Group 3 pulmonary hypertension (PH) is a common complication of chronic lung disease (CLD), including chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered ...breathing. Development of PH is associated with poor prognosis and may progress to right heart failure, however, in the majority of the patients with CLD, PH is mild to moderate and only a small number of patients develop severe PH. The pathophysiology of PH in CLD is multifactorial and includes hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, small vessel destruction, and fibrosis. The effects of PH on the right ventricle (RV) range between early RV remodeling, hypertrophy, dilatation, and eventual failure with associated increased mortality. The golden standard for diagnosis of PH is right heart catheterization, however, evidence of PH can be appreciated on clinical examination, serology, radiological imaging, and Doppler echocardiography. Treatment of PH in CLD focuses on management of the underlying lung disorder and hypoxia. There is, however, limited evidence to suggest that PH-specific vasodilators such as phosphodiesterase-type 5 inhibitors, endothelin receptor antagonists, and prostanoids may have a role in the treatment of patients with CLD and moderate-to-severe PH.
There is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to ...enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation.
Australia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362709.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights ► Randomized clinical trial of a novel adjuvanted H1N1/2009 pandemic influenza vaccine. ► Reports first pandemic use of a vaccine based on recombinant hemagglutinin. ► The recombinant ...vaccine was produced within 12 weeks of the pandemic. ► Advax™, a novel polysaccharide adjuvant, significantly improved vaccine responses.
Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH.
This randomized, placebo-controlled, ...double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness.
Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness “right now”—morning and evening—measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291).
Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness “right now” was higher on morphine compared with placebo both for morning mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = −0.22 (−0.6 to 0.2) and evening (M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = −0.33 (−0.8 to 0.1). All secondary measures of breathlessness were higher with morphine as were nausea and constipation.
This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.
Rivaroxaban is an orally active direct factor Xa inhibitor used to treat venous thromboembolism with approved starting dose of 15 mg twice-daily. We present a case of an accidental overdose in a ...patient with pulmonary thromboembolism, when the patient received two 150 mg doses of rivaroxaban, instead of 15 mg as prescribed, given 12 hours apart. This error was recognised ten minutes after the second dose, when 50 gm oral activated charcoal was given. Rivaroxaban was stopped and rivaroxaban concentrations, INR, and APTT were monitored. The overdose was uncomplicated and 15 mg twice-daily rivaroxaban was restarted on day two. Apparently unlikely and potentially hazardous dispensing errors do happen. Each oral anticoagulant has a different dosing schedule. In our patient, the prescription for 15 mg twice-daily rivaroxaban was misread as 150 mg twice-daily (a correct dose for dabigatran in atrial fibrillation). Such errors are preventable. Prompt administration of activated charcoal under monitoring of a specific rivaroxaban assay can greatly help management of unusual situations like this one.
Objective: The purpose of this study was to compare the effectiveness of small-bore intercostal catheters (SB ICCs; 10-14 Fr) to large-bore intercostal tubes (LB ICTs; >20 Fr) in the management of ...pleural diseases. Methods: A total of 52 patients (42 males) with a mean age of 55 ± 23 years undergoing pleural intervention were included in the analysis. Twenty-five patients (48.1%) had pneumothorax and rest (51.9%) had pleural effusion. Half of the patients underwent SB ICC (mean age: 63 ± 20 years) and the remaining 26 underwent LB ICT (mean age: 47 ± 25 years). Results: SB ICCs were predominantly used in patients with primary pleural effusion and LB ICTs in patients presenting with pneumothorax. Failures were in <20% of SB ICC patients (mainly from loculation) and in <30% with LB ICT patients (from persistent airleak) - difference that was not statistically significant. In both groups, no deaths or major complications directly related to the procedure were observed. However, the proportion that needed surgery was significantly different in two cohorts (18.5% OF SB ICC and 42.3% of LB ICT cohorts). The ICC dwell time was less in SB ICC (5 ± 4 days), compared to LB ICT (8 ± 6 days). SB ICCs were associated with less pain and seem to be tolerated better by the patients. Conclusions: In well-supervised tertiary hospital setting, SB ICCs are as effective as LB ICTs with better patient tolerance, reduced dwell time, and reduced likelihood for surgical intervention.
