Restoring microvascular circulation with diagnostic ultrasound and contrast agent: rationale and design of the REDUCE trial.

OBJECTIVES: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure. BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear. METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of 2 treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for 6 months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total. CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

Association of prehospital lactate levels with base excess in various emergencies - a retrospective study.

OBJECTIVES: Blood gas analysis, including parameters like lactate and base excess (BE), is crucial in emergency medicine but less commonly utilized prehospital. This study aims to elucidate the relationship between lactate and BE in various emergencies in a prehospital setting and their prognostic implications. METHODS: We conducted a retrospective analysis of prehospital emergency patients in Graz, Austria, from October 2015 to November 2020. Our primary aim was to assess the association between BE and lactate. This was assessed using Spearman's rank correlation and fitting a multiple linear regression model with lactate as the outcome, BE as the primary covariate of interest and age, sex, and medical emergency type as confounders. RESULTS: In our analysis population (n=312), lactate and BE levels were inversely correlated (Spearman's ρ, -0.75; p<0.001). From the adjusted multiple linear regression model (n=302), we estimated that a 1 mEq/L increase in BE levels was associated with an average change of -0.35 (95 % CI: -0.39, -0.30; p<0.001) mmol/L in lactate levels. Lactate levels were moderately useful for predicting mortality with notable variations across different emergency types. CONCLUSIONS: Our study highlights a significant inverse association between lactate levels and BE in the prehospital setting, underscoring their importance in early assessment and prognosis in emergency care. Additionally, the findings from our secondary aims emphasize the value of lactate in diagnosing acid-base disorders and predicting patient outcomes. Recognizing the nuances in lactate physiology is essential for effective prehospital care in various emergency scenarios.

Virtual Reality Distraction for Reducing Acute Postoperative Pain After Hip Arthroplasty: A Randomized Trial.

BACKGROUND: Relaxation and distraction provided by virtual reality presentations might be analgesic and reduce the need for opioid analgesia. We tested the hypothesis that a virtual reality program (AppliedVR) decreases acute postoperative pain and opioid requirements in patients recovering from hip arthroplasty. We also evaluated whether virtual reality distraction improves patient mobility and reduces the need for antiemetics. METHODS: We evaluated 106 adults who were recovering from elective primary total hip arthroplasty. Participating patients were randomized to 2- to 8-minute-long 3-dimensional immersive virtual reality relaxation and distraction video presentations (eg, guided breathing exercises, games, mindfulness) or to 2-dimensional presentations of nature short films (eg, forest wildlife) with neutral music that was chosen to be neither overly relaxing nor distracting, presented through identical headsets. Our primary outcome was pain after virtual reality or sham video presentations, adjusted for pretreatment scores. Secondary outcomes included total opioid consumption, pain scores obtained per routine by nurse staff, perception of video system usability, and pain 1 week after hospital discharge. RESULTS: Fifty-two patients were randomized to virtual reality distraction and relaxation, and 54 were assigned to 2-dimensional sham presentations. Virtual reality presentations were not found to affect pain scores before and after presentations, with an estimated difference in means (virtual reality minus sham video) of -0.1 points (95% confidence interval [CI], -0.5 to 0.2; P = .391) on a 0 to 10 scale, with 10 being the worst. The mean (standard error [SE]) after-intervention pain score was estimated to be 3.4 (0.3) in the virtual reality group and 3.5 (0.2) in the reference group. Virtual reality treatment was not found to affect postoperative opioid consumption in morphine milligram equivalents, with an estimated ratio of geometric means (virtual reality/sham video) of 1.2 (95% CI, 0.6-2.1; P = .608). Virtual reality presentations were not found to reduce pain scores collected every 4 hours by nursing staff, with an estimated difference in means of 0.1 points (95% CI, -0.9 to 0.7; P = .768). CONCLUSIONS: We did not observe statistically significant or clinically meaningful reductions in average pain scores or opioid consumption. As used in our trial, virtual reality did not reduce acute postoperative pain.

The association of vaping and electronic cigarette use with postoperative hypoxemia and respiratory complications: a retrospective cohort analysis.

