Inhaled fosamprenavir for laryngopharyngeal reflux: Toxicology and fluid dynamics modeling.

Objectives: Approximately 25% of Americans suffer from laryngopharyngeal reflux (LPR), a disease for which no effective medical therapy exists. Pepsin is a predominant source of damage during LPR and a key therapeutic target. Fosamprenavir (FOS) inhibits pepsin and prevents damage in an LPR mouse model. Inhaled FOS protects at a lower dose than oral; however, the safety of inhaled FOS is unknown and there are no inhalers for laryngopharyngeal delivery. A pre-Good Lab Practice (GLP) study of inhaled FOS was performed to assess safety and computational fluid dynamics (CFD) modeling used to predict the optimal particle size for a laryngopharyngeal dry powder inhaler (DPI). Methods: Aerosolized FOS, amprenavir (APR), or air (control) were provided 5 days/week for 4 weeks (n = 6) in an LPR mouse model. Organs (nasal cavity, larynx, esophagus, trachea, lung, liver, heart, and kidney) were assessed by a pathologist and bronchoalveolar lavage cytokines and plasma cardiotoxicity markers were assessed by Luminex assay. CFD simulations were conducted in a model of a healthy 49-year-old female. Results: No significant increase was observed in histologic lesions, cytokines, or cardiotoxicity markers in FOS or APR groups relative to the control. CFD predicted that laryngopharyngeal deposition was maximized with aerodynamic diameters of 8.1-11.5 µm for inhalation rates of 30-60 L/min. Conclusions: A 4-week pre-GLP study supports the safety of inhaled FOS. A formal GLP assessment is underway to support a phase I clinical trial of an FOS DPI for LPR. Level of Evidence: NA.

Rotational ThromboElastometry-guided blood component administration versus standard of care in patients with Cirrhosis and coagulopathy undergoing Invasive ProcEdures (RECIPE): study protocol for a randomised controlled trial.

BACKGROUND: Patients with cirrhosis often undergo invasive procedures both for management of complications of their advanced liver disease, including treatment for hepatocellular carcinoma, as well as underlying comorbidities. Despite a current understanding that most patients with cirrhosis are in a rebalanced haemostatic state (despite abnormalities in conventional coagulation tests, namely INR and platelet count), patients with cirrhosis are still often given prophylactic blood components based on these conventional parameters, in an effort to reduce procedure-related bleeding. Viscoelastic tests such as Rotational Thromboelastometry (ROTEM) provide a global measurement of haemostasis and have been shown to predict bleeding risk more accurately than conventional coagulation tests, and better guide blood product transfusion in a number of surgical and trauma-related settings. The aim of this study is to assess the utility of a ROTEM-based algorithm to guide prophylactic blood component delivery in patients with cirrhosis undergoing invasive procedures. We hypothesise that ROTEM-based decision-making will lead to a reduction in pre-procedural blood component usage, particularly fresh frozen plasma (FFP), compared with standard of care, whilst maintaining optimal clinical outcomes. METHODS: This is a multi-centre randomised controlled trial comparing ROTEM-guided prophylactic blood component administration to standard of care in patients with cirrhosis and coagulopathy undergoing invasive procedures. The primary efficacy outcome of the trial is the proportion of procedures requiring prophylactic transfusion, with the primary safety outcome being procedure-related bleeding complications. Secondary outcomes include the amount of blood products (FFP, platelets, cryoprecipitate) transfused, transfusion-related side effects, procedure-related complications other than bleeding, hospital length of stay and survival. DISCUSSION: We anticipate that this project will lead to improved prognostication of patients with cirrhosis, in terms of their peri-procedural bleeding risk. We hope to show that a significant proportion of cirrhotic patients, deemed coagulopathic on the basis of standard coagulation tests such as INR and platelet count, are actually in a haemostatic balance and thus do not require prophylactic blood product, leading to decreased and more efficient blood component use. TRIAL REGISTRATION: RECIPE has been prospectively registered with the Australia and New Zealand Clinical Trials Registry on the 30th April 2019 ( ACTRN12619000644167 ).

A sustainable vision for general practice: Understanding the challenges.

