Short-term association between black carbon exposure and cardiovascular diseases in Pakistan’s largest megacity

This study investigated the association between black carbon (BC) exposure and hospital admissions (HAs) and outpatient department/emergency room (OPD/ER) visits for cardiovascular diseases (CVD) among residents of Karachi, the largest city in Pakistan. We measured daily concentrations of BC in fine particulate matter (PM2.5) and collected records of HAs and OPD/ER visits for CVD from 2 major tertiary care hospitals serving Karachi for 6 weeks continuously during each quarter over 1 year (August 2008–August 2009). We subsequently analyzed daily counts of hospital and BC data over 0–3 lag days. Daily mean BC concentrations varied from 1 to 32 µg/m3 . Results suggest that BC concentrations are associated with CVD HAs and OPD/ER visits. However, associations were generally only observed when modeled with BC from Tibet Center, the commercial-residential site, as compared to Korangi, the industrial-residential site. Overall, low statistical significance suggests that while BC may be a valuable indicator for CVD health risks from combustion-derived particles, further evaluation of the constituents of PM2.5 and their relative contributions to CVD health impacts is necessary

Effect of air pollution on daily morbidity in Karachi, Pakistan

Levels of daily particulates (PM2.5) were monitored at two sites in Karachi, Pakistan. One site (Korangi) is an industrial and residential neighborhood, while the other (Tibet Center) is a commercial and residential area near a major highway. Monitoring was done daily for a period of six weeks during spring, summer, fall and winter. Particulate levels were extraordinarily high, with the great majority of days falling into the “unhealthy for sensitive groups” or “very unhealthy” categories. The mean PM2.5 levels in Karachi exceeded the WHO’s 24 h air quality guideline almost every day and often by a factor of greater than 5-fold. Daily emergency room (ER) visits and hospital admissions for cardiovascular diseases were obtained by review of medical records at three major tertiary and specialized hospitals. ER and hospitalizations were reported relative to days in which the concentration of PM2.5 was less than 50mg/m3 , and by 50 mg/m3 increments up to 300mg/m3 . There were statistically significant elevations in rates of hospital admissions at each of the PM2.5 categories at the Korangi site, and at concentrations .150mg/m3 at the Tibet Center site. ER visits were significantly elevated only at PM2.5 concentrations of between 151 and 200 mg/m3 at both sites. These results show that the extremely elevated concentrations of PM2.5 in Karachi, Pakistan are, as expected, associated with significantly elevated rates of hospital admission, and to a lesser extent, ER visits for cardiovascular disease

Short-term associations between PM2.5, black carbon, Delta-C, and cardiovascular diseases in a large developing megacity

Introduction: Association between ambient air pollution and cardiovascular disease (CVD) have been demonstrated by many epidemiological studies in developed countries, however few studies have been performed in developing countries of Asia. Objective: In this study, we evaluated fine particulate matter and its combustion-derived particles, black carbon (BC) and Delta-C (DC) (a proxy for UV-absorbing organic compounds), as metrics for evaluating CVD health effects of air pollution in Karachi, Pakistan. Methods: Yearlong (2008-2009) PM2.5 samples were collected at 2 sites at 24-hour intervals; a commercial-residential and industrial-residential site. Daily records of hospitalizations and ER visits for CVDs were collected at the 3 major tertiary hospitals serving Karachi. BC and DC measurements were obtained from PM2.5 filters using an optical transmissometer. Generalized linear time-series models were utilized to analyze daily counts of hospital, meteorological, and pollutant data over 0 to 3 day lags. Results/Discussion: PM2.5 concentrations ranged from 27 to 279 μg/m3. Daily mean BC concentrations varied from 1 to 32μg/m3, and DC ranged from 0 to 9 μg/m3. Higher effect estimates per 1 μg/3 for BC and DC compared with PM25 were observed. Effect estimates were generally higher with BC and DC from Tibet Center, the commercial-residential site, compared with Korangi, the industrial-residential site. These results suggest BC and DC were associated with CVD health effects that were not reflected quantitatively when modeled with PM2.5. Conclusions: This study provides new scientific evidence of the magnitude of CVD health effects associated with air pollution in an urban center of a large developing nation, evaluates BC and DC as additional indicators for evaluating CVD health impacts associated with ambient air pollution, and provides Pakistani officials with important information for policy planning. BC and DC are valuable additional air quality indicators for evaluating health risks from combustion-derived particles in developing megacities

The fitness landscapes of cis-acting binding sites in different promoter and environmental contexts.

