Engineering covalently bonded 2D layered materials by self-intercalation.

Two-dimensional (2D) materials1-5 offer a unique platform from which to explore the physics of topology and many-body phenomena. New properties can be generated by filling the van der Waals gap of 2D materials with intercalants6,7; however, post-growth intercalation has usually been limited to alkali metals8-10. Here we show that the self-intercalation of native atoms11,12 into bilayer transition metal dichalcogenides during growth generates a class of ultrathin, covalently bonded materials, which we name ic-2D. The stoichiometry of these materials is defined by periodic occupancy patterns of the octahedral vacancy sites in the van der Waals gap, and their properties can be tuned by varying the coverage and the spatial arrangement of the filled sites7,13. By performing growth under high metal chemical potential14,15 we can access a range of tantalum-intercalated TaS(Se)y, including 25% Ta-intercalated Ta9S16, 33.3% Ta-intercalated Ta7S12, 50% Ta-intercalated Ta10S16, 66.7% Ta-intercalated Ta8Se12 (which forms a Kagome lattice) and 100% Ta-intercalated Ta9Se12. Ferromagnetic order was detected in some of these intercalated phases. We also demonstrate that self-intercalated V11S16, In11Se16 and FexTey can be grown under metal-rich conditions. Our work establishes self-intercalation as an approach through which to grow a new class of 2D materials with stoichiometry- or composition-dependent properties.

The difficulty of computing stable and accurate neural networks: On the barriers of deep learning and Smale's 18th problem.

Deep learning (DL) has had unprecedented success and is now entering scientific computing with full force. However, current DL methods typically suffer from instability, even when universal approximation properties guarantee the existence of stable neural networks (NNs). We address this paradox by demonstrating basic well-conditioned problems in scientific computing where one can prove the existence of NNs with great approximation qualities; however, there does not exist any algorithm, even randomized, that can train (or compute) such a NN. For any positive integers K>2 and L, there are cases where simultaneously 1) no randomized training algorithm can compute a NN correct to K digits with probability greater than 1/2; 2) there exists a deterministic training algorithm that computes a NN with K ­1 correct digits, but any such (even randomized) algorithm needs arbitrarily many training data; and 3) there exists a deterministic training algorithm that computes a NN with K ­2 correct digits using no more than L training samples. These results imply a classification theory describing conditions under which (stable) NNs with a given accuracy can be computed by an algorithm. We begin this theory by establishing sufficient conditions for the existence of algorithms that compute stable NNs in inverse problems. We introduce fast iterative restarted networks (FIRENETs), which we both prove and numerically verify are stable. Moreover, we prove that only O(|log (ϵ)|) layers are needed for an ϵ-accurate solution to the inverse problem.

Monocyte recruitment in venous pulmonary embolism at time of cancer diagnosis in upper gastrointestinal cancer patients.

Upper gastrointestinal cancer is frequently complicated by venous thromboembolisms (VTE), especially pulmonary embolisms (PE) increase the mortality rate. Monocytes are a part of the innate immune system and up-regulation may indicate an ongoing inflammatory response or infectious disease and has lately been associated with a moderate risk of suffering from VTE. This prospectively study aims to compare the incidence of pulmonary embolism with markers of coagulation and compare it to the absolute monocyte count. A consecutive cohort of 250 patients with biopsy proven upper gastrointestinal cancer (i.e. pancreas, biliary tract, esophagus and gastric cancer) where included at the time of cancer diagnosis and before treatment. All patients underwent bilateral compression ultrasonography for detection of deep vein thrombosis (DVT). Of these 143 had an additionally pulmonary angiografi (CTPA) with the staging computer tomography. 13 of 250 patients (5.2%) had a DVT and 11 of 143 (7.7%) had CTPA proven PE. PE was significantly more common among patients with elevated D-dimer (OR 11.62, 95%CI: 1.13-119, P = 0.039) and elevated absolute monocyte count (OR 7.59, 95%CI: 1.37-41.98, P = 0.020). Only patients with pancreatic cancer had a significantly higher risk of DVT (OR 11.03, 95%CI: 1.25-97.43, P = 0.031). The sensitivity of absolute monocyte count was 63.6 (95%CI: 30.8-89.1) and specificity 80.3 (95%CI: 72.5-86.7), with a negative predictive value of 96.4 (95%CI: 91-99) in PE. An increased absolute monocyte count was detected in patients suffering from PE but not DVT, suggesting a possible interaction with the innate immune system.