PURPOSE: Initially introduced as a safer alternative to smoking, electronic cigarettes (e-cigarettes) and vaping have since been associated with lung injury. Nevertheless, there is limited perioperative data on their potential contribution to the harmful effects of mechanical ventilation on the lungs. We hypothesized that, in adults undergoing noncardiothoracic surgeries, preoperative vaping/e-cigarette use is associated with hypoxemia during the first postoperative hour, and with an increased incidence of intraoperative and postoperative pulmonary complications. METHODS: We conducted a retrospective cohort study in which we included patients reporting as vapers/e-cigarette users within one year before surgery as the exposure group, and nonvapers as the control group. The primary outcome was the time-weighted average (TWA) SpO2/FIO2 ratio in the postanesthesia care unit during the first postoperative hour. The secondary outcome was a composite of intraoperative and postoperative pulmonary complications until discharge. We used entropy balancing to adjust for confounding, and fit weighted linear regression and logistic regression models to estimate treatment effects. RESULTS: A total of 110,940 patients met the inclusion criteria, and 1,941 of these were vapers/e-cigarette users. The average treatment effect on the treated for TWA SpO2/FIO2 ratio (N = 109,217) was estimated to be a mean difference of 4 (95% confidence interval [CI], 1 to 8; P = 0.007). This is equivalent to a 4% change in SpO2 at a 30% FIO2 (or at a fixed FIO2). The difference was statistically significant. The average treatment effect on the treated for experiencing intraoperative and postoperative pulmonary complications (N = 110,940) was an odds ratio of 1.04 (95% CI, 0.71 to 1.54; P = 0.84). CONCLUSION: Vaping/e-cigarette use was neither associated with clinically significant hypoxemia during the first hour in the postanesthesia care unit nor with an increase in pulmonary complications. Nevertheless, our findings cannot definitively exclude the deleterious effects of vaping and e-cigarette use on the lungs, and anesthesiologists should consider potential perioperative complications.

RéSUMé: OBJECTIF: Initialement introduites comme une alternative plus sécuritaire au tabagisme, les cigarettes électroniques et le vapotage ont depuis été associés à des lésions pulmonaires. Néanmoins, il existe peu de données périopératoires concernant leur contribution potentielle aux effets nocifs de la ventilation mécanique sur les poumons. Nous avons émis l'hypothèse que, chez les adultes bénéficiant de chirurgies non cardiothoraciques, l'utilisation préopératoire de vapotage/de cigarette électronique était associée à une hypoxémie au cours de la première heure postopératoire et à une incidence accrue de complications pulmonaires peropératoires et postopératoires. MéTHODE: Nous avons mené une étude de cohorte rétrospective dans laquelle nous avons inclus les patient·es déclarant avoir vapoté ou utilisé des cigarettes électroniques dans l'année précédant la chirurgie comme groupe d'exposition, et les personnes ne vapotant pas comme groupe témoin. Le critère d'évaluation principal était le rapport de SpO2/FIO2 moyen pondéré dans le temps en salle de réveil pendant la première heure postopératoire. Le critère d'évaluation secondaire était un mélange de complications pulmonaires peropératoires et postopératoires jusqu'au congé de l'hôpital. Nous avons utilisé l'équilibrage d'entropie pour ajuster les facteurs de confusion et ajusté les modèles de régression linéaire pondérée et de régression logistique pour estimer les effets du traitement. RéSULTATS: Au total, 110 940 patient·es répondaient aux critères d'inclusion, dont 1941 étaient des vapoteurs ou vapoteuses/utilisaient des cigarettes électroniques. L'effet moyen du traitement sur le rapport de SpO2/FIO2 moyen pondéré dans le temps des personnes traitées (N = 109 217) a été estimé à une différence moyenne de 4 (intervalle de confiance [IC] à 95 %, 1 à 8; P = 0,007). Cela équivaut à une variation de 4 % de la SpO2 à 30% FIO2 (ou à une FIO2 fixe). La différence était statistiquement significative. L'effet moyen du traitement sur les personnes traitées pour des complications pulmonaires peropératoires et postopératoires (N = 110 940) était un rapport de cotes de 1,04 (IC 95 %, 0,71 à 1,54; P = 0,84). CONCLUSION: L'utilisation du vapotage et de la cigarette électronique n'était associée ni à une hypoxémie cliniquement significative au cours de la première heure en salle de réveil, ni à une augmentation des complications pulmonaires. Néanmoins, nos résultats ne peuvent exclure de manière définitive les effets délétères du vapotage et de l'utilisation de la cigarette électronique sur les poumons, et les anesthésiologistes devraient tenir compte des complications périopératoires potentielles.

