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Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.

Integrated population dynamics models use a variety of data types, and all the data used impact modeled processes and estimated dynamics. Paired age-length data treated as conditional age-at-length (CAAL) data are increasingly being used as a data component in stock assessment models. The original intent of the use of CAAL data was to directly estimate the length-at-age process, including the associated variability in length-at-age. However, we show that introduction of CAAL data that are not representative of the age-structure of the population can cause bias and imprecision in estimates of not only growth, but also dynamics and management quantities. Estimation of an appropriate age-based observations-modeled process may improve model performance. We also show that even the use of representative CAAL data in a model with misspecified age-based systems-modeled processes (natural mortality and time-varying growth) can lead to bias and imprecision in growth, dynamics, and management quantities. In these cases, estimation of an age-based observations-modeled process magnified the bias and imprecision. Greater consideration of this type of data is needed.

To determine optimal methods of patrol with license plate readers (LPRs) for maximizing detection and apprehension. Data from two randomized experiments were jointly analyzed. In the first, a four-officer squad conducted short daily operations to detect stolen and other vehicles of interest at randomly selected road segments (averaging 0.6 miles) at varying times of day for 2 weeks per location. Based on random assignment, the unit operated with LPRs on some routes and conducted extensive manual checks of license plates on others. In the second experiment, the squad conducted similar operations focused on larger hot spot areas (averaging 1 mile2) using the same research design. The first experiment emphasized longer surveillance on primary hot routes, while the second emphasized shorter visits to the main hot routes and more roving surveillance around these routes. Officer log data were used to examine the likelihood that the patrols resulted in detection of wanted vehicles, arrests, or recoveries of stolen vehicles. Chi-square tests and multivariate logistic regressions were used to examine LPR performance across experiments. LPRs increased the likelihood of all outcomes (which were generally rare) in both experiments, though only the effects on detections were statistically significant. Differences across the experiments were not statistically significant, but LPR performance was generally better during the second experiment, particularly with regard to how much LPR use improved performance over manual plate checks. Results suggest LPR patrols emphasizing roaming operations within larger hot spot areas may be most optimal, but the effects of LPR patrols may not be substantial without large-scale deployment.

Double-Sequential Defibrillation (DSD) is the near-simultaneous use of two defibrillators to treat refractory VF. We hypothesized that (1) risk of DSD-associated defibrillator damage depends on shock vector and (2) the efficacy of DSD depends on inter-shock time.Part 1: risk of defibrillator damage was assessed in three anaesthetized pigs by applying two sets of defibrillation electrodes in six different configurations (near-orthogonal or near-parallel vectors). Ten 360J shocks were delivered from one set of pads and peak voltage was measured across the second set. Part 2: the dependence of DSD efficacy on inter-shock time was assessed in ten anaesthetized pigs. Electrodes were applied in lateral-lateral (LL) and anterior-posterior positions. Control (LL Stacked Shocks; one vector, two shocks ∼10 s apart) and DSD therapies (Overlapping, 10 ms, 50 ms, 100 ms, 200 ms, 500 ms, 1000 ms apart) were tested in a block randomized design treating electrically-induced VF (n = ∼89 VF episodes/therapy). Shock energies were selected to achieve 25% shock success for a single LL shock.Part 1: peak voltage delivered was 1833 ± 48 V (mean ± 95%CI). Peak voltage exposure was, on average, 10-fold higher for parallel than orthogonal vectors (p 0.0001). Part 2: DSD efficacy compared to Stacked LL shocks was higher for Overlapping, 10 ms, and 100 ms (p 0.05); lower at 50 ms (p 0.05); and not different at 200 ms or longer inter-shock times.Risk of DSD-associated defibrillator damage can be mitigated by using near-orthogonal shock vectors. DSD efficacy is highly dependent on the inter-shock time and can be better, worse, or no different than stacked shocks from a single vector.University of Alabama at Birmingham Institutional Animal Care and Use Committee (IACUC) Protocol Number 06860.

Carbonate cementation of sandstones at channel bases is commonly interpreted to be a result of solutes generated from surrounding rocks in a burial-diagenetic regime. However, in rapidly buried and under-compacted conglomerates presented in this study, we interpret carbonate cements formed during early-diagenesis (1000–1600 m) to be precipitated directly from Ca- and CO2-rich saline formation water, derived from hypersaline lake water and driven by gravity and compaction. In the Bayindulan Sag of the Er'lian Basin, which is a continental rift basin, the sandstones and conglomerates of the A'ershan Formation (K1ba) were deposited in fan delta front settings during the syn-rift phase. Within these, tightly non-ferroan calcite-cemented conglomerates are present at the bases of distributary channels. In addition, some Fe-dolomite cements are present in sandstones with high present-day porosity, which are located in the upper parts of distributary channels. A petrographic analysis and fluid-inclusion microthermometry study show that the calcite cement predates the Fe-dolomite. Stable isotopic values indicate that both calcite and Fe-dolomite are characterized by enrichment of 13C and depletion of 18O (δ18OV-PDB: −15‰ to −8‰), and the value of δ13C V-PDB in calcite (+1.6‰ to +3.8‰) is less positive than that in Fe-dolomite (+3.1‰ to +8.4‰). Integrated analyses imply that the studied carbonate cements were probably formed within an open diagenetic system and were influenced by multiple diagenetic fluids. During deposition of the A'ershan Formation (K1ba), the lake water was brackish to hypersaline (Sr/Ba>1 and Sr content > 300 ppm). During deposition of the Tenggeer Formation (K1bt), the K1ba progressed rapidly into a deep burial phase (90 m/Ma), diagenetic fluids were controlled by hypersaline lake water, incursion of meteoric water occurred along faults, and methanogenic fermentation. Calcium was probably derived from the saline formation water and the transformation of smectite to illite in associated mudstones, leading to the precipitation of calcite (54–78 °C). In the Saihantala period, the K1ba experienced a slight uplift, the fault activity ceased, and the diagenetic fluids were derived from the saline formation water and were influenced by methanogenic fermentation, and Fe-dolomite began to precipitate. In deeper burial detrital feldspar grains and some calcite cement were probably dissolved by organic acid discharged from mudstones. In conclusion, the early diagenetic characteristics in the continental rift basins were controlled by the composition of the depositional waters and tectonics that controlled the opening and closing the diagenetic system thus influencing fluid composition.

Healthy and functional endothelial cells play important roles in maintaining vascular homeostasis, whereas endothelial dysfunction initiates and exacerbates vascular disease progression. Interventional studies with dietary fatty acids have shown that these molecules have varying effects on vascular function. It is hypothesized that the actions of dietary fatty acids on vascular function may be mediated in part through endothelial cells. This review summarizes the results of studies that have examined the acute and chronic effects of dietary fatty acids on endothelial function and vascular properties in humans, as well as the potential mechanisms by which n-3 polyunsaturated fatty acids regulate endothelial function. Altogether, this article provides an extensive review of how fatty acids contribute to vascular function through their ability to modulate endothelial cells and discusses relationships between dietary fatty acids and endothelial cells in the context of vascular dysfunction.