Preventing hypothermia in pediatric neurosurgery in Africa-A randomized controlled non-inferiority trial of insulation versus active warming.

PURPOSE: The objective of this study was to compare the efficacy of a low-cost heat-preserving method in preventing intraoperative hypothermia with that of forced-air warming in a resource-limited setting. METHODS: In this randomized controlled non-inferiority trial, we recruited children younger than 12 years scheduled for cranial neurosurgery in a large East-African hospital. Patients were block-randomized by age to intraoperative warming measures using Hibler's method (intervention) or warm air (comparator). Hibler's group patients were circumferentially wrapped in transparent plastic sheeting (providing a vapor-trap) over a layer of cotton blankets, then laid on an insulating foam mattress. Warm air group patients were treated with forced-air convection via an underlying Snuggle Warm™ Pediatric Full Body mattress. Allocated warming measures were initiated in the operating theatre and discontinued upon anesthesia emergence. Perioperative temperatures were measured using noninvasive forehead probes (SpotOn™). The primary outcome was incidence of hypothermia (core temperature < 36.0° for longer than 5 min). Our null hypothesis was that Hibler's method is inferior in efficacy to the warm air method by a margin exceeding 20%. Among secondary outcomes were duration of hypothermia as proportion of surgical duration, incidence of postoperative shivering and rescue measure requirements. RESULTS: We analyzed data for 77 participants (Hibler's = 38; warm air = 39). There was no significant difference between the Hibler's and warm air arms of the study in the primary outcome of incidence of hypothermia (59.0% vs. 60.5% respectively; OR 1.07; 95% CI 0.43-2.65; p = .890). However, the risk difference (1.55%; 95% CI -0.20 to -0.24) exceeded the 0.2 margin and non-inferiority could not be declared. There was considerable need for rescue measures in both groups (71.1 0% vs. 69.2%; OR 1.09; 95% CI 0.41-2.90; p = .861). There was no statistically significant difference between groups for any prespecified secondary outcome. CONCLUSION: Although perioperative core temperatures were not significantly different, we could not declare an inexpensive heat-preserving method non-inferior to warm air convection in preventing intraoperative hypothermia in children undergoing anesthesia for cranial neurosurgery in a resource-limited setting. The extensive need for rescue measures may have masked important differences. TRIAL REGISTRATION: US National Institutes of Health Clinicaltrials.gov database (ID no. NCT02975817).

Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported. METHODS: We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses. RESULTS: Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher's exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined. CONCLUSIONS: This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC. METHODS: We performed methylation-specific PCR of the SFRP1 genes' promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions. RESULTS: The study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%-61.7%) and 19.8% (95% CI 1.9-37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-months CONCLUSIONS: This indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.

On instabilities of deep learning in image reconstruction and the potential costs of AI.

Deep learning, due to its unprecedented success in tasks such as image classification, has emerged as a new tool in image reconstruction with potential to change the field. In this paper, we demonstrate a crucial phenomenon: Deep learning typically yields unstable methods for image reconstruction. The instabilities usually occur in several forms: 1) Certain tiny, almost undetectable perturbations, both in the image and sampling domain, may result in severe artefacts in the reconstruction; 2) a small structural change, for example, a tumor, may not be captured in the reconstructed image; and 3) (a counterintuitive type of instability) more samples may yield poorer performance. Our stability test with algorithms and easy-to-use software detects the instability phenomena. The test is aimed at researchers, to test their networks for instabilities, and for government agencies, such as the Food and Drug Administration (FDA), to secure safe use of deep learning methods.

