Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.

Humans coexisted and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here, we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 962 exonic splicing mutations that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than that in Neanderthals. Adaptively introgressed variants were enriched for moderate-effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a unique tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a unique Neanderthal introgressed alternative splicing variant in the gene HSPG2 that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide unique insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.

Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes.

To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5' splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical records of 3 ASD patients with TNRC6C variant revealed respiratory issues consistent with phenotypes observed in TNRC6 depleted mice. Overall, this study highlights the need for splicing analysis in determining variant pathogenicity, especially as it relates to ASD.

Nationwide Analysis of Firearm Injury Versus Other Penetrating Trauma: It's Not All the Same Caliber.

INTRODUCTION: Ballistic injuries cause both a temporary and permanent cavitation event, making them far more destructive and complex than other penetrating trauma. We hypothesized that global injury scoring and physiologic parameters would fail to capture the lethality of gunshot wounds (GSW) compared to other penetrating mechanisms. METHODS: The 2019 American College of Surgeons Trauma Quality Programs participant use file was queried for the mortality rate for GSW and other penetrating mechanisms. A binomial logistic regression model ascertained the effects of sex, age, hypotension, tachycardia, mechanism, Glasgow Coma Scale, ISS, and volume of blood transfusion on the likelihood of mortality. Subgroup analyses examined isolated injuries by body regions. RESULTS: Among 95,458 cases (82% male), GSW comprised 46.4% of penetrating traumas. GSW was associated with longer hospital length of stay (4 [2-9] versus 3 [2-5] days), longer intensive care unit length of stay (3 [2-6] versus 2 [2-4] days), and more ventilator days (2 [1-4] versus 2 [1-3]) compared to stab wounds, all P < 0.001. The model determined that GSW was linked to increased odds of mortality compared to stab wounds (odds ratio 4.19, 95% confidence interval 3.55-4.93). GSW was an independent risk factor for acute kidney injury, acute respiratory distress syndrome, venous thromboembolism, sepsis, and surgical site infection. CONCLUSIONS: Injury scoring systems based on anatomical or physiological derangements fail to capture the lethality of GSW compared to other mechanisms of penetrating injury. Adjustments in risk stratification and reporting are necessary to reflect the proportion of GSW seen at each trauma center. Improved classification may help providers develop quality processes of care. This information may also help shape public discourse on this highly lethal mechanism.

Initial Hemorrhage Control Procedure for Splenic Injuries May Affect Risk of Venous Thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE) continues to be a major cause of morbidity in trauma. It is unclear whether the type of hemorrhage control procedure (i.e., splenectomy versus angioembolization) is associated with an increased risk of VTE. We hypothesize that hemodynamically stable patients undergoing angioembolization for blunt high-grade splenic injuries have lower rates of VTE compared to those undergoing splenectomy. METHODS: The American College of Surgeons Trauma Quality Program dataset from 2017 to 2019 was queried to identify all patients with American Association for the Surgery of Trauma grade 3-5 blunt splenic injuries. Outcomes including VTE rates were compared between those who were managed with splenectomy versus angioembolization. Propensity score matching (1:1) was performed adjusting for age, sex, initial vital signs, Injury Severity Score, and splenic injury grade. RESULTS: The analysis included 4698 matched patients (splenectomy [n = 2349] and angioembolization [n = 2349]). The median (interquartile range) age was 41 (27-58) years and 69% were male. Patients were well matched between groups. Angioembolization was associated with significantly lower VTE than splenectomy (2.2% versus 3.4%, P = 0.010) despite less use of VTE chemoprophylaxis (70% versus 80%, P < 0.001), as well as a relative delay in initiation of chemoprophylaxis (44 h versus 33 h, P < 0.001). Hospital and intensive care unit length of stay and mortality were also significantly lower in the angioembolization group. CONCLUSIONS: Angioembolization is associated with a significantly lower incidence of VTE than splenectomy. Thus, angioembolization should be considered for initial management of hemodynamically stable patients with high-grade blunt splenic injuries in whom laparotomy is not otherwise indicated.

Survival of In-Hospital Cardiopulmonary Arrest in Trauma Patients.

