The receptor protein tyrosine phosphatase PTPRK promotes intestinal repair and catalysis-independent tumour suppression.

PTPRK is a receptor tyrosine phosphatase that is linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. PTPRK regulates cell-cell adhesion but is also reported to regulate numerous cancer-associated signalling pathways. However, the signalling mechanism of PTPRK remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.

Robot-Assisted Pelvic Dissection for Enlarged Lymph Nodes in Melanoma Improves Recovery with Equivalent Oncological Outcomes to Open Pelvic Dissection.

BACKGROUND: Robot-assisted pelvic lymph node dissection (rPLND) has been reported in heterogenous groups of patients with melanoma, including macroscopic or at-high-risk-for microscopic metastasis. With changing indications for surgery in melanoma, and availability of effective systemic therapies, pelvic dissection is now performed for clinically detected bulky lymph node metastasis followed by adjuvant drug therapy. rPLND has not been compared with open pelvic lymph node dissection (oPLND) for modern practice. METHODS: All patients undergoing pelvic node dissection for macroscopic melanoma at a single institution were reviewed as a cohort, observational study. RESULTS: Twenty-two pelvic lymph node dissections were identified (8 oPLND; 14 rPLND). The number of pelvic lymph nodes removed was similar (median oPLND 6.5 (interquartile range [IQR] 6.0-12.5] versus rPLND 6.0 [3.75-9.0]), with frequent matted nodes (11/22, 50.0%). Operative time (median oPLND 130 min [IQR 95.5-182] versus rPLND 126 min [IQR 97.8-160]) and complications (Clavien-Dindo scale) were similar. Length of hospital stay (median 5.34 days (IQR 3.77-6.94) versus 1.98 days (IQR 1.39-3.50) and time to postoperative adjuvant therapy (median 11.6 weeks [IQR 10.6-18.5] versus 7.71 weeks [IQR 6.29-10.4]) were shorter in the rPLND group. No differences in pelvic lymph node recurrence (p = 0.984), distant metastatic recurrence (p = 0.678), or melanoma-specific survival (p = 0.655) were seen (median follow-up 21.1 months [rPLND] and 25.7 months [oPLND]). CONCLUSIONS: rPLND is an effective way to remove bulky pelvic lymph nodes in melanoma, with a shorter recovery and reduced interval to initiating adjuvant therapy compared with oPLND. This group of patients may especially benefit from neoadjuvant systemic approaches to management.

IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage.

Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1-dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.

The peptide symporter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease representing a serious unmet medical need. The disease is associated with the loss of self-tolerance and exaggerated B cell activation, resulting in autoantibody production and the formation of immune complexes that accumulate in the kidney, causing glomerulonephritis. TLR7, an important mediator of the innate immune response, drives the expression of type-1 interferon (IFN), which leads to expression of type-1 IFN induced genes and aggravates lupus pathology. Because the lysosomal peptide symporter slc15a4 is critically required for type-1 interferon production by pDC, and for certain B cell functions in response to TLR7 and TLR9 signals, we considered it as a potential target for pharmacological intervention in SLE. We deleted the slc15a4 gene in C57BL/6, NZB, and NZW mice and found that pristane-challenged slc15a4-/- mice in the C57BL/6 background and lupus prone slc15a4-/- NZB/W F1 mice were both completely protected from lupus like disease. In the NZB/W F1 model, protection persisted even when disease development was accelerated with an adenovirus encoding IFNα, emphasizing a broad role of slc15a4 in disease initiation. Our results establish a non-redundant function of slc15a4 in regulating both innate and adaptive components of the immune response in SLE pathobiology and suggest that it may be an attractive drug target.

Comparison of patients satisfaction with aesthetic outcomes following lower extremity reconstruction: Muscle vs. fasciocutaneous free flaps.

