ACE-2 Blockade & TMPRSS2 Inhibition Mitigate SARS-CoV-2 Severity Following Cigarette Smoke Exposure in Airway Epithelial Cells In Vitro.

Cigarette smoking is associated with COVID-19 prevalence and severity, but the mechanistic basis for how smoking alters SARS-CoV-2 pathogenesis is unknown. A potential explanation is that smoking alters the expression of the SARS-CoV-2 cellular receptor and point of entry, angiotensin converting enzyme-2 (ACE-2), and its cofactors including transmembrane protease serine 2 (TMPRSS2). We investigated the impact of cigarette smoking on the expression of ACE-2, TMPRSS2, and other known cofactors of SARS-CoV-2 infection and the resultant effects on infection severity in vitro. Cigarette smoke extract (CSE) exposure increased ACE-2 and TMPRSS2 mRNA expression compared to air control in ferret airway cells, Calu-3 cells, and primary human bronchial epithelial (HBE) cells derived from normal and COPD donors. CSE-exposed ferret airway cells inoculated with SARS-CoV-2 had a significantly higher intracellular viral load versus vehicle-exposed cells. Likewise, CSE-exposure increased both SARS-CoV-2 intracellular viral load and viral replication in both normal and COPD HBE cells over vehicle control. Apoptosis was increased in CSE-exposed, SARS-CoV-2-infected HBE cells. Knockdown of ACE-2 via an antisense oligonucleotide (ASO) reduced SARS-CoV-2 viral load and infection in CSE-exposed ferret airway cells that was augmented by co-administration of camostat mesylate to block TMPRSS2 activity. Smoking increases SARS-CoV-2 infection via upregulation of ACE2 and TMPRSS2.

Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair.

Rationale: The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. Methods: Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. Results: Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. Conclusions: Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.

The Views of Police Officers Toward Gun Legislation and Public Health Policies Driven by Firearm Safety Concerns.

Gun violence is a principal cause of premature death in America. It has been suggested that solutions to gun violence may be found using a public health approach, which is broader than dealing with the problem via law enforcement alone. A component of a public health approach to gun violence is the implementation of policies or laws. Unfortunately, there is a serious gap in our understanding of how street-level police officers view proposed or existing firearms legislation. This is an important omission, because it is line-level personnel who are tasked with enforcing these policies within highly discretionary contexts. We surveyed police from three jurisdictions to establish a baseline understanding of officers' views about potential gun legislation and identify possible resistance and implementation barriers of firearms laws. The findings suggest that those responsible for enforcing new laws show limited or mixed support for the same. Officers were most supportive of laws that increase the presence of trained gun owners within certain contexts and ensure that individuals with criminal backgrounds or mental health concerns do not have access to firearms. Most officers support prohibiting gun ownership following conviction of a domestic violence offense. However, officers generally opposed gun legislation banning assault weapons, large capacity magazines, and internet ammunition purchases. Finally, officers with the Buffalo Police Department-which recently had experienced an active-shooter event-were more supportive of almost all types of legislation. Respondents expressing greater concern about officer safety related to firearms were supportive of several types of firearm legislation.

Closed-loop recyclable plastics from poly(ethyl cyanoacrylate).

Ethyl cyanoacrylate is a highly reactive monomer that has been used nearly exclusively to make Super Glue and related fast-setting adhesives. Here, we describe transformation of this highly abundant, readily available monomer into a closed-loop recyclable plastic that could supplant currently used (and often unrecycled/unrecyclable) plastics, such as poly(styrene). We report polymerization conditions, plastic-processing methods, and plastic-recycling protocols for poly(ethyl cyanoacrylate) plastics that make the Super Glue monomer a viable starting material for a next generation of closed-loop recyclable plastics. The processes described are scalable, and the plastics can be recycled in a closed-loop process with >90% yields, even when combined with a heterogeneous mixture of other types of plastic.

Mucociliary transport deficiency and disease progression in Syrian hamsters with SARS-CoV-2 infection.

