Therapeutic itineraries of snakebite victims and antivenom access in southern Mexico.

Access to antivenoms in cases of snakebite continues to be an important public health issue around the world, especially in rural areas with poorly developed health care systems. This study aims to evaluate therapeutic itineraries and antivenom accessibility following snakebites in the states of Oaxaca and Chiapas in southern Mexico. Employing an intercultural health approach that seeks to understand and bridge allopathic and traditional medical perceptions and practices, we conducted field interviews with 47 snakebite victims, documenting the therapeutic itineraries of 54 separate snakebite incidents that occurred between 1977 and 2023. Most victims used traditional remedies as a first line of treatment, often to withstand the rigors of a long journey to find antivenoms. The main obstacles to antivenom access were distance, poor antivenom availability, and cost. Standard antivenom treatment is highly valued and sought after, even as traditional beliefs and practices persist within a cultural framework known as the "hot-cold" system. The findings are crucial for informing future enhancements to antivenom distribution systems, health education initiatives, and other interventions aimed at mitigating the impact of snakebites in the region.

Associations between Historical Redlining and the Risk of Pregnancy Complications and Adverse Birth Outcomes in Massachusetts, 1995-2015.

Objective: To assess the impact of historical redlining on the risk of pregnancy complications and adverse birth outcomes in Massachusetts (MA) from 1995 to 2015. Methods: In total, 288,787 pregnant people from the MA Birth Registry had information on parental characteristics, pregnancy factors, and redlining data at parental residences at the time of delivery. Historic redlining data were based on MA Home Owners' Loan Corporation (HOLC) security maps, with grades assigned (A "best," B "still desirable," C "definitely declining," and D "hazardous"). We used covariate-adjusted binomial regression models to examine associations between HOLC grade and each chronic condition and pregnancy/birth outcome. Results: Living in HOLC grades B through D compared with A was associated with an increased risk of entering pregnancy with chronic conditions and adverse pregnancy/birth outcomes. The strongest associations were seen with pregestational diabetes (adjusted risk ratio [RR] Grade D: 1.7, 95% confidence interval [CI]: 1.3, 2.4) and chronic hypertension (adjusted RR Grade D: 1.5, 95% CI: 1.1, 1.9). Conclusions: Historical redlining policies from the 1930s were associated with adverse pregnancy outcomes and chronic conditions; associations were strongest for chronic conditions in pregnancy.

Variability in antivenom neutralization of Mexican viperid snake venoms.

BACKGROUND: Each year, 3,800 cases of snakebite envenomation are reported in Mexico, resulting in 35 fatalities. The only scientifically validated treatment for snakebites in Mexico is the use of antivenoms. Currently, two antivenoms are available in the market, with one in the developmental phase. These antivenoms, produced in horses, consist of F(ab')2 fragments generated using venoms from various species as immunogens. While previous studies primarily focused on neutralizing the venom of the Crotalus species, our study aims to assess the neutralization capacity of different antivenom batches against pit vipers from various genera in Mexico. METHODOLOGY: We conducted various biological and biochemical tests to characterize the venoms. Additionally, we performed neutralization tests using all three antivenoms to evaluate their effectiveness against lethal activity and their ability to neutralize proteolytic and fibrinogenolytic activities. RESULTS: Our results reveal significant differences in protein content and neutralizing capacity among different antivenoms and even between different batches of the same product. Notably, the venom of Crotalus atrox is poorly neutralized by all evaluated batches despite being the primary cause of envenomation in the country's northern region. Furthermore, even at the highest tested concentrations, no antivenom could neutralize the lethality of Metlapilcoatlus nummifer and Porthidium yucatanicum venoms. These findings highlight crucial areas for improving existing antivenoms and developing new products. CONCLUSION: Our research reveals variations in protein content and neutralizing potency among antivenoms, emphasizing the need for consistency in venom characteristics as immunogens. While Birmex neutralizes more LD50 per vial, Antivipmyn excels in specific neutralization. The inability of antivenoms to neutralize certain venoms, especially M. nummifer and P. yucatanicum, highlights crucial improvement opportunities, given the medical significance of these species.