Best Practice Alerts Informed by Inpatient Opioid Intake to Reduce Opioid Prescribing after Surgery (PRIOR): A Cluster Randomized Multiple Crossover Trial.

BACKGROUND: Overprescription of opioids after surgery remains common. Residual and unnecessarily prescribed opioids can provide a reservoir for nonmedical use. This study therefore tested the hypothesis that a decision-support tool embedded in electronic health records guides clinicians to prescribe fewer opioids at discharge after inpatient surgery. METHODS: This study included 21,689 surgical inpatient discharges in a cluster randomized multiple crossover trial from July 2020 to June 2021 in four Colorado hospitals. Hospital-level clusters were randomized to alternating 8-week periods during which an electronic decision-support tool recommended tailored discharge opioid prescriptions based on previous inpatient opioid intake. During active alert periods, the alert was displayed to clinicians when the proposed opioid prescription exceeded recommended amounts. No alerts were displayed during inactive periods. Carryover effects were mitigated by including 4-week washout periods. The primary outcome was oral morphine milligram equivalents prescribed at discharge. Secondary outcomes included combination opioid and nonopioid prescriptions and additional opioid prescriptions until day 28 after discharge. A vigorous state-wide opioid education and awareness campaign was in place during the trial. RESULTS: The total postdischarge opioid prescription was a median [quartile 1, quartile 3] of 75 [0, 225] oral morphine milligram equivalents among 11,003 patients discharged when the alerts were active and 100 [0, 225] morphine milligram equivalents in 10,686 patients when the alerts were inactive, with an estimated ratio of geometric means of 0.95 (95% CI, 0.80 to 1.13; P = 0.586). The alert was displayed in 28% (3,074 of 11,003) of the discharges during the active alert period. There was no relationship between the alert and prescribed opioid and nonopioid combination medications or additional opioid prescriptions written after discharge. CONCLUSIONS: A decision-support tool incorporated into electronic medical records did not reduce discharge opioid prescribing for postoperative patients in the context of vigorous opioid education and awareness efforts. Opioid prescribing alerts might yet be valuable in other contexts.(Anesthesiology 2023; 139:186-96).

The dynamics of SARS-CoV-2 infection in unvaccinated and vaccinated populations in Mumbai, India, between 28 December 2020 and 30 August 2021.

The emergence and evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants that could compromise vaccine efficacy (VE) with re-infections in immunized individuals have necessitated continuous surveillance of VE. Here, the occurrence and dynamics of SARS-CoV-2 infections in the context of vaccination during the second wave of infection in Mumbai were evaluated. RT-PCR cycle threshold (Ct) values of the open reading frame (ORF)/envelope (E)/nucleocapsid (N) genes obtained from a total of 42415 samples, comprising unvaccinated (96.88%) and vaccinated cases (3.12%) were analyzed between December 28, 2020, and August 30, 2021. A lower incidence of SARS-CoV-2 infection in fully vaccinated cases (5.07%) compared to partially vaccinated cases (6.5%) and unvaccinated cases (13.453%) was recorded. VE was significant after the first dose of vaccination (ORF gene p-value = 0.003429, and E/N gene p-value = 0.000866). Furthermore, VE was observed to be significant when the post-immunization (first dose) period was stratified to within 30 days (ORF gene p-value = 0.0094 and E/N gene p-value = 0.0023) and to 60 days following the second dose of vaccination (ORF gene p-value = 0.0238). Also, significantly higher efficacy was observed within individuals receiving two doses compared to a single dose (ORF gene p-value = 0.0132 and E/N gene p-value = 0.0387). The emergence of breakthrough infections was also evident (odds ratio= 0.34; 95% confidence interval= 0.27-0.43). Interestingly, viral loads trended towards being higher in some groups of partially vaccinated individuals compared to completely vaccinated and unvaccinated populations. Finally, our results delineated a significantly higher incidence of SARS-CoV-2 acquisition in males, asymptomatic individuals, individuals with comorbidities, and those who were unvaccinated.

Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis: a registry-based cluster randomized pilot trial.

BACKGROUND: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants' treating team, for severe or worsening symptoms as identified by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. METHODS: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. RESULTS: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. CONCLUSIONS: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A definitive national RCT is underway. TRIAL REGISTRATION: ACTRN12618001976279 (07/12/2018).