Substantial clinical evidence supports the notion that ciliary function in the airways is important in COVID-19 pathogenesis. Although ciliary damage has been observed in both in vitro and in vivo models, the extent or nature of impairment of mucociliary transport (MCT) in in vivo models remains unknown. We hypothesize that SARS-CoV-2 infection results in MCT deficiency in the airways of golden Syrian hamsters that precedes pathological injury in lung parenchyma. Micro-optical coherence tomography was used to quantitate functional changes in the MCT apparatus. Both genomic and subgenomic viral RNA pathological and physiological changes were monitored in parallel. We show that SARS-CoV-2 infection caused a 67% decrease in MCT rate as early as 2 days postinfection (dpi) in hamsters, principally due to 79% diminished airway coverage of motile cilia. Correlating quantitation of physiological, virological, and pathological changes reveals steadily descending infection from the upper airways to lower airways to lung parenchyma within 7 dpi. Our results indicate that functional deficits of the MCT apparatus are a key aspect of COVID-19 pathogenesis, may extend viral retention, and could pose a risk factor for secondary infection. Clinically, monitoring abnormal ciliated cell function may indicate disease progression. Therapies directed toward the MCT apparatus deserve further investigation.

The impact of COVID-19 on the spatial distribution of shooting violence in Buffalo, NY.

OBJECTIVES: This paper examines the extent to which hotspots of shooting violence changed following the emergence of COVID-19. METHODS: This analysis uses Andresen's Spatial Point Pattern test on 1500 by 1500 foot grid cells, correcting for multiple comparisons, on a 10-year sample of geocoded shooting data from Buffalo New York. RESULTS: This work finds zero micro-grid cells are not statistically different from pre to post COVID stay at home orders and instead that the observed rise in shootings in the sample appears to be a consistent proportional increase across the city. CONCLUSIONS: These findings provide law enforcement with useful information about how to respond to the recent rise in shooting violence, but additional work is needed to better understand what, among a number of competing theories, is driving the increase. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11292-021-09497-4.

Post-mortem blood lead analysis; a comparison between LeadCare II and graphite furnace atomic absorption spectrometry analysis results.

PURPOSE: A comparison of the LeadCare II (LCII) point-of-care (POC) device with the gold standard graphite furnace atomic absorption spectroscopy (GFAAS) device was done in the context of post-mortem blood lead concentrations to determine comparability for screening value. METHODS: Consecutive autopsy cases from March 2018 to March 2019 were examined by the forensic medicine center. Blood samples with lead concentrations <10 µg dL-1 by LCII analysis were excluded from GFAAS analysis. Samples were collected from femoral veins or cardiac chambers. Bland-Altman analysis was conducted to evaluate the agreement between both GFAAS and LCII lead values. Linear regression modeling was performed to predict GFAAS results based on LCII results. Five-hundred post-mortem blood samples were evaluated by LCII for blood lead. For 46 cases with LCII blood lead level (BLL) values more than 10 µg dL-1, further analysis was performed by GFAAS. RESULTS: Mean difference of BLL between the two methods was 5.92 µg dL-1 (SD = 7.51; range: -14 to 23.7). GFAAS BLL values were significantly higher than LCII values (p = 0.029). Moreover, substance-user samples had significantly higher GFAAS BLLs (p = 0.006; mean difference = 11.62 µg dL-1). A significant regression equation was found (F [1, 44] = 108.44, p < 0.001, with an R2 of 0.711). Based on Bland-Altman plot averages for both predicted GFAAS BLL and measured GFASS BLL showed a mean difference was 0.014 (SD = 7.51; range: -17.9 to 20). CONCLUSION: In conclusion, on post-mortem BLL samples, LCII and GFAAS show favorable correlation. LCII can be used as a screening technique for post-mortem blood lead analysis.

Blood lead concentrations among pediatric patients with abdominal pain: a prospective cross-sectional study.

BACKGROUND: Lead exposure is one of the most menacing of environmental exposures, particularly in children. Children are more susceptible to the effects of lead which manifest in many organ systems, including interference with mental and motor development. Lead poisoning can cause colicky abdominal pain. In this study, the authors sought to evaluate the prevalence of elevated blood lead level (BLL) and its contributing factors among pediatric patients presenting with abdominal pain. An epidemic of lead poisoning in adults was previously uncovered, and thus a concern for pediatric lead poisoning was raised. METHODS: Pediatric patients presenting to two pediatric clinics in Tehran with abdominal pain were eligible for enrollment in a descriptive prospective cross-sectional study. A predesigned questionnaire was filled for each patient by their consenting parents. The questionnaire queried demographic information, environmental, social, and other relevant parameters for lead exposure. After completion of the questionnaire, biometrics were obtained, and a blood sample was taken from each patient for measurement of BLL and complete blood count. RESULTS: A total of 187 patients were enrolled in the study. Of them, almost 20% had BLL ≥ 5 µg/dL. Univariate analysis showed that age (p = 0.002, OR 3.194, CI 95% 1.504-6.783), weight (p = 0.009, OR 2.817, CI 95% 1.266-6.269), height (p = 0.003, OR 3.155, CI 95% 1.443-6.899), and playing with both plastic and cotton toys (p = 0.03, OR 2.796, CI 95% 1.072-7.295) were significant predictors of high BLLs. Maternal level of education correlated with blood lead concentrations (p = 0.048, OR 2.524, CI 95% 1.006-6.331). CONCLUSIONS: A clinically significant number of cases of abdominal pain may have high BLLs. Specific attention should be paid to children presenting with abdominal pain, especially due to the detrimental effects of lead on their mental and motor development.