INTRODUCTION: Relative to other hospitalized patients, trauma patients are younger with fewer comorbidities, but the incidence and outcomes of in-hospital cardiopulmonary arrest (IHCA) with cardiopulmonary resuscitation (CPR) in this population is unknown. Therefore, we aimed to investigate factors associated with survival in trauma patients after IHCA to test the hypothesis that compared to other hospitalized patients, trauma patients with IHCA have improved survival. METHODS: Retrospective review of the Trauma Quality Improvement Program database 2017 to 2019 for patients who had IHCA with CPR. Primary outcome was survival to hospital discharge. Secondary outcomes were in-hospital complications, hospital length of stay, intensive care unit length of stay, and ventilator days. Data were compared with univariate and multivariate analyses at P < 0.05. RESULTS: In 22,346,677 admitted trauma patients, 14,056 (0.6%) received CPR. Four thousand three hundred seventy-seven (31.1%) survived to discharge versus 26.4% in a national sample of all hospitalized patients (P < 0.001). In trauma patients, median age was 55 y, the majority were male (72.2%). Mortality was higher for females versus males (70.3% versus 68.3%, P = 0.026). Multivariate regression showed that older age 1.01 (95% confidence interval (CI) 1.01-1.02), Hispanic ethnicity 1.21 (95% CI 1.04-1.40), and penetrating trauma 1.51 (95% CI 1.32-1.72) were risk factors for mortality, while White race was a protective factor 0.36 (95% CI 0.14-0.89). CONCLUSIONS: This is the first study to show that the incidence of IHCA with CPR is approximately six in 1000 trauma admissions and 31% survive to hospital discharge, which is higher than other hospitalized patients. Age, gender, racial, and ethnic disparities also influence survival.

Timing of Pediatric Incarcerated Inguinal Hernia Repair: A Review of Nationwide Readmissions Data.

INTRODUCTION: In pediatric patients, incarcerated inguinal hernias are often repaired on presentation. We hypothesize that in appropriate patients, repair may be safely deferred. METHODS: The Nationwide Readmissions Database was used to identify pediatric patients (aged < 18 y) with incarcerated inguinal hernia from 2010 to 2014. Patients were stratified by management approach (Early Repair versus Deferral). Overall frequencies of these operative strategies were calculated. Propensity score matching was then performed to control for patient age, comorbidities, perinatal conditions, and congenital anomalies. Outcomes including complications, surgical procedures, and readmissions were compared. Outpatient surgeries were not assessed. RESULTS: Among 6148 total patients with incarcerated inguinal hernia, the most common strategy was to perform Early Repair (88% versus 12% Deferral). Following propensity score matching, the cohort included 1288 patients (86% male, average age 1.7 ± 4.1 years). Deferral was associated with equivalent rates of readmission within one year (13% versus 15%, P = 0.143), but higher readmissions within the first 30 days (7% versus 3%, P = 0.002) than Early Repair. Deferral patients had lower rates of orchiectomy (2% versus 5%, P = 0.001), wound infections (< 2% versus 2%, P = 0.020), and other infections (7% versus 15%, P < 0.001). The frequency of other complications including bowel resection, oophorectomy, testicular atrophy, sepsis, and pneumonia were equivalent between groups. Three percent of Deferrals had a diagnosis of incarceration on readmission. CONCLUSIONS: Deferral of incarcerated inguinal hernia repair at index admission is associated with higher rates of hospital readmissions within the first 30 days but equivalent readmission within the entire calendar year. These patients are at risk of repeat incarceration but have significantly lower rates of orchiectomy than their counterparts who undergo inguinal hernia repair at the index admission. We propose that prospective studies be performed to identify good candidates for Elective Deferral following manual reduction and overnight observation. Such studies must capture outpatient surgical outcomes.

Mesh Type With Ventral Hernia Repair: A Systematic Review and Meta-analysis of Randomized Trials.