BACKGROUND: The COVID-19 pandemic has revealed the full extent of the crisis in general practice, which has emerged as nothing more than the tip of the iceberg of a health system in crisis. OBJECTIVE: This article introduces the systems and complexity thinking that frame the problems affecting general practice and the systemic challenges inherent in redesigning it. DISCUSSION: The authors show how embedded general practice is in the overall complex adaptive organisation of the health system. They allude to some of the key concerns that need to be dissolved in its redesign to achieve an effective, efficient, equitable and sustainable general practice system within a redesigned overall health system to achieve the best possible desired health experiences for patients.

A sustainable vision for general practice: Addressing the challenges

BACKGROUND: The systemic problems and challenges of general practice within the health system require systemic solutions. OBJECTIVE: Noting the complex adaptive nature of health, illness and disease, and its distribution within communities and general practice work, this article suggests a model for general practice that allows the full scope of practice to be developed while creating seamlessly integrated general practice colleges that support general practitioners on their journey to 'mastery' in their chosen discipline. DISCUSSION: The authors discuss the complex dynamics underpinning knowledge and skills development throughout doctors' careers, and the need for policy makers to evaluate health improvement and resourcing based on their interdependencies with all societal activity. To succeed, the profession would have to adopt the principles that form the foundation of generalism and complex adaptive organisations to strengthen its ability to successfully interact with all its stakeholders.

Troponin is unrelated to outcomes in heart failure patients discharged from the emergency department.

Background: Prior data has demonstrated increased mortality in hospitalized patients with acute heart failure (AHF) and troponin elevation. No data has specifically examined the prognostic significance of troponin elevation in patients with AHF discharged after emergency department (ED) management. Objective: Evaluate the relationship between troponin elevation and outcomes in patients with AHF who are treated and released from the ED. Methods: This was a secondary analysis of the Get with the Guidelines to Reduce Disparities in AHF Patients Discharged from the ED (GUIDED-HF) trial, a randomized, controlled trial of ED patients with AHF who were discharged. Patients with elevated conventional troponin not due to acute coronary syndrome (ACS) were included. Our primary outcome was a composite endpoint: time to 30-day cardiovascular death and/or heart failure-related events. Results: Of the 491 subjects included in the GUIDED-HF trial, 418 had troponin measured during the ED evaluation and 66 (16%) had troponin values above the 99th percentile. Median age was 63 years (interquartile range, 54-70), 62% (n = 261) were male, 63% (n = 265) were Black, and 16% (n = 67) experienced our primary outcome. There were no differences in our primary outcome between those with and without troponin elevation (12/66, 18.1% vs 55/352, 15.6%; P = 0.60). This effect was maintained regardless of assignment to usual care or the intervention arm. In multivariable regression analysis, there was no association between our primary outcome and elevated troponin (hazard ratio, 1.00; 95% confidence interval,  0.49-2.01, P = 0.994). Conclusion: If confirmed in a larger cohort, these findings may facilitate safe ED discharge for a group of patients with AHF without ACS when an elevated troponin is the primary reason for admission.

Multiple Upper Aerodigestive Tract Masses Presenting With Stridor-A Rare Case of Aggressive Multifocal Extramedullary Plasmacytoma.

Extramedullary plasmacytomas represent a rare group of B-cell malignancies that arise outside the bone marrow and their disease process is still poorly understood. Here, we will describe a case of a 76-year-old patient who presented with a large chest wall and subglottic mass causing airway compromise and stridor. Biopsies showed atypical plasma cells with prominent nucleoli which were in keeping with an extramedullary plasmacytoma. Disease progressed despite surgical debulking, targeted radiotherapy, and multiple chemotherapy regimens. Although response to treatment is classically good, patients occasionally present with aggressive disease.

The use of organ donor blood in liver transplantation.

BACKGROUND: Blood removed from organs during deceased donor organ procurement is routinely discarded but is a potential resource for donor-specific transfusion (DST) in subsequent liver transplantation (LT). This study retrospectively analyses the impact of DST on intraoperative bank blood product usage, long-term graft, and patient survival, as well as frequency of rejection post-LT. METHODS: A total of 992 adult LT performed from 1993 to 2018 in a single quaternary center were included. Intraoperative blood product usage, patient, and graft survival, as well as acute and chronic rejection were assessed in patients who received blood retrieved from the organ donor, the "donor blood" (DB) group (n = 437) and patients who did not, the "no donor blood" (NDB) group (n = 555). RESULTS: Processing of DB ensured safe levels of potassium, magnesium, and insulin. There were fewer units of bank red blood cells transfusion required in the DB group compared to NDB group (2 vs. 4 units, P = .01). Graft survival was significantly superior in the DB group (10-year survival 75% vs. 69%, respectively, P = .04) but DST was not an independent predictor of graft survival. There was no significant difference in patient survival or rejection between the groups. There was no difference in treated, biopsy-proven rejection between the two groups. CONCLUSIONS: This is the first large-cohort study assessing long-term outcomes of intraoperative DST in LT. The collection of organ donor blood and subsequent use in LT recipients appeared feasible with appropriate quality checks ensuring safety. DST resulted in a reduction in the use of packed red blood cells. There was no difference in the rate of rejection or graft or patient survival.