Stochastic fluid models have been widely used to model the level of a resource that changes over time, where the rate of variation depends on the state of some continuous-time Markov process. Latouche and Taylor (Queueing Syst 63:109–129, 2009) introduced an approach, using matrix analytic methods and the reduced load approximation for loss networks, to analyse networks of fluid models all driven by the same modulating process where the buffers are infinite. We extend the method to networks involving finite buffer models and illustrate the approach by deriving performance measures for a simple network as characteristics such as buffer size are varied. Our results provide insight into the situations where the infinite buffer model is a reasonable approximation to the finite buffer model.

Deep-water mudstones are often considered as background sediments, deposited by vertical suspension fallout, and the range of transport and depositional processes are poorly understood compared to their shallow-marine counterparts. Here, we present a dataset from a 538.50 m-thick coredsuccession through the Permian muddy lower Ecca Group of the Tanqua depocentre (southwest Karoo Basin, South Africa). This study aims to characterize the range of mudstone facies, transport and depositional processes, and stacking patterns recorded in deep-water environments prior to deposition of the Tanqua Karoo sandy basin-floor fans. A combination of macroscopic and microscopic description techniques and ichnological analysis has defined nine sedimentary facies that stack in a repeated pattern to produce 2–26-m-thick depositional units. The lower part of each unit is characterized by bedded mudstone deposited by dilute, low-density turbidity currents with evidence for hyperpycnal-flowprocesses and sediment remobilization. The upper part of each unit is dominated by more organic-rich bedded mudstone with common mudstone intraclasts, deposited by debris flows and transitional flows, with scarce indicators of suspension fallout. The intensity of bioturbation and burrow size increases upward through each depositional unit, consistent with a decrease in physicochemically stressed conditions, linked to a lower sediment accumulation rate. This vertical facies transition in the single well dataset can be interpreted to represent relative sea level variations, where the hyperpycnal stressed conditions in the lower part of the units were driven by sea level fall and the more bioturbated upper part of the unit represents backstepping, related to sea level rise. Alternatively, this facies transition may represent autogenic compensational stacking. The prevalence of sediment density flow deposits, even in positions distal or lateral to the sediment entry point, challenges the idea that deep-water mudstones are primarily the deposits of passive rainout along continental margins.

Deriving the time-dependent expected reward function associated with a continuous-time Markov chain involves the computation of its transient deviation matrix. In this paper we focus on the special case of a finite quasi-birth-and-death (QBD) process, motivated by the desire to compute the expected revenue lost in a MAP/PH/1/C queue. We use two different approaches in this context. The first is based on the solution of a finite system of matrix difference equations; it provides an expression for the blocks of the expected reward vector, the deviation matrix, and the mean first passage time matrix. The second approach, based on some results in the perturbation theory of Markov chains, leads to a recursive method to compute the full deviation matrix of a finite QBD process. We compare the two approaches using some numerical examples.

Motivated by a desire to calculate the optimal credit limit for a credit card account in terms of the card-holder’s purchasing behaviour, we consider a single-period inventory model in which the total value of all attempted purchases increases in jumps throughout the period. If a purchase does not cause the limit to be exceeded, then that purchase is approved and the total value of approved purchases is increased by its value. On the other hand, if the limit is exceeded, then the purchase is rejected and the total value of approved purchases remains at its previous level. We derive an equation for the Laplace–Stieltjes transform of the expected total value of approved purchases at the end of the period. Unfortunately this equation appears to be intractable, a situation that we address by providing upper and lower bounds. We provide numerical examples that show that these upper and lower bounds can be close, which leads to good upper and lower approximations for the optimal limit.

OBJECTIVERecent literature describing complications associated with spinopelvic fixation with iliac screws in adult patients has been limited but has suggested high complication rates. The authors’ objective was to report their experience with iliac screw fixation in a large series of patients with a 2-year minimum follow-up.METHODSOf 327 adult patients undergoing spinopelvic fixation with iliac screws at the authors’ institution between 2010 and 2015, 260 met the study inclusion criteria (age ≥ 18 years, first-time iliac screw placement, and 2-year minimum follow-up). Patients with active spinal infection were excluded. All iliac screws were placed via a posterior midline approach using fluoroscopic guidance. Iliac screw heads were deeply recessed into the posterior superior iliac spine. Clinical and radiographic data were obtained and analyzed.RESULTSTwenty patients (7.7%) had iliac screw–related complication, which included fracture (12, 4.6%) and/or screw loosening (9, 3.5%). No patients had iliac screw head prominence that required revision surgery or resulted in pain, wound dehiscence, or poor cosmesis. Eleven patients (4.2%) had rod or connector fracture below S1. Overall, 23 patients (8.8%) had L5–S1 pseudarthrosis. Four patients (1.5%) had fracture of the S1 screw. Seven patients (2.7%) had wound dehiscence (unrelated to the iliac screw head) or infection. The rate of reoperation (excluding proximal junctional kyphosis) was 17.7%. On univariate analysis, an iliac screw–related complication rate was significantly associated with revision fusion (70.0% vs 41.2%, p = 0.013), a greater number of instrumented vertebrae (mean 12.6 vs 10.3, p = 0.014), and greater postoperative pelvic tilt (mean 27.7° vs 23.2°, p = 0.04). Lumbosacral junction–related complications were associated with a greater mean number of instrumented vertebrae (12.6 vs 10.3, p = 0.014). Reoperation was associated with a younger mean age at surgery (61.8 vs 65.8 years, p = 0.014), a greater mean number of instrumented vertebrae (12.2 vs 10.2, p = 0.001), and longer clinical and radiological mean follow-up duration (55.8 vs 44.5 months, p < 0.001; 55.8 vs 44.6 months, p < 0.001, respectively). On multivariate analysis, reoperation was associated with longer clinical follow-up (p < 0.001).CONCLUSIONSPrevious studies on iliac screw fixation have reported very high rates of complications and reoperation (as high as 53.6%). In this large, single-center series of adult patients, iliac screws were an effective method of spinopelvic fixation that had high rates of lumbosacral fusion and far lower complication rates than previously reported. Collectively, these findings argue that iliac screw fixation should remain a favored technique for spinopelvic fixation.

Overt physical aggression in schools gains the most attention from educational professionals, yet researchers find that verbal aggression (VA) delivered directly is the most prevalent form. Perpetrators who engage in VA can experience a host of negative long-term outcomes and victims often experience anxiety, depression, and even suicide ideation. A review of the current literature about VA is essential to raise awareness of this form of aggression and to develop strategies to mollify its deleterious effects. Thus, the purpose of our review is to explore VA, specifically its prevalence and demographics, internalizing effects, and related risk and protective factors. We also examine student perspectives, school climate and safety, the relationship between academic performance and VA, and current interventions. We discuss future research, including the need to situate conceptually VA processes and cognitive events, mediators and moderators, proximal and distal outcomes of VA, and the need for efficient and effective interventions.

Criminological research has long suggested that attitudes concerned with honour and aggression, such as the ‘street code’, are related to violent offending and victimization. Comparatively, little information is known, however, about the mechanisms through which these attitudes increase violence. Drawing from interactionist perspectives of aggression and subcultural theories, we examine the mediating role of two conflict-related tendencies: disputatiousness and remedial actions. We also examine the extent to which remedial actions moderate the association between disputatiousness and violence. Predictions are tested using longitudinal data from a nationally representative sample of young adults in the United States. Results show that conflict-related tendencies mediate the pathways linking the street code to violent offending and victimization. In addition, remedial actions temper the association between disputatiousness and violence involvement.