INTRODUCTION: Synthetic mesh is widely utilized for clean ventral hernia repair; however, it is unclear if synthetic mesh provides the same benefits with high-risk patients or during contaminated cases. Many surgeons use biologic mesh in these settings, but there is little evidence to support this practice. Our objective was to compare the clinical outcomes of utilizing biologic mesh versus synthetic mesh during ventral hernia repair. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a review of the literature was conducted using Cochrane library, EMBASE, Clinicaltrials.gov, and PubMed for randomized controlled trials published that compared biologic versus synthetic mesh during ventral hernia repair. The primary outcome was major complications defined as deep or organ space surgical site infection, reoperations, and hernia recurrences. RESULTS: Of 1889 manuscripts screened, four publications were included. The four studies included a total of 758 patients, with 381 receiving biologic mesh and 377 receiving synthetic mesh. Compared to biologic mesh, synthetic mesh had lower rates of major complications (38.6% versus 23.4, risk ratio = 0.55, 95% confidence interval = 0.35 to 0.86, P = 0.009) and hernia recurrence (24.5 % versus 10.3%, risk ratio = 0.44, 95% confidence interval = 0.28 to 0.69, P = 0.004). In addition, there was a lower percentage of surgical site infection and reoperation in the synthetic mesh group. CONCLUSIONS: Contrary to current surgical teaching, placement of permanent synthetic mesh into a contaminated field yielded rates of complications that were comparable or reduced compared to biologic mesh.

COVID-19-related thrombotic complications experience before and during delta wave.

OBJECTIVE: Hypercoagulability and thrombotic complications seen in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as the associated pathophysiology, have been reported extensively. However, there is limited information regarding the factors related to this phenomenon and its association with the Coronavirus disease 2019 (COVID-19) Delta variant. METHODS: A retrospective review including patients admitted to a tertiary center with a COVID-19 positive test and at least one acute thrombotic event confirmed by imaging between June 2020 and August 2021 was performed. We compared the rates of thrombotic events in patients with COVID-19 before and during the Delta peak. We also analyzed the association of the thrombotic complications with demographic characteristics, comorbidities, anticoagulation strategies, and prothrombotic markers while describing other complications secondary to COVID-19 infection. RESULTS: Of 964 patients admitted with COVID-19 diagnosis, 26.5% (n = 256) had a thrombotic event evidenced by ultrasound or computed tomography scan. Venous thromboembolism was found in 60% (n = 153), arterial thrombosis in 23% (n = 60), and both venous and arterial thromboses in 17% (n = 17) of the study cohort. Of all patients, 94% were not vaccinated. Delta variant wave (DW) patients had thrombotic episodes in 34.7% (n = 50/144) of cases compared with 25% (n = 206/820) of non-Delta wave (NDW) patients, posing an estimated risk 1.36 times higher in patients infected with COVID-19 during the DW than NDW. Overall, DW subjects were significantly younger (P < .001) with lower body mass index (P = .021) compared with NDW patients. Statistical analyses showed African American patients were more likely to have arterial thrombosis compared with the other groups when testing positive for COVID-19 (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.04-3.05; P = .035, whereas immunosuppressed patients had less risk of arterial thrombosis (OR, 0.38; 95% CI, 0.15-0.96; P = .042). Female gender (OR, 2.15; 95% CI, 1.20-3.85; P = .009) and patients with active malignancy (OR, 5.99; 95% CI, 2.14-16.78; P = .001) had an increased risk of having multiple thrombotic events at different locations secondary to COVID-19. CONCLUSIONS: COVID-19 infection is associated with elevated rates of thrombotic complications and an especially higher risk in patients infected during the Delta variant peak. We highlight the importance of vaccination and the development of new anticoagulation strategies for patients with COVID-19 with additional hypercoagulable risk factors to prevent thrombotic complications caused by this disease.

Outcomes of Abdominal Firearm Injury and Damage Control Laparotomy in the Pediatric Population.

INTRODUCTION: Firearm injuries (GSW) in the pediatric population is a public health crisis. Little is known about the outcomes of damage control laparotomy (DCL) following abdominal GSW. This study aims to evaluate outcomes from abdominal GSWs in the pediatric population. METHODS: The trauma registry from an urban Level 1 trauma was queried for pediatric (0-18 y) GSW was queried from September 2013 to June 2020. Demographics, clinical variables, outcomes, readmissions, and recidivism were analyzed. RESULTS: Abdominal GSW were identified in 83 patients (17% of all GSW). The median age was 16 [15-17], 84% were male and 86% Black. Violent intent accounted for 90% of GSW. The injury severity score was 16 [9-26] and 80% went directly from the resuscitation bay to the operating room. Laparotomy was required in 87% of patients, and surgery was not required in any patient initially managed nonoperatively. The most common complications were intraabdominal infection (20%), other infections (13%), and small bowel obstruction (8%). DCL with temporary abdominal closure was performed in 16% of laparotomies and was associated with a longer length of stay, more infections, but similar rates of readmission and mortality. Overall mortality was 13%, with all but one patient expiring in the resuscitation bay or the operating room. All patients who underwent DCL survived to discharge. CONCLUSIONS: Abdominal firearm injuries have high morbidity and mortality in the pediatric population. Damage control operations for abdominal GSWs are a valuable surgical option with similar outcomes to primary abdominal closure after initial injury survival.