European coastal monitoring programmes may fail to identify impacts on benthic macrofauna caused by bottom trawling.

Bottom trawling (hereafter trawling) is the dominant human pressure impacting continental shelves globally. However, due to ongoing data deficiencies for smaller coastal vessels, the effects of trawling on nearshore seabed ecosystems are poorly understood. In Europe, the Water Framework Directive (WFD) provides a framework for the protection and improvement of coastal water bodies. It requires member states to track the status of 'biological quality elements' (including benthic macrofauna) using WFD-specific ecological indicators. While many of these metrics are sensitive to coastal pressures such as nutrient enrichment, little is known about their ability to detect trawling impacts. Here, we analysed a comprehensive data set of 5885 nearshore benthic samples - spatiotemporally matched to high-resolution trawling and environmental data - to examine how these pressures affect coastal benthos. In addition, we investigated the ability of 8 widely-used benthic monitoring metrics to detect impacts on benthic biological quality. We found that abundance (N) and species richness (S) were strongly impacted by bottom trawling. A clear response to trawling was also observed for the WFD-specific Benthic Quality Index (BQI). Relationships between N and S, and trawling were particularly consistent across the study area, indicating sensitivity across varying environmental conditions. In contrast, WFD indices such as AZTIs Marine Biotic Index (AMBI), multivariate AMBI (M-AMBI), and the Danish Quality Index (DKI), were unresponsive to trawling. In fact, some of the most heavily trawled areas examined were classified as being of 'high/good ecological status' by these indices. A likely explanation for this is that the indices are calculated using species sensitivity scores, based on expected species response to eutrophication and chemical pollution. While the BQI also uses species sensitivity scores, these are based on observed responses to disturbance gradients comprising a range of coastal pressures. Given the prominent use of AMBI and DKI throughout Europe, our results highlight the considerable risk that the metrics used to assess Good Ecological Status (GES) under the WFD may fail to identify trawling impacts. As trawling represents a widespread source of coastal disturbance, fishing impacts on benthic macrofauna may be underestimated, or go undetected, in many coastal monitoring programmes around Europe.

A one-time pneumatic jet-injection of 5-fluorouracil and triamcinolone acetonide for treatment of hypertrophic scars-A blinded randomized controlled trial.

BACKGROUND: Patients with hypertrophic scars (HTS) risk reduced quality of life due to itching, pain, poor cosmesis, and restriction of movement. Despite good clinical efficacy, patients are often reluctant to undergo repeated needle injections due to pain or needle phobia. OBJECTIVES: To evaluate the applicability of needle-free pneumatic jet injection (PJI) and assess changes in hypertrophic scars following a single PJI treatment with 5-fluorouracil (5-FU) and triamcinolone acetonide (TAC). METHODS: Twenty patients completed this blinded, randomized, controlled, split-scar trial. The intervention side of the HTS received a one-time treatment with PJIs containing a mixture of TAC + 5-FU injected at 5 mm intervals (mean 7 PJI per HTS); the control side received no treatment. Assessments were made at baseline and 4 weeks posttreatment. Outcome measures included change in (1) Vancouver Scar Scale (VSS) total score and subscores, (2) scar volume and surface area assessed by three-dimensional imaging, (3) skin microarchitecture measured by optical-coherence tomography (OCT), (4) photo-assessed scar cosmesis (0-100), (5) patient-reported pain and satisfaction (0-10), and (6) depiction of drug biodistribution after PJI. RESULTS: PJI with TAC + 5-FU significantly decreased both HTS height (-1 VSS; p = 0.01) and pliability (-1 VSS; p < 0.01) with a nonstatistically significant reduction of -1 in total VSS score (0 in control; p = 0.09). On 3D imaging, a 33% decrease in scar volume (p = 0.016) and a 37% decrease in surface area (p = 0.008) was observed. OCT indicated trends towards smoother scar surface (Ra 11.1-10.3; p = 0.61), normalized dermal microarchitecture (attenuation coefficient: 1.52-1.68; p = 0.44), and a reduction in blood flow between 9% and 17% (p = 0.50-0.79). Despite advances in VSS subscores and OCT, no improved photo-assessed cosmesis was found (-3.2 treatment vs. -1.4 control; p = 0.265). Patient-reported pain was low (2/10) and 90% of the patients that had previously received needle injections preferred PJI to needle injection. Depositions of TAC + FU were imaged reaching deep into the scar at levels corresponding to the reticular dermis. CONCLUSION: A single PJI injection containing 5-FU and TAC can significantly improve the height and pliability of HTS. PJI is favored by the patients and may serve as a complement to conventional needle injections, especially for patients with needle phobia.

