Peripubertal exposure to oxyfluorfen, a diphenyl herbicide, delays pubertal development in the male rat by antagonizing androgen receptor activity.

We recently identified the herbicide oxyfluorfen as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), a key step in thyroid hormone synthesis, using in vitro assays. We also observed a suppression of serum T4 and T3 in juvenile rats exposed orally to oxyfluorfen for 4-8 days. The purpose of the present study was to further evaluate effects of an extended 31-day oral exposure using a male pubertal rat study (15 to 500 mg/kg). Oxyfluorfen delayed puberty at all doses (1.3 -3.5 days) suppressing ventral prostate at 62.5 mg/kg and above and seminal vesicle weights at 31.25 mg/kg and above with no effect on testosterone or luteinizing hormone. Serum T4 and T3 were suppressed by all doses up to 80%, with a linear increase in serum TSH. Based on delayed puberty without changes in testosterone, we hypothesized that oxyfluorfen interferes with androgen receptor (AR) function. Results from our Hershberger study, with oxyfluorfen (62.5 and 125 mg/kg) co-treated with testosterone proprionate (TP , 1 mg/kg) for 10 days showed 3 of 5 of the androgenic tissue weights were suppressed compared to TP alone indicating AR antagonism. We next confirmed this effect in an in vitro AR transcriptional activation reporter assay (0-20 µM) with 125 pM 5αDH-11-ketotestosterone and found concentration-dependent inhibition of AR luminescence activity (EC50 1.75 µM) without cytotoxicity. Here, we confirmed the endocrine disrupting effects of oxyfluorfen using both in vitro and in vivo evaluations of the thyroid hormone and AR pathways. This abstract doesn't necessarily reflect U.S. EPA policy.

Opting out of the Quality and Outcomes Framework (QOF) and impact on practices' performance.

Background: Financial incentives are being increasingly adopted to help improve standards of care within general practice. However their effects on care quality are unclear. This study aimed to evaluate the impact of practices opting out of the Quality and Outcomes Framework (QOF), a financial incentive scheme in UK general practice. Study design: A retrospective before and after study of all practices in Tower Hamlets, east London. Methods: Practices were given an option by local commissioners of opting out of QOF without a financial penalty and instead opting for a locally designed financial incentive scheme that promoted more holistic care. We compared those practices which opted out of QOF to those which continued. We used national, publicly available QOF achievement data from 2016/17 and 2017/18. We undertook a sub-analysis of 16 QOF indicators to better understand the impact of the intervention. Results: Of the 36 practices in Tower Hamlets, 7 decided to continue with QOF and 29 opted out. The intervention resulted in a small but statistically significant reduction in the total QOF achievement scores of practices which opted out of QOF. The sub-analysis of 16 QOF indicators showed statistically significant reductions in most of achievement scores net of exceptions for the practices that opted out. The differences in performance between the two cohorts of practices became smaller when exceptions were included. Conclusions: The removal of QOF financial incentives can result in a reduction in achievement of QOF-related indicators but the size of the effect seems to depend on the QOF exception rates. An alternative incentive scheme that promotes a more holistic approach to care seems to be welcomed by general practices.

Social needs screening in primary care: A tool in the fight for health equity?

Progress on addressing health inequalities is slow and in many places around the world the gap between the privileged and the disadvantaged is widening. This is driven largely by an unfair and unequal distribution of the social determinants of health. While upstream policy and agenda commitment is needed to improve social determinants of health at a population level, healthcare also has a role. Currently social information is sporadically collected and used in healthcare. Improving our understanding of social problems is crucial in targeting services and to reduce the overreliance on area-level measures of deprivation. This has the potential to improve patient care as well as more accurately capture socio-economic disadvantage. Here we argue that there is a role for primary care in screening for social needs to help address inequalities. Social needs screening, more commonly used in North America than Europe, aims to systematically collect social information in health and care settings. Healthcare professionals ask patients about social issues including employment, finances, housing, education and social isolation and this information is used to prompt referral to community services to address any need identified. Social needs screening has potential to address negative impacts of social determinants of health at an individual and population level. Providing a reliable measure of social need, screening gives healthcare professionals an opportunity to tailor and improve quality of care for patients and offer individualised support. It has been shown to improve individual social and health outcomes and positively impact healthcare utilisation. At a population level, social needs screening can improve the data on social determinants of health and therefore support policy makers and service delivery leaders to target resources and services more effectively to the communities most in need. Implementing social needs screening must take account of local healthcare service capacity and available community resources but where sustainable, effective programmes can be introduced, the potential benefits are manifold. While primary care alone cannot solve the root causes of health inequalities, we argue it could be a powerful actor in the fight for health equity.