Hospital Development of a Hybrid Emergency Department-Inpatient Care Observation Unit.

INTRODUCTION: This project aimed to design and implement an emergency department-managed observation unit that improves inpatient bed and emergency department stretcher capacity, decreases observation patient length of stay, earns high patient satisfaction scores, and generates a positive fiscal impact on the organization. METHODS: This quality improvement project followed a 1-group, pre- and postprogram implementation design. RESULTS: In the first year of operations, 40% of the total observation patients treated in this hospital were managed in the new observation unit. Emergency department observation unit length of stay across all patient complaints was half of the average length of stay for observation patients located on hospital inpatient units. In most cases, the emergency department observation unit was in the top 25 percentile of hospital Press Ganey inpatient satisfaction categories. The hospital estimates a contribution margin of three-quarters of a million dollars in the first year. DISCUSSION: This effective and efficient hybrid observation unit possessed specific aspects of inpatient and emergency department patient care models. Placing providers and nurses at the workstation for faster communication expedited care. Prioritizing all observation patient testing, transportation, phlebotomy, and intravenous (IV) services shortened disposition times. Emergency nurses transitioning to the observation unit were challenged to acquire inpatient care knowledge. Observation unit management struggled to maintain staffing while under an inpatient productivity model managed by the inpatient house supervisor. Reducing patient disposition time required clear communication between observation unit and inpatient staffing managers, between physician consultants and advanced practice nursing providers, and among nurses, patients, and providers. Observation units are 1 solution to decrease observation patient length of stay and improve emergency department capacity.

Recombinant SARS-CoV-2 envelope protein traffics to the trans-Golgi network following amphipol-mediated delivery into human cells.

The severe acute respiratory syndrome coronavirus 2 envelope protein (S2-E) is a conserved membrane protein that is important for coronavirus (CoV) assembly and budding. Here, we describe the recombinant expression and purification of S2-E in amphipol-class amphipathic polymer solutions, which solubilize and stabilize membrane proteins, but do not disrupt membranes. We found that amphipol delivery of S2-E to preformed planar bilayers results in spontaneous membrane integration and formation of viroporin cation channels. Amphipol delivery of the S2-E protein to human cells results in plasma membrane integration, followed by retrograde trafficking to the trans-Golgi network and accumulation in swollen perinuclear lysosomal-associated membrane protein 1-positive vesicles, likely lysosomes. CoV envelope proteins have previously been proposed to manipulate the luminal pH of the trans-Golgi network, which serves as an accumulation station for progeny CoV particles prior to cellular egress via lysosomes. Delivery of S2-E to cells will enable chemical biological approaches for future studies of severe acute respiratory syndrome coronavirus 2 pathogenesis and possibly even development of "Trojan horse" antiviral therapies. Finally, this work also establishes a paradigm for amphipol-mediated delivery of membrane proteins to cells.

Prolonged Blood Storage and Risk of Posttransfusion Acute Kidney Injury.

BACKGROUND: Erythrocyte transfusions are independently associated with acute kidney injury. Kidney injury may be consequent to the progressive hematologic changes that develop during storage. This study therefore tested the hypothesis that prolonged erythrocyte storage increases posttransfusion acute kidney injury. METHODS: The Informing Fresh versus Old Red Cell Management (INFORM) trial randomized 31,497 patients to receive either the freshest or oldest available matching erythrocyte units and showed comparable mortality with both. This a priori substudy compared the incidence of posttransfusion acute kidney injury in the randomized groups. Acute kidney injury was defined by the creatinine component of the Kidney Disease: Improving Global Outcomes criteria. RESULTS: The 14,461 patients included in this substudy received 40,077 erythrocyte units. For patients who received more than one unit, the mean age of the blood units was used as the exposure. The median of the mean age of blood units transfused per patient was 11 days [interquartile range, 8, 15] in the freshest available blood group and 23 days [interquartile range, 17, 30] in the oldest available blood group. In the primary analysis, posttransfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk (95% CI) of 0.94 (0.86 to 1.02; P = 0.132). The secondary analysis treated blood age as a continuous variable (defined as duration of storage in days), with an estimated relative risk (95% CI) of 1.00 (0.96 to 1.04; P = 0.978) for a 10-day increase in the mean age of erythrocyte units. CONCLUSIONS: In a population of patients without severely impaired baseline renal function receiving fewer than 10 erythrocyte units, duration of blood storage had no effect on the incidence of posttransfusion acute kidney injury.