Pitfalls in the assessment of disseminated intravascular coagulation in patients on dabigatran.

Dabigatran is an orally administrated anticoagulant that directly inhibits thrombin. However, the drug can affect routine coagulation tests such as prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT), as well as haemostasis assays, (e.g., clot-based coagulation factor assays). There are limited data on the effect of dabigatran on some fibrinogen measurements and on D-dimer assays, both important components in the laboratory assessment of disseminated intravascular coagulation (DIC). The objectives of this study were: (1) to determine the effects of various concentrations of dabigatran on fibrinogen and D-Dimer assays; and (2) to compare the von Clauss method of fibrinogen measurement using two reagents with differing thrombin concentrations (35 UNIH/mL and 100 UNIH/mL) and PT-derived fibrinogen measurement in the presence of the drug. Aliquots of pooled normal plasma were spiked with different concentrations of dabigatran to reflect in vivo on-therapy levels as well as levels observed in cases of massive accumulation of the drug. Of the routine coagulation assays, in ascending order of sensitivity to dabigatran were PT, APTT and TT. The von Clauss method of measuring fibrinogen using a reagent with low thrombin concentration was affected even at drug levels corresponding to in vivo trough concentrations, whereas the reagent with higher thrombin concentration was only affected at drug levels that were above observed peak concentrations in patients taking 150 mg of the drug twice daily. PT-derived fibrinogen was affected at approximately in vivo peak drug concentrations. The D-dimer assay was affected only at drug concentrations well above peak drug levels. Attempts at in vitro neutralisation of the drug with DOAC-Stop resulted in 'correction' of some of these measurements depending on drug concentration. Like the routine coagulation assays, there is a dabigatran concentration dependent effect on the accuracy of fibrinogen and D-dimer assays. Falsely low fibrinogen results due to dabigatran may confound the assessment of DIC and diagnostic laboratories need to evaluate the performance of their own reagents.

Research Trends in Anticoagulation Therapy over the Last 25 Years.

A large volume of literature has become available to practitioners prescribing anticoagulants. The aim of this study was to analyze the bibliometric characteristics of the top 100 most cited articles related to anticoagulation over the past 25 years, with special consideration to impact of direct or "nonvitamin K antagonist" oral anticoagulants (NOACs) compared with vitamin K antagonists. A bibliometric analysis of the 100 most cited journal articles related to anticoagulants published between 1994 and 2019 was performed in April 2019. The top 100 articles by citation count were analyzed to extract bibliometric data related to journal title, impact factor, year of publication, place of publication, anticoagulant studied, indication for anticoagulation, study design, and conflicts of interest. The median (interquartile range) number of citations per article was 806 (621-1,085). The anticoagulant most frequently researched was warfarin (37%). NOAC publications (21%) grew at a relative rate of 3.4 times faster compared with all publications. The indication most commonly researched was venous thromboembolism (26%). Eighty articles constituted level I or II evidence, with randomized controlled trials the most common type of study (74). A financial conflict of interest was declared in 87% of articles with private, for-profit organizations the most common source of funding (26%). In summary, top research related to anticoagulation is highly impactful but may be at risk of sponsorship bias. High-level evidence for NOACs continues to expand across a range of indications with citation metrics likely to soon approach or surpass that of older drugs.

Emergency airway training: "Who are you going to FONA?"