Arteria lusoria: a trick of nature.

Dysphagia has several typical causes. In this case report a young adult with difficulties in swallowing since childhood is diagnosed with a rare anatomical variation of the aortal branches.

The development of race effects in face processing from childhood through adulthood: Neural and behavioral evidence.

Most adults are better at recognizing recently encountered faces of their own race, relative to faces of other races. In adults, this race effect in face recognition is associated with differential neural representations of own- and other-race faces in the fusiform face area (FFA), a high-level visual region involved in face recognition. Previous research has linked these differential face representations in adults to viewers' implicit racial associations. However, despite the fact that the FFA undergoes a gradual development which continues well into adulthood, little is known about the developmental time-course of the race effect in FFA responses. Also unclear is how this race effect might relate to the development of face recognition or implicit associations with own- or other-races during childhood and adolescence. To examine the developmental trajectory of these race effects, in a cross-sectional study of European American (EA) children (ages 7-11), adolescents (ages 12-16) and adults (ages 18-35), we evaluated responses to adult African American (AA) and EA face stimuli, using functional magnetic resonance imaging and separate behavioral measures outside the scanner. We found that FFA responses to AA and EA faces differentiated during development from childhood into adulthood; meanwhile, the magnitudes of race effects increased in behavioral measures of face-recognition and implicit racial associations. These three race effects were positively correlated, even after controlling for age. These findings suggest that social and perceptual experiences shape a protracted development of the race effect in face processing that continues well into adulthood.

Evaluating the Sensitivity of PM2.5-Mortality Associations to the Spatial and Temporal Scale of Exposure Assessment.

BACKGROUND: The temporal and spatial scales of exposure assessment may influence observed associations between fine particulate air pollution (PM2.5) and mortality, but few studies have systematically examined this question. METHODS: We followed 2.4 million adults in the 2001 Canadian Census Health and Environment Cohort for nonaccidental and cause-specific mortality between 2001 and 2011. We assigned PM2.5 exposures to residential locations using satellite-based estimates and compared three different temporal moving averages (1, 3, and 8 years) and three spatial scales (1, 5, and 10 km) of exposure assignment. In addition, we examined different spatial scales based on age, employment status, and urban/rural location, and adjustment for O3, NO2, or their combined oxidant capacity (Ox). RESULTS: In general, longer moving averages resulted in stronger associations between PM2.5 and mortality. For nonaccidental mortality, we observed a hazard ratio of 1.11 (95% CI = 1.08, 1.13) for the 1-year moving average compared with 1.23 (95% CI = 1.20, 1.27) for the 8-year moving average. Respiratory and lung cancer mortality were most sensitive to the spatial scale of exposure assessment with stronger associations observed at smaller spatial scales. Adjustment for oxidant gases attenuated associations between PM2.5 and cardiovascular mortality and strengthened associations with lung cancer. Despite these variations, PM2.5 was associated with increased mortality in nearly all of the models examined. CONCLUSIONS: These findings support a relationship between outdoor PM2.5 and mortality at low concentrations and highlight the importance of longer-exposure windows, more spatially resolved exposure metrics, and adjustment for oxidant gases in characterizing this relationship.