Linking chondrocyte and synovial transcriptional profile to clinical phenotype in osteoarthritis.

OBJECTIVES: To determine how gene expression profiles in osteoarthritis joint tissues relate to patient phenotypes and whether molecular subtypes can be reproducibly captured by a molecular classification algorithm. METHODS: We analysed RNA sequencing data from cartilage and synovium in 113 osteoarthritis patients, applying unsupervised clustering and Multi-Omics Factor Analysis to characterise transcriptional profiles. We tested the association of the molecularly defined patient subgroups with clinical characteristics from electronic health records. RESULTS: We detected two patient subgroups in low-grade cartilage (showing no/minimal degeneration, cartilage normal/softening only), with differences associated with inflammation, extracellular matrix-related and cell adhesion pathways. The high-inflammation subgroup was associated with female sex (OR 4.12, p=0.0024) and prescription of proton pump inhibitors (OR 4.21, p=0.0040). We identified two independent patient subgroupings in osteoarthritis synovium: one related to inflammation and the other to extracellular matrix and cell adhesion processes. A seven-gene classifier including MMP13, APOD, MMP2, MMP1, CYTL1, IL6 and C15orf48 recapitulated the main axis of molecular heterogeneity in low-grade knee osteoarthritis cartilage (correlation ρ=-0.88, p<10-10) and was reproducible in an independent patient cohort (ρ=-0.85, p<10-10). CONCLUSIONS: These data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments.

Distinct Concentration-Dependent Molecular Pathways Regulate Bone Cell Responses to Cobalt and Chromium Exposure from Joint Replacement Prostheses.

Systemic cobalt (Co) and chromium (Cr) concentrations may be elevated in patients with metal joint replacement prostheses. Several studies have highlighted the detrimental effects of this exposure on bone cells in vitro, but the underlying mechanisms remain unclear. In this study, we use whole-genome microarrays to comprehensively assess gene expression in primary human osteoblasts, osteoclast precursors and mature resorbing osteoclasts following exposure to clinically relevant circulating versus local periprosthetic tissue concentrations of Co2+ and Cr3+ ions and CoCr nanoparticles. We also describe the gene expression response in osteoblasts on routinely used prosthesis surfaces in the presence of metal exposure. Our results suggest that systemic levels of metal exposure have no effect on osteoblasts, and primarily inhibit osteoclast differentiation and function via altering the focal adhesion and extracellular matrix interaction pathways. In contrast, periprosthetic levels of metal exposure inhibit both osteoblast and osteoclast activity by altering HIF-1α signaling and endocytic/cytoskeletal genes respectively, as well as increasing inflammatory signaling with mechanistic implications for adverse reactions to metal debris. Furthermore, we identify gene clusters and KEGG pathways for which the expression correlates with increasing Co2+:Cr3+ concentrations, and has the potential to serve as early markers of metal toxicity. Finally, our study provides a molecular basis for the improved clinical outcomes for hydroxyapatite-coated prostheses that elicit a pro-survival osteogenic gene signature compared to grit-blasted and plasma-sprayed titanium-coated surfaces in the presence of metal exposure.

Transcatheter Aortic Valve Implantation (TAVI) Versus Surgical Aortic Valve Replacement for Aortic Stenosis (SAVR): A Cost-Comparison Study.

