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The past few years have seen an explosion in sensitive and specific assays for cerebrospinal fluid (CSF) and blood biomarkers for Alzheimer's disease (AD) and related disorders, as well as some novel assays based on pathological seed‐induced protein misfolding in patient samples. Here, I review this exciting field that promises to transform dementia diagnostics and disease monitoring. I discuss data on biomarkers for amyloid beta (Aβ) and tau pathology, neurodegeneration, and glial activation, mention the most promising biomarkers for α‐synuclein and TDP‐43 pathology, and highlight the need for further research into common co‐pathologies. Finally, I consider practical aspects of blood‐based biomarker‐supported AD diagnostics and emphasize the importance of biomarker interpretation in a full clinical context.

Owing to the high tissue contrast, multiparametric MRI (mpMRI) has already been the most widely applied imaging method for prostate cancer. Recently, prostate-specific membrane antigen (PSMA) ligands for nuclear imaging are emerging as a promising modality in prostate cancer, especially since the 2 PET/CT agents ((68)Ga-PSMA-11 and (18)F-DCFPy) approved by U.S. Food and Drug Administration (FDA). However, limited studies have performed the comparison of mpMRI versus recently approved (18)F-DCFPyL PET/CT. In this issue of AJNMMI, Lu et al. compared the performance of (18)F-DCFPyL PET/CT and pelvic mpMRI in intermediate-high risk and biochemical recurrent prostate cancer patients. The results demonstrated the two modalities have a good concordance rate for patient-based analysis, and (18)F-DCFPyL PET/CT has a better diagnostic performance in detecting lymph node metastases and bone metastases for lesion-based analysis. The use of (18)F-DCFPyL PET/CT provides more diagnostic confidence to better assess prostate cancer lesions.

Studies have shown that air pollution exposures during pregnancy are associated with an increased risk of autism spectrum disorder (ASD) in children, and the risk appears to be greater for boys. However, studies assessing gestational windows of susceptibility have been mostly limited by trimesters.We identified sensitive windows of exposure to regional air pollution and risk of ASD and examined sex differences in a large birth cohort.This population-based retrospective cohort study included 294,937 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals from 2001 to 2014. Children were followed using electronic medical records until clinical ASD diagnosis, non-KPSC membership, death, or 31 December 2019, whichever came first. Weekly mean fine particulate matter [PM with an aerodynamic diameter ofThere were 5,694 ASD diagnoses (4,636 boys, 1,058 girls). SensitiveExposures to

Per- and polyfluoroalkyl substances (PFAS) are widespread persistent pollutants. Evidence regarding neurodevelopmental effects of PFAS have been mixed. The relation between PFAS exposure and anatomical markers that have been suggested to correlate with fetal brain development have not been studied.We investigated the association between prenatal PFAS exposures and three craniofacial features in children measured at 5 years of age.Measures of palpebral fissure length (PFL), philtrum groove, and upper-lip thickness were generated from standardized digital facial photographs from 656 children in the Danish National Birth Cohort. PFL was classified into two groups (shorter; normal), and the philtrum (grooved; smooth; normal) and upper-lip (thick; thin; normal) measures into three groups each. Six PFAS were measured in maternal plasma (Prenatal exposure to each PFAS was associated with elevated odds for a shorter PFL, with the strongest association observed for perfluorodecanoic acid (PFDA; per doublingPrenatal PFAS exposures might influence fetal craniofacial development. A larger study is needed to replicate the potential modifying effects observed for alcohol exposure and to clarify whether associations of craniofacial markers observed reflect specific neurologic deficits. https://doi.org/10.1289/EHP9478.