Exploring venom diversity in Mixcoatlus browni and Mixcoatlus barbouri: A comparative analysis of two rare Mexican snake species with crotoxin-like presence.

The genus Mixcoatlus is composed of three species: Mixcoatlus barbouri, M. browni, and M. melanurus, of which the venom composition of M. melanurus, the most common species of the three, has only recently been described. However, very little is known about the natural history of M. barbouri and M. browni, and the venom composition of these two species has remained thus far unexplored. In this study we characterize the proteomic profiles and the main biochemical and toxic activities of these two venoms. Proteomic data obtained by shotgun analysis of whole venom identified 12 protein families for M. barbouri, and 13 for M. browni. The latter venom was further characterized by using a quantitative 'venomics' protocol, which revealed that it is mainly composed of 51.1 % phospholipases A2 (PLA2), 25.5 % snake venom serine proteases (SVSP), 4.6 % l-amino oxidases (LAO), and 3.6 % snake venom metalloproteases (SVMP), with lower percentages other six protein families. Both venoms contained homologs of the basic and acidic subunits of crotoxin. However, due to limitations in M. barbouri venom availability, we could only characterize the crotoxin-like protein of M. browni venom, which we have named Mixcoatlutoxin. It exhibited a lethal potency in mice like that described for classical rattlesnake crotoxins. These findings expand knowledge on the distribution of crotoxin-like heterodimeric proteins in viper snake species. Further investigation of the bioactivities of the venom of M. barbouri, on the other hand, remains necessary.

Fangs and foliage: Unearthing the haemotoxic secrets of cannabis-dwelling rattlesnakes.

Despite a recent surge in high-throughput venom research that has enabled many species to be studied, some snake venoms remain understudied. The long-tailed rattlesnakes (Crotalus ericsmithi, C. lannomi, and C. stejnegeri) are one group where such research lags, largely owing to the rarity of these snakes and the hazardous areas, ripe with drug (marijuana and opium) production, they inhabit in Mexico. To fill this knowledge gap, we used multiple functional assays to examine the coagulotoxic (including across different plasma types), neurotoxic, and myotoxic activity of the venom of the long-tailed rattlesnakes. All crude venoms were shown to be potently anticoagulant on human plasma, which we discovered was not due to the destruction of fibrinogen, except for C. stejnegeri displaying minor fibrinogen destruction activity. All venoms exhibited anticoagulant activity on rat, avian, and amphibian plasmas, with C. ericsmithi being the most potent. We determined the mechanism of anticoagulant activity by C. ericsmithi and C. lannomi venoms to be phospholipid destruction and inhibition of multiple coagulation factors, leading to a net disruption of the clotting cascade. In the chick biventer assay, C. ericsmithi and C. lannomi did not exhibit neurotoxic activity but displayed potential weak myotoxic activity. BIRMEX® (Faboterápico Polivalente Antiviperino) antivenom was not effective in neutralising this venom effect. Overall, this study provides an in-depth investigation of venom function of understudied long-tailed rattlesnakes and provides a springboard for future venom and ecology research on the group.

Grouped mixtures of air pollutants and seasonal temperature anomalies and cardiovascular hospitalizations among U.S. Residents.

BACKGROUND: Air pollution is a recognized risk factor for cardiovascular disease (CVD). Temperature is also linked to CVD, with a primary focus on acute effects. Despite the close relationship between air pollution and temperature, their health effects are often examined separately, potentially overlooking their synergistic effects. Moreover, fewer studies have performed mixture analysis for multiple co-exposures, essential for adjusting confounding effects among them and assessing both cumulative and individual effects. METHODS: We obtained hospitalization records for residents of 14 U.S. states, spanning 2000-2016, from the Health Cost and Utilization Project State Inpatient Databases. We used a grouped weighted quantile sum regression, a novel approach for mixture analysis, to simultaneously evaluate cumulative and individual associations of annual exposures to four grouped mixtures: air pollutants (elemental carbon, ammonium, nitrate, organic carbon, sulfate, nitrogen dioxide, ozone), differences between summer and winter temperature means and their long-term averages during the entire study period (i.e., summer and winter temperature mean anomalies), differences between summer and winter temperature standard deviations (SD) and their long-term averages during the entire study period (i.e., summer and winter temperature SD anomalies), and interaction terms between air pollutants and summer and winter temperature mean anomalies. The outcomes are hospitalization rates for four prevalent CVD subtypes: ischemic heart disease, cerebrovascular disease, heart failure, and arrhythmia. RESULTS: Chronic exposure to air pollutant mixtures was associated with increased hospitalization rates for all CVD subtypes, with heart failure being the most susceptible subtype. Sulfate, nitrate, nitrogen dioxide, and organic carbon posed the highest risks. Mixtures of the interaction terms between air pollutants and temperature mean anomalies were associated with increased hospitalization rates for all CVD subtypes. CONCLUSIONS: Our findings identified critical pollutants for targeted emission controls and suggested that abnormal temperature changes chronically affected cardiovascular health by interacting with air pollution, not directly.