The biophysical nature of the interaction between a transcription factor and its target sequences in vitro is sufficiently well understood to allow for the effects of DNA sequence alterations on affinity to be predicted. But even in relatively simple in vivo systems, the complexities of promoter organization and activity have made it difficult to predict how altering specific interactions between a transcription factor and DNA will affect promoter output. To better understand this, we measured the relative fitness of nearly all Escherichia coli sigma(70) -35 binding sites in different promoter and environmental contexts by competing four randomized -35 promoter libraries controlling the expression of the tetracycline resistance gene (tet)against each other in increasing concentrations of drug. We sequenced populations after competition to determine the relative enrichment of each -35 sequence. We observed a consistent relationship between the frequency of recovery of each -35 binding site and its predicted affinity for sigma(70) that varied depending on the sequence context of the promoter and drug concentration. Overall the relative fitness of each promoter could be predicted by a simple thermodynamic model of transcriptional regulation, in which the rate of transcriptional initiation (and hence fitness) is dependent upon the overall stability of the initiation complex, which in turn is dependent upon the energetic contributions of all sites within the complex. As implied by this model, a decrease in the free energy of association at one site could be compensated for by an increase in the binding energy at another to produce a similar output. Furthermore, these data show that a large and continuous range of transcriptional outputs can be accessed by merely changing the -35, suggesting that evolved or engineered mutations at this site could allow for subtle and precise control over gene expression

Global trends in ozone concentration and attributable mortality for urban, peri-urban, and rural areas between 2000 and 2019: a modelling study

BACKGROUND: Data on long-term trends of ozone exposure and attributable mortality across urban-rural catchment areas worldwide are scarce, especially for low-income and middle-income countries. This study aims to estimate trends in ozone concentrations and attributable mortality for urban-rural catchment areas worldwide. METHODS: In this modelling study, we used a health impact function to estimate ozone concentrations and ozone-attributable chronic respiratory disease mortality for urban areas worldwide, and their surrounding peri-urban, peri-rural, and rural areas. We estimated ozone-attributable respiratory health outcomes using a modified Global Burden of Diseases, Injuries, and Risk Factors 2019 Study approach. We evaluate long-term trends with linear regressions of annual ozone concentrations and ozone-attributable mortality against time in years, and examined the influence of each health impact function input parameter to temporal changes in ozone-attributable disease burden estimates for 12 946 cities worldwide by region, from 2000 to 2019. FINDINGS: Ozone-attributable mortality worldwide increased by 46% from 2000 (290 400 deaths [95% CI 151 800-457 600]) to 2019 (423 100 deaths [95% CI 223 200-659 400]). The fraction of global ozone-attributable mortality occurring in peri-urban areas remained unchanged from 2000 to 2019 (56%), whereas urban areas gained in their share of global ozone-attributable burden (from 35% to 37%; 54 000 more deaths). Across all cities studied, average population-weighted mean ozone concentration increased by 11% (46 parts per billion [ppb] to 51 ppb). The number of cities with concentrations above the WHO peak season ozone standard (60 μg/m) increased from 11 568 (89%) of 12 946 cities in 2000 to 12 433 (96%) cities in 2019. Percent change in ozone-attributable mortality averaged across 11 032 cities within each region from 2000 to 2019 ranged from -62% in eastern Europe to 350% in tropical Latin America. The contribution of ozone concentrations, population size, and baseline chronic respiratory disease rates to the change in ozone-attributable mortality differed regionally. INTERPRETATION: Ozone exposure is increasing worldwide, contributing to disproportionate ozone mortality in peri-urban areas and increasing ozone exposure and attributable mortality in urban areas worldwide. Reducing ozone precursor emissions in areas affecting urban and peri-urban exposure can yield substantial public health benefits. FUNDING: NASA Health and Air Quality Applied Sciences Team, the National Institute for Occupational Safety and Health, and the NOAA Co-operative Agreement with the Cooperative Institute for Research in Environmental Sciences

Discovery and multimerization of cross-reactive single-domain antibodies against SARS-like viruses to enhance potency and address emerging SARS-CoV-2 variants

Abstract Coronaviruses have been the causative agent of three epidemics and pandemics in the past two decades, including the ongoing COVID-19 pandemic. A broadly-neutralizing coronavirus therapeutic is desirable not only to prevent and treat COVID-19, but also to provide protection for high-risk populations against future emergent coronaviruses. As all coronaviruses use spike proteins on the viral surface to enter the host cells, and these spike proteins share sequence and structural homology, we set out to discover cross-reactive biologic agents targeting the spike protein to block viral entry. Through llama immunization campaigns, we have identified single domain antibodies (VHHs) that are cross-reactive against multiple emergent coronaviruses (SARS-CoV, SARS-CoV-2, and MERS). Importantly, a number of these antibodies show sub-nanomolar potency towards all SARS-like viruses including emergent CoV-2 variants. We identified nine distinct epitopes on the spike protein targeted by these VHHs. Further, by engineering VHHs targeting distinct, conserved epitopes into multi-valent formats, we significantly enhanced their neutralization potencies compared to the corresponding VHH cocktails. We believe this approach is ideally suited to address both emerging SARS-CoV-2 variants during the current pandemic as well as potential future pandemics caused by SARS-like coronaviruses