Background: Few studies have investigated air pollution exposure disparities by race/ethnicity and income across criteria air pollutants, locations, or time. Objective: The objective of this study was to quantify exposure disparities by race/ethnicity and income throughout the contiguous United States for six criteria air pollutants, during the period 1990 to 2010. Methods: We quantified exposure disparities among racial/ethnic groups (non-Hispanic White, non-Hispanic Black, Hispanic (any race), non-Hispanic Asian) and by income for multiple spatial units (contiguous United States, states, urban vs. rural areas) and years (1990, 2000, 2010) for carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), particulate matter with aerodynamic diameter ≤2.5μm (PM2.5; excluding year-1990), particulate matter with aerodynamic diameter ≤10μm (PM10), and sulfur dioxide (SO2). We used census data for demographic information and a national empirical model for ambient air pollution levels. Results: For all years and pollutants, the racial/ethnic group with the highest national average exposure was a racial/ethnic minority group. In 2010, the disparity between the racial/ethnic group with the highest vs. lowest national-average exposure was largest for NO2 [54% (4.6 ppb)], smallest for O3 [3.6% (1.6 ppb)], and intermediate for the remaining pollutants (13%–19%). The disparities varied by U.S. state; for example, for PM2.5 in 2010, exposures were at least 5% higher than average in 63% of states for non-Hispanic Black populations; in 33% and 26% of states for Hispanic and for non-Hispanic Asian populations, respectively; and in no states for non-Hispanic White populations. Absolute exposure disparities were larger among racial/ethnic groups than among income categories (range among pollutants: between 1.1 and 21 times larger). Over the period studied, national absolute racial/ethnic exposure disparities declined by between 35% (0.66μg/m3; PM2.5) and 88% (0.35 ppm; CO); relative disparities declined to between 0.99× (PM2.5; i.e., nearly zero change) and 0.71× (CO; i.e., a ∼29% reduction). Discussion: As air pollution concentrations declined during the period 1990 to 2010, absolute (and to a lesser extent, relative) racial/ethnic exposure disparities also declined. However, in 2010, racial/ethnic exposure disparities remained across income levels, in urban and rural areas, and in all states, for multiple pollutants. https://doi.org/10.1289/EHP8584

Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure.We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum.Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers (In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. https://doi.org/10.1289/EHP8562.

Epidemiologic studies have linked transportation noise to increased morbidity and mortality, particularly for cardiovascular outcomes. However, studies investigating metabolic outcomes such as diabetes are limited and have focused only on noise exposures estimated for the loudest residential façade.We aimed to examine the influence of long-term residential exposure to transportation noise at the loudest and quietest residential façades and the risk for type 2 diabetes.Road traffic and railway noise exposures (Lden) at the most and least exposed façades were estimated for all dwellings in Denmark during 1990-2017. Aircraft noise was estimated in 5-dB categories. Ten-year time-weighted mean noise exposures were estimated forHazard ratios (HRs) and 95% confidence intervals (CIs) for type 2 diabetes in association with 10-dB increases in 10-y mean road traffic noise at the most and least exposed façades, respectively, were 1.05 (95% CI: 1.04, 1.05) and 1.09 (95% CI: 1.08, 1.10). Following subsequent adjustment for fine particulate matter [particulate matterLong-term exposure to road, railway, and possibly aircraft traffic noise was associated with an increased risk of type 2 diabetes in a nationwide cohort of Danish adults. Our findings suggest that diabetes should be included when estimating the burden of disease due to transportation noise. https://doi.org/10.1289/EHP9146.

Background: Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. Objective: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. Methods: Within the Generation R Study, a population-based cohort in Netherlands (n=776), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at 25 weeks of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18–25 and >25 weeks of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation. Results: The average EFW at 18–25 wk and >25wk was 369 and 1,626g, respectively, and the average birth weight was 3,451g. Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18–25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2–Q4) had 26g [95% confidence intervals (CI):−38, −13], 35g (95% CI: −55, −15), and 27g (95% CI: −54, 1) lower EFW compared with those in the first quartile (Q1). A similar dose–response pattern was observed at >25wk, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1–Q2 or Q1–Q3. However, fetuses in Q4 had 91g (95% CI: −258, 76) lower birth weight in comparison with those in Q1. Results observed at 18–25 and >25wk were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference. Discussion: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178