Nonthrombotic intracranial venous occlusive disease (NIVOD) has been implicated in the pathophysiology of idiopathic intracranial hypertension (IIH) and various non-IIH headache syndromes. Endovascular stenting of stenotic, dominant transverse sinuses (TSs) may reduce trans-stenosis pressure gradients, decrease intracranial pressure, and alleviate symptoms in a subset of NIVOD patients. We present a case in which concurrent stenting of the occipito-marginal sinus obliterated the residual trans-stenosis pressure gradient across an initially stented dominant TS. We hypothesize that this observation may be explained using an electric-hydraulic analogy, and that this patient’s dominant TS and occipito-marginal sinus may be modeled as a parallel hemodynamic circuit. Neurointerventionalists should be aware of parallel hemodynamic drainage patterns and consider manometry and possibly additional stenting of stenotic, parallel venous outflow pathways if TS stenting alone fails to obliterate the trans-stenosis pressure gradient.

Background Suicidal outcomes, including ideation, attempt, and completed suicide, are an important drug safety issue, though few epidemiological studies address the accuracy of suicidal outcome ascertainment. Our primary objective was to evaluate validated methods for suicidal outcome classification in electronic health care database studies. Methods We performed a systematic review of PubMed and EMBASE to identify studies that validated methods for suicidal outcome classification published 1 January 1990 to 15 March 2016. Abstracts and full texts were screened by two reviewers using prespecified criteria. Sensitivity, specificity, and predictive value for suicidal outcomes were extracted by two reviewers. Methods followed PRISMA-P guidelines, PROSPERO Protocol: 2016: CRD42016042794. Results We identified 2202 citations, of which 34 validated the accuracy of measuring suicidal outcomes using International Classification of Diseases (ICD) codes or algorithms, chart review or vital records. ICD E-codes (E950-9) for suicide attempt had 2–19% sensitivity, and 83–100% positive predictive value (PPV). ICD algorithms that included events with ‘uncertain’ intent had 4–70% PPV. The three best-performing algorithms had 74–92% PPV, with improved sensitivity compared with E-codes. Read code algorithms had 14–68% sensitivity and 0–56% PPV. Studies estimated 19–80% sensitivity for chart review, and 41–97% sensitivity and 100% PPV for vital records. Conclusions Pharmacoepidemiological studies measuring suicidal outcomes often use methodologies with poor sensitivity or predictive value or both, which may result in underestimation of associations between drugs and suicidal behaviour. Studies should validate outcomes or use a previously validated algorithm with high PPV and acceptable sensitivity in an appropriate population and data source.

Introduction In order to prevent youth and young adult partner abuse, it is necessary to have a better understanding of dating relationship dynamics as the context for potential abusive interactions. Methods Youth and young adults (ages 10–18 at baseline) were surveyed along with a matched parent/caregiver. Data, including parent and youth responses (n = 437 youth/parent dyads), are drawn from the nationally representative Survey on Teen Relationships and Intimate Violence (STRiV). Results Applying latent class analytic techniques with seven different positive and problematic descriptors of dating relationships, this study found four classes of relationship dynamics representing healthy, unhealthy, intense, and disengaged relationships. The intense relationship dynamic class exhibits the strongest associations with reports of any youth and young adult partner abuse, as well as distinctly with the subtypes of psychological, physical, and sexual victimization and perpetration. Conclusions Results demonstrate the importance of clinicians, parents and other responsible adults attending to an array of youth and young adult dating relationship dynamics rather than single indicators, to assess youth and young adult risk for involvement in abusive relationships.

We use observations of surface waves in the ambient noise field recorded at a dense seismic array to image the North Anatolian Fault zone (NAFZ) in the region of the 1999 magnitude 7.6 Izmit earthquake in western Turkey. The NAFZ is a major strike-slip fault system extending ∼1200 km across northern Turkey that poses a high level of seismic hazard, particularly to the city of Istanbul. We obtain maps of phase velocity variation using surface wave tomography applied to Rayleigh and Love waves and construct high-resolution images of S-wave velocity in the upper 10 km of a 70 × 30 km region around Lake Sapanca. We observe low S-wave velocities ( km s−1) associated with the Adapazari and Pamukova sedimentary basins, as well as the northern branch of the NAFZ. In the Armutlu Block, between the two major branches of the NAFZ, we image higher velocities (>3.2 km s−1) associated with a shallow crystalline basement. We measure azimuthal anisotropy in our phase velocity observations, with the fast direction seeming to align with the strike of the fault at periods shorter than 4 s. At longer periods up to 10 s, the fast direction aligns with the direction of maximum extension for the region (∼45∘). The signatures of both the northern and southern branches of the NAFZ are clearly associated with strong gradients in seismic velocity that also denote the boundaries of major tectonic units. Our results support the conclusion that the development of the NAFZ has exploited this pre-existing contrast in physical properties.

BACKGROUND: Novel oils high in monounsaturated fatty acids (MUFAs) and low in saturated fatty acids (SFAs) are an alternative to partially hydrogenated oils high in trans-unsaturated fatty acids. There is widespread use of high-MUFA oils across the food industry; however, limited knowledge of their cardiovascular impact exists. OBJECTIVES: We investigated the effects of diets containing canola oil, high-oleic acid canola oil (HOCO), and a control oil blend (diet formulated to emulate a Western fat profile) on lipids, lipoproteins, and apolipoproteins (apos), as secondary outcomes of the trial. METHODS: In a multi-center, double-blind, randomized, 3-period crossover, controlled feeding trial, men (n = 44) and women (n = 75) with a mean age of 44 y, mean body mass index (BMI; in kg/m(2)) of 31.7, and an increased waist circumference plus ≥1 metabolic syndrome criteria consumed prepared, weight-maintenance diets containing canola oil [17.5% MUFAs, 9.2% polyunsaturated fatty acids (PUFAs), 6.6% SFAs], HOCO (19.1% MUFAs, 7.0% PUFAs, 6.4% SFAs), or control oil (10.5% MUFAs, 10.0% PUFAs, 12.3% SFAs) for 6 wk with ≥4-wk washouts. Fasting serum lipids were assessed at baseline and 6 wk. Diet effects were examined using a repeated measures mixed model. RESULTS: Compared with the control, canola and HOCO diets resulted in lower endpoint total cholesterol (TC; −4.2% and −3.4%; P

In Sub-Saharan Africa, groundwater use is a vital strategy to meet rapid increases in freshwater demand projected this century and to adapt to the region’s substantial variabilities in rainfall and surface water resources, amplified by climate change. Four studies are considered, which constitute a topical collection of articles that provide new insight into the characteristics and processes by which groundwater is replenished, using recently compiled long-term groundwater-level records together with evidence from satellite data of the sustainability of exploited aquifer systems.