A novel mortality risk score for emphysematous pyelonephritis: A multicenter study of the Global Research in the Emphysematous Pyelonephritis group.

Background: Emphysematous pyelonephritis (EPN) is a necrotizing infection of the kidney and the surrounding tissues associated with considerable mortality. We aimed to formulate a score that classifies the risk of mortality in patients with EPN at hospital admission. Materials and methods: Patients diagnosed with EPN between 2013 and 2020 were retrospectively included. Data from 15 centers (70%) were used to develop the scoring system, and data from 7 centers (30%) were used to validate it. Univariable and multivariable logistic regression analyses were performed to identify independent factors related to mortality. Receiver operating characteristic curve analysis was performed to construct the scoring system and calculate the risk of mortality. A standardized regression coefficient was used to quantify the discriminating power of each factor to convert the individual coefficients into points. The area under the curve was used to quantify the scoring system performance. An 8-point scoring system for the mortality risk was created (range, 0-7). Results: In total, 570 patients were included (400 in the test group and 170 in the validation group). Independent predictors of mortality in the multivariable logistic regression were included in the scoring system: quick Sepsis-related Organ Failure Assessment score ≥2 (2 points), anemia, paranephric gas extension, leukocyte count >22,000/µL, thrombocytopenia, and hyperglycemia (1 point each). The mortality rate was <5% for scores ≤3, 83.3% for scores 6, and 100% for scores 7. The area under the curve was 0.90 (95% confidence interval, 0.84-0.95) for test and 0.91 (95% confidence interval, 0.84-0.97) for the validation group. Conclusions: Our score predicts the risk of mortality in patients with EPN at presentation and may help clinicians identify patients at a higher risk of death.

Exposure-response associations between chronic exposure to fine particulate matter and risks of hospital admission for major cardiovascular diseases: population based cohort study.

OBJECTIVE: To estimate exposure-response associations between chronic exposure to fine particulate matter (PM2.5) and risks of the first hospital admission for major cardiovascular disease (CVD) subtypes. DESIGN: Population based cohort study. SETTING: Contiguous US. PARTICIPANTS: 59 761 494 Medicare fee-for-service beneficiaries aged ≥65 years during 2000-16. Calibrated PM2.5 predictions were linked to each participant's residential zip code as proxy exposure measurements. MAIN OUTCOME MEASURES: Risk of the first hospital admission during follow-up for ischemic heart disease, cerebrovascular disease, heart failure, cardiomyopathy, arrhythmia, valvular heart disease, thoracic and abdominal aortic aneurysms, or a composite of these CVD subtypes. A causal framework robust against confounding bias and bias arising from errors in exposure measurements was developed for exposure-response estimations. RESULTS: Three year average PM2.5 exposure was associated with increased relative risks of first hospital admissions for ischemic heart disease, cerebrovascular disease, heart failure, cardiomyopathy, arrhythmia, and thoracic and abdominal aortic aneurysms. For composite CVD, the exposure-response curve showed monotonically increased risk associated with PM2.5: compared with exposures ≤5 µg/m3 (the World Health Organization air quality guideline), the relative risk at exposures between 9 and 10 µg/m3, which encompassed the US national average of 9.7 µg/m3 during the study period, was 1.29 (95% confidence interval 1.28 to 1.30). On an absolute scale, the risk of hospital admission for composite CVD increased from 2.59% with exposures ≤5 µg/m3 to 3.35% at exposures between 9 and 10 µg/m3. The effects persisted for at least three years after exposure to PM2.5. Age, education, accessibility to healthcare, and neighborhood deprivation level appeared to modify susceptibility to PM2.5. CONCLUSIONS: The findings of this study suggest that no safe threshold exists for the chronic effect of PM2.5 on overall cardiovascular health. Substantial benefits could be attained through adherence to the WHO air quality guideline.