Background: Residential moves (displacement) owing to climate- and weather-related disasters may significantly impact mental health. Despite the growing risk from climate change, health impacts of environmental-mobility remain understudied. Objectives: We assessed the effects of displacement on the association between landslides and changes in perceived mental well-being in Banjarnegara, Indonesia. We also investigated whether sociodemographics (age, sex, level of education, household-level income, or employment in agriculture) and landslide characteristics (number and severity of landslides) were associated with differing odds of relocation after experiencing landslides. Methods: In this cross-sectional study, we surveyed 420 individuals who experienced landslides between 2014 and 2018 to assess perceived changes in mental well-being, comparing after landslide exposure to before landslide exposure. We used a novel six-item measure that was created in collaboration with the local community to compare perceived changes between those who were displaced by landslides and those who were not displaced, using logistic and multinomial regressions adjusted for sociodemographic characteristics. We then assessed whether the odds of displacement differed based on sociodemographic characteristics and landslide exposure characteristics, using logistic regressions. Results: Those who were displaced were more likely than those who were not displaced to report perceived increases in economic stability [odds ratio (OR)=3.06; 95% confidence interval (CI): 1.45, 6.46], optimism (OR=4.01; 95% CI: 1.87, 8.61), safety (OR=2.71; 95% CI: 1.44, 5.10), religiosity (OR=1.92; 95% CI: 1.03, 3.65), and closeness with community (OR=1.90; 95% CI: 1.10, 3.33) after landslides compared with before their first landslide during the study period. More frequent landslide exposures were associated with reduced odds of relocation, but more severe landslides were associated with increased odds of relocation. Discussion: These findings suggest that landslides affect the mental well-being not only of those who are displaced but also of those who are left behind. Further, this work supports the need for community-based participatory research to fully capture the health impacts of environmental mobility. https://doi.org/10.1289/EHP9391

Emerging evidence links ambient air pollution with coronavirus 2019 (COVID-19) disease, an association that is methodologically challenging to investigate.We examined the association between long-term exposure to air pollution with SARS-CoV-2 infection measured through antibody response, level of antibody response among those infected, and COVID-19 disease.We contacted 9,605 adult participants from a population-based cohort study in Catalonia between June and November 2020; most participants were between 40 and 65 years of age. We drew blood samples from 4,103 participants and measured immunoglobulin M (IgM), IgA, and IgG antibodies against five viral target antigens to establish infection to the virus and levels of antibody response among those infected. We defined COVID-19 disease using self-reported hospital admission, prior positive diagnostic test, or more than three self-reported COVID-19 symptoms after contact with a COVID-19 case. We estimated prepandemic (2018-2019) exposure to fine particulate matter [PM with an aerodynamic diameter ofAmong those tested for SARS-CoV-2 antibodies, 743 (18.1%) were seropositive. Air pollution levels were not statistically significantly associated with SARS-CoV-2 infection: Adjusted RRs per interquartile range were 1.07 (95% CI: 0.97, 1.18) forExposure to air pollution was associated with a higher risk of COVID-19 disease and level of antibody response among infected but not with SARS-CoV-2 infection. https://doi.org/10.1289/EHP9726.

The 2030 Sustainable Development Goals (SDGs) set an ambitious new benchmark for safely managed drinking water services (SMDWs), but many countries lack national data on the availability and quality of drinking water.We quantified the availability and microbiological quality of drinking water, monitored SMDWs, and examined risk factors forA new water quality module for household surveys was implemented in 27 Multiple Indicator Cluster Surveys. Teams used portable equipment to measureCross-sectional water quality data can be collected in household surveys and can be used to assess inequalities in service levels, to track the SDG indicator of SMDWs, and to examine risk factors for contamination. There is an urgent need for better risk management to reduce widespread exposure to fecal contamination through drinking water services in LMICs. https://doi.org/10.1289/EHP8459.

The COVID-19 pandemic continues to influence every aspect of human life across the globe. It was reported that vascular angiogenesis of COVID-19 was elevated in patients with equally severe influenza virus infection. In this issue of AJNMMI, Farolfi et al. reported that there was lung uptake not related to prostate cancer in almost all COVID-19 patients who performed (68)Ga-PSMA-11 PET/CT scans and most of the lung uptake lesions were matched with typical CT patterns of COVID-19. With the advantages of having various tracers for whole-body imaging, PET provides opportunities to study the mechanism of COVID-19 from different aspects and obtain patterns of extrapulmonary lesions in COVID-19, which helps explore more effective treatments for the patients. This case series opened the door to many future studies. Furthermore, such a multi-national/multi-institutional collaboration in the pandemic truly encouraged us that science is indeed without borders.

This perspective briefly reviewed the applications of (18)F-FDG PET/CT in the clinical management of lymphoma and the need for lesion segmentation in those applications. It discussed the limitations of existing segmentation technologies and the great potential of using deep learning convolutional neural network (DLCNN) to accomplish automatic lymphoma segmentation and characterizations. Finally, the authors shared perspectives on the technical challenges that need to be addressed to fully unleash the potential of DLCNN and (18)F-FDG PET/CT in the diagnosis, prognosis, and treatment of lymphoma.

Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States.We evaluated the association between time-varying, 10-y average fine particulate matter (Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-basedWe report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y averageIn this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to

The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations.We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care.Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795.

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Oil and natural gas extraction may produce environmental pollution at levels that affect reproductive health of nearby populations. Available studies have primarily focused on unconventional gas drilling and have not accounted for local population changes that can coincide with drilling activity.Our study sought to examine associations between residential proximity to oil and gas drilling and adverse term birth outcomes using a difference-in-differences study design.We created a retrospective population-based term birth cohort in Texas between 1996 and 2009 composed of mother-infant dyads (The adjusted mean difference in term birth weight for mothers living 0-1 vs.Residing near oil and gas drilling sites during pregnancy was associated with a small reduction in term birth weight but not SGA, with some evidence of environmental injustices. Additional work is needed to investigate specific drilling-related exposures that might explain these associations. https://doi.org/10.1289/EHP7678.

Background: Thousands of per- and polyfluoroalkyl substances (PFAS) with diverse structures have been detected in the ambient environment. Apart from a few well-studied PFAS, the structure-related toxicokinetics of a broader set of PFAS remain unclear. Objectives: To understand the toxicokinetics of PFAS, we attempted to characterize the metabolism pathways of 74 structurally diverse PFAS samples from the U.S. Environmental Protection Agency’s PFAS screening library. Methods: Using the early life stages of zebrafish (Danio rerio) as a model, we determined the bioconcentration factors and phenotypic toxicities of 74 PFAS. Then, we applied high-resolution mass spectrometry–based nontargeted analysis to identify metabolites of PFAS in zebrafish larvae after 5 d of exposure by incorporating retention time and mass spectra. In vitro enzymatic activity experiments with human recombinant liver carboxylesterase (hCES1) were employed to validate the structure-related hydrolysis of 11 selected PFAS. Results: Our findings identified five structural categories of PFAS prone to metabolism. The metabolism pathways of PFAS were highly related to their structures as exemplified by fluorotelomer alcohols that the predominance of β-oxidation or taurine conjugation pathways were primarily determined by the number of hydrocarbons. Hydrolysis was identified as a major metabolism pathway for diverse PFAS, and perfluoroalkyl carboxamides showed the highest in vivo hydrolysis rates, followed by carboxyesters and sulfonamides. The hydrolysis of PFAS was verified with recombinant hCES1, with strong substrate preferences toward perfluoroalkyl carboxamides. Conclusions: We suggest that the roadmap of the structure-related metabolism pathways of PFAS established in this study would provide a starting point to inform the potential health risks of other PFAS. https://doi.org/10.1289/EHP7169

Background: Both human health and the health systems we depend on are increasingly threatened by a range of environmental crises, including climate change. Paradoxically, health care provision is a significant driver of environmental pollution, with surgical and anesthetic services among the most resource-intensive components of the health system. Objectives: This analysis aimed to summarize the state of life cycle assessment (LCA) practice as applied to surgical and anesthetic care via review of extant literature assessing environmental impacts of related services, procedures, equipment, and pharmaceuticals. Methods: A state-of-the-science review was undertaken following a registered protocol and a standardized, LCA-specific reporting framework. Three bibliographic databases (Scopus®, PubMed, and Embase®) and the gray literature were searched. Inclusion criteria were applied, eligible entries critically appraised, and key methodological data and results extracted. Results: From 1,316 identified records, 44 studies were eligible for inclusion. The annual climate impact of operating surgical suites ranged between 3,200,000 and 5,200,000 kg CO2e. The climate impact of individual surgical procedures varied considerably, with estimates ranging from 6 to 1,007 kg CO2e. Anesthetic gases; single-use equipment; and heating, ventilation, and air conditioning system operation were the main emissions hot spots identified among operating room- and procedure-specific analyses. Single-use equipment used in surgical settings was generally more harmful than equivalent reusable items across a range of environmental parameters. Life cycle inventories have been assembled and associated climate impacts calculated for three anesthetic gases (2–85 kg CO2e/MAC-h) and 20 injectable anesthetic drugs (0.01–3.0 kg CO2e/gAPI). Discussion: Despite the recent proliferation of surgical and anesthesiology-related LCAs, extant studies address a miniscule fraction of the numerous services, procedures, and products available today. Methodological heterogeneity, external validity, and a lack of background life cycle inventory data related to many essential surgical and anesthetic inputs are key limitations of the current evidence base. This review provides an indication of the spectrum of environmental impacts associated with surgical and anesthetic care at various scales. https://doi.org/10.1289/EHP8666