Disease assimilation: The mortality impacts of fine particulate matter on immigrants to Canada.

BACKGROUND: Immigrants make up 20% of the Canadian population; however, little is known about the mortality impacts of fine particulate matter (PM2.5) air pollution on immigrants compared with non-immigrants, or about how impacts may change with duration in Canada. DATA AND METHODS: This study used the 2001 Canadian Census Health and Environment Cohort, a longitudinal cohort of 3.5 million individuals, of which 764,000 were classified as immigrants (foreign-born). Postal codes from annual income tax files were used to account for mobility among respondents and to assign annual PM2.5 concentrations from 1998 to 2016. Exposures were estimated as a three-year moving average prior to the follow-up year. Cox survival models were used to determine hazard ratios (HRs) for cause-specific mortality, comparing the Canadian and foreign-born populations, with further stratification by year of immigration grouped into 10-year cohorts. RESULTS: Differences in urban-rural settlement patterns resulted in greater exposure to PM2.5 for immigrants compared with non-immigrants (mean = 9.3 vs. 7.5 µg/m3), with higher exposures among more recent immigrants. In fully adjusted models, immigrants had higher HRs per 10 µg/m3 increase in PM2.5 concentration compared with Canadian-born individuals for cardiovascular mortality (HR [95% confidence interval] = 1.22 [1.12 to 1.34] vs. 1.12 [1.07 to 1.18]) and cerebrovascular mortality (HR = 1.25 [1.03 to 1.52] vs. 1.03 [0.93 to 1.15]), respectively. However, tests for differences between the two groups were not significant when Cochran's Q test was used. No significant associations were found for respiratory outcomes, except for lung cancer in non-immigrants (HR = 1.10 [1.02 to 1.18]). When stratified by year of immigration, differences in HRs across varied by cause of death. DISCUSSION: In Canada, PM2.5 is an equal-opportunity risk factor, with immigrants experiencing similar if not higher mortality risks compared with non-immigrants for cardiovascular-related causes of death. Some notable differences also existed with cerebrovascular and lung cancer deaths. Continued reductions in air pollution, particularly in urban areas, will improve the health of the Canadian population as a whole.

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma.

Cancer-associated venous thrombosis (VTE) increases mortality and morbidity. However, limited tools are available to identify high risk patients. Upon activation, neutrophils release their content through different mechanisms, thereby prompting thrombosis. We explored plasma microRNAs (miRNAs) and neutrophil activation markers to predict VTE in pancreatic ductal adenocarcinoma (PDAC) and distal extrahepatic cholangiocarcinoma (DECC). Twenty-six PDAC and 6 DECC patients recruited at cancer diagnosis, were examined for deep vein thrombosis and pulmonary embolisms, and were then followed-up with clinical examinations, blood collections, and biCUS. Ten patients developed VTE and were compared with 22 age- and sex-matched controls. miRNA expression levels were measured at diagnosis and right before VTE, and neutrophil activation markers (cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase) were measured in every sample obtained during follow-up. We obtained a profile of 7 miRNAs able to estimate the risk of future VTE at diagnosis (AUC = 0.95; 95% Confidence Interval (CI) (0.987, 1)) with targets involved in the pancreatic cancer and complement and coagulation cascades pathways. Seven miRNAs were up- or down-regulated before VTE compared with diagnosis. We obtained a predictive model of VTE with calprotectin as predictor (AUC = 0.77; 95% CI (0.57, 0.95)). This is the first study that addresses the ability of plasma miRNAs and neutrophil activation markers to predict VTE in PDAC and DECC.

Correction to: Measuring and understanding adherence in a home-based exercise intervention during chemotherapy for early breast cancer.

In the original publication, the sixth author name was published incorrectly as A. Wood. The correct author name should read as W. A. Wood.