OBJECTIVES: To demonstrate face and content validity of a home-made simulation model as a training tool for front of neck access (FONA) procedures. DESIGN: This was a prospective evaluation study, in which experienced otolaryngologists and trainees were recruited to complete 3 tasks using our FONA model. SETTING: The study was completed during regular simulation training days and international conferences. PARTICIPANTS: A total of 52 participants completed the questionnaire and were included in the study; 25 were experts and 27 were trainees. MAIN OUTCOME MEASURES: All participants completed a validated 15-item questionnaire using a 5-point likert scale to assess the model across 4 domains: face validity (FV), global content (GC), task-specific content (TSC) and curriculum applicability (CTR). RESULTS: There were no statistically significant differences between the groups ratings for FV, GC, TSC or CTR (P = .76, .13, .4 and .67, respectively). The model achieved a median FV of 4 (IQR 4-5) with the agreement of experienced and trainee groups (68.9% and 92%, respectively). The median GC validity score was 5 (IQR 4-5) with the agreement of 87.6% and 98.4% in respected groups. The model achieved a median TSC of 4.8 (IQR 4-5) with the agreement of 54.5% and 99% in respected groups. The median CTR score was 5 (IQR 4-5) with the agreement of 54.4% and 100% in respected groups. CONCLUSION: Our home-made FONA model achieved face and content validity for training and is safe and affordable for teaching basic front of neck access skills to otolaryngology trainees.

The potential role of antibodies against minor blood group antigens in renal transplantation.

Blood group antigens are red blood cell (RBC) surface markers comprising specific carbohydrate moieties attached to the glycolipids and glycoproteins within the membrane. In addition to the major ABO blood group antigens, at least 35 minor blood group antigens have been defined to date. These antigens have immunogenic potential and may cause a transfusion reaction. There is evidence for renal expression of antigens from the Kidd, MNS, Duffy and Lewis groups and therefore the potential for antibodies directed against these antigens to cross-react in a transplanted kidney. In individuals lacking a specific RBC antigen, antibodies may develop after de novo exposure to that antigen, in addition to the potential presence of pre-existing innate antibodies. Relatively little attention has been paid to non-ABO system antibodies, with most reports in the literature focusing on transfusion reactions rather than on any putative role in allograft rejection. Here, we review each of these antigens in the context of renal transplantation and what limited evidence there is on how such immunological risk may be assessed and managed.

A national review of the clinical use of group O D- red blood cell units.

BACKGROUND: There has been an international decline in the demand for red blood cell (RBC) units. In Australia, there has been a 21% reduction in demand between 2012 and 2015. In contrast, the demand for the "universal" group O D- RBC units is in fact proportionally increasing. STUDY DESIGN AND METHODS: The clinical use of the entire O D- RBC distribution for a 5-week period throughout Australia was reviewed. Fate data on each unit issued (n = 9733) were collected that included the indication and urgency of transfusion, reason for discard, component age, and patient demographics. RESULTS: A total of 74% of audit forms were returned (n = 7143). The national discard rate of issued units was 7.9%. A total of 6387 units were transfused into an estimated total of 3008 patients (55% males) with median patient age of 67 years and median RBC age of 21 days. Forty-seven percent were transfused to group O D- patients. A total of 17.4% were chosen for specific phenotype requirements, 24.5% of units were transfused close to expiry, and 24.5% were transfused into patients of other ABO groups. CONCLUSION: The data appear broadly representative of the current transfusion and inventory management practices surrounding the use of group O D- RBC units. Strategies to reduce O D RBC demand include reevaluation of inventory holdings particularly at smaller centers, increasing the panel of phenotyped RBC units across all ABO groups, more regular rotation of units between hospitals to minimize time expiry, and continuing education for promoting transfusion of ABO-identical RBC units.

Cytomegalovirus in Australian blood donors: seroepidemiology and seronegative red blood cell component inventories.

BACKGROUND: Cytomegalovirus (CMV) can lead to severe disease in high-risk subpopulations. To prevent transfusion-transmitted CMV in these patient groups, the Australian Red Cross Blood Service maintains inventories of CMV-seronegative fresh blood components. STUDY DESIGN AND METHODS: Donor demographic data and CMV seroscreening results for all blood donations and blood components issued in Australia between financial years (FYs) 2008/09 to 2012/13 inclusive were obtained. Population estimates were also extracted for the calculation of age-weighted seroprevalence estimates. Linear regression was used to model trends in red blood cell (RBC) component acquisition and demand. RESULTS: The estimated age-weighted seroprevalence of CMV in 20- to 69-year old Australians was 76.12 ± 0.13%, with higher seroprevalence in females and older age groups. Seroprevalence decreased over the study period, while the demand for CMV-seronegative RBC components increased. It was predicted that component acquisition may be insufficient by FY 2017/18 if current trends persist. CONCLUSION: These findings represent an evaluation of CMV seroepidemiology in Australia and form a basis to predict the future status of CMV-seronegative RBC component inventories. The results will serve to guide Blood Service operations and inform current international debate on CMV-safe blood components.