BACKGROUND: The microsurgical reconstruction of complex lower limb defects has become a routine procedure with high success rates. The emphasis has changed from ensuring flap 'success' to providing a reconstruction, which is also aesthetically pleasing. The aim of this study was to compare patients' satisfaction with aesthetic outcomes, following muscle or fasciocutaneous free flap reconstruction to the lower limb. METHODS: Data were collected retrospectively between July, 2013 and May, 2018 at a single institution. The inclusion criteria were adult patients who had successful free tissue transfers to the lower limb following any aetiology. A Likert Scale questionnaire was sent to all patients who met these criteria. The questionnaire included questions related to the reconstruction and donor site. RESULTS: Questionnaires were sent to 83 patients who met the inclusion criteria. Forty-seven (57%) patients responded, of which 22 (47%) underwent reconstruction with muscular flap and 25 (53%) with fasciocutaneous flap. A statistically significant difference between the two groups was found in relation to flap texture (p = 0.003). Patients with fasciocutaneous flap reconstruction being more satisfied. No significant difference was observed for contour, similarity to the contralateral side, bulkiness of flap, colour match, scar, or overall appearance. The comparison of donor site results revealed no significant difference between the two groups CONCLUSIONS: Despite increase in success in lower extremity reconstruction, many patients still find aesthetic results suboptimal and this affects an individual's global sense of well-being. Aesthetic restoration should be viewed as an integral part of lower limb reconstruction. LEVEL OF EVIDENCE: Therapeutic, III.

The Overall Poor Specificity of MRCP in the Preoperative Evaluation of the Jaundiced Patient Will Increase the Incidence of Nontherapeutic ERCP.

Laparoscopic cholecystectomy remains one of the most common surgical operations. Common bile duct stones (CBDS) are estimated to be present in 10%-20% of individuals with symptomatic gallstones. Preoperative magnetic resonance cholangiopancreatography (MRCP) and intraoperative cholangiography (IOC) remain the most common methods of evaluation, with subsequent endoscopic retrograde cholangiopancreatography (ERCP) for stone extraction if positive for CBDS. We examined our experience with preoperative MRCP versus IOC for the management of the jaundiced patient with cholelithiasis. This is a retrospective single-institution study that examined all laparoscopic cholecystectomies performed over a 15-month period between 2017 and 2018. Outpatient elective cases were excluded from the analysis. Charts were reviewed for demographics, operative details, and whether an MRCP, IOC, or ERCP was performed. Data were evaluated using a 2-sample t-test. A total of 460 patients underwent laparoscopic cholecystectomy over a 15-month period. Of those, 147 underwent either an MRCP or an IOC for clinical suspicion for CBDS. ERCP after MRCP was nontherapeutic in 11/32 (34%) compared with 2/12 (17%) of patients following IOC. The sensitivity and specificity of MRCP were 91% and 80%, respectively, with a positive predictive value of 66% and a negative predictive value of 96%. The sensitivity and specificity of IOC were 83% and 97%, respectively, with a positive predictive value of 83% and a negative predictive value of 97%. MRCP and IOC have unique advantages and disadvantages. MRCP has greater sensitivity, but poor specificity, resulting in unnecessary ERCPs with associated morbidity and increased costs to the patient.

Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP.

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Stinggt/gt mice, but not in Cgas-/- mice. Abolishing cGAMP production in Cgas-/- tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.

CD96 functions as a co-stimulatory receptor to enhance CD8+ T cell activation and effector responses.

CD96 is a member of the poliovirus receptor (PVR, CD155)-nectin family that includes T cell Ig and ITIM domain (TIGIT) and CD226. While CD96, TIGIT, and CD226 have important roles in regulating NK cell activity, and TIGIT and CD226 have also been shown to regulate T cell responses, it is unclear whether CD96 has inhibitory or stimulatory function in CD8+ T cells. Here, we demonstrate that CD96 has co-stimulatory function on CD8+ T cells. Crosslinking of CD96 on human or mouse CD8+ T cells induced activation, effector cytokine production, and proliferation. CD96 was found to transduce its activating signal through the MEK-ERK pathway. CD96-mediated signaling led to increased frequencies of NUR77- and T-bet-expressing CD8+ T cells and enhanced cytotoxic effector activity, indicating that CD96 can modulate effector T cell differentiation. Antibody blockade of CD96 or genetic ablation of CD96 expression on CD8+ T cells impaired expression of transcription factors and proinflammatory cytokines associated with CD8+ T cell activation in in vivo models. Taken together, CD96 has a co-stimulatory role in CD8+ T cell activation and effector function.

