Phase I, randomized, observer-blind, placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of an investigational non-typeable Haemophilus influenzae (NTHi) protein vaccine in adults

Background: Non-typeable Haemophilus influenzae (NTHi) is a major cause of various respiratory diseases. The development of an effective vaccine against NTHi mandates new approaches beyond conjugated vaccines as this opportunistic bacterium is non-encapsulated. Here we report on the safety, reactogenicity and immunogenicity of a multi-component investigational vaccine based on three conserved surface proteins from NTHi (proteins D [PD],E [PE] and Pilin A [PilA]) in two observer-blind phase I studies. Methods: In the first study (NCT01657526), 48 healthy 18-40 year-olds received two vaccine formulations (10 or 30 mu g of each antigen [PD and a fusion protein PE-PilA]) or saline placebo at months 0 and 2. In the second study (NCT01678677), 270 50-70 year-olds, current or former smokers, received eight vaccine formulations (10 or 30 mu g antigen/dose non-adjuvanted or adjuvanted with alum, AS01(E) or ASO4(c)) or saline placebo at months 0,2 and 6 (plain and alum-adjuvanted groups) and at months 0 and 2 (AS-adjuvanted groups). Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post-vaccination, respectively; potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) throughout the studies. Humoral and antigen-specific T-cell immunity (in study 2 only) responses were assessed up to 12 months post-vaccination. Results: Observed reactogenicity was highest in the AS-adjuvanted groups but no safety concerns were identified with any of the NTHi vaccine formulations. One fatal SAE (cardiac arrest) not considered related to vaccination, and one pIMD (non-serious psoriasis) in the Placebo group, were reported post-dose 3 in Study 2. All formulations generated a robust antibody response while the AS01-adjuvanted formulations produced the highest humoral and cellular immune responses. Conclusion: This study confirms that the NTHi vaccine formulations had an acceptable reactogenicity and safety profile and were immunogenic in adults. These results justify further clinical development of this NTHi vaccine candidate

Causal inference concepts applied to three observational studies in the context of vaccine development : from theory to practice

Background Randomized controlled trials are considered the gold standard to evaluate causal associations, whereas assessing causality in observational studies is challenging. Methods We applied Hill's Criteria, counterfactual reasoning, and causal diagrams to evaluate a potentially causal relationship between an exposure and outcome in three published observational studies: a) one burden of disease cohort study to determine the association between type 2 diabetes and herpes zoster, b) one post-authorization safety cohort study to assess the effect of AS04-HPV-16/18 vaccine on the risk of autoimmune diseases, and c) one matched case-control study to evaluate the effectiveness of a rotavirus vaccine in preventing hospitalization for rotavirus gastroenteritis. Results Among the 9 Hill's criteria, 8 (Strength, Consistency, Specificity, Temporality, Plausibility, Coherence, Analogy, Experiment) were considered as met for study c, 3 (Temporality, Plausibility, Coherence) for study a, and 2 (Temporary, Plausibility) for study b. For counterfactual reasoning criteria, exchangeability, the most critical assumption, could not be tested. Using these tools, we concluded that causality was very unlikely in study b, unlikely in study a, and very likely in study c. Directed acyclic graphs provided complementary visual structures that identified confounding bias and helped determine the most accurate design and analysis to assess causality. Conclusions Based on our assessment we found causal Hill's criteria and counterfactual thinking valuable in determining some level of certainty about causality in observational studies. Application of causal inference frameworks should be considered in designing and interpreting observational studies

Adverse impact of STATCOM on the performance of distance relay

FACTS devices like the Static Synchronous Compensator (STATCOM), are mostly used to enhance the maximum power transfer capability of the transmission Line (TL) system. AMatlab simulation model of Distance Relay protection ofTL, with connected STATCOM at the mid-point for optimum power transfer is presented. The STATCOM’s impact on the operation of the relay is assessed with the effects on the relay misoperation in the third zone of protection coverage, during fault conditions, in four different locations.The wrong measured fault impedance by relay resulted to misoperation in zone 3 (under reach phenomena). The simulation result indicates a slight increase in the measured impedance of 1.33 Ω over the actually expected impedance setting (72.02 Ω) of the relay at 220 km protection coverage of zone 3 along the TL. This variation is about 4 km distance outside the expected distance protection coverage for fault in zone 3 as proven

Strange Attractors in Dissipative Nambu Mechanics : Classical and Quantum Aspects

We extend the framework of Nambu-Hamiltonian Mechanics to include dissipation in $R^{3}$ phase space. We demonstrate that it accommodates the phase space dynamics of low dimensional dissipative systems such as the much studied Lorenz and R\"{o}ssler Strange attractors, as well as the more recent constructions of Chen and Leipnik-Newton. The rotational, volume preserving part of the flow preserves in time a family of two intersecting surfaces, the so called {\em Nambu Hamiltonians}. They foliate the entire phase space and are, in turn, deformed in time by Dissipation which represents their irrotational part of the flow. It is given by the gradient of a scalar function and is responsible for the emergence of the Strange Attractors. Based on our recent work on Quantum Nambu Mechanics, we provide an explicit quantization of the Lorenz attractor through the introduction of Non-commutative phase space coordinates as Hermitian $N \times N$ matrices in $R^{3}$. They satisfy the commutation relations induced by one of the two Nambu Hamiltonians, the second one generating a unique time evolution. Dissipation is incorporated quantum mechanically in a self-consistent way having the correct classical limit without the introduction of external degrees of freedom. Due to its volume phase space contraction it violates the quantum commutation relations. We demonstrate that the Heisenberg-Nambu evolution equations for the Quantum Lorenz system give rise to an attracting ellipsoid in the $3 N^{2}$ dimensional phase space.Comment: 35 pages, 4 figures, LaTe

Soil carbon dioxide efflux and atmospheric impact in a 10-year-old Dipterocarpus recovering lowland tropical forest, Peninsular Malaysia

The recovering logged-over forest ecosystem increases the CO2 efflux into the atmospheric carbon pool in response to environmental factors to changes in the soil temperature and moisture. These CO2 outbursts can have a marked influence on the ecosystem carbon balance and thereby affect the atmospheric carbon pool. The study was conducted in the 10-year-old logged-over forest of Sungai Menyala forest, Port Dickson, Negeri Sembilan, Malaysia. The measurements of soil CO2 efflux were conducted using the continuous open flow chamber technique connected to a multi gas-handling unit and infrared CO2/H2O gas analyser. The aim of this study was to determine the soil CO2 efflux and the environmental variables and likewise the impact of environmental factors on soil CO2 efflux. Post-hoc comparisons were made using the Tukey test (p < 0.05), and multiple linear regression to determine the impact of environmental factors on soil CO2 efflux. Soil CO2 efflux ranged from 100.22-553.40 mg m-2 h-1 with the highest efflux in the afternoon attributed to an increase in soil temperature and low moisture. A higher soil temperature and low moisture signify an influential factor as the forest is recovering from logging activity. Furthermore, the predictor environmental variables: SOC (soil organic carbon), TOC (total organic carbon), SMC (soil moisture content), Bulk Density, SOCstock (soil organic carbon stock), TAGB (total above ground carbon biomass), Below Ground Carbon Biomass, soil pH, Nitrogen to Carbon ratio account for the spatial and temporal variation in soil CO2 efflux into the atmosphere. The analysis revealed a strong correlation between soil CO2 efflux, changes soil properties and environmental factors with an R2 more than 0.80 at p < 0.01. This is proven that logging activity accounts for the changes in environmental factors to influence soil CO2 efflux rate within 10-years of logging and forest recovering

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups