Patient and Family Financial Burden in Cancer: A Focus on Differences across Four Provinces, and Reduced Spending Including Decisions to Forego Care in Canada.

GOAL: This study aimed to examine provincial differences in patient spending for cancer care and reductions in household spending including decisions to forego care in Canada. METHODS: Nine-hundred and one patients with cancer, from twenty cancer centers across Canada, completed a self-administered questionnaire (P-SAFE version 7.2.4) (344 breast, 183 colorectal, 158 lung, and 216 prostate) measuring direct and indirect costs and spending changes. RESULTS: Provincial variations showed a high mean out-of-pocket cost (OOPC) of CAD 938 (Alberta) and a low of CAD 280 (Manitoba). Differences were influenced by age and income. Income loss was highest for Alberta (CAD 2399) and lowest for Manitoba (CAD 1126). Travel costs were highest for Alberta (CAD 294) and lowest for British Columbia (CAD 67). Parking costs were highest for Ontario (CAD 103) and lowest for Manitoba (CAD 53). A total of 41% of patients reported reducing spending, but this increased to 52% for families earning

Magnetic Stress-Driven Metal-Insulator Transition in Strongly Correlated Antiferromagnetic CrN.

Traditionally, the Coulomb repulsion or Peierls instability causes the metal-insulator phase transitions in strongly correlated quantum materials. In comparison, magnetic stress is predicted to drive the metal-insulator transition in materials exhibiting strong spin-lattice coupling. However, this mechanism lacks experimental validation and an in-depth understanding. Here we demonstrate the existence of the magnetic stress-driven metal-insulator transition in an archetypal material, chromium nitride. Structural, magnetic, electronic transport characterization, and first-principles modeling analysis show that the phase transition temperature in CrN is directly proportional to the strain-controlled anisotropic magnetic stress. The compressive strain increases the magnetic stress, leading to the much-coveted room-temperature transition. In contrast, tensile strain and the inclusion of nonmagnetic cations weaken the magnetic stress and reduce the transition temperature. This discovery of a new physical origin of metal-insulator phase transition that unifies spin, charge, and lattice degrees of freedom in correlated materials marks a new paradigm and could lead to novel device functionalities.

Is vaccine hesitancy justified? Benchmarking post-market vaccine risks with five commonly used medicinal products in Canada.

OBJECTIVE: Although vaccines are one of the most cost-effective, low-risk healthcare approaches that save thousands of lives every year, paradoxical fear about vaccine safety is a major roadblock for achieving widespread vaccination coverage. The objective of this study is to change public perception of vaccine safety by presenting real-world incidence of adverse events following immunization (AEFIs). METHODS: In this study, we used Canadian post-market adverse events data to estimate the real-world risk of AEFI and benchmarked them against five commonly used drug types-ACE inhibitors, beta2 adrenergic receptors, penicillins, proton pump inhibitors, and HMG-CoA reductase inhibitors. RESULTS: Our analysis shows that post-market AEFIs are rare, and vaccination generally carries a significantly lower risk compared to some commonly used medicinal product types. CONCLUSION: Despite some limitations with using post-trial adverse events data, we believe that the evidence presented in this study, especially the comparative risk analysis between vaccines and medicinal products, when communicated through proper channels, can help vaccine-hesitant individuals overcome their perceived safety concerns with regard to vaccines.

RéSUMé: OBJECTIFS: Bien que les vaccins soient l'une des approches de soins de santé les plus rentables et à faible risque qui sauvent des milliers de vies chaque année, la peur paradoxale de la sécurité des vaccins est un obstacle majeur à la réalisation d'une couverture vaccinale généralisée. L'objectif de cette étude est de changer la perspective publique de la sécurité des vaccins en présentant l'incidence actuelle des événements indésirables post-commercialisation après la vaccination. MéTHODES: Dans cette étude, nous avons utilisé les données canadiennes sur les événements indésirables post-commercialisation pour estimer le risque réel d'événements indésirables après la vaccination et les avons comparés à cinq types de médicaments couramment utilisés ­ inhibiteurs de l'ECA (enzyme de conversion de l'angiotensine), récepteur bêta-2-adrénergique, pénicillines, inhibiteurs de la pompe à protons et inhibiteurs de l'HMG-CoA réductase. RéSULTATS: Notre analyse montre que les événements indésirables post-commercialisation après la vaccination sont rares et que la vaccination comporte généralement un risque significativement plus faible par rapport à certains types de médicaments couramment utilisés. CONCLUSION: Malgré certaines limites à l'utilisation des données sur les événements indésirables post-essai, nous pensons que les preuves présentées dans cette étude, en particulier l'analyse comparative des risques entre les vaccins et les médicaments, lorsqu'elle est communiquée par des canaux appropriés, peuvent aider les personnes hésitantes à surmonter leurs préoccupations perçues en matière d'innocuité des vaccins.