Many of society's systemic implicit biases against older persons predate COVID-19. A perfect storm of these biases now rages against older persons much more explicitly and visibly during the COVID-19 pandemic. They comprise of blends of discrimination based on age ("ageism"), multiplied by the prejudice against persons with mental symptoms (mentalism), and by notions against persons with disabilities (ableism). The collective result of this tragedy has caused a devastating impact on older persons' lives and flagrant violation of their human rights. We explore the evidence to better understand the drivers of these biases and ways to mitigate their impact. We also review strategies to alleviate the effects of ageism, mentalism, and ableism using a prevention model.

Background: In utero exposure to heavy metals lead (Pb), mercury (Hg), and cadmium (Cd) may be associated with higher childhood blood pressure (BP), whereas trace elements selenium (Se) and manganese (Mn) may have protective antioxidant effects that modify metal-BP associations. Objectives: We examined the individual and joint effects of in utero exposure to Pb, Hg, Cd, Se, and Mn on childhood BP. Methods: We used data from the Boston Birth Cohort (enrolled 2002–2013). We measured heavy metals and trace elements in maternal red blood cells collected 24–72 h after delivery. We calculated child BP percentile per the 2017 American Academy of Pediatrics Clinical Practice Guideline. We used linear regression models to estimate the association of each metal, and Bayesian kernel machine regression (BKMR) to examine metal coexposures, with child BP between 3 to 15 years of age. Results: Our analytic sample comprised 1,194 mother-infant pairs (61% non-Hispanic Black, 20% Hispanic). Hg and Pb were not associated with child systolic BP (SBP). Se and Mn were inversely associated with child SBP percentiles, which, on average, were 6.23 points lower with a doubling of Se (95% CI: −11.51, −0.96) and 2.62 points lower with a doubling of Mn (95% CI: −5.20, −0.04). BKMR models showed similar results. Although Cd was not associated with child SBP overall, the inverse association between Mn and child SBP was stronger at higher levels of Cd (p-interaction=0.04). Consistent with this finding, in utero exposure to cigarette smoke modified the Mn–child SBP association. Among children whose mothers smoked during pregnancy, a doubling of Mn was associated with a 10.09-point reduction in SBP percentile (95% CI: −18.03, −2.15), compared with a 1.49-point reduction (95% CI: −4.21, 1.24) in children whose mothers did not smoke during pregnancy (p-interaction=0.08). Conclusion: Se and Mn concentrations in maternal red blood cells collected 24–72 h after delivery were associated with lower child SBP at 3 to 15 years of age. There was an interaction between Mn and Cd on child SBP, whereby the protective association of Mn on child SBP was stronger among mothers who had higher Cd. The association of Mn and child SBP was also modified by maternal cigarette smoking—a source of Cd—during pregnancy. Optimizing in utero Se levels, as well as Mn levels in women who had high Cd or smoked during pregnancy, may protect offspring from developing high BP during childhood. https://doi.org/10.1289/EHP8325

Coronavirus disease 2019 (COVID-19) is characterized by a gender disparity in severity, with men exhibiting higher hospitalization and mortality rates than women. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, infects cells following recognition and attachment of the viral spike glycoprotein to the angiotensin-converting enzyme 2 transmembrane protein, followed by spike protein cleavage and activation by cell surface transmembrane protease serine 2 (TMPRSS2). In prostate cancer cells, androgen acting on the androgen receptor increases TMPRSS2 expression, which has led to the hypothesis that androgen-dependent expression of TMPRSS2 in the lung may increase men’s susceptibility to severe COVID-19 and that, accordingly, suppressing androgen production or action may mitigate COVID-19 severity by reducing SARS-CoV-2 amplification. Several ongoing clinical trials are testing the ability of androgen deprivation therapies or anti-androgens to mitigate COVID-19. This perspective discusses clinical and molecular advances on the rapidly evolving field of androgen receptor (AR) action on cell surface transmembrane protease serine 2 (TMPRSS2) expression and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of anti-androgens on coronavirus disease 2019 (COVID-19) severity in male patients. It discusses limitations of current studies and offers insight for future directions.

BACKGROUND: Glyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood. OBJECTIVES: We examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case-control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico. METHODS: GLY and AMPA in urine samples collected at 18±2 (Visit 1) and 26±2 (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor originating from endothelial cells. Since ultrasound findings of EHE are nonspecific, computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used for diagnosing the disease. Accumulating evidence indicates that (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has implemental value in diagnosing EHE. In this Perspective, we outline the most recent evidence reporting the diagnostic value of (18)F-FDG PET/CT in EHE. The combinational use of CT, MRI, and (18)F-FDG PET/CT may help clinicians diagnose the disease in its earlier stages.

The epidemiological literature of associations between atmospheric pollutant exposure and breast cancer incidence has recently strongly evolved.We aimed to performWe conducted a literature review and random-effects meta-analyses of epidemiological studies examining the association of fine particulate matter with aerodynamic diameter less than or equal toThe review identified 32, 27, and 36 effect estimates forThese findings suggest that decreasing long-term

Cervical carcinoma is the second most common cause of cancer deaths in women worldwide. Treatments have not changed for decades and survival rates for advanced disease remain low. An exciting new molecular target for the treatment of cervical squamous cell carcinoma (SCC), and possibly for SCCs at other anatomical sites, is the oncostatin M receptor (OSMR). This cell surface cytokine receptor is commonly copy number gained and overexpressed in advanced cervical SCC, changes that are associated with significantly worse clinical outcomes. OSMR overexpression in cervical SCC cells results in enhanced responsiveness to the major ligand oncostatin M (OSM), which induces several pro-malignant effects, including a pro-angiogenic phenotype and increased cell migration and invasiveness. OSMR is a strong candidate for antibody-mediated inhibition, a strategy that has had a major impact on haematological malignancies and various solid tumours such as HER2-positive breast cancers. © 2013 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Polymerases ϵ and δ are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through Watson–Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations (EDMs) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma (CRC). POLD1 mutations also predispose to endometrial cancer (EC). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading-associated polyposis (PPAP). Somatic POLE EDMs have also been found in sporadic CRCs and ECs, although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an ‘ultramutated’, apparently microsatellite-stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Graphical abstract, The development of diabetic vascular complications is initiated, at least in part, by mitochondrial reactive oxygen species (ROS) production in endothelial cells. Hyperglycemia induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction. Hydrogen sulfide (H2S) supplementation has been shown to reduce the mitochondrial oxidant production and shows efficacy against diabetic vascular damage in vivo. However, the half-life of H2S is very short and it is not specific for the mitochondria. We have therefore evaluated two novel mitochondria-targeted anethole dithiolethione and hydroxythiobenzamide H2S donors (AP39 and AP123 respectively) at preventing hyperglycemia-induced oxidative stress and metabolic changes in microvascular endothelial cells in vitro. Hyperglycemia (HG) induced significant increase in the activity of the citric acid cycle and led to elevated mitochondrial membrane potential. Mitochondrial oxidant production was increased and the mitochondrial electron transport decreased in hyperglycemic cells. AP39 and AP123 (30–300 nM) decreased HG-induced hyperpolarisation of the mitochondrial membrane and inhibited the mitochondrial oxidant production. Both H2S donors (30–300 nM) increased the electron transport at respiratory complex III and improved the cellular metabolism. Targeting H2S to mitochondria retained the cytoprotective effect of H2S against glucose-induced damage in endothelial cells suggesting that the molecular target of H2S action is within the mitochondria. Mitochondrial targeting of H2S also induced >1000-fold increase in the potency of H2S against hyperglycemia-induced injury. The high potency and long-lasting effect elicited by these H2S donors strongly suggests that these compounds could be useful against diabetic vascular complications.

Graphical abstract, Prostate cancer remains one of the leading causes of cancer death in men around the world, regardless of intense research and development of novel therapies in the last 10 years. One of the new avenues that has been tested ⿿ inhibition of angiogenesis ⿿ has been disappointing so far in clinical studies in spite of strong evidence that determinants of angiogenesis (e.g. vascular endothelial growth factor) are strongly associated with disease progression. One of the reasons for these outcomes may be our poor understanding of the biology of angiogenesis in prostate cancer (and probably other cancers as well) resulting in inhibition of both detrimental and favourable molecules. We discuss here novel targeted and more specific approaches to inhibit angiogenesis in prostate cancer as well as a completely new therapeutic modality to do this ⿿ modulation of alternative splicing ⿿ that may be applicable to other molecules/biological processes as well.