Background: Ibrance Real World Insights (IRIS) is a multi-country study aimed to describe clinical characteristics, treatment patterns and clinical outcomes of patients receiving palbociclib plus aromatase inhibitor. Previously the results on the overall population within the US have been communicated. The current analysis focuses on subgroups stratified by age, performance status and visceral status. Materials and methods: A retrospective chart review of HR+/HER2- ABC/MBC patients who received palbociclib plus aromatase inhibitor as initial endocrine based therapy for their advanced disease was conducted between June and October 2017. Physicians completed electronic case report forms, extracting data on patient demographics, clinical characteristics, treatment history/patterns and clinical outcomes.Progression free and survival rates at 12 and 24 months were estimated via Kaplan-Meier analysis. Results: Data for the US are reported here. In total 63 physicians completed 360 eCRFs with a mean follow up time since palbociclib initiation of 12 months. Majority of the patients were >65 years (53%), and had ECOG status of 0 (30%) or 1 (56%). Overall 293 (81%) patients had metastatic disease, of which 50% had visceral metastases. Across all sub-groups, majority of patients prescribed an initial palbociclib dose of 125mg did not require a change of dose while on treatment. The 12-month and 24-month progression free and overall survival rates across subgroups are presented in Table 1. Patients with a performance status of ECOG=1 had a slightly lower progression and survival rates at 12 and 24 months compared to those with a score =0. Likewise, patients with visceral disease were observed to have slightly lower progression free and survival rates than others. Table 1:Clinical Outcomes for the different sub-groups.Patient Sub-groups AgeECOG statusVisceral Status Up to 65 n=169Over 65 n=1910 n=1071 n=200Visceral metastases n=147Non-visceral metastases n=146Progression free survival rate at 12 months, %86.382.194.386.580.285.8Progression free survival rate at 24 months, %59.769.071.267.450.780.6Overall survival rate At 12 months, %97.992.8100.099.590.599.3Overall survival rate at 24 months, %95.185.695.796.487.290.7 Conclusions: The analysis indicates consistent trends in different clinical outcomes were observed with palbociclib plus aromatase inhibitor across patients sub-groups based on age, performance status and visceral metastases. Citation Format: Taylor-Stokes G, Mitra D, Waller J, Gibson K, Milligan G, Zhan L, Iyer S. Real world treatment patterns and outcomes of patients receiving palbociclib plus aromatase inhibitor in the United States: Sub-groups analysis based on age, performance status and sites of metastases from the IRIS study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-36.

Background: Ibrance Real World Insights (IRIS) is a multi-country study aimed to describe the clinical characteristics and understand treatment patterns and clinical outcomes of patients receiving palbociclib plus fulvestrant in real world clinical practice. Previously the results on the overall population within the US have been communicated. The current analyses focus on subgroups stratified by age, performance status and visceral status. Materials and methods: A retrospective chart review of HR+/HER2- ABC/MBC patients was conducted between June and October 2017. Physicians extracted data from patient medical records for HR+/HER2- ABC patients who received palbociclib plus fulvestrant following disease progression with endocrine based therapy for their advanced disease. Electronic case report forms collected data covering patient demographics, clinical characteristics, treatment history/patterns and clinical outcomes.Progression free rates and survival rates at 6 and 12 months were estimated via Kaplan-Meier analysis. Results: Data for the US are reported here. In total, 65 physicians extracted data for 292 patients who had a mean follow up time of 7.4 months. Majority of the patients were >65 years (54%), and had ECOG status of 0 (32%) or 1 (48%). Overall 224 (77%) patients had metastatic disease, of which 93 (42%) had visceral metastases. Across all sub-groups, majority of patients prescribed an initial palbociclib dose of 125mg did not require a change of dose while on treatment. The 6-month and 12-month progression free and survival rates across subgroups are presented in Table 1. Patients with a performance status of ECOG ≥ 2 had a slightly lower progression and survival rates at 6 and 12 months compared to those with a score Table 1:Clinical Outcomes by Patient Sub-groups.Patient Sub-groups AgeECOGstatusVisceral Status Up to 65 n=158Over 65 n=1340 n=931 n=1392+ n=60Visceral Metastases n=93Non-visceral Metastases n=131Progression free survival rate at 6 months, %95.293.297.893.490.689.694.8Progression free survival rate at 12 months, %81.277.884.683.0-73.276.5Survival rate at 6 months, %98.096.3100.098.290.692.298.9Survival rate at 12 months, %90.085.197.695.1-80.892.7 Conclusions: The analysis indicates consistent trends in different clinical outcomes were observed with palbociclib plus fulvestrant across patients sub-groups based on age, performance status and visceral metastases. Citation Format: Waller J, Mitra D, Taylor-Stokes G, Gibson K, Milligan G, Zhan L, Iyer S. Real world treatment patterns and outcomes of patients receiving palbociclib plus fulvestrant in the United States: Sub-groups analysis based on age, performance status and sites of metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-21.

Dietary PUFA and their effects on adipose tissue have been well studied, but oxylipins, the oxygenated metabolites of PUFA, have been sparsely studied in adipose tissue. To determine the oxylipin profile and to examine their potential importance in various adipose sites, female and male rats were provided control, high linoleic acid (LA), or high LA and high α-linolenic acid (LA + ALA) diets for six weeks. Analysis of gonadal (GAT), mesenteric (MAT), perirenal (PAT), and subcutaneous adipose tissues (SAT) revealed higher numbers of oxylipins in MAT and SAT, primarily due to 20–22 carbon cytochrome P450 oxylipins, as well as metabolites of cyclooxygenase derived oxylipins. LA oxylipins made up 75–96% of the total oxylipin mass and largely determined the total relative amounts between depots (GAT > MAT > PAT > SAT). However, when the two most abundant LA oxylipins (TriHOMEs) were excluded, MAT had the highest mass of oxylipins and exhibited the most sex differences. These differences existed despite comparable PUFA composition between depots. Dietary LA increased oxylipins derived from n-6 PUFA, and the addition of ALA generally returned n-6 PUFA oxylipins to levels similar to control and elevated some n-3 oxylipins. These data on oxylipin profiles in adipose depots from different anatomical sites and the effects of diet and sex provide fundamental knowledge that will aid future studies investigating the physiological effects of adipose tissue.

Selectivity is a key parameter in stock assessments that describes how fisheries interact with different ages and sizes of fish. It is usually confounded with other processes (e.g., natural mortality and recruitment) in stock assessments and the assumption of selectivity can strongly affect stock assessment outcome. Here, we introduce a new semi-parametric selectivity method, which we implement and test in Stock Synthesis. This selectivity method includes a parametric component and an autocorrelated nonparametric component consisting of deviations from the parametric component. We explore the new selectivity method using two simulation experiments, which show that the two autocorrelation parameters for selectivity deviations of data-rich fisheries are estimable using either mixed-effect or simpler sample-based algorithms. When selectivity deviations of a data-rich fishery are highly autocorrelated, using the new method to estimate the two autocorrelation parameters leads to more precise estimations of spawning biomass and fully selected fishing mortality. However, this new method fails to improve model performance in low data quality cases where measurement error in the data overwhelms the pattern caused by the autocorrelated process. Finally, we use a case study involving North Sea herring (Clupea harengus) to show that our new method substantially reduces autocorrelations in the Pearson residuals in fit to age composition data.

Despite extensive research regarding patterns and outcomes of victimization in dating relationships, there has been limited investigation of the developmental profiles of the perpetration of adolescent dating abuse (ADA). We estimated longitudinal latent growth models of ADA perpetration in a sample of 2,269 U.S. adolescents/young adults ages 12-18 at baseline, drawing on four waves (2013-2017) of data from the nationally representative Survey of Teen Relationships and Intimate Violence. Model results revealed three classes representing "nondaters," respondents showing "increasing dating/ADA," and respondents with "high/stable dating/ADA." Results support prior research finding heightened patterns of ADA perpetration by older youth, and distinguish individual and family characteristics associated with adolescent/young adults' ADA perpetration for the purpose of informing individual and programmatic prevention efforts.