The Gag protein PEG10 binds to RNA and regulates trophoblast stem cell lineage specification.

Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development. It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains. Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation. Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.

CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1.

Natural killer (NK) cell recognition of tumor cells is mediated through activating receptors such as CD226, with suppression of effector functions often controlled by negative regulatory transcription factors such as FOXO1. Here we show that CD226 regulation of NK cell cytotoxicity is facilitated through inactivation of FOXO1. Gene-expression analysis of NK cells isolated from syngeneic tumors grown in wild-type or CD226-deficient mice revealed dysregulated expression of FOXO1-regulated genes in the absence of CD226. In vitro cytotoxicity and stimulation assays demonstrated that CD226 is required for optimal killing of tumor target cells, with engagement of its ligand CD155 resulting in phosphorylation of FOXO1. CD226 deficiency or anti-CD226 antibody blockade impaired cytotoxicity with concomitant compromised inactivation of FOXO1. Furthermore, inhibitors of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector responses. These results define a pathway by which CD226 exerts control of NK cell responses against tumors.

Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation.

Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence to show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of GSDMD. Macrophages from caspase-11-processing dead KI mice (Casp11Prc D285A/D285A ) exhibit defective caspase-11 auto-processing and phenocopy Casp11-/- and caspase-11 enzymatically dead KI (Casp11Enz C254A/C254A ) macrophages in attenuating responses to cytoplasmic LPS or Gram-negative bacteria infection. GsdmdD276A/D276A KI macrophages also fail to cleave GSDMD and are hypo-responsive to inflammasome stimuli, confirming that the GSDMD Asp276 residue is a nonredundant and indispensable site for proteolytic activation of GSDMD. Our data highlight the role of caspase-11 self-cleavage as a critical regulatory step for GSDMD processing and response against Gram-negative bacteria.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Korean Survivors of the Japanese "Comfort Women" System: Understanding the Lifelong Consequences of Early Life Trauma.

Prior to and during World War II, thousands of girls and young women were abducted from Korea and forced into sexual slavery by the Japanese government. Termed comfort women, these girls and young women suffered extreme sexual, physical, and emotional abuse and trauma. Research on this group is not well-developed and people know little of the impact of this early life trauma on the lives of these women who are now in later life. Using snowball sampling, 16 older adult survivors of the comfort women system participated in semistructured qualitative interviews. Thematic analysis was conducted to gain an understanding of the trauma that these women suffered and how it impacted their lives. Results revealed the depths of the abuse these women suffered, including repeated rapes, physical beatings, humiliation, forced surgery and sterilization, and social exclusion. These early traumatic experiences appeared to reverberate throughout their lives in their family relations, their inability to marry and to conceive children, and their emotional and physical well-being throughout the life course and into later life. The experiences of these survivors illustrate the lasting impact of early-life trauma and can guide interventions with current survivors of sexual abuse or trafficking.

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1ß processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1ß maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1ß secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.

Effect of body mass index on angle of needle insertion during ultrasound-guided lateral sagittal infraclavicular brachial plexus block.

STUDY OBJECTIVES: The aim of our study was to establish the angle of needle insertion from the anterior chest wall during ultrasound-guided infraclavicular brachial plexus block and to examine for any correlation between body mass index (BMI) and insertion angle. DESIGN: This is a prospective observational study. SETTING: The setting is at an operating room, university-affiliated teaching hospital. PATIENTS: The patients are 23 American Society of Anesthesiologists physical status 1-3 patients scheduled to undergo elbow, forearm, or hand surgery under regional anesthesia with or without general anesthesia. INTERVENTIONS: The intervention is infraclavicular brachial plexus block with or without perineural catheter insertion. MEASUREMENTS: The measurement is the angle of needle insertion in relation to the anterior chest wall, BMI, and needle visibility as graded by the anesthesiologist. MAIN RESULTS: Twenty-three patients were studied. The mean (SD) BMI was 28.5 (5.4). The median (range) of angle of needle insertion was 50 (33-60). The Pearson correlation coefficient for BMI and angle of needle insertion was 0.357. There were no reported complications. CONCLUSIONS: The median (range) angle of needle insertion in relation to chest for our study patients was 50° (33°-60°). The needle visibility was rated difficult, requiring hydrolocation or "heeling-in," in 39% of cases. There was a moderate correlation between BMI and angle of insertion. Despite difficulties with needle visualization, the ultrasound-guided infraclavicular brachial plexus block provided reliable analgesia.