Evaluation of the diphenyl herbicide, oxyfluorfen, for effects on thyroid hormones in the juvenile rat.

Recently, oxyfluorfen, a pre- and post-emergent diphenyl ether herbicide, was identified in our laboratory as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), the first key step in the synthesis of thyroid hormones (THs). This inhibition was observed in vitro, using both a human NIS engineered cell line (hNIS-HEK293T-EPA) and a rat thyroid follicular cell line (FRTL-5). Oxyfluorfen was found to be a potent inhibitor of NIS activity with an EC50 of approximately 2 µM in both cell lines with no observed cytotoxicity at any concentration tested up to 100 µM. The current research tested the hypothesis that oxyfluorfen alters circulating concentrations of THs. This hypothesis was first tested in a pilot study with both juvenile male and female rats exposed to oxyfluorfen for 4 days at 0, 125, 250 and 500 mg/kg/day. Once we identified that this short-term 4-day oxyfluorfen exposure suppressed both total serum thyroxine (T4) and triiodothyronine (T3) at all doses, we tested seven lower concentrations of oxyfluorfen (0.8125 to 62.5 mg/kg day) in an 8-day exposure paradigm to more closely evaluate the dose-response. We found that oxyfluorfen suppressed serum T4 with a LOEL of 3.25 mg/kg/day and T3 with a LOEL 62.5 mg/kg/day. Analytical chemistry of the serum showed an accumulation over time following oral exposure to oxyfluorfen in both the 4- and 8-day groups. Analytical chemistry of the thyroid glands in the 8-day study revealed higher accumulation in the thyroid as compared to the serum (2 to 3- fold at 62.5 mg/kg). No changes in thyroid weight or serum TSH were observed following the 8-day exposure. This study is the first to demonstrate an effect of oxyfluorfen on serum thyroid hormones in the rat. Additional studies are needed to further evaluate the effects on thyroid homeostasis with extended exposures and the potential implications of the observed effects.

Mediating pathways that link adverse childhood experiences with cardiovascular disease.

OBJECTIVES: There is uncertainty about which factors mediate the association between adverse childhood experiences (ACEs) and cardiovascular disease (CVD). This could inform secondary prevention targets. STUDY DESIGN: Mediation analysis of a prospective cohort study. METHODS: English Longitudinal Study of Ageing (ELSA) wave 3 data (2006/7) were used to measure retrospective exposure to 12 individual ACEs and waves 2 to 4 (2004/5 to 2008/9) data to measure current exposure to potential mediators [smoking, physical activity, alcohol consumption, body mass index, depression, and C-reactive protein (CRP)]. Waves 4 to 9 ELSA data (2008/9 to 2018/19) were used to measure incident CVD. Cumulative ACE exposure was categorised into experiencing 0, 1 to 3, or ≥4 individual ACEs. Associations were tested between ACE categories, potential mediators, and incident CVD, to inform which variables were analysed in causal mediation models. RESULTS: The analytical cohort consisted of 4547 participants (56% women), with a mean age of 64 years (standard deviation = 9 years). At least one ACE had been experienced by 45% of the cohort, and 24% developed incident CVD over a median follow-up period of 9.7 years (interquartile range: 5.3-11.4 years). After adjusting for potential confounders, experiencing ≥4 ACEs compared with none was associated with incident CVD [odds ratio (OR): 1.55; 95% confidence interval (CI): 1.10, 2.17], and the association of one to three ACEs compared with none was non-significant (OR: 1.08; 95% CI: 0.93, 1.24). There were two statistically significant mediators of the association between ≥4 ACEs and incident CVD: CRP and depression, which accounted for 10.7% and 10.8% of the association, respectively. CONCLUSIONS: Inflammation and depression partially mediated the association between ACEs and CVD. Targeting these factors may reduce the future incidence of CVD.

Identifying canonical and replicable multi-scale intrinsic connectivity networks in 100k+ resting-state fMRI datasets.

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

Macroevolutionary constraints on global microbial diversity.