Research indicates that actors who intentionally bring about harmful consequences are blamed more for their actions than those who do so unintentionally. However, in many instances of harmful behav...

The Bell Island and Wabana groups together comprise a ca. 150-m-thick succession of interbedded clastic andchemical sedimentary rocks composed of eight distinct lithofacies that accumulated along the northern marginof the Rheic Ocean. Lithofacies stacking patterns indicate that deposition occurred during a marine transgressionwith superimposed small-scale sea level fluctuations producing at least six parasequences. Parasequences containingironstone are 10 to 20-m-thick and composed of hummocky cross-stratified sandstone interbeddedwith organic-rich mudstone and phosphatic Fe-silicate-bearing siltstone,which is overlain by hematitic granularironstone capped by an erosive flooding surface.This lithofacies association is interpreted to record the deposition of upwelling-related ironstone on a stormdominatedshelf. The close relationship between Fe-silicates and phosphorite typical of upwelling systemssuggests that Fe was delivered from deep, anoxic, nutrient-rich seawater that also stimulated high surface productivities.The result was the precipitation of authigenic sedimentary apatite in anoxic organic-rich sedimentsthat accumulated near the upwelling front. The gradual advection of Fe-rich waters away from the upwellingfront, initiated precipitation of Fe-silicate coated grains and cements in suboxic pore-waters. Iron pumpedinto shallower environments through advection and Fe-redox cycling is interpreted to have precipitated Fe-(oxyhydr)oxide grains in sediment of the oxygenated middle shelf. These coated grains were subsequentlyconcentrated by fairweather and storm currents on the shoreface to create granular economic Fe deposits.We challenge conventional models of Paleozoic ironstone deposition that rely on a continental source of Fe byproposing a hydrothermal source that supplied Fe2+ to the shelf through upwelling. It also highlights the potentialconnection between the delivery of anoxic, ferruginous seawater to the margins of the Rheic Ocean and theEarly Ordovician extinctions that punctuated the beginning of the Great Ordovician Biodiversification Event.

The SMART coil (Penumbra Inc., Alameda, CA, USA) is a new microcoil designed to enhance deliverability. Although prior studies have described its perioperative safety and efficacy, the follow-up outcomes after embolization of intracranial aneurysms using SMART coils have not been reported. Therefore, the aim of this retrospective cohort study is to assess the angiographic outcomes at interim follow-up after aneurysm embolization with SMART coils. We reviewed data from consecutive patients with intracranial aneurysms who underwent endovascular treatment using SMART coils between June 2016 and August 2017. Baseline data and follow-up angiographic outcomes using the modified Raymond-Roy classification (MRRC) were recorded. The study cohort comprised 33 patients with 34 aneurysms who underwent SMART coil embolization and had sufficient follow-up data. The mean age was 57 years, and 82% were female. The mean aneurysm maximum diameter and neck width were 6.1 ± 2.2 mm and 3.2 ± 1.2 mm, respectively, and 14.7% of aneurysms were ruptured. The overall complication rate was 12%. Initial mean coil packing density was 26%, and the initial MRRC was I, II, IIIa, and IIIb in 24%, 26%, 35%, and 15%, respectively. At last follow-up (mean duration 7.7 ± 3.2 months), the MRRC was I, II, IIIa, and IIIb in 62%, 26%, 3%, and 9%, respectively. The retreatment rate was 14.7%. The SMART coil is efficacious for the treatment of appropriately selected aneurysms, with an acceptable risk profile. The majority of residual aneurysms after the initial embolization procedure will progress to complete or near-complete occlusion at interim follow-up.

Neoadjuvant endovascular embolization of skull base meningiomas may facilitate surgical resection, thereby potentially decreasing operative morbidity. However, due to variation in the reported efficacy and complication rates, the utility of embolization remains incompletely defined. The aim of this systematic review is to assess the outcomes of preoperative embolization for skull base meningiomas. A literature review was performed to identify studies reporting outcomes of patients with skull base meningiomas who underwent preoperative embolization. Baseline, treatment, and outcomes data were analyzed. Major complications included death, new cranial neuropathy, retinal artery ischemia, permanent neurologic deficit, or intracerebral hemorrhage. The pooled analysis consisted of 15 studies, comprising a total of 403 patients with skull base meningiomas treated with preoperative embolization. The most common locations were the sphenoid wing (34%, 87/256 cases), petroclival region (31%, 80/256 cases), and cavernous sinus (12%, 31/256 cases). The median tumor size ranged from 5.0 to 8.0 cm. Based on pooled data, angiographic absence of tumor blush was achieved in 17% (13/79 cases). The median estimated blood loss (EBL) ranged from 225 to 580 mL. Simpson grade I-III resection was achieved in 74% (40/54) of patients. The overall complication, major complication, and mortality rates were 12% (47/403 patients), 6% (21/328 patients), and 0.2% (1/403 patients), respectively. Preoperative embolization is a reasonable adjunct to resection for appropriately selected skull base meningiomas. Future comparative analyses are necessary to ascertain the benefits of preoperative embolization of skull base meningiomas with respect to extent of resection, operative duration, operative blood loss, and surgical morbidity.

The self-assembly and crystal packing of a unique series of nanocrystalline fluoride ion-encapsulated polyhedral oligomeric silsesquioxane compounds (F-POSS), with substituted electron-withdrawing group (EWG) perfluorinated alkyl chain arms of varying lengths was investigated. The fluorine-encapsulated T8[(CH2)n-EWG]8F--18-crown-6-ether-M+ and T8[(CH2)n-EWG]8F--tetrabutyl ammonium TBA+ compounds with fluorinated alkyl chain arms, were synthesized and subsequently analyzed using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and simultaneous small- and wide-angle X-ray scattering SAXS/WAXS techniques. DSC and TGA of the compounds showed that the melting temperatures occurred below 100 °C and were thermally stable above their melting temperatures. SAXS/WAXS data probed the crystalline structure and self-assembly of the nanocrystalline compounds. At ambient temperatures, the crystalline structures of the compounds were seen to be complex with triclinic unit cells. On cooling from the melt, the self-assembly of the compounds with shorter fluorinated alkyl chain arms is dominated by the ionic attraction between the cages such that the arms form a disordered state that only reorder on standing. In contrast, the self-assembly of the compounds with longer fluorinated alkyl chain arms is dominated by the alignment of the arms into rod-like morphologies such that a fully ordered solid is formed from the melt. Electrical characterization has revealed that the POSS cages exhibited an insulating behavior. The POSS cages with or without fluoride ion encapsulation had similar AC conductivities but cages without fluoride ion encapsulation have the highest relative permittivity. The results show that due to the inorganic-organic-ionic nature the F-POSS ion encapsulated compounds and nanocrystalline self-assembly, they have great potential as interfacial compatibilizers enhancing miscibility of polymer composites and aiding interactions between polar and non-polar solvents as ionic liquids.

