisol immunoassays, with some also displaying a gender difference. Cortisol immunoassay performance is affected by serum matrix effects such as changes in steroid binding proteins and presence of interfering steroids which can be altered in various clinical settings. This study investigates cortisol immunoassay bias in pregnancy, renal failure and intensive care patients. METHODS: Serum remaining after routine analysis from pregnant patients, patients on the intensive care unit and patients with renal failure were obtained prior to disposal and used to create 20 anonymous samples per group. A male and female serum pool was prepared and spiked with cortisol. Samples were aliquoted and distributed to four hospitals for cortisol analysis by immunoassays from four different manufacturers. Cortisol was also measured by an isotope dilution-gas chromatography-mass spectrometry method for comparison of assay bias. RESULTS: Differences in cortisol immunoassay bias were observed across the different patient groups. A negative bias compared to pooled serum samples was observed for pregnancy serum, whilst a more positive bias was seen in renal failure and intensive care patients. Variation in bias was greatest in renal failure with the Roche E170 the most affected and the Abbott architect the least (interquartile ranges 44% and 14%, respectively). CONCLUSIONS: Cortisol immunoassay bias may be affected by gender and differences in serum matrix from patients with various clinical conditions. Users of cortisol assays should be aware of differing matrix effects on their assay and the relevance of these for the interpretation of clinical results.

A randomized double-blind placebo-controlled cross-over trial of the impact on quality of life of continuing dexamethasone beyond 24 h following adjuvant chemotherapy for breast cancer.

Uncertainty remains about the optimal anti-emetic regimen for control of delayed nausea and vomiting after adjuvant chemotherapy for breast cancer. Many patients receive dexamethasone but complain of insomnia, anxiety/agitation, and indigestion. The aim was to determine if patients receiving chemotherapy for breast cancer prefer treatment with dexamethasone or placebo for prophylaxis against delayed nausea and vomiting, and to compare quality of life (QOL) between the two treatments. In this randomized, double-blind, cross-over trial, we compared oral dexamethasone (4 mg twice daily for 2 days) versus placebo for chemotherapy-naïve patients with breast cancer. All patients received intravenous granisetron and dexamethasone pre-chemotherapy and oral granisetron on day 2. Primary endpoints were: (i) patient preference; (ii) difference between cycles in change of QOL from days 1 to 8. Median age of the 94 women was 51 years (range 27-76): 79 received fluorouracil/epirubicin/cyclophosphamide and 15 received doxorubicin/cyclophosphamide. Thirteen withdrew pre-cycle 2 with no differences between arms. Of 80 patients stating a preference, 31 preferred placebo (39 %, 95 % CI: 28-50 %) and 37 (46 %, 95 % CI: 35-58 %) preferred dexamethasone; 12 had no preference. There were no differences in intensity of vomiting, nausea, or time to onset of vomiting. There was greater decrease in global QOL (p = 0.06) when patients received dexamethasone. No other symptom/QOL domains differed significantly. In conclusion, no significant difference was found in patient preference, QOL, or symptoms regardless of whether dexamethasone or placebo was used after adjuvant chemotherapy.

Gene expression analysis reveals HBP1 as a key target for the osteoarthritis susceptibility locus that maps to chromosome 7q22.

OBJECTIVES: An osteoarthritis (OA) susceptibility locus has been mapped to chromosome 7q22, to a region of high-linkage disequilibrium encompassing six genes: PRKAR2B, HBP1, COG5, GPR22, DUS4L and BCAP29. The authors assessed whether these genes were subject to cis-acting regulatory polymorphisms that are active in joint tissues and which could contribute to the association signal. METHODS: Using joint tissues from 156 patients with OA, and control cartilage from 25 patients who had neck of the femur fractures, the authors measured the overall gene expression by quantitative PCR and the allelic expression of the genes, using an assay that can distinguish mRNA output from each allele of a transcript single nucleotide polymorphism. RESULTS: Five of the genes were expressed in joint tissues, the exception being GPR22, which the authors could not detect. In OA cartilage compared with control cartilage, significantly reduced expression levels were observed for these five genes. Carriers of the OA-associated alleles showed a significant reduction in expression of HBP1 in cartilage (p=0.0002) and synovium (p=0.02), and of DUS4L in fat pad (p=0.04). HBP1 and DUS4L also demonstrated allelic expression imbalance across a range of different joint tissues, with carriers of the associated allele showing an HBP1 allelic expression imbalance profile that was significantly different from non-carriers (p=0.008). CONCLUSION: Cis-acting regulatory polymorphisms acting on HBP1 contribute to the OA association signal at chromosome 7q22. HBP1 codes for a transcription factor and studies by the authors have enabled them to prioritise this gene for further investigation.

Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma.

BACKGROUND AND PURPOSE: IL-13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. Here we describe the preclinical in vitro and in vivo characterization of CAT-354, an IL-13-neutralizing IgG4 monoclonal antibody (mAb), currently in clinical development. EXPERIMENTAL APPROACH: In vitro the potency, specificity and species selectivity of CAT-354 was assayed in TF-1 cells, human umbilical vein endothelial cells and HDLM-2 cells. The ability of CAT-354 to modulate disease-relevant mechanisms was tested in human cells measuring bronchial smooth muscle calcium flux induced by histamine, eotaxin generation by normal lung fibroblasts, CD23 upregulation in peripheral blood mononuclear cells and IgE production by B cells. In vivo CAT-354 was tested on human IL-13-induced air pouch inflammation in mice, ovalbumin-sensitization and challenge in IL-13 humanized mice and antigen challenge in cynomolgus monkeys. KEY RESULTS: CAT-354 has a 165 pM affinity for human IL-13 and functionally neutralized human, human variant associated with asthma and atopy (R130Q) and cynomolgus monkey, but not mouse, IL-13. CAT-354 did not neutralize human IL-4. In vitro CAT-354 functionally inhibited IL-13-induced eotaxin production, an analogue of smooth muscle airways hyperresponsiveness, CD23 upregulation and IgE production. In vivo in humanized mouse and cynomolgus monkey antigen challenge models CAT-354 inhibited airways hyperresponsiveness and bronchoalveolar lavage eosinophilia. CONCLUSIONS AND IMPLICATIONS: CAT-354 is a potent and selective IL-13-neutralizing IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate to severe uncontrolled asthma.

Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus.

OBJECTIVE: The common single nucleotide polymorphism (SNP) rs143383 in the 5' untranslated region (5'UTR) of growth and differentiation factor 5 (GDF5) is strongly associated with osteoarthritis (OA) and influences GDF5 allelic expression in vitro and in the joint tissues of OA patients. This effect is modulated in cis by another common SNP, also located within the 5'UTR, whilst a common SNP in the 3'UTR influences allelic expression independent of rs143383. DNA variants can be common, rare or extremely rare/unique. To therefore enhance our understanding of the allelic architecture of this very important OA susceptibility locus we sequenced the gene for potentially functional and novel rare variants. METHOD: Using the Sanger method we sequenced GDF5 in 992 OA patients and 944 controls, with DNA changes identified by sequencing software. We encompassed the protein-coding region of the two GDF5 exons, both untranslated regions and approximately 100 bp of the proximal promoter of the gene. RESULTS: We detected 13 variants. Six were extremely rare with minor allele frequencies (MAFs) of ≤ 0.0006. One is in a predicted transcription factor binding site in the GDF5 promoter whilst two substitute conserved amino acids. The remaining seven variants were common and are previously known variants, with MAFs ranging from 0.025 to 0.39. There was a complete absence of variants with frequencies in-between the extremely rare (n=6) and the common (n=7). CONCLUSIONS: This is the first report of the deep sequencing of an OA susceptibility locus. The absence of rare variants informs us that within the regions of the gene that we have sequenced GDF5 does not harbour any novel variants that are able to contribute, at a population level, to the OA association signal mediated by rs143383 nor does it harbour, at a population level, any novel variants that can influence OA susceptibility independent of rs143383.