A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition.

Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.

Posttranscriptional regulation of PER1 underlies the oncogenic function of IREα.

Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-α substrate, thereby pointing toward an increased IRE1α activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development.

Transfusion-related acute lung injury (TRALI): a case report and literature review.

Transfusion-related acute lung injury (TRALI), a previously ill-defined transfusion reaction, has emerged as the leading cause of transfusion-related morbidity and mortality reported to the Food and Drug Administration (FDA). A 3-year-old male with a history of acute lymphoblastic leukemia (ALL) developed TRALI after receiving three units of platelets and a partial unit of packed red cells. He recovered after 24 hours in the pediatric intensive care unit. Laboratory investigation revealed that two of the four blood donors, from which the platelets and packed red cells had derived, had positive human leukocyte antigen (HLA) antibody screens. Further testing of these two donors revealed that one had a specific HLA antibody matching an antigen of the patient. This donor was implicated in the TRALI reaction. TRALI is often mistaken for other transfusion reactions, most notably pulmonary edema caused by circulatory overload or congestive heart failure. It is difficult to gauge which transfusion recipients are at risk for TRALI. Good judgment and transfusion practices when ordering blood products and recognition of the clinical manifestations, diagnosis and treatment of TRALI is critical.

Intrathecal opioid versus ultrasound guided fascia iliaca plane block for analgesia after primary hip arthroplasty: study protocol for a randomised, blinded, noninferiority controlled trial.

BACKGROUND: Hip replacement surgery is increasingly common due to an ageing population, and rising levels of obesity. The provision of excellent pain relief with minimal side effects is important in order to facilitate patient mobilisation and rehabilitation.Spinal opioids provide excellent analgesia but are associated with adverse effects. The fascia-iliaca block is an alternative technique which provides analgesia to the nerves innervating the hip. The success of fascia iliaca blocks has been demonstrated to be superior when using ultrasound compared to landmark techniques. However, the clinical benefit of this improvement has yet to be investigated.The aim of this study is to compare the efficacy and safety of ultrasound guided fascia iliaca block with spinal morphine for hip replacement surgery. METHODS/DESIGN: This study is a randomised, blinded, placebo-controlled, noninferiority trial. Patients scheduled to undergo unilateral primary hip arthroplasty will receive a study information sheet and consent will be obtained in keeping with the Declaration of Helsinki. Patients will be randomised to receive either; (i) Ultrasound guided fascia iliaca block using levobupivacaine, plus spinal anaesthesia with hyperbaric bupivacaine containing no morphine, or (ii) sham ultrasound guided fascia iliaca block performed with sterile saline, and spinal anaesthesia containing hyperbaric bupivacaine and 0.1 mg of spinal morphine.A total of 108 patients will be recruited. Primary outcome is post-operative morphine consumption in a 24 hour period. Secondary outcomes include; pain scores at 3, 6, 12, 24, 36 and 48 hours, episodes of respiratory depression, hypotension, nausea and vomiting, pruritus, sedation, time to first mobilisation and patient satisfaction. CONCLUSIONS: There are no studies to date comparing ultrasound guided fascia iliaca block with spinal morphine for pain control after hip arthroplasty. If the ultrasound guided fascia iliaca block provides pain relief which is not inferior to spinal morphine, then morphine could be removed from the spinal injection. This could reduce side effects and improve patient safety. TRIAL REGISTRATION: This study has been approved by the West of Scotland Research Ethics Committee 4 (reference no. 10/S0704/43) and is registered with ClinicalTrials.gov (reference no. NCT01217294).