The effectiveness of influenza vaccination in reducing influenza-related hospitalizations among patients with COPD is not well described, and influenza vaccination uptake remains suboptimal.Data were analyzed from a national, prospective, multicenter cohort study including patients with COPD, hospitalized with any acute respiratory illness or exacerbation between 2011 and 2015. All patients underwent nasopharyngeal swab screening with polymerase chain reaction (PCR) testing for influenza. The primary outcome was an influenza-related hospitalization. We identified influenza-positive cases and negative control subjects and used multivariable logistic regression with a standard test-negative design to estimate the vaccine effectiveness for preventing influenza-related hospitalizations.Among 4,755 hospitalized patients with COPD, 4,198 (88.3%) patients with known vaccination status were analyzed. The adjusted analysis showed a 38% reduction in influenza-related hospitalizations in vaccinated vs unvaccinated individuals. Influenza-positive patients (n = 1,833 [38.5%]) experienced higher crude mortality (9.7% vs 7.9%; P = .047) and critical illness (17.2% vs 12.1%; P .001) compared with influenza-negative patients. Risk factors for mortality in influenza-positive patients included age75 years (OR, 3.7 [95% CI, 0.4-30.3]), cardiac comorbidity (OR, 2.0 [95% CI, 1.3-3.2]), residence in long-term care (OR, 2.6 [95% CI, 1.5-4.5]), and home oxygen use (OR, 2.9 [95% CI, 1.6-5.1]).Influenza vaccination significantly reduced influenza-related hospitalization among patients with COPD. Initiatives to increase vaccination uptake and early use of antiviral agents among patients with COPD could reduce influenza-related hospitalization and critical illness and improve health-care costs in this vulnerable population.ClinicalTrials.govNo.:NCT01517191; URL www.clinicaltrials.gov.

Global climate targets have highlighted the need for a whole-systems approach to decarbonisation, one that includes targeted national policy and industry specific change. Situated within this context, this research examines policy and pricing barriers to decarbonisation of the UK steel industry. Here the techno-economic modelling of UK green steelmaking provides a technical contribution to analysis of pricing barriers and policy solutions to these barriers in the UK specifically, but also to the broader industrial decarbonisation literature. Estimated costs and associated emissions projections reveal relevant opportunities for UK steel in contributing to national climate and emissions targets. Modelling demonstrates that green steelmaking options have been put at price disadvantages compared to emissions-intensive incumbents and that fossil-free hydrogen-based steelmaking has lower emissions and lower levelised costs than carbon capture and storage options, including top gas recycling blast furnace (TGR-BF) with CCS, and HIsarna smelter with CCS. Two primary policy recommendations are made: the removal of carbon pricing discrepancies and reductions in industrial electricity prices that would level the playing field for green steel producers in the UK. The research also provides relevant policy considerations for the international community in other industrial decarbonisation efforts and the policies that must accompany these decarbonisation choices.

Partial replacement of saturated fatty acids (SFA) with unsaturated fatty acids is recommended to reduce cardiovascular disease (CVD) risk. Monounsaturated fatty acids (MUFA), including oleic acid, are associated with lower CVD risk. Measurement of flow-mediated dilation of the brachial artery (FMD) is the gold standard for measuring endothelial function and predicts CVD risk. This study examined the effect of partially replacing SFA with MUFA from conventional canola oil and high-oleic acid canola oil on FMD. Participants (n = 31) with an elevated waist circumference plus ≥1 additional metabolic syndrome criterion completed FMD measures as part of the Canola Oil Multi-Centre Intervention Trial 2 (COMIT-2), a multi-center, double-blind, three-period crossover, controlled feeding randomized trial. Diet periods were 6 weeks, separated by ≥4-week washouts. Experimental diets were provided during all feeding periods. Diets only differed by the fatty acid profile of the oils: canola oil (CO; 17.5% energy from MUFA, 9.2% polyunsaturated fatty acids (PUFA), 6.6% SFA), high-oleic acid canola oil (HOCO; 19.1% MUFA, 7.0% PUFA, 6.4% SFA), and a control oil blend (CON; 11% MUFA, 10% PUFA, 12% SFA). Multilevel models were used to examine the effect of the diets on FMD. No significant between-diet differences were observed for average brachial artery diameter (CO: 6.70 ± 0.15 mm, HOCO: 6.57 ± 0.15 mm, CON: 6.73 ± 0.14 mm; p = 0.72), peak brachial artery diameter (CO: 7.11 ± 0.15 mm, HOCO: 7.02 ± 0.15 mm, CON: 6.41 ± 0.48 mm; p = 0.80), or FMD (CO: 6.32 ± 0.51%, HOCO: 6.96 ± 0.49%, CON: 6.41 ± 0.48%; p = 0.81). Partial replacement of SFA with MUFA from CO and HOCO had no effect on FMD in participants with or at risk of metabolic syndrome.

Background: Chordomas are rare neuraxial tumors arising from remnants of primitive notochord. They are generally slow-growing malignant neoplasms. Only four adult cases of multicentric chordomas have been reported, all with aggressive and rapid growth. Here, we present an unusual case of indolent multicentric chordomas involving cervical and thoracic spine, sacrum, and calvarium. Case Description: A 60-year-old male was found to have multiple lesions throughout his neuroaxis incidentally on workup for colitis. A needle biopsy documented the diagnosis of chordoma. This has been followed for more than 4 years with no progression. Conclusion: We present the first reported case of indolent multicentric chordomas. Due to the extreme rarity of indolent multicentric chordomas, close follow-up is needed and recommended.

Background Although playgrounds are designed to promote outdoor play, children with disabilities may be unable to engage in these spaces due to intrinsic and extrinsic factors. Previous research has examined inclusive/accessible playground design when developing new playgrounds; however, it is unclear if there is a best-practice tool for evaluating the inclusivity of existing playground structures. Objective A scoping review of both peer-reviewed and grey literature will be employed to explore evaluation tools for playground inclusivity, to enable the participation of children with disabilities. Methods The conduct of this study will adhere to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. A search for peer-reviewed research studies will be conducted in the following electronic databases: MEDLINE, Scopus, CINAHL, and Embase. Grey literature will be examined via a three-step process: (1) a search in the Canadian Health Research Collection Database; (2) a targeted Google search; and (3) reference list searching. Titles, abstracts, keywords, and full texts of identified studies will be independently screened for inclusion by two reviewers. A synthesis of included articles will describe the publication and auditing tool details. A summary of the findings will highlight the types of playgrounds measured, types of disability considered, measures of inclusion used, and psychometric properties. Results Database searches for peer-reviewed articles were completed in December 2021. A total of 1471 unique records were returned after the removal of 559 duplicate records. Full texts of 167 studies meeting eligibility criteria will be reviewed. The peer-reviewed research search will guide the grey literature search. The scoping review is planned for completion in 2022. Conclusions A rigorous search of the literature will determine the availability of tools for evaluating existing playground structures for the inclusivity of children with disabilities. The results will inform recommendations on tool applications, and applicable knowledge translation activities. International Registered Report Identifier (IRRID) DERR1-10.2196/37312