Characteristics and Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction Compared to Heart Failure With Reduced Ejection Fraction: Insights From the VCOR Heart Failure Snapshot.

BACKGROUND: Heart failure is increasing in prevalence, creating a greater public health and economic burden on our health care system. With a rising proportion of hospitalisations for heart failure with preserved ejection fraction (HFpEF) compared to heart failure with reduced ejection fraction (HFrEF) and lack of proven therapies for HFpEF, patient characterisation and defining clinical outcomes are important in determining optimal management of heart failure patients. There is scarce Australian-specific data with regards to the burden of disease of patients with HFpEF which further limits our ability to appropriately manage this syndrome. AIM: To determine the characteristics, management practices and outcomes of patients with HFpEF compared to patients diagnosed with HFrEF. METHOD: Data was sourced from the Victorian Cardiac Outcomes Registry-Heart Failure (VCOR-HF) snapshot of patients admitted with acute heart failure to one of 16 Victorian health services between 2014-2017 over one consecutive month annually. Outcomes measured were in-hospital mortality, and 30-day readmission and mortality. RESULTS: Of the 1,132 HF patients, 436 patients were diagnosed with HFpEF and were more likely to be female (59%) and older (81.5±9.8 vs 73.2±14.5 years). They were also more likely to have hypertension (80%), atrial fibrillation (59.9%), chronic obstructive airways disease (36.2%) and chronic kidney disease (68.8%). Patients with HFrEF were more likely to have ischaemic heart disease with a history of previous myocardial infarction (36.6%), percutaneous coronary intervention and cardiac bypass surgery (35.2%). There were no significant differences in 30-day mortality between HFpEF and HFrEF (10.2% vs 7.8%; p=0.19, respectively) and 30-day readmission rates (22.1% vs 25.9%; p=0.15, respectively). CONCLUSION: VCOR-HF Snapshot data provides important insight into the burden of acute heart failure. Whilst patients with HFpEF and HFrEF have differing clinical profiles, morbidity, mortality and re-admission rates are similar.

Cardio-geriatric model of care in acute heart failure: initial experience of a multidisciplinary approach in complex elderly patients.

A 'cardio-geriatric' heart failure model of care was implemented to address the high rates of readmission in elderly acute decompensated heart failure patients. Despite demonstrably intensified management in both the cardiology and geriatric domains, this study did not demonstrate a positive effect on the primary outcome of all cause readmissions at 30 days.

The Effect of Transitional Care on 30-Day Outcomes in Patients Hospitalised With Acute Heart Failure.

BACKGROUND: Patients admitted to hospital with acute heart failure (AHF) are at increased risk of readmission and mortality post-discharge. The aim of the study was to examine health service utilisation within 30 days post-discharge from an AHF hospitalisation. METHODS: This was a prospective, observational, non-randomised study of consecutive patients hospitalised with acute HF to one of 16 Victorian hospitals over a 30-day period each year and followed up for 30 days post-discharge. The project was conducted annually over three consecutive years from 2015 to 2017. RESULTS: Of the 1,197 patients, 56.3% were male with an average age of 77±13.23 years. Over half of the patients (711, 62.5%) were referred to an outpatient clinic and a third (391, 34.4%) to a HF disease management program. In-hospital mortality was 5.1% with 30 day-mortality of 9% and readmission rate of 24.4%. Patients who experienced a subsequent readmission less than 10 days post-discharge and between 11 and 20 days post-discharge had a five- to six-fold increase in risk of mortality (adjusted OR 5.02, 95% CI 2.11-11.97; OR 6.45, 95% CI 2.69-15.42; respectively) compared to patients who were not readmitted to hospital. An outpatient appointment within 30 days post-discharge significantly reduced the risk of 30-day mortality by 81% (95% CI 0.09-0.43). CONCLUSION: Patients admitted to hospital with AHF who experience a subsequent readmission within 20 days post-discharge are at increased risk of dying. However, early follow-up post-discharge may reduce this risk. Early post-discharge follow-up is vital to address this vulnerable period after a HF admission.