Multilayer Laue lenses at high X-ray energies: performance and applications.

X-ray microscopy at photon energies above 15 keV is very attractive for the investigation of atomic and nanoscale properties of technologically relevant structural and bio materials. This method is limited by the quality of X-ray optics. Multilayer Laue lenses (MLLs) have the potential to make a major impact in this field because, as compared to other X-ray optics, they become more efficient and effective with increasing photon energy. In this work, MLLs were utilized with hard X-rays at photon energies up to 34.5 keV. The design, fabrication, and performance of these lenses are presented, and their application in several imaging configurations is described. In particular, two "full field" modes of imaging were explored, which provide various contrast modalities that are useful for materials characterisation. These include point projection imaging (or Gabor holography) for phase contrast imaging and direct imaging with both bright-field and dark-field illumination. With high-efficiency MLLs, such modes offer rapid data collection as compared with scanning methods as well as a large field of views.

How to Compute Spectra with Error Control.

Computing the spectra of operators is a fundamental problem in the sciences, with wide-ranging applications in condensed-matter physics, quantum mechanics and chemistry, statistical mechanics, etc. While there are algorithms that in certain cases converge to the spectrum, no general procedure is known that (a) always converges, (b) provides bounds on the errors of approximation, and (c) provides approximate eigenvectors. This may lead to incorrect simulations. It has been an open problem since the 1950s to decide whether such reliable methods exist at all. We affirmatively resolve this question, and the algorithms provided are optimal, realizing the boundary of what digital computers can achieve. Moreover, they are easy to implement and parallelize, offer fundamental speed-ups, and allow problems that before, regardless of computing power, were out of reach. Results are demonstrated on difficult problems such as the spectra of quasicrystals and non-Hermitian phase transitions in optics.

Co-incorporation of alkali metal ions during amorphous calcium carbonate precipitation and their stabilizing effect.

Calcium carbonate formation has been studied extensively due to its central role in biomineralization and geochemistry. Specifically, the effect of additives incorporated during the formation process has been described in several works related to inorganic, small organic, molecular or macromolecular additives. However, in these previous experiments the presence of counter ions and their possible role has been mostly disregarded. Co-incorporation of counter ions into calcite at low supersaturations has been studied in detail but their incorporation in and effect on the formation and stability of the amorphous phase, which precedes the formation of the crystalline phase at high supersaturations, has not been studied. To address this, we have investigated the incorporation of alkali metal ions into the amorphous phase using various carbonate salts as a carbonate source. We show that the incorporation is the highest for Rb+ with the highest measured value being 5.8 at% Rb+/(Rb+ + Ca2+). The extent of ion incorporation follows the ion size of Rb+ > K+ > Na+ > Li+ which is opposite to that observed in calcite formed at low supersaturation. The presence of these ions in the amorphous phase increases the crystallization temperature, which can be shifted by as much as 200 °C depending on the concentration of alkali metal ions incorporated. However, the lifetime of ACC in solution was similar for all the different carbonate sources.

Evaluation of a method to indirectly adjust for unmeasured covariates in the association between fine particulate matter and mortality.

