SARS-CoV-2: comparison of IgG levels at 9 months post second dose of vaccination in COVID-survivor and COVID-naïve healthcare workers

Background: Natural (asymptomatic/symptomatic COVID-19 infection) and artificial (vaccination) exposure to the pathogen represent two modes of acquiring active immunity. No definitive guidelines exist regarding whether COVID-survivors (with infection/re-infection/re-re-infection in the three COVID-19 waves) require a modified vaccination schedule. Most countries are offering a third vaccine dose and many are contemplating a fourth dose. Our aim was to gauge the IgG-antibody levels 9m post second vaccination in healthcare workers (HCW) and compare these with IgG-levels 1m post-vaccination in the same cohort for any decline, and to compare the post-vaccination IgG-levels in COVID-survivors and COVID-naïve HCW at 9m.Methods: This prospective observational single-centric cohort study included 63 HCW of either sex, aged 18-70y who completed 9m post-vaccination. The IgG-titre was tested at 9-10m post second vaccination in COVID-survivors and COVID-naïve HCW.Results: At 1m and 9m post-vaccination IgG-levels in COVID-survivors (23.097±4.58 and 15.103±4.367 respectively; p<0.0001) and COVID-naïve HCW (16.277±6.36 and 9.793±6.928 respectively; p=0.0013) had unequal variance (Welsch test; p=0.0022 at 9m). 9/31 COVID-naïve HCW but none of the 32 COVID-survivors tested COVID-positive in the second wave post second vaccination. 11/31 and 3/32 HCW belonging to the former and latter groups developed COVID-19 in the third wave consequently deferring their third/precautionary vaccination.Conclusions: Although HCW with IgG-levels in all brackets developed COVID-19, the severity of symptoms corresponded with the IgG-levels. COVID-19 is here to stay, but in peaceful co-existence in endemic proportions. Considering evidence that immunity acquired by vaccination/natural infection is ephemeral, re-invention of vaccines to match the ever-mutating virus is foreseen.

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Genotypic, Phenotypic and Clinical Validation of GeneXpert in Extra-Pulmonary and Pulmonary Tuberculosis in India.

BACKGROUND:Newer molecular diagnostics have brought paradigm shift in early diagnosis of tuberculosis [TB]. WHO recommended use of GeneXpert MTB/RIF [Xpert] for Extra-pulmonary [EP] TB; critics have since questioned its efficiency. METHODS:The present study was designed to assess the performance of GeneXpert in 761 extra-pulmonary and 384 pulmonary specimens from patients clinically suspected of TB and compare with Phenotypic, Genotypic and Composite reference standards [CRS]. RESULTS:Comparison of GeneXpert results to CRS, demonstrated sensitivity of 100% and 90.68%, specificity of 100% and 99.62% for pulmonary and extra-pulmonary samples. On comparison with culture, sensitivity for Rifampicin [Rif] resistance detection was 87.5% and 81.82% respectively, while specificity was 100% for both pulmonary and extra-pulmonary TB. On comparison to sequencing of rpoB gene [Rif resistance determining region, RRDR], sensitivity was respectively 93.33% and 90% while specificity was 100% in both pulmonary and extra-pulmonary TB. GeneXpert assay missed 533CCG mutation in one sputum and dual mutation [517 & 519] in one pus sample, detected by sequencing. Sequencing picked dual mutation [529, 530] in a sputum sample sensitive to Rif, demonstrating, not all RRDR mutations lead to resistance. CONCLUSIONS:Current study reports observations in a patient care setting in a high burden region, from a large collection of pulmonary and extra-pulmonary samples and puts to rest questions regarding sensitivity, specificity, detection of infrequent mutations and mutations responsible for low-level Rif resistance by GeneXpert. Improvements in the assay could offer further improvement in sensitivity of detection in different patient samples; nevertheless it may be difficult to improve sensitivity of Rif resistance detection if only one gene is targeted. Assay specificity was high both for TB detection and Rif resistance detection. Despite a few misses, the assay offers major boost to early diagnosis of TB and MDR-TB, in difficult to diagnose pauci-bacillary TB

Samples with Discordant Results.

<p>Samples with Discordant Results.</p

Study flow diagram.

<p>Diagnostic workflow of the patients included in the study.</p

Performance of the GeneXpert for the diagnosis of TB: Sensitivity, Specificity of GeneXpert MTB/RIF in comparison with Composite Reference Standards.

<p>Performance of the GeneXpert for the diagnosis of TB: Sensitivity, Specificity of GeneXpert MTB/RIF in comparison with Composite Reference Standards.</p

GeneXpert Detection of mutations in <i>rpoB</i> RRDR region.

<p>Results from twenty-five Rif resistant samples are shown. The results produced by each sample are indicated by a single vertical line on which the C_T value of each of the five <i>rpoB</i>-specific molecular beacons [probes A to E] is plotted. Twenty-three samples were correctly identified as Rif resistant. Two samples [731GE, 919GE] were missed by GeneXpert but showed mutations in RRDR region on <i>rpoB</i> gene Sequencing [533CGG, 517AAG and 519CAC respectively] [Genbank Accession Numbers KP658669-658720]. Two strains with 531TTG mutation were detected owing to difference between the C_T value being >4 and not due to loss of probe.</p

Forest plot showing Genexpert MTB/RIF sensitivity and specificity for tuberculosis detection against the composite reference standards, in different types of Extra-pulmonary samples when compared with other published studies.

<p>The squares represent the sensitivity and specificity; the black line indicates the confidence interval. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149258#pone.0149258.ref042" target="_blank">42</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149258#pone.0149258.ref046" target="_blank">46</a>]</p