Incorporation of reduced inorganic sulfur (S) into organic matter (OM) in euxinic environments is considered a vital route through which OM is preserved for millions of years. However, precipitation of iron sulfides is believed to compete with OM preservation via sulfurisation. High resolution geochemical, petrographic, and electron microprobe (EMPA) analyses were employed to better understand S controls on OM preservation with particular focus on iron sulfides precipitation in organic S-rich mudstones from the Kimmeridge Clay (KCF), Monterey (MF), and Whitby Mudstone [Grey Shale (GS) and Jet Rock (JR) Members] Formations. Analyses indicated that S in the KCF and MF is mostly bound to OM as shown by the relatively high abundance of organic sulfur compounds (OSCs) in their pyrolysates. The relatively low amounts of iron (Fe) in these mudstones permitted extensive reaction of S and OM to occur efficiently, promoting preservation of high amounts OM through sulfurisation. State-of-the-art EMPA imaging of total S and Fe indicated that the S was mainly bound to organics, supporting the geochemical analyses. In contrast, S in the GS and JR was predominantly sequestered as pyrite (FeS2) rather than organically bound, as indicated by the relatively low quantity/absence of OSCs in their pyrolysates, hence, preservation through sulfurisation was less significant in these settings. EMPA imaging of S in these mudstones shows discrete shapes ranging in geometry and size and in most cases correlated with Fe in the corresponding Fe EMPA images, confirming that the S exists in discrete authigenic FeS2. Overall, in line with previous research, this study indicates that preservation of OM through sulfurisation is an important pathway for sequestration of OM. However, an abundance of reactive Fe could hinder this process by preferentially reacting with reduced S, to form iron sulfides (mainly FeS2), thus impeding reactions between OM and S to occur efficiently.

Oxylipins are oxygenated derivatives of polyunsaturated fatty acids, generated by COX, LOX and CYP enzymes, that regulate various aspects of endothelial cell physiology. Although 15-LOX and its products are positively associated with atherosclerosis, the relevant mechanisms have not been explored. The current study examined the effects of PD146176 (PD), a putative 15-LOX inhibitor, on EA.hy926 endothelial cell functions in the growing and confluent states. The effects of PD on endothelial cell oxylipin production (profiled by LC/MS/MS), cell viability, proliferation, eNOS activity, ICAM-1 and VE-cadherin levels were assessed. The contribution of signaling pathways relevant to endothelial function (p38 MAPK, Akt, PPARα) were also investigated. PD treatment for 30 min did not block formation of individual 15-LOX oxylipins, but 20 μM PD stimulated the accumulation of total LOX and COX products, while reducing several individual CYP products generated by epoxygenase. At 20 μM, the accumulated total oxylipins were primarily LOX-derived (86%) followed by COX (12%) and CYP (2%). PD altered cell functions by upregulating p38 MAPK and PPARα and downregulating Akt in a dose-dependent fashion. These observations suggest a link between PD-induced changes in oxylipins and altered endothelial cell functions via specific signaling pathways. In conclusion, the results of this study imply that PD does not function as a 15-LOX inhibitor in EA.hy926 endothelial cells, and instead inhibits CYP epoxygenase. These findings suggest that the cellular function changes induced by PD may be contingent upon its ability to modulate total oxylipin production, particularly by the LOX and CYP families.

Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome.We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15-32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test-second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302.From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points [95% CI -0·98 to 1·67], p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine [11%] participants in the memantine group and 12 [15%] in the placebo group) and transient dizziness (eight [10%] in the memantine group and six [8%] in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease.Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work.Alana Foundation.For the Portuguese translation of the abstract see Supplementary Materials section.

This session will showcase four case studies from the UK, followed by a discussion on the lessons learned and their application globally.

Not-at-random missingness presents a challenge in addressing missing data in many health research applications. In this article, we propose a new approach to account for not-at-random missingness after multiple imputation through weighted analysis of stacked multiple imputations. The weights are easily calculated as a function of the imputed data and assumptions about the not-at-random missingness. We demonstrate through simulation that the proposed method has excellent performance when the missingness model is correctly specified. In practice, the missingness mechanism will not be known. We show how we can use our approach in a sensitivity analysis framework to evaluate the robustness of model inference to different assumptions about the missingness mechanism, and we provide R package StackImpute to facilitate implementation as part of routine sensitivity analyses. We apply the proposed method to account for not-at-random missingness in human papillomavirus test results in a study of survival for patients diagnosed with oropharyngeal cancer.

This paper quantitatively characterises the microstructure in shales across five scales in 3D, builds a multi-scale model of CH 4 and CO 2 flow pathways and storage, and assesses the potential of enhanced gas recovery and CO 2 storage simultaneously. Injection of CO 2 into shale reservoirs to enhance gas recovery and simultaneously sequester greenhouse gases is a potential contributor towards the carbon-neutral target. It offers a low-carbon, low-cost, low-waste and large-scale solution during the energy transition period. A precondition to efficient gas storage and flow is a sound understanding of how the shale's micro-scale impacts on these phenomena. However, the heterogeneous and complex nature of shales limits the understanding of microstructure and pore systems, making feasibility analysis challenging. This study qualitatively and quantitatively investigates the Bowland shale microstructure in 3D at five length scales: artificial fractures at 10–100 μm scale, matrix fabric at 1–10 μm-scale, individual mineral grains and organic matter particles at 100 nm–1 μm scale, macropores and micro-cracks at 10–100 nm scale and organic matter and mineral pores at 1–10 nm-scale. For each feature, the volume fraction variations along the bedding normal orientation, the fractal dimensions and the degrees of anisotropy were analysed at all corresponding scales for a multi-scale heterogeneity analysis. The results are combined with other bulk laboratory measurements, including supercritical CO 2 and CH 4 adsorption at reservoir conditions, pressure-dependent permeability and nitrogen adsorption pore size distribution, to perform a comprehensive analysis on the storage space and flow pathways. A cross-scale pore size distribution, ranging from 2 nm to 3 μm, was calculated with quantified microstructure. The cumulative porosity is calculated to be 8%. The cumulative surface area is 17.6 m 2 g −1 . A model of CH 4 and CO 2 flow pathways and storage with quantified microstructure is presented and discussed. The feasibility of simultaneously enhanced gas recovery and subsurface CO 2 storage in Bowland shale, the largest shale gas potential formation in the UK, was assessed based using multi-scale microstructure analysis. The potential is estimated to store 19.0–21.2 Gt CO 2 as free molecules, together with 18.3–28.5 Gt CO 2 adsorbed onto pore surfaces, implying a theoretical maximum of 47.5–49.5 Gt carbon storage in the current estimate of 38 trillion cubic metres (∼1300 trillion cubic feet) of Bowland shale. Simple estimates suggest 6.0–15.8 Gt CO 2 may be stored in practice.

BACKGROUND The COVID-19 pandemic is taking a toll on people’s mental health, particularly as people are advised to adhere to social distancing, self-isolation measures, and government-imposed national lockdowns. Digital health technologies have an important role to play in keeping people connected and in supporting their mental health and well-being. Even before the COVID-19 pandemic, mental health and social services were already strained. OBJECTIVE Our objective was to evaluate the 12-week outcomes of the digitally delivered Gro Health intervention, a holistic digital behavior change app designed for self-management of mental well-being, sleep, activity, and nutrition. METHODS The study used a quasi-experimental research design consisting of an open-label, single-arm, pre-post intervention engagement using a convenience sample. Adults who had joined the Gro Health app (intervention) and had a complete baseline dataset (ie, 7-item Generalized Anxiety Disorder scale, Perceived Stress Scale, and 9-item Patient Health Questionnaire) were followed up at 12 weeks (n=273), including 33 (12.1%) app users who reported a positive COVID-19 diagnosis during the study period. User engagement with the Gro Health platform was tracked by measuring total minutes of app engagement. Paired t tests were used to compare pre-post intervention scores. Linear regression analysis was performed to assess the relationship between minutes of active engagement with the Gro Health app and changes in scores across the different mental health measures. RESULTS Of the 347 study participants, 273 (78.67%) completed both the baseline and follow-up surveys. Changes in scores for anxiety, perceived stress, and depression were predicted by app engagement, with the strongest effect observed for changes in perceived stress score (F1,271=251.397; R2=0.479; P CONCLUSIONS A digital behavior change platform that provides remote mental well-being support can be effective in managing depression, anxiety, and perceived stress during times of crisis such as the current COVID-19 pandemic. The outcomes of this study may also support the implementation of remote digital health apps supporting behavior change and providing support for low levels of mental health within the community.