Adult Lead Poisoning Caused by Contaminated Opium: A Two-Year Longitudinal Follow-Up Study.

Background: A major episode of lead poisoning caused by lead-adulterated opium occurred in Iran in 2016. Patients were removed from exposure and treated with chelating agents. A subset of those patients was evaluated in this follow-up study to evaluate treatment efficacy in relation to patient outcome. Methods: Between March 2016 and December 2017, thirty-five male cases of lead poisoning due to ingestion of lead-adulterated opium were followed for two years. There are three patient groups: 1) those who abstained from opium use; 2) those who continued to use potentially contaminated opium; and 3) those who abstained from opium and were placed on maintenance therapy. Maintenance therapy included: methadone and opium tincture, offered by the Opioid Maintenance Therapy (OMT) clinics. Amongst the three patient groups Blood Lead Levels (BLL), complete blood count, and kidney and liver function tests were compared. Findings: The results of BLL, hemoglobin, hematocrit, and aspartate aminotransferase were significantly different between the admission time and follow-up. Of the three patient groups, no difference was detected in these measures. Conclusions: Treatment of lead poisoning combined with OMT proved an effective method to prevent recurrent lead poisoning.

Environmental assessment of pediatric Lead exposure in Tehran; a prospective cross-sectional study.

BACKGROUND: Ingestion and inhalation are common routes of exposure for lead in humans. Developing countries still have unacceptably high rates of lead toxicity, especially in children. Studies on probable risk factors of lead poisoning in Iranian children are insufficient. In this study, we aimed to evaluate possible environmental factors in children with high blood lead concentrations living in Tehran and neighboring cities. METHODS: In a prospective cross-sectional study between March 2018 and March 2019 we followed all children referred from two pediatric gastrointestinal clinics with blood lead level (BLL) > 5 µg/dL in metropolitan Tehran to investigate possible environmental risk factors in their home. Household specimens including scratched wall paint, house floor dust, windowsill dust, tap water, and consumed spice were evaluated using atomic absorption method to detect lead concentrations. Epidemiological and environmental data collected through in-depth interviews with parents/guardians. Industrial areas were defined based on municipality maps on industrial places. RESULTS: Thirty of 56 parents/guardians with BLL > 5 µg/dL agreed to be followed through environmental investigation. The only categorical statistically significant risk factor was a history of lead poisoning in the family and living in an industrial zone. There was a positive correlation between BLL and interior windowsills dust lead level, r = 0.46, p = 0.01. Scratched paint lead level and BLL showed a significant positive correlation, r = 0.50, p = 0.005. House floor dust lead level (median = 77.4, p < 0.001) and interior windowsill dust lead level (median = 291, p = 0.011) were both significantly higher than the environmental protection agency (EPA) standards of 40 µg/ft2, 250 µg/ft2. Interior windowsill dust lead concentrations were significantly higher in industrial areas (p = 0.026). CONCLUSION: Children's playing environment should be cleaned more often to reduce dust. Moreover, specific rules may need to be implemented for paint lead concentrations and air pollution, especially in industrial areas.

Proposed mechanism for reduced jugular vein flow in microgravity.

Internal jugular flow is reduced in space compared with supine values, which can be associated with internal jugular vein (IJV) thrombosis. The mechanism is unknown but important to understand to prevent potentially serious vein thromboses on long duration flights. We used a novel, microgravity-focused numerical model of the cranial vascular circulation to develop hypotheses for the reduced flow. This model includes the effects of removing hydrostatic gradients and tissue compressive forces - unique effects of weightlessness. The IJV in the model incorporates sensitivity to transmural pressure across the vein, which can dramatically affect resistance and flow in the vein. The model predicts reduced IJV flow in space. Although tissue weight in the neck is reduced in weightlessness, increasing transmural pressure, this is more than offset by the reduction in venous pressure produced by the loss of hydrostatic gradients and tissue pressures throughout the body. This results in a negative transmural pressure and increased IJV resistance. Unlike the IJV, the walls of the vertebral plexus are rigid; transmural pressure does not affect its resistance and so its flow increases in microgravity. This overall result is supported by spaceflight measurements, showing reduced IJV area inflight compared with supine values preflight. Significantly, this hypothesis suggests that interventions that further decrease internal IJV pressure (such as lower body negative pressure), which are not assisted by other drainage mechanisms (e.g. gravity), might lead to stagnant flow or IJV collapse with reduced flow, which could increase rather than decrease the risk of venous thrombosis.

When COVID-19 and guns meet: A rise in shootings.

OBJECTIVE: The present study examines the impact of the COVID-19 stay-at-home order on gun violence in Buffalo, New York: fatal shootings, all non-fatal shootings, non-fatal shootings with injury, and non-fatal shootings without injury. It also estimated its impact on gang and non-gang related shootings. METHODS: Weekly crime data are analyzed at the city level using ARIMA and poisson models. Forecasting is used to verify the validity of both ARIMA and poisson models. RESULTS: The effect of the pandemic was conditional upon the types of gun violence and impact models of intervention. The pandemic caused a temporary increase in fatal shootings while leading to a long-term increase in all non-fatal shootings, non-fatal shootings with injury, non-fatal shootings without injury, and gang related shootings. CONCLUSIONS: The pandemic has changed the volume of gun violence possibly due to increased strain and/or changed routine activities. This study not only promotes further research but also has policy implications for public health and safety. From a public policy perspective, criminal justice agencies should focus more attention and resources on gun violence resulting from a sense of strain and fear among individuals during the pandemic.

Urinary Calcium for Tracking Bone Loss and Kidney Stone Risk in Space.

INTRODUCTION: Urinary calcium (Uca) levels in space reflect bone loss and kidney stone risk and could be measured using portable devices. This project evaluated the repeatability of Uca measurements to assess how many repeated measurements would be needed to detect significant urinary calcium elevations in space.METHODS: A total of six subjects collected 24-h urine samples weekly for 8 wk and took 500 mg of oral calcium carbonate and 400 IU of vitamin D daily in week 7 and 8. Uca concentration was analyzed using a calcein-based system. The effect of the intake of calcium and vitamin D on Uca levels and the correlation between first void concentration and 24-h mass were assessed with linear mixed effect models. The reproducibility coefficient (RPC) for Uca was determined using Bland-Altman analysis on pairs of measurements at different time points.RESULTS: Oral supplementation did not significantly affect 24-h mass. First void concentration correlated with 24-h mass. The 24-h mass RPCs were 167.0, 116.8, and 108.1 mg for 1-, 2-, and 3-wk average measurements. First void concentration RPCs were 90.6, 76.6, and 72.8 mg L1. Skylab astronauts 24-h mass increased by 88.9 76.0, 123.5 58.3, 142.2 56.5, and 159.9 83.4 mg after 1, 2, 3, and 4 wk in flight.DISCUSSION: Averaging multiple Uca measurements reduced variability effectively and allowed increases likely to be seen in space to be detected. Consecutive Uca measurements could be tracked over time in space to assess the effectiveness of the countermeasure program. First void concentration could potentially be used rather than 24-h collections.Ren J, Stankovic AS, Knaus DA, Phillips SD, Kynor DB, Buckey JC. Urinary calcium for tracking bone loss and kidney stone risk in space. Aerosp Med Hum Perform. 2020; 91(9):689696.

Lead poisoning; a neglected potential diagnosis in abdominal pain.