Biologists have long sought to quantify the number of species on Earth. Often missing from these efforts is the contribution of microorganisms, the smallest but most abundant form of life on the planet. Despite recent large-scale sampling efforts, estimates of global microbial diversity span many orders of magnitude. It is important to consider how speciation and extinction over the last 4 billion years constrain inventories of biodiversity. We parameterized macroevolutionary models based on birth-death processes that assume constant and universal speciation and extinction rates. The models reveal that richness beyond 1012 species is feasible and in agreement with empirical predictions. Additional simulations suggest that mass extinction events do not place hard limits on modern-day microbial diversity. Together, our study provides independent support for a massive global-scale microbiome while shedding light on the upper limits of life on Earth.

Evaluation of the national governmental efforts between 1997 and 2010 in reducing health inequalities in England.

OBJECTIVES: The pandemic has compounded existing inequalities. In the UK, there have been calls for a new cross-government health inequalities strategy. This study aims to evaluate the effectiveness of national governmental efforts between 1997 and 2010, referred to as the National Health Inequalities Strategy (NHIS). STUDY DESIGN: population-based observational study. METHODS: Using Global Burden of Disease data, age-standardised years of life lost due to premature mortality (YLL) rates per 10,000 were extracted for 150 Upper Tier Local Authority (UTLA) regions in England for every year between 1990 and 2019. The slope index of inequality was calculated using YLL rates for all causes, individual conditions, and risk factors. Joinpoint regression was used to assess the trends of any changes which arose before, during or after the NHIS. RESULTS: Absolute inequalities in YLL rates for all causes remained stable between 1990 and 2000, before decreasing over the following 10 years. After 2010, improvements slowed. A similar trend can be observed amongst inequalities in YLLs for individual causes, including ischaemic heart disease, stroke, breast cancer and lung cancer amongst females, and ischaemic heart disease stroke, diabetes and self-harm amongst males. This trend was also observed amongst certain risk factors, notably blood pressure, cholesterol, tobacco and dietary risks. Inequalities were generally greater in males than in females; however, trends were similar across both sexes. The NHIS coincided with significant reductions in inequalities in YLLs due to ischaemic heart disease and lung cancer. CONCLUSIONS: The findings suggest that the NHIS coincided with a reduction in health inequalities in England. Policy makers should consider a new cross-government strategy to tackle health inequalities drawing from the success of the previous NHIS.

Phthalates impact on the epigenetic factors contributed specifically by the father at fertilization.

BACKGROUND: Preconception exposure to phthalates such as the anti-androgenic dibutyl-phthalate (DBP) impacts both male and female reproduction, yet how this occurs largely remains unknown. Previously we defined a series of RNAs expressly provided by sperm at fertilization and separately, and in parallel, those that responded to high DBP exposure. Utilizing both populations of RNAs, we now begin to unravel the impact of high-DBP exposure on those RNAs specifically delivered by the father. RESULTS: Enrichment of RNAs altered by DBP exposure within the Molecular Signature Database highlighted cellular stress, cell cycle, apoptosis, DNA damage response, and gene regulation pathways. Overlap within each of these five pathways identified those RNAs that were specifically (≥ fivefold enriched) or primarily (≥ twofold enriched) provided as part of the paternal contribution compared to the oocyte at fertilization. Key RNAs consistently altered by DBP, including CAMTA2 and PSME4, were delivered by sperm reflective of these pathways. The majority (64/103) of overlapping enriched gene sets were related to gene regulation. Many of these RNAs (45 RNAs) corresponded to key interconnected CRREWs (Chromatin remodeler cofactors, RNA interactors, Readers, Erasers, and Writers). Modeling suggests that CUL2, PHF10, and SMARCC1 may coordinate and mechanistically modulate the phthalate response. CONCLUSIONS: Mediated through a CRREW regulatory network, the cell responded to exposure presenting stressed-induced changes in the cell cycle-DNA damage-apoptosis. Interestingly, the majority of these DBP-responsive epigenetic mediators' direct acetylation or deacetylation, impacting the sperm's cargo delivered at fertilization and that of the embryo.

A method for estimating and characterizing explicitly nonlinear dynamic functional network connectivity in resting-state fMRI data.