Pragmatic pharmacoeconomic analyses by using post-market adverse drug reaction reports: an illustration using infliximab, adalimumab, and the Canada vigilance adverse reaction database.

BACKGROUND: The prediction of the real-world cost of adverse drug reactions (ADRs) has historically relied on the data from randomized controlled trials (RCT). However, trial conditions do not always reflect the real-world applications of pharmaceutical products; hence, they may not accurately portray the actual risks of ADRs associated with them. The objective of this study is two-fold: (a) demonstrate whether and how post-market and RCT ADR data could lead to different conclusions for a set of drugs of interest, and (b) evaluate the potential economic impact of the post-market ADRs associated with those drugs. METHODS: We selected two TNF-α inhibitor biologics, infliximab and adalimumab, and used the Canada Vigilance Adverse Reaction (CVAR) online database as a source of post-market ADR data. Adverse reaction data from RCTs were obtained from ClinicalTrials.gov . Direct healthcare costs associated with adverse reactions were obtained from Canadian Institute for Health Information (CIHI) or Interactive Health Data Application, Alberta. We calculated post-market ADR rates and compared them with those found in the randomized controlled trials of these two drugs. Using the post-market data, we estimated the costs associated with serious ADRs from three perspectives: patient, health system, and societal. RESULTS: For both drugs, the post-market and RCT data exhibited significantly different adverse reaction rates for several different clinical outcomes. As a general trend, more serious adverse reactions, such as death, appeared to have a higher rate in post-market applications compared to the clinical trials. The estimated average annual economic burden of the severe adverse reaction outcomes ranged from $10 million to $20 million for infliximab and $6 million to $19 million for adalimumab. CONCLUSIONS: The frequency and severity of post-market adverse reactions associated with pharmaceutical products may significantly differ from those detected in the clinical trials. Despite possible methodological differences, this is due to the fact that post-market data reflect the externalities of the real-world that are absent in RCTs. The economic burden of adverse reactions can be substantial, and the cost calculated using post-market data is better reflective of the cost of ADRs in the real-world.

Creating Ferromagnetic Insulating La0.9Ba0.1MnO3 Thin Films by Tuning Lateral Coherence Length.

In this work, heteroepitaxial vertically aligned nanocomposite (VAN) La0.9Ba0.1MnO3 (LBMO)-CeO2 films are engineered to produce ferromagnetic insulating (FMI) films. From combined X-ray photoelectron spectroscopy, X-ray diffraction, and electron microscopy, the elimination of the insulator-metal (I-M) transition is shown to result from the creation of very small lateral coherence lengths (with the corresponding lateral size ∼ 3 nm (∼7 u.c.)) in the LBMO matrix, achieved by engineering a high density of CeO2 nanocolumns in the matrix. The small lateral coherence length leads to a shift in the valence band maximum and reduction of the double exchange (DE) coupling. There is no "dead layer" effect at the smallest achieved lateral coherence length of ∼3 nm. The FMI behavior obtained by lateral dimensional tuning is independent of substrate interactions, thus intrinsic to the film itself and hence not related to film thickness. The unique properties of VAN films give the possibility for multilayer spintronic devices that can be made without interface degradation effects between the layers.

Patient and family financial burden associated with cancer treatment in Canada: a national study.

