An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis (DEFINE):A Phase Ib/IIa Randomised Controlled Trial

RATIONALE: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. OBJECTIVES: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. METHODS: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. MEASUREMENTS AND MAIN RESULTS: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2–7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. CONCLUSIONS: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020–002230–32)

Patterns of thermal preference and Visual Thermal Landscaping model in the workplace

The main purpose of research on occupant behaviour is to enhance building energy performance. However, it is difficult to reduce the energy use without understanding the occupant, their needs and preferences. Individual differences and preferences for the thermal environment in relation to the spatial context are overlooked in the main stream of research. This study investigates the patterns of occupant thermal preference based on individual differences in perceiving the thermal environment to enhance user comfort and energy performance. A novel method of Visual Thermal Landscaping is used, which is a qualitative method to analyse occupant comfort and user behaviour according to the spatial context. This method drives away from the notion of ‘thermal neutrality’ and generic results, rather it opens to details and meaning through a qualitative analysis of personal-comfort, based on individual differences and spatial context information. Field test studies of thermal comfort were applied in five office buildings in the UK, Sweden and Japan with overall 2,313 data sets. The primary contribution of the study was the recognition of four patterns of thermal preference, including consistent directional preference; fluctuating preference; high tolerance and sensitive to thermal changes; and high tolerance and not-sensitive to thermal changes. The results were further examined in a longitudinal field test study of thermal comfort. In several cases, occupant thermal comfort and preferences were observed to be influenced by the impact of outdoor conditions, when the windows were fixed. Practical solutions for research, practice and building design were recommended with direct implications on occupant comfort and energy use

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Green occupants for green buildings : the missing link?

Green buildings, often defined as those featuring natural ventilation capabilities, i.e. low-energy or free-running buildings, are now at the forefront of building research and climate change mitigation scenarios. This paper follows the results of recent post-occupancy evaluation (POE) surveys within two academic office buildings located in sub-tropical Sydney, Australia. Supplemented with an environmental attitudes questionnaire, based upon the New Ecological Paradigm [1]), it was found that occupant satisfaction levels on the POE were positively associated with environmental beliefs. Occupants with higher levels of environmental concern were more forgiving of their building, particularly those featuring aspects of green design, such as natural ventilation through operable windows. Despite their criticisms of the building’s indoor environmental quality, the ‘green’ occupants were prepared to overlook and forgive less-than-ideal conditions more so than their ‘brown’ (non-green) counterparts. These results support the hypothesis that pro-environmental attitudes are closely associated with the stronger ‘forgiveness factor’ often observed in green buildings, but the question of causality remains moot.7 page(s

Is it hot in here or is it just me? Validating the post-occupancy evaluation

Historically, post-occupancy evaluation (POE) was developed to evaluate actual building performance, providing feedback for architects and building managers to potentially improve the quality and operation of the building. Whilst useful in gathering information based on user satisfaction, POE studies have typically lacked contextual information, continued feedback and physical measurements of the building's indoor climate. They, therefore, sometimes over-exaggerate poor building performance. POEs conducted in two academic office buildings: a mixed-mode (MM) and a naturally ventilated (NV) building located within a university in Sydney, Australia, suggest high levels of occupant dissatisfaction, especially in the MM building. In order to test the validity of the POE results, parallel thermal comfort studies were conducted to investigate the differences in occupant satisfaction and comfort perceptions between these two questionnaires. Instrumental measurements of each building's indoor environment reveal that occupants tended to over-exaggerate their POE comfort responses. Analysis of thermal satisfaction and acceptability in each building indicate that occupants of the NV building were more tolerant of their thermal environment despite experiencing significantly warmer temperatures than their MM counterparts. In discussing these results, along with participant comments and anecdotal evidence from each building, this article contends that POE does not accurately evaluate building performance, suggesting occupants can and do use POE as a vehicle for complaint about general workplace issues, unrelated to their building. In providing a critical review of current POE methods, this article aims to provide recommendations as to how they can be improved, encouraging a more holistic approach to building performance evaluation.23 page(s