We aimed to assess adherence to the Australian national guideline (COPD-X) against audited practice, and to document the outcomes of patients hospitalised with an acute exacerbation of chronic ...obstructive pulmonary disease (COPD) at discharge and 28 days after.
A prospective clinical audit of COPD hospital admission from five tertiary care hospitals in five states of Australia was conducted. Post-discharge follow-up was conducted via telephone to assess for readmission and health status.
There were 207 admissions for acute exacerbation (171 patients; mean 70.2 years old; 50.3% males). Readmission rates at 28 days were 25.4%, with one (0.6%) death during admission and eight (6.1%) post-discharge within 28 days. Concordance to the COPD-X guidance was variable; 22.7% performed spirometry, 81.1% had blood gases collected when forced expiratory volume in 1 s was <1 L, 99.5% had chest radiography performed, 95.1% were prescribed systemic corticosteroids and 95% were prescribed antibiotic therapy. There were 89.1% given oxygen therapy and 92.6% when arterial oxygen tension was <80 mmHg; 65.6% were given ventilatory assistance when pH was <7.35. Only 32.4% were referred to pulmonary rehabilitation but 76.8% had general practitioner follow-up arranged.
When compared against clinical practice guidelines, we found important gaps in management of patients admitted with COPD throughout tertiary care centres in Australia. Strategies to improve guideline uptake are needed to optimise care.
Timely vaccine supply is critical during influenza pandemics but is impeded by current virus-based manufacturing methods. The 2009 H1N1/2009pdm 'swine flu' pandemic reinforced the need for innovation ...in pandemic vaccine design. We report on insights gained during rapid development of a pandemic vaccine based on recombinant haemagglutinin (rHA) formulated with Advax™ delta inulin adjuvant (Panblok-H1/Advax). Panblok-H1/Advax was designed and manufactured within 1 month of the pandemic declaration by WHO and successfully entered human clinical testing in under 3 months from first isolation and sequencing of the novel pandemic virus, requiring several major challenges to be overcome. Panblok-H1/Advax successfully induced neutralising antibodies against the pandemic strain, but also induced cross-neutralising antibodies in a subset of subjects against an H1N1 strain (A/Puerto Rico/8/34) derived from the 1918 Spanish flu, highlighting the possibility to use Advax to induce more broadly cross-protective antibody responses. Interestingly, the rHA from H1N1/2009pdm exhibited variants in the receptor binding domain that had a major impact on receptor binding and hemagglutination ability. We used an in silico structural modeling approach to better understand the unusual behavior of the novel hemagglutinin, thereby demonstrating the power of computational modeling approaches for rapid characterization of new pandemic viruses. While challenges remain in ensuring ultrafast vaccine access for the entire population in response to future pandemics, the adjuvanted recombinant Panblok-H1/Advax vaccine proved its utility during a real-life pandemic situation.
Abstract
Background
The aim of the current study was to determine the safety and immunogenicity of trivalent inactivated influenza vaccine (TIV) alone or formulated with Advax delta inulin adjuvant ...in those who were older (aged >60 years) or had chronic disease.
Methods
Over 4 consecutive years from 2008 through 2011, adult participants with chronic disease or >60 years of age were recruited into a randomized controlled study to assess the safety, tolerability and immunogenicity of Advax-adjuvanted TIV (TIV + Adj) versus standard TIV. The per-protocol population with ≥1 postbaseline measurement of influenza antibodies comprised 1297 participants, 447 in the TIV and 850 in the TIV + Adj) group.
Results
No safety issues were identified. Variables negatively affecting vaccine responses included obesity and diabetes mellitus. Advax adjuvant had a positive impact on anti-influenza immunoglobulin M responses and on H3N2 and B strain seropositivity as assessed by hemagglutination inhibition.
Conclusions
TIV + Adj was safe and well tolerated in individuals with chronic disease. There is an ongoing need for research into improved influenza vaccines for high-risk populations.
Clinical Trials Registration
Australia New Zealand Clinical Trial Registry: ACTRN 12608000364370.
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