GOAL: To determine patient-reported financial and family burden associated with treatment of cancer in the previous 28 days across Canada. METHODS: A self-administered questionnaire (P-SAFE v7.2.4) was completed by 901 patients with cancer from twenty cancer centres nationally (344 breast, 183 colorectal, 158 lung, 216 prostate) measuring direct and indirect costs related to cancer treatment and foregone care. Monthly self-reported out-of-pocket-costs (OOPCs) included drugs, homecare, homemaking, complementary/ alternative medicines, vitamins/supplements, family care, accommodations, devices, and "other" costs. Travel and parking costs were captured separately. Patients indicated if OOPC, travel, parking, and lost income were a financial burden. RESULTS: Mean 28-day OOPCs were CA$518 (US Purchase Price Parity [PPP] $416), plus CA$179 (US PPP $144) for travel and CA$84 (US PPP $67) for parking. Patients self-reporting high financial burden had total OOPCs (33%), of CA$961 (US PPP $772), while low-burden participants (66%) had OOPCs of CA$300 (US PPP $241). "Worst burden" respondents spent a mean of 50.7% of their monthly income on OOPCs (median 20.8%). Among the 29.4% who took time off work, patients averaged 18.0 days off. Among the 26.0% of patients whose caregivers took time off work, caregivers averaged 11.5 days off. Lastly, 41% of all patients had to reduce spending. Fifty-two per cent of those who reduced spending were families earning < CA$50,000/year. CONCLUSIONS: In our Canadian sample, high levels of financial burden exist for 33% of patients, and the severity of burden is higher for those with lower household incomes.

Compositional Tuning of the Aurivillius Phase Material Bi5Ti3-2xFe1+xNbxO15 (0 ≤ x ≤ 0.4) Grown by Chemical Solution Deposition and its Influence on the Structural, Magnetic, and Optical Properties of the Material.

A series of Aurivillius phase materials, Bi5Ti 3 - 2x Fe 1 + x NbxO15 ( [Formula: see text], 0.1, 0.2, 0.3, and 0.4), was fabricated by chemical solution deposition. The effects of aliovalent substitution for the successful inclusion of Fe 3+ and Nb 5+ by replacing Ti 4+ were explored as a potential mechanism for increasing magnetic ion content within the material. The structural, optical, piezoelectric, and magnetic properties of the materials were investigated. It was found that a limit of x = 0.1 was achieved before the appearance of secondary phases as determined by the X-ray diffraction. Absorption in the visible region increased with increasing values of x corresponding to the transition from the valence band to the conduction band of the Fe- [Formula: see text] energy level. Piezoresponse force microscopy measurements demonstrated that the lateral piezoelectric response increased with increasing values of x . Magnetic measurements of Bi5Ti2.8Fe1.1Nb0.1O15 exhibited a weak ferromagnetic response at 2, 150, and 300 K of 2.2, 1.6, and 1.5 emu/cm3 with Hc of  âˆ¼ 40 , 36, and 34 Oe, respectively. The remanent magnetization MR of this sample was found to be higher than the range of reported values for the Bi5Ti3Fe1O15 parent phase. Elemental analysis of this sample by energy-dispersive X-ray analysis did not provide any evidence for the presence of iron-rich secondary phases. However, it is noted that a series of measurements at varying sample volumes and instrument resolutions is still required in order to put a defined confidence level on the Bi5Ti2.8Fe1.1Nb0.1O15 material being a single-phase multiferroic.

Nanoengineering room temperature ferroelectricity into orthorhombic SmMnO3 films.

Orthorhombic RMnO3 (R = rare-earth cation) compounds are type-II multiferroics induced by inversion-symmetry-breaking of spin order. They hold promise for magneto-electric devices. However, no spontaneous room-temperature ferroic property has been observed to date in orthorhombic RMnO3. Here, using 3D straining in nanocomposite films of (SmMnO3)0.5((Bi,Sm)2O3)0.5, we demonstrate room temperature ferroelectricity and ferromagnetism with TC,FM ~ 90 K, matching exactly with theoretical predictions for the induced strain levels. Large in-plane compressive and out-of-plane tensile strains (-3.6% and +4.9%, respectively) were induced by the stiff (Bi,Sm)2O3 nanopillars embedded. The room temperature electric polarization is comparable to other spin-driven ferroelectric RMnO3 films. Also, while bulk SmMnO3 is antiferromagnetic, ferromagnetism was induced in the composite films. The Mn-O bond angles and lengths determined from density functional theory explain the origin of the ferroelectricity, i.e. modification of the exchange coupling. Our structural tuning method gives a route to designing multiferroics.

Adverse Drug Reactions in Canada (2009-2018): Insights from the Canada Vigilance Database.