In the 2 decades since Andersson and Pearson (Academy of Management Review, 24, 452, 1999) suggested workplace incivility occurs in dyadic relationships between two employees, research has only studied incivility from the perspective of either the target or the instigator. In doing so, it implicitly treats experienced and instigated incivility as though they solely reflect (viz., dispositional and situational) characteristics of targets and instigators, ignoring that incivility is also attributable to the unique relationship between dyad members. The present study draws on the norm of reciprocity to examine workplace incivility in dyadic relationships and how it differs across individuals. Using dyads as the unit of analysis, we test our predictions among employees at a U.S. restaurant chain (Sample 1); a technology manufacturer in China (Sample 2); and across a range of industries, organizations, and jobs in the U.S. (Sample 3). We find that experienced and instigated incivility exhibit substantial variation at the dyad level, that the two are related within dyads after accounting for individuals' general tendencies to experience and instigate incivility, and that the within-dyad association between experienced and instigated incivility is moderated by perceived descriptive and injunctive norms regarding uncivil behavior. Implications and future research directions are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Faecal indicator organisms (FIOs) are limited in their ability to protect public health from the microbial contamination of drinking water because of their transience and time required to deliver a result. We evaluated alternative rapid, and potentially more resilient, approaches against a benchmark FIO of thermotolerant coliforms (TTCs) to characterise faecal contamination over 14 months at 40 groundwater sources in a Ugandan town. Rapid approaches included: in-situ tryptophan-like fluorescence (TLF), humic-like fluorescence (HLF), turbidity; sanitary inspections; and total bacterial cells by flow cytometry. TTCs varied widely in six sampling visits: a third of sources tested both positive and negative, 50% of sources had a range of at least 720 cfu/100 mL, and a two-day heavy rainfall event increased median TTCs five-fold. Using source medians, TLF was the best predictor in logistic regression models of TTCs ≥10 cfu/100 mL (AUC 0.88) and best correlated to TTC enumeration (ρs 0.81), with HLF performing similarly. Relationships between TLF or HLF and TTCs were stronger in the wet season than the dry season, when TLF and HLF were instead more associated with total bacterial cells. Source rank-order between sampling rounds was considerably more consistent, according to cross-correlations, using TLF or HLF (min ρs 0.81) than TTCs (min ρs 0.34). Furthermore, dry season TLF and HLF cross-correlated more strongly (ρs 0.68) than dry season TTCs (ρs 0.50) with wet season TTCs, when TTCs were elevated. In-situ TLF or HLF are more rapid and resilient indicators of faecal contamination risk than TTCs.

OBJECTIVES: Angiotensin-converting enzyme 2 (ACE2) is a transmembrane protein located on the surface of endothelial cells that promotes vasodilation by promoting the hydrolysis of angiotensin II. However, ACE2 also serves as the cellular receptor for SARS-CoV-2. Infection by SARS-CoV-2 can promote endothelial dysfunction which in turn is associated with greater infection severity. Long chain omega-3 fatty acids (n3 PUFA) like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are reported to prevent endothelial dysfunction. Thus, we hypothesize that treatment with n3 PUFA may suppress the actions of SARS-CoV-2 on endothelial cells, potentially through endothelial ACE2. The objective of the study was therefore to investigate whether changes in ACE2 levels occur as part of the endothelial response to n3 PUFA treatment. METHODS: Male fa/fa Zucker rats were randomised into 4 PUFA-based diet groups: α-linoleic acid (ALA), EPA, DHA, and linoleic acid (LA), for 8 weeks. EA.hy926 cells were cultured to sub-confluent and quiescent states and treated with various doses of DHA, EPA, and ALA for 8 or 24 h. ACE2 levels in tissues and cells were quantified by Western blotting. RESULTS: In contrast to ALA and EPA, DHA treatment significantly reduced ACE2 levels in rat heart, aorta, and kidney but not lungs after 8 weeks of diet intervention. EPA only showed this reduction compared to ALA in kidney. Interestingly, when applied to human endothelial cells in culture, DHA decreased ACE2 levels of growing EA.hy926 cells even at relatively low doses, but no significant effect was observed in quiescent cells. EPA also had an effect, but only at an extremely high dose. CONCLUSIONS: DHA reduced ACE2 levels in key organs and human endothelial cells, which should produce beneficial effects by lowering the susceptibility of cells to SARS-CoV-2. FUNDING SOURCES: St Boniface Hospital Foundation - Research Without Borders and University of Manitoba - GETS

OBJECTIVES: One of the earliest events in atherosclerotic plaque formation is the migration of monocytes to damaged blood vessels, and the accumulation of cholesterol in monocyte-derived macrophages. The omega-3 fatty acid docosahexaenoic acid (DHA) is known to inhibit this process. While there is limited evidence suggesting α-linolenic acid (ALA) has a similar effect, ALA has not been directly compared to DHA. The primary objective of this study was to compare the gene expression profiles of monocytes that have been exposed to either ALA or DHA and examine the effect of these fatty acids on monocyte cholesterol content and migration in a cell culture model. METHODS: Transcriptome analysis was performed on total mRNA isolated from human THP-1 monocytes treated with ALA, DHA or vehicle for 48 h. Candidate genes identified via fold change and Ingenuity Pathway Analysis were validated by qPCR. Functional assays to measure total cholesterol content and migration were then performed on monocytes treated with ALA or DHA. RESULTS: Transcriptome analysis identified a series of genes associated with cholesterol metabolism and cell migration altered by ALA and DHA treatment. Changes in mRNA levels for candidate genes were validated by qPCR, with similar expression patterns as in the transcriptome analysis. Based on these data, both fatty acids were predicted to reduce cholesterol synthesis, ALA would increase migration and DHA would have no effect. Functional assays were then performed and revealed that ALA and DHA decreased cholesterol content to a similar extent. Additionally, contrary to our predictions, DHA significantly decreased migration, while ALA had no effect. CONCLUSIONS: The results suggest ALA and DHA may influence monocyte migration through distinct gene pathways, while cholesterol metabolism may be regulated by a common mechanism. Furthermore, only DHA treatment reduced monocyte migration in functional assays, while both fatty acids reduced cholesterol content. Due to the critical role of monocyte migration and cholesterol content in the pathophysiology of atherosclerosis, it may be concluded from this study that both DHA and ALA may exert protective effects involving different mechanisms as they relate to individuals at risk for cardiovascular disease. FUNDING SOURCES: CIHR, NSERC