BACKGROUND: Indirect adjustment via partitioned regression is a promising technique to control for unmeasured confounding in large epidemiological studies. The method uses a representative ancillary dataset to estimate the association between variables missing in a primary dataset with the complete set of variables of the ancillary dataset to produce an adjusted risk estimate for the variable in question. The objective of this paper is threefold: 1) evaluate the method for non-linear survival models, 2) formalize an empirical process to evaluate the suitability of the required ancillary matching dataset, and 3) test modifications to the method to incorporate time-varying exposure data, and proportional weighting of datasets. METHODS: We used the association between fine particle air pollution (PM2.5) with mortality in the 2001 Canadian Census Health and Environment Cohort (CanCHEC, N = 2.4 million, 10-years follow-up) as our primary dataset, and the 2001 cycle of the Canadian Community Health Survey (CCHS, N = 80,630) as the ancillary matching dataset that contained confounding risk factor information not available in CanCHEC (e.g., smoking). The main evaluation process used a gold-standard approach wherein two variables (education and income) available in both datasets were excluded, indirectly adjusted for, and compared to true models with education and income included to assess the amount of bias correction. An internal validation for objective 1 used only CanCHEC data, whereas an external validation for objective 2 replaced CanCHEC with the CCHS. The two proposed modifications were applied as part of the validation tests, as well as in a final indirect adjustment of four missing risk factor variables (smoking, alcohol use, diet, and exercise) in which adjustment direction and magnitude was compared to models using an equivalent longitudinal cohort with direct adjustment for the same variables. RESULTS: At baseline (2001) both cohorts had very similar PM2.5 distributions across population characteristics, although levels for CCHS participants were consistently 1.8-2.0 µg/m3 lower. Applying sample-weighting largely corrected for this discrepancy. The internal validation tests showed minimal downward bias in PM2.5 mortality hazard ratios of 0.4-0.6% using a static exposure, and 1.7-3% when a time-varying exposure was used. The external validation of the CCHS as the ancillary dataset showed slight upward bias of -0.7 to -1.1% and downward bias of 1.3-2.3% using the static and time-varying approaches respectively. CONCLUSIONS: The CCHS was found to be fairly well representative of CanCHEC and its use in Canada for indirect adjustment is warranted. Indirect adjustment methods can be used with survival models to correct hazard ratio point estimates and standard errors in models missing key covariates when a representative matching dataset is available. The results of this formal evaluation should encourage other cohorts to assess the suitability of ancillary datasets for the application of the indirect adjustment methodology to address potential residual confounding.

Low concentrations of fine particle air pollution and mortality in the Canadian Community Health Survey cohort.

BACKGROUND: Approximately 2.9 million deaths are attributed to ambient fine particle air pollution around the world each year (PM2.5). In general, cohort studies of mortality and outdoor PM2.5 concentrations have limited information on individuals exposed to low levels of PM2.5 as well as covariates such as smoking behaviours, alcohol consumption, and diet which may confound relationships with mortality. This study provides an updated and extended analysis of the Canadian Community Health Survey-Mortality cohort: a population-based cohort with detailed PM2.5 exposure data and information on a number of important individual-level behavioural risk factors. We also used this rich dataset to provide insight into the shape of the concentration-response curve for mortality at low levels of PM2.5. METHODS: Respondents to the Canadian Community Health Survey from 2000 to 2012 were linked by postal code history from 1981 to 2016 to high resolution PM2.5 exposure estimates, and mortality incidence to 2016. Cox proportional hazard models were used to estimate the relationship between non-accidental mortality and ambient PM2.5 concentrations (measured as a three-year average with a one-year lag) adjusted for socio-economic, behavioural, and time-varying contextual covariates. RESULTS: In total, 50,700 deaths from non-accidental causes occurred in the cohort over the follow-up period. Annual average ambient PM2.5 concentrations were low (i.e. 5.9 µg/m3, s.d. 2.0) and each 10 µg/m3 increase in exposure was associated with an increase in non-accidental mortality (HR = 1.11; 95% CI 1.04-1.18). Adjustment for behavioural covariates did not materially change this relationship. We estimated a supra-linear concentration-response curve extending to concentrations below 2 µg/m3 using a shape constrained health impact function. Mortality risks associated with exposure to PM2.5 were increased for males, those under age 65, and non-immigrants. Hazard ratios for PM2.5 and mortality were attenuated when gaseous pollutants were included in models. CONCLUSIONS: Outdoor PM2.5 concentrations were associated with non-accidental mortality and adjusting for individual-level behavioural covariates did not materially change this relationship. The concentration-response curve was supra-linear with increased mortality risks extending to low outdoor PM2.5 concentrations.