BACKGROUND: Comparative costing studies using real-world data stratified by patient case-mix, are valuable to decision makers for making reimbursement decisions of new interventions. This study evaluated real-world hospital admissions and short-term costs of transcatheter aortic valve implantation (TAVI) and isolated surgical aortic valve replacement (SAVR) for patients with aortic stenosis, stratified by the Society of Thoracic Surgeons (STS) risk scores. METHODS: Retrospective analysis of consecutive patients with a principal diagnosis of aortic stenosis who underwent isolated valve replacement at a single tertiary hospital, January 2012-December 2017. Patients were followed-up for 30 days post-procedure or until hospital discharge if index hospitalisation was greater than 30 days. Intensive care unit (ICU) and hospital length of stay (days), and costs in 2018 Australian dollars for the index procedure and 30-day follow-up were assessed. Multivariable generalised linear and two-part models with gamma distribution and log link function adjusting for Society of Thoracic Surgeons (STS) risk group and key sociodemographic characteristics were used. RESULTS: Of 488 patients, 61% males, median age 78 years (IQR 14 years), 221 (45%) received transcatheter aortic valve replacement (TAVI) and 267 (55%) received surgical aortic valve replacement (SAVR). STS risk scores were low (28%), intermediate (46%) and high (26%) for TAVI patients, and low (85%), intermediate (12%) and high (3%) for SAVR patients. When adjusted, TAVI length of stay was 57% shorter than SAVR (95% CI 31-83%, p<0.001) for intensive care unit (ICU) admission, and 64% shorter (95% CI 47-81%, p<0.001) for hospital admissions. TAVI costs were 13% lower than SAVR (95% CI 4-22%, p=0.005). CONCLUSION: This data suggests short-term health care costs are lower for patients with aortic stenosis undergoing TAVI than SAVR. A further roll-out of the TAVI program in hospitals across Australia may result in savings to the health system.

JZL184, A Monoacylglycerol Lipase Inhibitor, Induces Bone Loss in a Multiple Myeloma Model of Immunocompetent Mice.

Multiple myeloma (MM) patients develop osteolysis characterised by excessive osteoclastic bone destruction and lack of osteoblast bone formation. Pharmacological manipulation of monoacylglycerol lipase (MAGL), an enzyme responsible for the degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG), reduced skeletal tumour burden and osteolysis associated with osteosarcoma and advanced breast and prostate cancers. MM and hematopoietic, immune and bone marrow cells express high levels of type 2 cannabinoid receptor and osteoblasts secrete 2-AG. However, the effects of MAGL manipulation on MM have not been investigated. Here, we report that treatment of pre-osteoclasts with non-cytotoxic concentrations of JZL184, a verified MAGL inhibitor, enhanced MM- and RANKL-induced osteoclast formation and size in vitro. Exposure of osteoblasts to JZL184 in the presence of MM cell-derived factors reduced osteoblast growth but had no effect on the ability of these cells to mature or form bone nodules. In vivo, administration of JZL184 induced a modest, yet significant, bone loss at both trabecular and cortical compartments of long bones of immunocompetent mice inoculated with the syngeneic 5TGM1-GFP MM cells. Notably, JZL184 failed to inhibit the in vitro growth of a panel of mouse and human MM cell lines, or reduce tumour burden in mice. Thus, MAGL inhibitors such as JZL184 can exacerbate MM-induced bone loss.

Cryptococcal meningitis in an immunocompetent patient.

Cryptococcal meningitis is a fungal infection that is most commonly thought of as an opportunistic infection affecting immunocompromised patients, classically patients with Human Immunodeficiency (HIV) infection. It is associated with a variety of complications including disseminated disease as well as neurologic complications including intracranial hypertension, cerebral infarcts, vision loss and other neurologic deficits. It is diagnosed by lumbar puncture with CSF studies, including fungal culture and cryptococcal antigen testing. We present a case of cryptococcal meningitis and fungemia in a previously healthy male patient who presented after multiple emergency department visits with persistent headache. After multiple visits, he underwent a lumbar puncture consistent with cryptococcal infection, and he was admitted to the hospital for initiation of antifungal therapy. His workup revealed no known underlying condition leading to immune compromise.

Quality of life among caregivers of people with end-stage kidney disease managed with dialysis or comprehensive conservative care.