The past 10 years have seen an explosion of approaches that focus on the study of time-resolved change in functional connectivity (FC). FC characterization among networks at a whole-brain level is frequently termed functional network connectivity (FNC). Time-resolved or dynamic functional network connectivity (dFNC) focuses on the estimation of transient, recurring, whole-brain patterns of FNC. While most approaches in this area have attempted to capture dynamic linear correlation, we are particularly interested in whether explicitly nonlinear relationships, above and beyond linear, are present and contain unique information. This study thus proposes an approach to assess explicitly nonlinear dynamic functional network connectivity (EN dFNC) derived from the relationship among independent component analysis time courses. Linear relationships were removed at each time point to evaluate, typically ignored, explicitly nonlinear dFNC using normalized mutual information (NMI). Simulations showed the proposed method estimated explicitly nonlinearity over time, even within relatively short windows of data. We then, applied our approach on 151 schizophrenia patients, and 163 healthy controls fMRI data and found three unique, highly structured, mostly long-range, functional states that also showed significant group differences. In particular, explicitly nonlinear relationships tend to be more widespread than linear ones. Results also highlighted a state with long range connections to the visual domain, which were significantly reduced in schizophrenia. Overall, this work suggests that quantifying EN dFNC may provide a complementary and potentially valuable tool for studying brain function by exposing relevant variation that is typically ignored.

Clinical Evaluation of Scout Accelerated Motion Estimation and Reduction Technique for 3D MR Imaging in the Inpatient and Emergency Department Settings.

BACKGROUND AND PURPOSE: A scout accelerated motion estimation and reduction (SAMER) framework has been developed for efficient retrospective motion correction. The goal of this study was to perform an initial evaluation of SAMER in a series of clinical brain MR imaging examinations. MATERIALS AND METHODS: Ninety-seven patients who underwent MR imaging in the inpatient and emergency department settings were included in the study. SAMER motion correction was retrospectively applied to an accelerated T1-weighted MPRAGE sequence that was included in brain MR imaging examinations performed with and without contrast. Two blinded neuroradiologists graded images with and without SAMER motion correction on a 5-tier motion severity scale (none = 1, minimal = 2, mild = 3, moderate = 4, severe = 5). RESULTS: The median SAMER reconstruction time was 1 minute 47 seconds. SAMER motion correction significantly improved overall motion grades across all examinations (P < .005). Motion artifacts were reduced in 28% of cases, unchanged in 64% of cases, and increased in 8% of cases. SAMER improved motion grades in 100% of moderate motion cases and 75% of severe motion cases. Sixty-nine percent of nondiagnostic motion cases (grades 4 and 5) were considered diagnostic after SAMER motion correction. For cases with minimal or no motion, SAMER had negligible impact on the overall motion grade. For cases with mild, moderate, and severe motion, SAMER improved the motion grade by an average of 0.3 (SD, 0.5), 1.1 (SD, 0.3), and 1.1 (SD, 0.8) grades, respectively. CONCLUSIONS: SAMER improved the diagnostic image quality of clinical brain MR imaging examinations with motion artifacts. The improvement was most pronounced for cases with moderate or severe motion.

Projected decrease in trail access in the Arctic.

Transportation systems in northern Canada are highly sensitive to climate change. We project how access to semi-permanent trails on land, water, and sea ice might change this century in Inuit Nunangat (the Inuit homeland in northern Canada), using CMIP6 projections coupled with trail access models developed with community members. Overall trail access is projected to diminish, with large declines in access for sea ice trails which play a central role for Inuit livelihoods and culture; limits to adaptation in southern regions of Inuit Nunangat within the next 40 years; a lengthening of the period when no trails are accessible; and an unequal distribution of impacts according to the knowledge, skills, equipment, and risk tolerance of trail users. There are opportunities for adaptation through efforts to develop skillsets and confidence in travelling in more marginal environmental conditions, which can considerably extend the envelope of days when trails are accessible and months when this is possible. Such actions could reduce impacts across emissions scenarios but their potential effectiveness declines at higher levels of global warming, and in southern regions only delays when sea ice trails become unusable.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Allied health professionals: A promising ally in the work against health inequalities- A rapid review.