Future directions for high-throughput splicing assays in precision medicine.

Classification of variants of unknown significance is a challenging technical problem in clinical genetics. As up to one-third of disease-causing mutations are thought to affect pre-mRNA splicing, it is important to accurately classify splicing mutations in patient sequencing data. Several consortia and healthcare systems have conducted large-scale patient sequencing studies, which discover novel variants faster than they can be classified. Here, we compare the advantages and limitations of several high-throughput splicing assays aimed at mitigating this bottleneck, and describe a data set of ~5,000 variants that we analyzed using our Massively Parallel Splicing Assay (MaPSy). The Critical Assessment of Genome Interpretation group (CAGI) organized a challenge, in which participants submitted machine learning models to predict the splicing effects of variants in this data set. We discuss the winning submission of the challenge (MMSplice) which outperformed existing software. Finally, we highlight methods to overcome the limitations of MaPSy and similar assays, such as tissue-specific splicing, the effect of surrounding sequence context, classifying intronic variants, synthesizing large exons, and amplifying complex libraries of minigene species. Further development of these assays will greatly benefit the field of clinical genetics, which lack high-throughput methods for variant interpretation.

The Cfd1 Subunit of the Nbp35-Cfd1 Iron Sulfur Cluster Scaffolding Complex Controls Nucleotide Binding.

The cytosolic iron sulfur cluster assembly (CIA) scaffold biosynthesizes iron sulfur cluster cofactors for enzymes residing in the cytosol and the nucleus. In fungi and animals, it comprises two homologous ATPases, called Nbp35 and Cfd1 in yeast, which can form homodimeric and heterodimeric complexes. Both proteins are required for CIA function, but their individual roles are not well understood. Here we investigate the nucleotide affinity of each form of the scaffold for ATP and ADP to reveal any differences that could shed light on the functions of the different oligomeric forms of the protein or any distinct roles of the individual subunits. All forms of the CIA scaffold are specific for adenosine nucleotides and not guanosine nucleotides. Although the Cfd1 homodimer has no detectable ATPase activity, it binds ATP with an affinity comparable to that of the hydrolysis competent forms, Nbp352 and Nbp35-Cfd1. Titrations to determine the number of nucleotide binding sites combined with site-directed mutagenesis demonstrate that the nucleotide must bind to the Cfd1 subunit of the heterodimer before it can bind to Nbp35 and that the Cfd1 subunit is hydrolysis competent when bound to Nbp35 in the heterodimer. Altogether, our work reveals the distinct roles of the Nbp35 and Cfd1 subunits in their heterodimeric complex. Cfd1 controls nucleotide binding, and the Nbp35 subunit is required to activate nucleotide hydrolysis.

Changes in Statin Prescription Patterns in Patients Admitted to an Australian Geriatric Subacute Unit.

BACKGROUND: Assessment of demographic and clinical factors influencing the decision of statin discontinuation in the elderly population admitted to subacute geriatric unit. The aim of this study is to assess the clinical factors impacting the decision-making process of statin discontinuation in the elderly. METHODS: We retrospectively assessed changes in statin discontinuation and prescription among patients (≥60 years old) discharged from a geriatric evaluation and management unit by reviewing hospital digital medical records at Western Health - The Williamstown Hospital over a 12-month period from 4 February 2012 until 4 February 2013 inclusive. The main outcome of the study was to determine the independent predictors of statin discontinuation using logistic regression analysis. RESULTS: Of the studied population, 46% were already prescribed statins prior to their admission. Statins were discontinued in 17.5% of patients at discharge. Predictors of statin de-prescription included octogenarian status, primary prevention indication, poor functional recovery, residential care facility discharge destination and lower cognitive function. The presence of previous cardiovascular disease history and the burden of comorbidities were not predictors of statin discontinuation. CONCLUSIONS: We observed that factors that conveyed poor prognosis such as advanced age, poor functional recovery, worse cognitive function, being discharged to a residential care facility as well as primary prevention indication for statin prescription are predictors of statin discontinuation in the geriatric unit.