Long-term exposure to ambient PM2.5, particulate constituents and hospital admissions from non-respiratory infection.

The association between PM2.5 and non-respiratory infections is unclear. Using data from Medicare beneficiaries and high-resolution datasets of PM2.5 and its constituents across 39,296 ZIP codes in the U.S between 2000 and 2016, we investigated the associations between annual PM2.5, PM2.5 constituents, source-specific PM2.5, and hospital admissions from non-respiratory infections. Each standard deviation (3.7-µg m-3) increase in PM2.5 was associated with a 10.8% (95%CI 10.8-11.2%) increase in rate of hospital admissions from non-respiratory infections. Sulfates (30.8%), Nickel (22.5%) and Copper (15.3%) contributed the largest weights in the observed associations. Each standard deviation increase in PM2.5 components sourced from oil combustion, coal burning, traffic, dirt, and regionally transported nitrates was associated with 14.5% (95%CI 7.6-21.8%), 18.2% (95%CI 7.2-30.2%), 20.6% (95%CI 5.6-37.9%), 8.9% (95%CI 0.3-18.4%) and 7.8% (95%CI 0.6-15.5%) increases in hospital admissions from non-respiratory infections. Our results suggested that non-respiratory infections are an under-appreciated health effect of PM2.5.

Modification of the PM2.5- and extreme heat-mortality relationships by historical redlining: a case-crossover study in thirteen U.S. states.

BACKGROUND: Redlining has been associated with worse health outcomes and various environmental disparities, separately, but little is known of the interaction between these two factors, if any. We aimed to estimate whether living in a historically-redlined area modifies the effects of exposures to ambient PM2.5 and extreme heat on mortality by non-external causes. METHODS: We merged 8,884,733 adult mortality records from thirteen state departments of public health with scanned and georeferenced Home Owners Loan Corporation (HOLC) maps from the University of Richmond, daily average PM2.5 from a sophisticated prediction model on a 1-km grid, and daily temperature and vapor pressure from the Daymet V4 1-km grid. A case-crossover approach was used to assess modification of the effects of ambient PM2.5 and extreme heat exposures by redlining and control for all fixed and slow-varying factors by design. Multiple moving averages of PM2.5 and duration-aware analyses of extreme heat were used to assess the most vulnerable time windows. RESULTS: We found significant statistical interactions between living in a redlined area and exposures to both ambient PM2.5 and extreme heat. Individuals who lived in redlined areas had an interaction odds ratio for mortality of 1.0093 (95% confidence interval [CI]: 1.0084, 1.0101) for each 10 µg m-3 increase in same-day ambient PM2.5 compared to individuals who did not live in redlined areas. For extreme heat, the interaction odds ratio was 1.0218 (95% CI 1.0031, 1.0408). CONCLUSIONS: Living in areas that were historically-redlined in the 1930's increases the effects of exposures to both PM2.5 and extreme heat on mortality by non-external causes, suggesting that interventions to reduce environmental health disparities can be more effective by also considering the social context of an area and how to reduce disparities there. Further study is required to ascertain the specific pathways through which this effect modification operates and to develop interventions that can contribute to health equity for individuals living in these areas.

Quantifying venom production: A study on Micrurus snakes in Mexico.

Our study quantifies venom production in nine Mexican coral snake species (Micrurus), encompassing 76 specimens and 253 extractions. Noteworthy variations were observed, with M. diastema and M. laticollaris displaying diverse yields, ranging from 0.3 mg to 59 mg. For animals for which we have length data, there is a relationship between size and venom quantity. Twenty-eight percent of the observed variability in venom production can be explained by snake size, suggesting that other factors influence the amount of obtained venom. These findings are pivotal for predicting venom effects and guiding antivenom interventions. Our data offer insights into Micrurus venom yields, laying the groundwork for future research and aiding in medical response strategies. This study advances understanding coral snake venom production, facilitating informed medical responses to coral snake bites.

Long-term exposure to PM2.5 species and all-cause mortality among Medicare patients using mixtures analyses.

BACKGROUND: The relationship between long-term exposure to PM2.5 and mortality is well-established; however, the role of individual species is less understood. OBJECTIVES: In this study, we assess the overall effect of long-term exposure to PM2.5 as a mixture of species and identify the most harmful of those species while controlling for the others. METHODS: We looked at changes in mortality among Medicare participants 65 years of age or older from 2000 to 2018 in response to changes in annual levels of 15 PM2.5 components, namely: organic carbon, elemental carbon, nickel, lead, zinc, sulfate, potassium, vanadium, nitrate, silicon, copper, iron, ammonium, calcium, and bromine. Data on exposure were derived from high-resolution, spatio-temporal models which were then aggregated to ZIP code. We used the rate of deaths in each ZIP code per year as the outcome of interest. Covariates included demographic, temperature, socioeconomic, and access-to-care variables. We used a mixtures approach, a weighted quantile sum, to analyze the joint effects of PM2.5 species on mortality. We further looked at the effects of the components when PM2.5 mass levels were at concentrations below 8 µg/m3, and effect modification by sex, race, Medicaid status, and Census division. RESULTS: We found that for each decile increase in the levels of the PM2.5 mixture, the rate of all-cause mortality increased by 1.4% (95% CI: 1.3%-1.4%), the rate of cardiovascular mortality increased by 2.1% (95% CI: 2.0%-2.2%), and the rate of respiratory mortality increased by 1.7% (95% CI: 1.5%-1.9%). These effects estimates remained significant and slightly higher when we restricted to lower concentrations. The highest weights for harmful effects were due to organic carbon, nickel, zinc, sulfate, and vanadium. CONCLUSIONS: Long-term exposure to PM2.5 species, as a mixture, increased the risk of all-cause, cardiovascular, and respiratory mortality.

Long-term noise exposures and cardiovascular diseases mortality: A study in 5 U.S. states.

BACKGROUND: Previous studies have linked noise exposure with adverse cardiovascular events. However, evidence remains inconsistent, and most previous studies only focused on traffic noise, excluding other anthropogenic sources like constructions, industrial process and commercial activities. Additionally, few studies have been conducted in the U.S. or evaluated the non-linear exposure-response relationships. METHODS: We conducted a relative incidence analysis study using all cardiovascular diseases mortality as cases (n = 936,019) and external causes mortality (n = 232,491) as contrast outcomes. Mortality records geocoded at residential addresses were obtained from five U.S. states (Indiana, 2007; Kansas, 2007-2009, Missouri, 2010-2019, Ohio, 2007-2013, Texas, 2007-2016). Time-invariant long-term noise exposure was obtained from a validated model developed based on acoustical measurements across 2000-2014. Noises from both natural sources (natural activities, including animals, insects, winds, water flows, thunder, etc.) and anthropogenic sources (human activities, including transportation, industrial activities, community facilities & infrastructures, commercial activities, entertainments, etc.) were included. We used daytime and nighttime total anthropogenic noise & day-night average sound pressure level combining natural and anthropogenic sources as exposures. Logistic regression models were fit controlling for Census tract-level & individual-level characteristics. We examined potential modification by sex by interaction terms and potential non-linear associations by thin plate spline terms. RESULTS: We observed positive associations for daytime anthropogenic L50 (sound level exceeded 50% of time) noise (10-dBA OR = 1.047, 95%CI 1.025-1.069), nighttime anthropogenic L50 noise (10-dBA OR = 1.061, 95%CI 1.033-1.091) in a two-exposure-term model, and overall Ldn (day-night average) sound pressure level (10-dBA OR = 1.064, 95%CI 1.040-1.089) in single-exposure-term model. Females were more susceptible to all three exposures. All exposures showed monotonic positive associations with cardiovascular mortality up to certain thresholds around 45-55 dBA, with a generally flattened or decreasing trend beyond those thresholds. CONCLUSIONS: Both daytime anthropogenic and nighttime anthropogenic noises were associated with cardiovascular disease mortality, and associations were stronger in females.

Venom of the neotropical rattlesnake, Crotalus culminatus: Intraspecific variation, neutralization by antivenoms, and immunogenicity in rabbits.

Crotalus culminatus is a medically significant species of rattlesnake in Mexico [1]. While the proteomic composition of its venom has been previously reported for both juvenile and adult specimens, there has been limited research into its functional properties, with only a few studies, including one focusing on coagulotoxicity mechanisms. In this study, we aimed to compare the biochemical and biological activities of the venom of juvenile and adult snakes. Additionally, we assessed antibody production using the venoms of juveniles and adults as immunogens in rabbits. Our findings reveal lethality and proteolytic activity differences between the venoms of juveniles and adults. Notably, juvenile venoms exhibited high proportions of crotamine, while adult venoms displayed a reduction of this component. A commercially available antivenom demonstrated effective neutralization of lethality of both juvenile and adult venoms in mice. However, it failed to neutralize the paralytic activity induced by crotamine, which, in contrast, was successfully inhibited by antibodies obtained from hyperimmunized rabbits. These results suggest the potential inclusion of C. culminatus venom from juveniles in commercial antivenom immunization schemes to generate antibodies targeting this small myotoxin.

Adrenal malakoplakia a rare lesion that mimics a neoplasm.

Background: Malakoplakia is a rare disorder 75% of the reported cases affect mainly the genitourinary tract, its occurrence in the adrenal gland is extremely rare. Case presentation: A 65-year-old female patient presented to the emergency department for chronic abdominal pain. Radiographic and biochemical studies revealed a left adrenal incidentaloma and left adrenalectomy was performed. Histological examination showed the presence of Michaelis-Gutmann bodies, compatible with a malakoplakia of the adrenal gland. Conclusions: Malakoplakia is a rare disorder, with non-standardized treatment, medical and surgical therapies appear to be effective in treating the condition.

Long-term association of air pollution and incidence of lung cancer among older Americans: A national study in the Medicare cohort.

BACKGROUND: Despite strong evidence of the association of fine particulate matter (PM2.5) exposure with an increased risk of lung cancer mortality, few studies had investigated associations of multiple pollutants simultaneously, or with incidence, or using causal methods. Disparities were also understudied. OBJECTIVES: We investigated long-term effects of PM2.5, nitrogen dioxide (NO2), warm-season ozone, and particle radioactivity (PR) exposures on lung cancer incidence in a nationwide cohort. METHODS: We conducted a cohort study with Medicare beneficiaries (aged ≥ 65 years) continuously enrolled in the fee-for-service program in the contiguous US from 2001 to 2016. Air pollution exposure was averaged across three years and assigned based on ZIP code of residence. We fitted Cox proportional hazards models to estimate the hazard ratio (HR) for lung cancer incidence, adjusted for individual- and neighborhood-level confounders. As a sensitivity analysis, we evaluated the causal relationships using inverse probability weights. We further assessed effect modifications by individual- and neighborhood-level covariates. RESULTS: We identified 166,860 lung cancer cases of 12,429,951 studied beneficiaries. In the multi-pollutant model, PM2.5 and NO2 exposures were statistically significantly associated with increased lung cancer incidence, while PR was marginally significantly associated. Specifically, the HR was 1.008 (95% confidence interval [CI]: 1.005, 1.011) per 1-µg/m3 increase in PM2.5, 1.013 (95% CI: 1.012, 1.013) per 1-ppb increase in NO2, and 1.005 (0.999, 1.012) per 1-mBq/m3 increase in PR. At low exposure levels, all pollutants were associated with increased lung cancer incidence. Men, older individuals, Blacks, and residents of low-income neighborhoods experienced larger effects of PM2.5 and PR. DISCUSSION: Long-term PM2.5, NO2, and PR exposures were independently associated with increased lung cancer incidence among the national elderly population. Low-exposure analysis indicated that current national standards for PM2.5 and NO2 were not restrictive enough to protect public health, underscoring the need for more stringent air quality regulations.

Ontogenetic change in the venom composition of one Mexican black-tailed rattlesnake (Crotalus molossus nigrescens) from Durango, Mexico.

To corroborate the ontogenetic shift in the venom composition of the Mexican Black-tailed Rattlesnake (Crotalus molossus nigrescens) previously reported through the census approach, we evaluated the shift in the protein profile, lethality, and proteolytic and phospholipase activities of four venom samples obtained in 2015, 2018, 2019, and 2021 from one C. m. nigrescens individual (CMN06) collected in Durango, Mexico. We demonstrated that the venom of C. m. nigrescens changed from a myotoxin-rich venom to a phospholipase A2 and snake venom metalloproteinase-rich venom. Additionally, the proteolytic and phospholipase activities increased with age, but the lethality decreased approximately three times.

Additive effects of 10-year exposures to PM2.5 and NO2 and primary cancer incidence in American older adults.

Epidemiologic evidence on the relationships between air pollution and the risks of primary cancers other than lung cancer remained largely lacking. We aimed to examine associations of 10-year exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) with risks of breast, prostate, colorectal, and endometrial cancers. Methods: For each cancer, we constructed a separate cohort among the national Medicare beneficiaries during 2000 to 2016. We simultaneously examined the additive associations of six exposures, namely, moving average exposures to PM2.5 and NO2 over the year of diagnosis and previous 2 years, previous 3 to 5 years, and previous 6 to 10 years, with the risk of first cancer diagnosis after 10 years of follow-up, during which there was no cancer diagnosis. Results: The cohorts included 2.2 to 6.5 million subjects for different cancers. Exposures to PM2.5 and NO2 were associated with increased risks of colorectal and prostate cancers but were not associated with endometrial cancer risk. NO2 was associated with a decreased risk of breast cancer, while the association for PM2.5 remained inconclusive. At exposure levels below the newly updated World Health Organization Air Quality Guideline, we observed substantially larger associations between most exposures and the risks of all cancers, which were translated to hundreds to thousands new cancer cases per year within the cohort per unit increase in each exposure. Conclusions: These findings suggested substantial cancer burden was associated with exposures to PM2.5 and NO2, emphasizing the urgent need for strategies to mitigate air pollution levels.

Comparative Analysis of Alpha-1 Orthosteric-Site Binding by a Clade of Central American Pit Vipers (Genera Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium).

The distribution and relative potency of post-synaptic neurotoxic activity within Crotalinae venoms has been the subject of less investigation in comparison with Elapidae snake venoms. No previous studies have investigated post-synaptic neurotoxic activity within the Atropoides, Metlapilcoatlus, Cerrophidion, and Porthidium clade. Given the specificity of neurotoxins to relevant prey types, we aimed to uncover any activity present within this clade of snakes that may have been overlooked due to lower potency upon humans and thus not appearing as a clinical feature. Using biolayer interferometry, we assessed the relative binding of crude venoms to amphibian, lizard, bird, rodent and human α-1 nAChR orthosteric sites. We report potent alpha-1 orthosteric site binding in venoms from Atropoides picadoi, Metlapilcoatlus occiduus, M. olmec, M. mexicanus, M. nummifer. Lower levels of binding, but still notable, were evident for Cerrophidion godmani, C. tzotzilorum and C. wilsoni venoms. No activity was observed for Porthidium venoms, which is consistent with significant alpha-1 orthosteric site neurotoxicity being a trait that was amplified in the last common ancestor of Atropoides/Cerrophidion/Metlapilcoatlus subsequent to the split by Porthidium. We also observed potent taxon-selective activity, with strong selection for non-mammalian targets (amphibian, lizard, and bird). As these are poorly studied snakes, much of what is known about them is from clinical reports. The lack of affinity towards mammalian targets may explain the knowledge gap in neurotoxic activity within these species, since symptoms would not appear in bite reports. This study reports novel venom activity, which was previously unreported, indicating toxins that bind to post-synaptic receptors may be more widespread in pit vipers than previously considered. While these effects appear to not be clinically significant due to lineage-specific effects, they are of significant evolutionary novelty and of biodiscovery interest. This work sets the stage for future research directions, such as the use of in vitro and in vivo models to determine whether the alpha-1 orthosteric site binding observed within this study confers neurotoxic venom activity.