Graphical abstract Tumor-infiltrang immune cells such as metastasis-associated macrophages (MAM), regulatory T (Tregreg) cells, and myeloid-derived suppressor cells (MDSC) are reported to promote establishment of the lethal metasta-c foci and restrict efficacy of cytotoxic drugs or tumoricidal immune responses by natural killer (NK) and CD8+ T cells. Recent studies suggest that these pro-tumor immune cells are accumulated a chemokine network established in the tumor microenvironment. Therefore, blockade of these chemokine signals could improve therapeu-c efficacy of chemotherapy and immunotherapy., Metastatic breast cancer is incurable by current therapies including chemotherapy and immunotherapy. Accumulating evidence indicates that tumor-infiltrating macrophages promote establishment of the lethal metastatic foci and contribute to therapeutic resistance. Recent studies suggest that the accumulation of these macrophages is regulated by a chemokine network established in the tumor microenvironment. In this perspective paper, we elaborate on the chemokine signals that can attract monocytes/macrophages to the site of metastasis, and discuss whether inhibition of these chemokine signals can represent a new therapeutic strategy for metastatic breast cancer.

Hybrid scanners such as PET/CT have in the past emerged as a valuable modality in clinical routine as well as an important research tool. Recently, the newly developed fully integrated PET/MR scanners were introduced to the market, raising high expectations especially due to the excellent soft tissue contrast and functional imaging capabilities of MRI. In this issue of the American Journal of Nuclear Medicine and Molecular Imaging, initial experiences using a hybrid PET/MR scanner for carotid artery imaging in a group of patients with increased risk for atherosclerosis are described. This represents a proof-of-principle study, which could stimulate future applications of this powerful modality in atherosclerotic plaque imaging.

Positron Emission Tomography (PET) has become a popular imaging technique widely used for diagnostic purposes. To date, much attention has been devoted to (18)F-fluoride because of the characteristics of its nuclear decay, as well as its relative ease of preparation from (18)O-water. However, with a half-life of 110 minutes, swift and efficient incorporation of (18)F-fluorine into biomolecules is necessary to minimize loss of activity. Therefore, the discovery of rapid and reliable incorporation of (18)F-fluorine atoms into biomolecules would be highly beneficial, especially if these protocols can be carried out directly in irradiated 18O-water. In the study published in the American Journal of Nuclear Medicine and Molecular Imaging, cyclo-RGD-(18)F-aryltrifluoroborate conjugates were prepared based on one-step and one-pot-two-step methods. This paper represents recent efforts on the design and development of novel PET tracers based on the "Kit like" (18)F labeling method.

Unprecedented progress has been made in genomic personalized medicine in the last several years, allowing for more individualized healthcare assessments and recommendations than ever before. However, most of this progress in prostate cancer (PCa) care has focused on developing and selecting therapies for late-stage disease. To address this issue of limited focus, we propose a model for incorporating genomic-based personalized medicine into all levels of PCa care, from prevention and screening to diagnosis, and ultimately to the treatment of both early-stage and late-stage cancers. We have termed this strategy the "Pyramid Model" of personalized cancer care. In this perspective paper, our objective is to demonstrate the potential application of the Pyramid Model to PCa care. This proactive and comprehensive personalized cancer care approach has the potential to achieve three important medical goals: reducing mortality, improving quality of life and decreasing both individual and societal healthcare costs.

Dual isotope single photon emission computed tomography (SPECT) and dual tracer positron emission tomography (PET) imaging have great potential in clinical and molecular applications in the pediatric as well as the adult populations in many areas of brain, cardiac, and oncologic imaging as it allows the exploration of different physiological and molecular functions (e.g., perfusion, neurotransmission, metabolism, apoptosis, angiogenesis) under the same physiological and physical conditions. This is crucial when the physiological functions studied depend on each other (e.g., perfusion and metabolism) hence requiring simultaneous assessment under identical conditions, and can reduce greatly the quantitation errors associated with physical factors that can change between acquisitions (e.g., human subject or animal motion, change in the attenuation map as a function of time) as is detailed in this editorial. The clinical potential of simultaneous dual isotope SPECT, dual tracer PET and dual SPECT/PET imaging are explored and summarized. In this issue of AJNMMI (http://www.ajnmmi.us), Chapman et al. explore the feasibility of simultaneous and sequential SPECT/PET imaging and conclude that down-scatter and crosstalk from 511 keV photons preclude obtaining useful SPECT information in the presence of PET radiotracers. They report on an alternative strategy that consists of performing sequential SPECT and PET studies in hybrid microPET/SPECT/CT scanners, now widely available for molecular imaging. They validate their approach in a phantom consisting of a 96-well plate with variable (99m)Tc and (18)F concentrations and illustrate the utility of such approaches in two sequential SPECT-PET/CT studies that include (99m)Tc-MAA/(18)F-NaF and (99m)Tc-Pentetate/(18)F-NaF. These approaches will need to be proven reproducible, accurate and robust to variations in the experimental conditions before they can be accepted by the molecular imaging community and be implemented in routine molecular microPET and microSPECT explorations. Although currently not accepted as standard procedures in the molecular imaging community, such approaches have the potential to open the way to new SPECT/PET explorations that allow studying molecular mechanisms and pathways in the living animal under similar physiological conditions. Although still premature for the clinical setting, these approaches can be extended to clinical research once proven accurate and precise in vivo in small and large animal models.

The radioiodinated thymidine analogue, FIAU, is a tracer that has been developed for reporter gene, for cells that were transfected with herpes simplex virus thymidine kinase, HSV-TK. FIAU is also a specific substrate of bacterial TK due to the homology between viral and bacterial TK. In this issue of AJNMMI (http://www.ajnmmi.us), Pullamb-hatla et al. reported that the accumulation of (125)I-FIAU in pulmonary infectious foci correlated with the bacterial burden in the lungs. (125)I-FIAU could be used to monitor the efficacy of anti-microbial therapy in mice. Potentially (124)I-FIAU PET could be used to discriminate microbial from sterile inflammation in patients with prosthetic implants.

Quantum dots (QDs) have many intriguing properties suitable for biomedical imaging applications. The poor tissue penetration of optical imaging in general, including those using QDs, has motivated the development of various QD-based dual-modality imaging agents. In this issue of AJNMMI (http://www.ajnmmi.us), Sun et al. reported the synthesis and in vitro/in vivo characterization of intrinsically radio-labeled QDs (r-QDs), where (109)Cd was incorporated into the core/shell of QDs of various compositions. These r-QDs emit in the near-infrared range, have long circulation half-life, are quite stable with low cytotoxicity, exhibit small size and low accumulation in the reticuloendothelial system, and can allow for accurate measurement of their biodistribution in mice. With these desirable features demonstrated in this study, future development and optimization will further enhance the biomedical potential of intrinsically radio-labeled QDs.

Metabotropic glutamate receptors (mGluRs) belong to a family of G-protein coupled receptors involved in the modulation of fast excitatory transmission. In particular, the subtype-5 receptor (mGluR5) was found to be an attractive target for the treatment and diagnosis of variety of psychiatric and neurological disease including anxiety, depression, epilepsy, drug addiction, and Parkinson's disease. Positron emission tomography (PET) is a highly sensitive imaging technique that holds great potential for the diagnosis of a brain disorder. In the study published in the American Journal of Nuclear Medicine and Molecular Imaging, a (18)F labelled PET probe was developed targeting mGluR5. This paper represents the efforts and challenges on the design and development of novel PET tracers for mGluR5 imaging.

Non-invasive and quantitative imaging of tumor angiogenesis is essential for lesion detection, patient stratification, drug development, and personalized anti-cancer therapies. In particular, the right timing is critical for anti-angiogenic cancer therapy and non-invasive imaging can help determine whether to start and when to start such treatment. In this inaugural issue of the American Journal of Nuclear Medicine and Molecular Imaging, a peptoid-based positron emission tomography (PET) tracer was reported for imaging of VEGFR expression in a prostate cancer model. This important proof-of-principle study opened the door to a fertile area of research, which holds tremendous potential for various applications in future personalized medicine.

Utilizing novel imaging modalities for defining response and predicting long-term outcome after treatment may have a significant impact on cancer patient management. (18)F-FDG PET/CT has great potential for use in early assessment of response to cancer therapy. However, the lack of a general consensus on a specific set of response criteria makes adoption of PET difficult for the oncology community. The optimal time after initiating therapy for assessing response to treatment also has yet to be clearly determined.