Dietary nitrate supplementation in cardiovascular health: an ergogenic aid or exercise therapeutic?

Oral consumption of inorganic nitrate, which is abundant in green leafy vegetables and roots, has been shown to increase circulating plasma nitrite concentration, which can be converted to nitric oxide in low oxygen conditions. The associated beneficial physiological effects include a reduction in blood pressure, modification of platelet aggregation, and increases in limb blood flow. There have been numerous studies of nitrate supplementation in healthy recreational and competitive athletes; however, the ergogenic benefits are currently unclear due to a variety of factors including small sample sizes, different dosing regimens, variable nitrate conversion rates, the heterogeneity of participants' initial fitness levels, and the types of exercise tests used. In clinical populations, the study results seem more promising, particularly in patients with cardiovascular diseases who typically present with disruptions in the ability to transport oxygen from the atmosphere to working tissues and reduced exercise tolerance. Many of these disease-related, physiological maladaptations, including endothelial dysfunction, increased reactive oxygen species, reduced tissue perfusion, and muscle mitochondrial dysfunction, have been previously identified as potential targets for nitric oxide restorative effects. This review is the first of its kind to outline the current evidence for inorganic nitrate supplementation as a therapeutic intervention to restore exercise tolerance and improve quality of life in patients with cardiovascular diseases. We summarize the factors that appear to limit or maximize its effectiveness and present a case for why it may be more effective in patients with cardiovascular disease than as ergogenic aid in healthy populations.

Impact of limited English proficiency on presentation and outcomes of patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction.

Doctor-patient language discordance has been shown to lead to worse clinical outcomes. In this study of patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction at an Australian health service, we demonstrated that limited English proficiency (LEP) is an independent predictor of prolonged symptom-to-door time, but does not lead to worse 30-day mortality compared with English-proficient patients. More effort needs to be placed in providing public health education in varied languages to encourage early presentation to hospital for patients with LEP.

Inorganic nitrate as a treatment for acute heart failure: a protocol for a single center, randomized, double-blind, placebo-controlled pilot and feasibility study.

BACKGROUND: Acute heart failure (AHF) is a frequent reason for hospitalization worldwide and effective treatment options are limited. It is known that AHF is a condition characterized by impaired vasorelaxation, together with reduced nitric oxide (NO) bioavailability, an endogenous vasodilatory compound. Supplementation of inorganic sodium nitrate (NaNO3) is an indirect dietary source of NO, through bioconversion. It is proposed that oral sodium nitrate will favorably affect levels of circulating NO precursors (nitrate and nitrite) in AHF patients, resulting in reduced systemic vascular resistance, without significant hypotension. METHODS AND OUTCOMES: We propose a single center, randomized, double-blind, placebo-controlled pilot trial, evaluating the feasibility of sodium nitrate as a treatment for AHF. The primary hypothesis that sodium nitrate treatment will result in increased systemic levels of nitric oxide pre-cursors (nitrate and nitrite) in plasma, in parallel with improved vasorelaxation, as assessed by non-invasively derived systemic vascular resistance index. Additional surrogate measures relevant to the known pathophysiology of AHF will be obtained in order to assess clinical effect on dyspnea and renal function. DISCUSSION: The results of this study will provide evidence of the feasibility of this novel approach and will be of interest to the heart failure community. This trial may inform a larger study.

Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing.

Cells transiently adapt to hypoxia by globally decreasing protein translation. However, specific proteins needed to respond to hypoxia evade this translational repression. The mechanisms of this phenomenon remain unclear. We screened for and identified small molecules that selectively decrease HIF-2a translation in an mTOR-independent manner, by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to a recently reported iron-responsive element (IRE) within the 5'-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia derepresses HIF-2a translation by disrupting the IRP1-HIF-2a IRE interaction. Thus, this chemical genetic analysis describes a molecular mechanism by which translation of the HIF-2a message is maintained during conditions of cellular hypoxia through inhibition of IRP-1-dependent repression. It also provides the chemical tools for studying this phenomenon.

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI).

AIM: Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this double-blind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 µmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6-8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6-8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size -0.7% 95% CI: -2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6-8 days and at 6 months and final infarct size (FIS) measured at 6 months. CONCLUSIONS: Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size.