Generating a geospatial database of U.S. regional feedstock production for use in evaluating the environmental footprint of biofuels.

UNLABELLED: The potential environmental effects of increased U.S. biofuel production often vary depending upon the location and type of land used to produce biofuel feedstocks. However, complete, annual data are generally lacking regarding feedstock production by specific location. Corn is the dominant biofuel feedstock in the U.S., so here we present methods for estimating where bioethanol corn feedstock is grown annually and how much is used by U.S. ethanol biorefineries. We use geospatial software and publicly available data to map locations of biorefineries, estimate their corn feedstock requirements, and estimate the feedstock production locations and quantities. We combined these data and estimates into a Bioethanol Feedstock Geospatial Database (BFGD) for years 2005-2010. We evaluated the performance of the methods by assessing how well the feedstock geospatial model matched our estimates of locally-sourced feedstock demand. On average, the model met approximately 89 percent of the total estimated local feedstock demand across the studied years-within approximately 25-to-40 kilometers of the biorefinery in the majority of cases. We anticipate that these methods could be used for other years and feedstocks, and can be subsequently applied to estimate the environmental footprint of feedstock production. IMPLICATIONS: Methods used to develop the Bioethanol Feedstock Geospatial Database (BFGD) provide a means of estimating the amount and location of U.S. corn harvested for use as U.S. bioethanol feedstock. Such estimates of geospatial feedstock production may be used to evaluate environmental impacts of bioethanol production and to identify conservation priorities. The BFGD is available for 2005-2010, and the methods may be applied to additional years, locations, and potentially other biofuels and feedstocks.

Cytomegalovirus disease in immunocompetent adults.

Cytomegalovirus (CMV) is a highly prevalent and globally distributed virus. CMV infection in healthy adults is usually asymptomatic or causes a mild mononucleosis-like syndrome. CMV disease causes significant morbidity and mortality in neonates and severely immunocompromised adults. CMV disease can present with a wide range of manifestations, with colitis being the most common. The incidence of severe CMV disease in immunocompetent adults appears to be greater than previously thought, which may be partly due to immune dysfunction related to comorbidities such as kidney disease or diabetes mellitus. CMV disease can mimic an array of alternative diagnoses and pose a significant diagnostic challenge, especially in immunocompetent adults, leading to delayed diagnosis, adverse health outcomes and unnecessary financial expense. Non-invasive testing for CMV is widely available and can facilitate early diagnosis if used appropriately. Although limited, current evidence suggests that targeted antiviral therapy with ganciclovir or valganciclovir is appropriate for severe CMV disease in immunocompetent adults.

Women with cardiovascular disease have increased risk of osteoporotic fracture.

This study investigated whether women with cardiovascular disease (CVD) would have an increased risk of fractures as osteoporosis and CVD share many common risk factors. From February 2006 to January 2007, 17,033 women aged ≥50 years (mean 71.8, range 50-106) were recruited by 1,248 primary care practitioners and interviewed by trained nurses. For each woman, 10-year probability of a future major osteoporotic fracture was estimated using the World Health Organization Fracture Risk Assessment Tool (FRAX). The study showed that the 10-year probability of a major osteoporotic fracture was higher for 6,219 CVD women compared to 10,814 non-CVD women after adjustment for age, BMI, current smoking, and alcohol use (adjusted geometric means 14.3 and 13.8%, respectively; P < 0.001). With regard to high risk of fracture (i.e., 10-year probability ≥ 20%), the adjusted odds ratio for CVD was 1.23 (95% CI 1.13-1.35, P < 0.001). However, compared to non-CVD women, CVD women were more likely to report a previous fracture, to have a secondary osteoporosis, and to use glucocorticoids. Among the 4,678 women who were classified as having a high fracture risk, current use rate of bone-related medications (i.e., any one of bisphosphonates, raloxifene, PTH, vitamin D, calcium, or hormone therapy) was 50.2% in the CVD group and 56.9% in the non-CVD group. Women with CVD were at increased risk of fracture partly due to bone-specific risk factors such as history of previous fracture, use of glucocorticoids, and secondary osteoporosis. This risk is not being treated appropriately by primary health physicians.