BACKGROUND: Abdominal pain may be a presenting symptom of lead poisoning and is often difficult to diagnose. This study aimed to determine the prevalence of abdominal pain in patients seen in the Laghman Hakim Hospital ED and GI clinic who were lead-intoxicated, with or without opiate use disorder. METHODS: Between July 2017 and January 2018, patients seen in the ED and GI clinic of Loghman Hakim Hospital with unexplained abdominal pain or abdominal pain resistant to treatment were enrolled. Informed consent was obtained from potential enrollees. For standardization, a pre-designed data collection tool was developed for uniform data acquisition. Opiate use was determined historically. For this study, lead poisoning was defined as a blood lead level (BLL) greater than or equal to 30 µg/dL (1.45 µmol/L) with concomitant GI symptoms. RESULTS: Of 125 patients admitted, 28 (22.4%) had BLLs higher than 30 µg/dL. None of the patients had signs and symptoms of opioid withdrawal syndrome during evaluation. Elevated BLLs were significantly correlated with oral opium use/abuse, history of addiction for over the preceding 12 years. The daily opium use was more than 2.75 g. There was a statistical correlation between lead toxicity and abdominal pain consistency and intensity, constipation, and paresthesias. Anemia, leukocytosis, and abnormal liver enzyme tests were laboratory findings associated with lead toxicity. Four patients died, one of whom was diagnosed with lead toxicity. CONCLUSION: Lead toxicity should be considered in the potential differential diagnosis of severe and resistant abdominal pain in patients referring to general EDs or GI clinics if a positive history of opium abuse exists.

Poly(carboxypyrrole)s That Depolymerize from Head to Tail in the Solid State in Response to Specific Applied Signals.

This Article describes the design, synthesis, and analysis of a new class of polymer that is capable of depolymerizing continuously, completely, and cleanly from head to tail when a detection unit on the head of the polymer is exposed to a specific applied signal. The backbone of this polymer consists of 1,3-disubstituted pyrroles and carboxy linkages similar to polyurethanes. Diverse side chains or reactive end-groups can be introduced readily, which provides modular design of polymer structure. The designed depolymerization mechanism proceeds through spontaneous release of carbon dioxide and azafulvene in response to a single triggering reaction with the detection unit. These poly(carboxypyrrole)s depolymerize readily in nonpolar environments, and even in the bulk as solid-state plastics.

Higher US Rural Mortality Rates Linked To Socioeconomic Status, Physician Shortages, And Lack Of Health Insurance.

All-cause mortality rates in rural areas have exceeded those in urban areas of the US since the 1980s, and the gap continues to widen. Yet no definitive causes of this difference are known, and within-state differences that might be amenable to state-level policy have not been explored. An analysis of 2016 state-level data indicated that rural mortality exceeded urban mortality in all but three states, with substantial variability in both rates across states. Overall, higher rural mortality at the state level can be mainly explained by three factors: socioeconomic deprivation, physician shortages, and lack of health insurance. To a certain degree, these factors reflect a state's health policies, such as expansion of eligibility for Medicaid, health infrastructure, and socioeconomic conditions. Our findings suggest that state and federal policy efforts to address rural-urban disparities in these areas could alleviate the higher rates of all-cause mortality faced by rural US residents.

Lead poisoning due to ingestion of lead-contaminated opium: A diagnostic study on patients' imaging findings.

OBJECTIVES: Our study attempts to determine if for patients following ingestion of lead-contaminated opium, radiographs [plain X-ray (KUB)] or unenhanced computed tomography (CT scan) of the abdomen may be predictive of lead poisoning. METHODS: Our study is concerned with patients of >21 years with elevated lead concentrations, who had undergone KUB or CT. Patients with other toxicities who had undergone similar imaging profiles but who had low blood lead level (BLL) were enrolled as controls. RESULTS: We evaluated a total of 79 cases and 79 controls with median [IQR] BLLs of 126 [97.4, 160] µg/dL and 8.7 [5.5, 15] µg/dL. All cases and eleven controls (13.9%) were addicted to oral opium, and of these cases, anemia (94.9%) and abdominal pain (92.4%) were the two most common clinical manifestations. Two radiologists reviewed the X-ray and non-contrast CTs. Fifty (63.3%) and 53 (67.1%) cases and controls underwent CT scanning with 34 (68%) vs. 6 (11.3%) positive CTs (P < 0.001) while 43 (54.4%) and 39 (43.3%) underwent X-rays with 21 (48.8%) vs. 4 (11.8%) positive X-rays, respectively (P < 0.001). Positive CT is associated with BLL between 10 and 45 µg/dL with a specificity of 96.9%, 88.7% and positive predictive value of 97.5% and 85% respectively. CONCLUSIONS: In suspected cases of lead exposure due to ingested opium, and if BLL is not readily available, a positive imaging result may guide radiologists and physicians to consider lead poisoning.