Objectives: Allied Health Professionals (AHPs) have a crucial role in reducing health inequalities. However, there is a lack of evidence regarding the ways they can fulfil this role. This rapid review explores the ways in which AHPs can decrease health care or health outcome inequalities; address inequalities in the social determinants of health; and support disadvantaged groups at an individual, organisational and system level. Study design: Rapid review following Cochrane criteria and narrative synthesis. Methods: MEDLINE, EMBASE, CINAHL, Web of Science and AMED were searched combined with grey literature, to identify quantitative or qualitative review articles published between January 2010 and February 2021. Results: From 8727 references, 36 met the inclusion criteria. The methodological quality of the studies was assessed with the AMSTAR tool and was generally low. Meta-analysis was not possible due to the heterogeneity of the studies, and a narrative synthesis was produced. Three themes emerged at patient and organisational level: 1) access to AHP services; 2) quality of care; and 3) social determinants of health. Two themes emerged at system level: 1) unequal workforce distribution and 2) lack of inclusive clinical guidelines. Conclusions: This rapid review offers a broad range of evidence on the ways AHPs can contribute to the reduction of inequalities in health care, both in terms of access and quality of care and in health outcomes. More research is needed to further understand the impact of AHPs on inequalities affecting specific groups and their contribution to equitable distribution of social determinants of health.

Moving beyond the 'CAP' of the Iceberg: Intrinsic connectivity networks in fMRI are continuously engaging and overlapping.

Resting-state functional magnetic resonance imaging is currently the mainstay of functional neuroimaging and has allowed researchers to identify intrinsic connectivity networks (aka functional networks) at different spatial scales. However, little is known about the temporal profiles of these networks and whether it is best to model them as continuous phenomena in both space and time or, rather, as a set of temporally discrete events. Both categories have been supported by series of studies with promising findings. However, a critical question is whether focusing only on time points presumed to contain isolated neural events and disregarding the rest of the data is missing important information, potentially leading to misleading conclusions. In this work, we argue that brain networks identified within the spontaneous blood oxygenation level-dependent (BOLD) signal are not limited to temporally sparse burst moments and that these event present time points (EPTs) contain valuable but incomplete information about the underlying functional patterns. We focus on the default mode and show evidence that is consistent with its continuous presence in the BOLD signal, including during the event absent time points (EATs), i.e., time points that exhibit minimum activity and are the least likely to contain an event. Moreover, our findings suggest that EPTs may not contain all the available information about their corresponding networks. We observe distinct default mode connectivity patterns obtained from all time points (AllTPs), EPTs, and EATs. We show evidence of robust relationships with schizophrenia symptoms that are both common and unique to each of the sets of time points (AllTPs, EPTs, EATs), likely related to transient patterns of connectivity. Together, these findings indicate the importance of leveraging the full temporal data in functional studies, including those using event-detection approaches.

Solution Oligonucleotide APIs: Regulatory Considerations.

Manufacture of oligonucleotide active pharmaceutical ingredients (APIs) typically consists of solid-phase synthesis, deprotection and cleavage, purification and filtration, and isolation from aqueous solutions through lyophilization. In the first step of drug product manufacture, the API is dissolved in water again and excipients are added. While isolation of oligonucleotide APIs can be meaningful in many cases, there may be cases where keeping the API in solution provides benefit, and multiple technical aspects must be taken into account and balanced when determining the appropriate API form. A significant factor is whether an API in solution will contain additional components. While APIs in solution containing additional components (so-called formulated APIs) are well established for biological products, there are regulatory guidelines in place that represent hurdles for industry to using a formulated API approach for oligonucleotide drugs. The present communication outlines conditions where a formulated API approach can be chosen in compliance with existing guidelines. Relevant aspects pertaining to risk management, GMP standards, facility design, control strategies, and regulatory submission content are discussed. In addition, the authors propose that existing guidelines be modernized to enable the use of a formulated API approach for additional reasons than the ones described in the existing regulatory framework. The manuscript aims to promote a dialog with regulators in this field.

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer's Disease and Related Research.

Neuroimaging serves a variety of purposes in Alzheimer's disease (AD) and related dementias (ADRD) research - from measuring microscale neural activity at the subcellular level, to broad topological patterns seen across macroscale-brain networks, and everything in between. In vivo imaging provides insight into the brain's structure, function, and molecular architecture across numerous scales of resolution; allowing examination of the morphological, functional, and pathological changes that occurs in patients across different AD stages (1). AD is a complex and potentially heterogenous disease, with no proven cure and no single risk factor to isolate and measure, whilst known risk factors do not fully account for the risk of developing this disease (2). Since the 1990's, technological advancements in neuroimaging have allowed us to visualise the wide organisational structure of the brain (3) and later developments led to capturing information of brain 'functionality', as well as the visualisation and measurement of the aggregation and accumulation of AD-related pathology. Thus, in vivo brain imaging has and will continue to be an instrumental tool in clinical research, mainly in the pre-clinical disease stages, aimed at elucidating the biological complex processes and interactions underpinning the onset and progression of cognitive decline and dementia. The growing societal burden of AD/ADRD means that there has never been a greater need, nor a better time, to use such powerful and sensitive tools to aid our understanding of this undoubtedly complex disease. It is by consolidating and reflecting on these imaging advancements and developing long-term strategies across different disciplines, that we can move closer to our goal of dementia prevention. This short commentary will outline recent developments in neuroimaging in the field of AD and dementia by first describing the historical context of AD classification and the introduction of AD imaging biomarkers, followed by some examples of significant recent developments in neuroimaging methods and technologies.

A global reconnaissance of particulates and metals/metalloids in untreated drinking water sources.

Metal and metalloid contamination in drinking water sources is a global concern, particularly in developing countries. This study used hollow membrane water filters and metal-capturing polyurethane foams to sample 71 drinking water sources in 22 different countries. Field sampling was performed with sampling kits prepared in the lab at Hope College in Holland, MI, USA. Filters and foams were sent back to the lab after sampling, and subsequent analysis of flushates and rinsates allowed the estimation of suspended solids and metal and other analayte concentrations in source waters. Estimated particulate concentrations were 0-92 mg/L, and consisted of quartz, feldspar, and clay, with some samples containing metal oxides or sulfide phases. As and Cu were the only analytes which occurred above the World Health Organization (WHO) guidelines of 10 µg/L and 2000 µg/L, respectively, with As exceeding the guideline in 45% of the sources and Cu in 3%. Except for one value of ~ 285 µg/L, As concentrations were 45-200 µg/L (river), 65-179 µg/L (well), and 112-178 µg/L (tap). Other metals (Ce, Fe, Mg, Mn, Zn) with no WHO guideline were also detected, with Mn the most common. This study demonstrated that filters and foams can be used for reconnaissance characterization of untreated drinking water. However, estimated metal and other analyte concentrations could only be reported as minimum values due to potential incomplete retrieval of foam-bound analytes. A qualitative reporting methodology was used to report analytes as "present" if the concentration was below the WHO guideline, and "present-recommend retesting" if the concentration was quantifiable and above the WHO guideline.

Associations among temporal and large artery abnormalities on vascular ultrasound in giant cell arteritis.

Objectives: Giant cell arteritis (GCA) can manifest in cranial and/or extracranial arteries. We investigated the distribution of affected arteries on vascular ultrasound (VUS) among patients with new-onset or prior-onset GCA.Method: We retrospectively studied patients with either new-onset or prior-onset GCA and an abnormal VUS, from 2013 to 2017. Trained vascular technologists imaged the bilateral temporal arteries and carotid, axillary, and subclavian arteries. Vascular medicine physicians interpreted the images. Vasculitis-related abnormalities in individual vessels and their distribution (temporal artery, large artery, or both) were evaluated. Phi coefficients (φ) and Fisher's exact test were used to assess correlations among individual abnormal arteries.Results: Among 66 GCA patients, 28.8% had prior-onset GCA (median duration 17.8 months). Acute arteritis on VUS was observed in the majority of patients with both new-onset (72.3%) and prior-onset GCA (68.4%); the remainder had hyperechoic wall thickening without acute arteritis. Involvement of the temporal arteries only (45.5%) or large arteries only (34.8%) was more common than involvement of both (19.7%); this finding was similar in new-onset and prior-onset GCA. There were moderate positive correlations among temporal artery branches (φ = 0.51-0.58, p < 0.003) and among axillary and subclavian arteries (φ = 0.51-0.77, p < 0.003), and moderate negative correlations between abnormalities in the temporal and large arteries (φ = -0.46 to -0.58, p < 0.003).Conclusion: On VUS, vasculitis-related abnormalities in the temporal arteries only or large arteries only were more common than concurrent temporal and large artery abnormalities in patients with both new-onset GCA and prior-onset GCA.