A number of studies have found differing associations of disease outcomes with PM2.5 components (or species) and sources (e.g., biomass burning, diesel vehicles and gasoline vehicles). Here, a unique ...method of fusing daily chemical transport model (Community Multiscale Air Quality Modeling) results with observations has been utilized to generate spatiotemporal fields of the concentrations of major gaseous pollutants (CO, NO2, NOx, O3, and SO2), total PM2.5 mass, and speciated PM2.5 (including crustal elements) over North Carolina for 2002–2010. The fused results are then used in chemical mass balance source apportionment model, CMBGC-Iteration, which uses both gas constraint and particulate matter concentrations to quantify source impacts. The method, as applied to North Carolina, quantifies the impacts of ten source categories and provides estimates of source contributions to PM2.5 concentrations. The ten source categories include both primary sources (diesel vehicles, gasoline vehicles, dust, biomass burning, coal-fired power plants and sea salt) and secondary components (ammonium sulfate, ammonium bisulfate, ammonium nitrate and secondary organic carbon). The results show a steady decrease in anthropogenic source impacts, especially from diesel vehicles and coal-fired power plants. Secondary pollutant components accounted for approximately 70% of PM2.5 mass. This study demonstrates an ability to provide spatiotemporal fields of both PM components and source impacts using a chemical transport model fused with observation data, linked to a receptor-based source apportionment method, to develop spatiotemporal fields of multiple pollutants.
Generate fields of total PM2.5 and its constituent species based on a data fusion method which combines observations and simulation results from CMAQ. Use this result and a receptor model to apportion PM2.5 and analyze spatial and temporal variations of sources to PM2.5. The method is computationally effective and can be applied on various scales. Display omitted
●Fusing observations and simulations to generate pollution fields●A computationally effective method based on data fusion and receptor model to apportion PM2.5●Spatial and temporal variations of sources to PM2.5 in North Carolina
Monitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European ...LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level <1% to 2% with a <1-log change between any 2 positive samples collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD−; 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.
•Postchemotherapy, of 100 CRMRD+ patients, 42% remained progression free at 1 year (spontaneous CRMRD− or low-level NPM1mut persistence).•Relapse is associated with FLT3-ITD and poor NPM1mut MRD response after chemotherapy. MRD-directed preemptive therapy may prolong remission.
Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional ...diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations.
Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated.
Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (
<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%;
=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%;
=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL interquartile range, -536 to 153 mL versus -14 mL interquartile range, -282 to 335 mL;
=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL;
=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (
=0.02) and all other neurohormones were similar (
<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (
=0.20) or renal dysfunction (
>0.11 for all biomarkers), whereas both serum magnesium (
<0.001) and uric acid levels (
=0.008) improved.
Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.
Diet is thought to play a role in the development of inflammatory bowel disease (IBD), though it is unknown whether gluten intake confers risk of IBD. The aim of this study was to determine the ...relationship between gluten intake and risk of incident Crohn's disease (CD) and ulcerative colitis (UC).
We performed a prospective cohort study of 208,280 US participants from the Nurses' Health Study (1986-2016), Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016) who did not have IBD at baseline or celiac disease, and who completed semiquantitative food frequency questionnaires. We used Cox proportional hazards modeling to estimate the risk of IBD according to quintiles of cumulative average energy-adjusted dietary gluten intake over the follow-up period.
We documented 337 CD cases and 447 UC cases over 5,115,265 person-years of follow-up evaluation. Dietary gluten intake was not associated with risk of IBD. Compared with participants in the lowest quintile of gluten intake, the adjusted hazard ratios and 95% CIs for participants in the highest quintile of gluten intake were 1.16 (95% CI, 0.82-1.64; P
= .41) for CD and 1.04 (95% CI, 0.75-1.44; P
= .64) for UC. Adjusting for primary sources of gluten intake did not materially change our estimates.
In 3 large adult US prospective cohorts, gluten intake was not associated with risk of CD or UC. Our findings are reassuring at a time when consumption of gluten has been increasingly perceived as a trigger for chronic gastrointestinal diseases.
Microscopic colitis is a common cause of chronic watery diarrhea among the elderly. Although the prevalence of celiac disease appears to be higher in patients with microscopic colitis, the ...relationship between dietary gluten intake and risk of microscopic colitis among individuals without celiac disease has not been explored.
We conducted a prospective study of 160,744 US women without celiac disease enrolled in the Nurses' Health Study (NHS) and the NHSII. Dietary gluten intake was estimated using validated food frequency questionnaires every 4 years. Microscopic colitis was confirmed through medical records review. We used Cox proportional hazard modeling to estimate the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI).