Mixed-mode buildings : a double standard in occupants' comfort expectations

This paper investigates how mixed-mode (MM) ventilation affects occupant comfort by presenting results from a longitudinal field study within an academic office building from a tertiary educational institution in sub-tropical Sydney, Australia. The building automatically switches into air-conditioned (AC) mode whenever indoor temperatures exceed 25 °C. Coincident indoor and outdoor climate measurements along with 1359 subjective comfort questionnaires were collected. Thermal sensations during natural ventilation did not conform to those predicted using Fanger's PMV-PPD [1]. Differences in thermal perception were also apparent between these two modes. Within AC mode, a PMV = +1 environment elicited much 'warmer-than-neutral' thermal sensations than the same PMV = +1 environment within naturally-ventilated (NV) mode, suggesting thermal subjective perceptions were affected by the building's mode of operation over and above the objective indoor climatic conditions. These discrepancies emphasize the complexity of thermal perception and the inadequacy of using PMV models to describe occupant comfort in MM buildings. ASHRAE's Standard 55 [2] currently classifies MM buildings as AC buildings, and as such, limits the operation of these buildings to the more restrictive PMV-PPD range of indoor thermal conditions. In contrast, EN15251 [3] permits the more flexible adaptive comfort standard to be applied to buildings operating under NV mode. Results from this study favour EN15251's application of the adaptive comfort model instead of PMV-PPD to MM buildings when they are operating in NV mode.8 page(s

A Synoptic climatology of pollen concentrations during the six warmest months in Sydney, Australia

This paper takes an air mass approach to investigating the influence of weather on pollen concentrations in the atmosphere in Sydney, Australia, by producing a synoptic classification of pollen concentrations measured in the Sydney Basin. This synoptic classification has been produced using multivariate statistical techniques including principal component analysis and cluster analysis, to assign days into meteorologically homogenous categories. Surface and upper air meteorological data for warm months (October–March) over a 10-year period were used as input into the statistical analyses. Eleven synoptic categories were found in Sydney during the warm months. Pollen concentrations for the total pollen load and five individual families measured over a 3.5-year period have been investigated for each of the synoptic categories. High pollen concentrations during the warm months in Sydney are found to be influenced by the presence of a region of low surface pressure located to the south of the continent, bringing fast dry westerly gradient winds to Sydney. It is envisaged that these results will be important from a pollen forecast and associated public health perspective.12 page(s

Towards a Brazilian standard for naturally ventilated buildings: guidelines for thermal and air movement acceptability

In 2001, Brazil suffered an electricity energy crisis as a result of meteorological conditions and poor strategic investments. One of the most important outcomes was the establishment of the energy efficiency law by the Federal Government, after long ten years of politic process. After this landmark event, the Brazilian Government has been promoting energy conservation initiatives including the Thermal Performance in Buildings-Brazilian Bioclimatic Zones and Building Guidelines for Low-Cost Houses (ABNT, NBR 15220-3, 2005) and the Federal Regulation for Voluntary Labelling of Energy Efficiency Levels in Commercial, Public and Service Buildings (Carlo and Lamberts, 2008). These new regulations summarize an immense effort in order to provide guidelines based on Brazil's climate requirements for designers with specific items related to lighting systems, HVAC and building's thermal envelope. Yet requirements for naturally ventilated indoor environments appear as an open category. This paper summarizes a first attempt in order to define guidelines for naturally ventilated environments in which specifications for thermal and air movement acceptability goals must be achieved.11 page(s

Predicting thermal pleasure experienced in dynamic environments from simulated cutaneous thermoreceptor activity

Research into human thermal perception indoors has focused on ‘neutrality’ under steady-state conditions. Recent interest in thermal alliesthesia has highlighted the hedonic dimension of our thermal world that has been largely overlooked by science. Here, we show the activity of sensory neurons can predict thermal pleasure under dynamic exposures. A numerical model of cutaneous thermoreceptors was applied to skin temperature measurements from 12 human subjects. A random forest model trained on simulated thermoreceptor impulses could classify pleasure responses (F1-score of 67%) with low false positives/negatives (4%). Accuracy increased (83%) when excluding the few extreme (dis)pleasure responses. Validation on an independent dataset confirmed model reliability. This is the first empirical demonstration of the relationship between thermoreceptors and pleasure arising from thermal stimuli. Insights into the neurophysiology of thermal perception can enhance the experience of built environments through designs that promote sensory excitation instead of neutrality