Temporal distribution and genetic variants in influenza A(H1N1)pdm09 virus circulating in Mexico, seasons 2012 and 2013

The 2012 and 2013 annual influenza epidemics in Mexico were characterized by presenting different seasonal patterns. In 2012 the A(H1N1)pdm09 virus caused a high incidence of influenza infections after a two-year period of low circulation; whereas the 2013 epidemic presented circulation of the A(H1N1)pdm09 virus throughout the year. We have characterized the molecular composition of the Hemagglutinin (HA) and Neuraminidase (NA) genes of the A(H1N1)pdm09 virus from both epidemic seasons, emphasizing the genetic characteristics of viruses isolated from Yucatan in Southern Mexico. The molecular analysis of viruses from the 2012 revealed that all viruses from Mexico were predominantly grouped in clade 7. Strikingly, the molecular characterization of viruses from 2013 revealed that viruses circulating in Yucatan were genetically different to viruses from other regions of Mexico. In fact, we identified the occurrence of two genetic variants containing relevant mutations at both the HA and NA surface antigens. There was a difference on the temporal circulation of each genetic variant, viruses containing the mutations HA-A141T / NA-N341S were detected in May, June and July; whereas viruses containing the mutations HA-S162I / NAL206S circulated in August and September. We discuss the significance of these novel genetic changes

Phylogenetic tree of NA sequences of the A(H1N1)pdm09 viruses for the period 2013.

<p>Sequences from Yucatan are indicated in blue, from other regions of Mexico in red and worldwide in black. Additional amino acid changes at the node are also indicated.</p

Amino acid changes and frequency of occurrence in the hemagglutinin (HA) protein of the influenza A(H1N1)pdm09 viruses isolated in Yucatan.

<p>Frequencies of detection for each mutation are also indicated for sequences from other regions of Mexico (non-Yucatan) and worldwide for the period 2012–2013. Percentages were calculated based on the total number of sequences analysed in this study (<i>n</i>). Empty cells indicate values = 0.</p

Schematic representation of the HA molecule of the A(H1N1)pdm09 virus.

<p>HA molecules were modelled using as template the crystal structure of A 2009 H1N1 virus hemagglutinin from A/California/04/2009 (PDB 3LZG). Molecules were generated under flusurver structural model database (<a href="http://flusurver.bii.a-star.edu.sg/" target="_blank">http://flusurver.bii.a-star.edu.sg</a>). Protein sequences were blast against A/California/07/2009 to identify differences on amino acid composition. Right side HA molecule was modelled based on the strain A/Yucatan/116/2013 to indicate localization of the amino acid change S162I (red oval). The HA molecule in the middle represents the amino acidic composition of the strain A/Yucatan/81/2013 indicating the position of the mutation A141T (blue oval). Mutations at residues V234I, K283E and E499K (HA2) placed these viruses in clade 6C. Left side molecule corresponds to the HA protein sequence of the strain A/Yucatan/18/2012.</p

Temporal occurrence of genetic variants in Yucatan.

<p>Viruses from Yucatan with changes in HA and NA were distributed in time from epidemiological week 23 to 38. The bars represent the total number of influenza cases reported by the Regional Laboratory. The clear section indicates the number of confirmed cases of influenza A(H1N1)pdm09 and the grey section indicates the number of influenza A(H1N1)pdm09 viruses with genetic changes in HA and NA (HA–A141T / HA–S162I / NA–N341S / NA–L206S). The black section corresponds to the number of samples negative to influenza A(H1N1)pdm09 virus.</p

Amino acid changes and frequency of detection in the Neuraminidase (NA) protein of the influenza A(H1N1)pdm09 virus isolated from Yucatan, Mexico (non-Yucatan) and other regions of the world for the period 2012–2013.

<p>Percentages were calculated based on the total number of sequences analysed in this study (<i>n</i>). Empty cells indicate values = 0.</p

Treatments for intracranial hypertension in acute brain-injured patients: grading, timing, and association with outcome. Data from the SYNAPSE-ICU study

Purpose: Uncertainties remain about the safety and efficacy of therapies for managing intracranial hypertension in acute brain injured (ABI) patients. This study aims to describe the therapeutical approaches used in ABI, with/without intracranial pressure (ICP) monitoring, among different pathologies and across different countries, and their association with six&nbsp;months mortality and neurological outcome. Methods: A preplanned subanalysis of the SYNAPSE-ICU study, a multicentre, prospective, international, observational cohort study, describing the ICP treatment, graded according to Therapy Intensity Level (TIL) scale, in patients with ABI during the first week of intensive care unit (ICU) admission. Results: 2320 patients were included in the analysis. The median age was 55 (I-III quartiles = 39-69) years, and 800 (34.5%) were female. During the first week from ICU admission, no-basic TIL was used in 382 (16.5%) patients, mild-moderate in 1643 (70.8%), and extreme in 295 cases (eTIL, 12.7%). Patients who received eTIL were younger (median age 49 (I-III quartiles = 35-62) vs 56 (40-69) years, p &lt; 0.001), with less cardiovascular pre-injury comorbidities (859 (44%) vs 90 (31.4%), p &lt; 0.001), with more episodes of neuroworsening (160 (56.1%) vs 653 (33.3%), p &lt; 0.001), and were more frequently monitored with an ICP device (221 (74.9%) vs 1037 (51.2%), p &lt; 0.001). Considerable variability in the frequency of use and type of eTIL adopted was observed between centres and countries. At six&nbsp;months, patients who received no-basic TIL had an increased risk of mortality (Hazard ratio, HR = 1.612, 95% Confidence Interval, CI = 1.243-2.091, p &lt; 0.001) compared to patients who received eTIL. No difference was observed when comparing mild-moderate TIL with eTIL (HR = 1.017, 95% CI = 0.823-1.257, p = 0.873). No significant association between the use of TIL and neurological outcome was observed. Conclusions: During the first week of ICU admission, therapies to control high ICP are frequently used, especially mild-moderate TIL. In selected patients, the use of aggressive strategies can have a beneficial effect on six&nbsp;months mortality but not on neurological outcome

A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA) : Rationale, Design, and Baseline Data

Altres ajuts: F. Hoffmann-La Roche Ltd.Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. Trial Registration: NCT03100149