We documented 219 incident cases of microscopic colitis over more than 20 years of follow-up encompassing 3,716,718 person-years (crude incidence rate: 5.9/100,000 person-years) in NHS and NHSII. Dietary gluten intake was not associated with risk of microscopic colitis (Ptrend = 0.88). Compared to individuals in the lowest quintile of energy-adjusted gluten intake, the adjusted HR of microscopic colitis was 1.18 (95% CI: 0.77-1.78) for the middle quintile and 1.03 (95% CI: 0.67-1.58) for the highest quintile. Additional adjustment for primary dietary sources of gluten including refined and whole grains did not materially alter the effect estimates (All Ptrend ≥ 0.69). The null association did not differ according to lymphocytic or collagenous subtypes (Pheterogeneity = 0.72) and was not modified by age, smoking status, or body mass index (All Pinteraction ≥ 0.17).
Dietary gluten intake during adulthood was not associated with risk of microscopic colitis among women without celiac disease.
Mortality from thoracic injuries has declined significantly from 63% in the Civil War to 3% in Vietnam. We reviewed the injury patterns, procedures, blood products, and mortality of US soldiers ...sustaining a thoracic injury during Operation Enduring Freedom and Iraqi Freedom (OEF/OIF).
Data on US soldiers with a thoracic injury during OEF/OIF from January 2003 to May 2011 was collected from the Joint Theater Trauma Registry. Coalition forces, civilians, and soldiers killed in action were excluded. Injuries and procedures were identified using DRG International Classification of Diseases-9th Rev. and Abbreviated Injury Scale (AIS) codes. Data are presented as mean (SD). Statistical analysis used χ analysis and t test where appropriate.
Thoracic injuries occurred in 2,049 of 23,797 wounded US military personnel for a prevalence of 8.6%. Mean (SD) age was 26 (6.6) years, and mean (SD) chest AIS score was 2.9 (0.9). Penetrating trauma was the most common mechanism of injury (61.5%), and explosive devices were the most common cause of injury (61.9%). Of 6,030 thoracic injuries identified, pneumothorax and pulmonary contusions were most common (51.8% and 50.2%, respectively). Of 1,541 surgical procedures performed in theater, the most common was tube thoracostomy (47.1%). Most patients with penetrating fragmentation injuries (84%) were managed with tube thoracostomy as sole therapeutic intervention. The fresh frozen plasma-to-packed red blood cells ratio was 0.86. Overall mortality was 8.3%. Acute respiratory distress syndrome and inhalation injury were associated with mortality (p < 0.006).
Most penetrating fragmentation injuries can be managed with tube thoracostomy. Mortality of patients with chest injury in OEF/OIF is higher than in Korea and Vietnam. This most likely represents advances in prehospital care, personal protective equipment, and rapid transport that have resulted in more severely injured patients arriving alive to a medical facility.
Epidemiologic study, level IV.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no ...approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression.
Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2.
We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology.
We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.
Brucellosis is a zoonotic disease, caused by some species within the
Brucella
genus. The primary and secondary objectives of this cross-sectional study were to determine the seroprevalence of
...Brucella
antibodies in humans and cows and identify risk factors for exposure to
Brucella
spp. among people in Shahjadpur sub-district, Bangladesh. Twenty-five villages were randomly selected from the 303 milk-producing villages in the sub-district. We randomly selected 5% of the total households from each village. At each household, we collected demographic information and history of potential exposure to
Brucella
spp. in humans. In addition, we collected serum from household participants and serum and milk from cattle and tested to detect antibodies to
Brucella
sp. Univariate analysis was performed to detect associations between seropositivity and demographics, risk factors, and behaviors in households. We enrolled 647 households, 1313 humans, and 698 cows.
Brucella
antibodies were detected in sera from 27 household participants (2.1%, 95% confidence interval 95%CI: 1.2–2.9%). Eleven (1.6%, 95%CI 0.6–2.4%) cows had detectable
Brucella
antibodies in either milk or serum. About half (53%) of the 698 cows exhibited more than one reproductive problem within the past year; of these, seven (2%) had
Brucella
antibodies. Households with seropositive individuals more frequently reported owning cattle (78% vs. 32%,
P
< 0.001). Despite a low prevalence of
Brucella
seropositivity in the study, the public health importance of brucellosis cannot be ruled out. Further studies would help define
Brucella
prevalence and risk factors in this region and nationally.
Although jobs in science, technology, engineering, and math (STEM) fields are projected to grow at twice the rate of other professions, too many students, especially women and minoritized students, ...choose not to study or drop out of STEM fields, in part because they do not identify with STEM. With Communication Theory of Identity as a sensitizing framework, this study focused on a group of students who are 'at risk' for dropping out of STEM due to unmet financial need who are participating in a scholarship program designed both to close their financial need gap and to build their STEM identities. Based on Interpretive Phenomenological Analysis of 20 semi-structured interviews, the findings show that these students largely, but not exclusively, saw being a 'STEM person' as positive, but also expressed varying degrees of certainty and potential 'identity gaps' about their STEM identities. Enacted and relational STEM identities were of particular importance to how these students understood and experienced STEM identity. Women and minoritized students spoke of the importance of seeing and interacting with STEM people who share their social identities in developing their own STEM identities. Implications for a communication theory of STEM identities are discussed.
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