BACKGROUND: To measure health-related and care-related quality of life among informal caregivers of older people with end-stage kidney disease (ESKD), and to determine the association between caregiver quality of life and care recipient's treatment type. METHODS: A prospective cross-sectional study was conducted. Three renal units in the UK and Australia were included. Informal caregivers of people aged ≥75 years with ESKD managed with dialysis or comprehensive conservative non-dialytic care (estimated glomerular filtration (eGFR) ≤10 mL/min/1.73m2) participated. Health-related quality of life (HRQoL) was assessed using Short-Form six dimensions (SF-6D, 0-1 scale) and care-related quality of life was assessed using the Carer Experience Scale (CES, 0-100 scale). Linear regression assessed associations between care-recipient treatment type, caregiver characteristics and the SF-6D utility index and CES scores. RESULTS: Of 63 caregivers, 49 (78%) were from Australia, 26 (41%) cared for an older person managed with dialysis, and 37 (59%) cared for an older person managed with comprehensive conservative care. Overall, 73% were females, and the median age of the entire cohort was 76 years [IQR 68-81]. When adjusted for caregiver sociodemographic characteristics, caregivers reported significantly worse carer experience (CES score 15.73, 95% CI 5.78 to 25.68) for those managing an older person on dialysis compared with conservative care. However, no significant difference observed for carer HRQoL (SF-6D utility index - 0.08, 95% CI - 0.18 to 0.01) for those managing an older person on dialysis compared with conservative care. CONCLUSIONS: Our data suggest informal caregivers of older people on dialysis have significantly worse care-related quality of life (and therefore greater need for support) than those managed with comprehensive conservative care. It is important to consider the impact on caregivers' quality of life when considering treatment choices for their care recipients.

Nurse-led advance care planning with older people who have end-stage kidney disease: feasibility of a deferred entry randomised controlled trial incorporating an economic evaluation and mixed methods process evaluation (ACReDiT).

BACKGROUND: Advance Care Planning is recommended for people with end-stage kidney disease but evidence is limited. Robust clinical trials are needed to investigate the impact of advance care planning in this population. There is little available data on cost-effectiveness to guide decision makers in allocating resources for advance care planning. Therefore we sought to determine the feasibility of a randomised controlled trial and to test methods for assessing cost-effectiveness. METHODS: A deferred entry, randomised controlled feasibility trial, incorporating economic and process evaluations, with people with end-stage kidney disease, aged 65 years or older, receiving haemodialysis, in two renal haemodialysis units in Northern Ireland, UK. A nurse facilitator helped the patient make an advance care plan identifying: a surrogate decision-maker; what the participant would like to happen in the future; any advance decision to refuse treatment; preferred place of care at end-of-life. RESULTS: Recruitment lasted 189 days; intervention and data collection 443 days. Of the 67 patients invited to participate 30 (45%) declined and 36 were randomised to immediate or deferred advance care plan groups. Twenty-two (61%) made an advance care plan and completed data collection at 12 weeks; 17 (47.2%) were able to identify a surrogate willing to be named in the advance care plan document. The intervention was well-received and encouraged end-of-life conversations, but did not succeed in helping patients to fully clarify their values or consider specific treatment choices. There was no significant difference in health system costs between the immediate and deferred groups. CONCLUSIONS: A trial of advance care planning with participants receiving haemodialysis is feasible and acceptable to patients, but challenging. A full trial would require a pool of potential participants five times larger than the number required to complete data collection at 3 months. Widening eligibility criteria to include younger (under 65 years of age) and less frail patients, together with special efforts to engage and retain surrogates may improve recruitment and retention. Traditional advance care planning outcomes may need to be supplemented with those that are defined by patients, helping them to participate with clinicians in making medical decisions. TRIAL REGISTRATION: Registered December 16, 2015. ClinicalTrials.gov Identifier: NCT02631200 .

Vitriolage by Sulfuric Acid: Unique Challenges and Considerations in Patient Resuscitation.

BACKGROUND: In the United States, over 1 million burns require medical treatment each year. Chemical burns represent an infrequent but devastating percentage of all burns, which account for a large proportion of all burn-related deaths. Of the various causes of chemical burns, sulfuric acid is most commonly involved in occupational and accidental burns, and even cases of assault. CASE REPORT: We describe the case of a 27-year-old man who presented to our Emergency Department (ED) after an assault with sulfuric acid. During his presentation, particular attention and care was given to his decontamination, airway management, and correction of life-threatening metabolic derangements. After stabilization in the ED he survived an extensive hospital admission. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patient outcomes and prognosis after chemical burns are dependent on prompt recognition/suspicion and rapid initiation of treatment. Even with prompt treatment, severe physiologic and psychologic injuries often afflict the patient. While encountering these devastating injuries, the emergency physician must carry a heightened sense of care and protection for both patient and staff to ensure optimum outcomes.

The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

BACKGROUND: Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown. QUESTIONS/PURPOSES: We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis. METHODS: The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken. RESULTS: Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ≤ 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ≤ 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ≤ 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ≤ 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10). CONCLUSIONS: We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease. CLINICAL RELEVANCE: The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.