Annually, thousands of individuals die and tens of thousands are hospitalized in association with suspected adverse drug reactions (ADRs) in Canada. We analyzed the reports from the Canada Vigilance Adverse Reaction online database and present a synopsis of the state of ADRs in Canada between 2009 and 2018. Our synopsis includes both cross-sectional and longitudinal insights into ADR demographics, outcomes, associated drugs and disease indications. In closing, we highlight five overarching issues uncovered in our analysis, which have potential implications for future policy formulation. Further in-depth exploration is required to shine some additional light on these issues.

Achieving ferromagnetic insulating properties in La0.9Ba0.1MnO3 thin films through nanoengineering.

Strongly correlated manganites have a wide range of fascinating magnetic and electronic properties, one example being the coexistence of ferromagnetic and insulating properties in lightly-doped bulk. However, it is difficult to translate bulk properties to films. Here, this problem is overcome by thin film nanoengineering of the test case system, La0.9Ba0.1MnO3 (LBMO). This was achieved by using vertically aligned nanocomposite (VAN) thin films of LBMO + CeO2 in which CeO2 nanocolumns form embedded in a LBMO matrix. The CeO2 columns produce uniform tensile straining of the LBMO. Also light Ce doping of intrinsic cation vacancies in the LBMO occurs. Together, these factors strongly reduced the double exchange coupling and metallicity. Hence, while standard plain reference films showed an insulator-to-metal transition at >200 K, originating from defects and complex structural relaxation, the VAN LBMO films exhibited ferromagnetic insulating properties (while maintaining a Tc of 188 K). This is the first time that a combined strain + doping method is used in a VAN system to realise exemplary properties which cannot be realised in plain films. This work represents an important step in engineering high performance spintronic and multiferroic thin film devices.

Vertical Strain-Driven Antiferromagnetic to Ferromagnetic Phase Transition in EuTiO3 Nanocomposite Thin Films.

Three-dimensional (3D) strain induced in self-assembled vertically aligned nanocomposite (VAN) epitaxial films provides an unrivaled method to induce very large strains in thin films. Here, by growing VAN films of EuTiO3 (ETO)-Eu2O3 (EO) with different EO fractions, the vertical strain was systematically increased in ETO, up to 3.15%, and the Eu-Ti-Eu bond angle along ⟨111⟩ decreased by up to 1°, leading to a weakening of the antiferromagnetic interactions and switching from antiferromagnetic to ferromagnetic behavior. Our work has shown for the first time that Eu-Ti-Eu superexchange interactions play a key role in determining the magnetic ground state of ETO. More broadly, our work serves as an exemplar to show that multifunctionalities in strong spin-lattice coupling perovskite oxides can be uniquely tuned at the atomic scale using simple VAN structures.

The TRIM-NHL protein NHL-2 is a co-factor in the nuclear and somatic RNAi pathways in C. elegans.

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 is a bona fide RNA binding protein and, along with RNA-seq data point to a small RNA independent role for NHL-2 in regulating transcripts at the level of RNA stability. Collectively, our data implicate NHL-2 as an essential hub of gene regulatory activity in both the germline and soma.

Size and space controlled hexagonal arrays of superparamagnetic iron oxide nanodots: magnetic studies and application.

Highly dense hexagonally arranged iron oxide nanodots array were fabricated using PS-b-PEO self-assembled patterns. The copolymer molecular weight, composition and choice of annealing solvent/s allows dimensional and structural control of the nanopatterns at large scale. A mechanism is proposed to create scaffolds through degradation and/or modification of cylindrical domains. A methodology based on selective metal ion inclusion and subsequent processing was used to create iron oxide nanodots array. The nanodots have uniform size and shape and their placement mimics the original self-assembled nanopatterns. For the first time these precisely defined and size selective systems of ordered nanodots allow careful investigation of magnetic properties in dimensions from 50 nm to 10 nm, which delineate the nanodots are superparamagnetic, well-isolated and size monodispersed. This diameter/spacing controlled iron oxide nanodots systems were demonstrated as a resistant mask over silicon to fabricate densely packed, identical ordered, high aspect ratio silicon nanopillars and nanowire features.

Superspin glass mediated giant spontaneous exchange bias in a nanocomposite of BiFeO3-Bi2Fe4O9.

We observe an enormous spontaneous exchange bias (~300-600 Oe)--measured in an unmagnetized state following zero-field cooling--in a nanocomposite of BiFeO(3) (~94%)-Bi(2)Fe(4)O(9) (~6%) over a temperature range 5-300 K. Depending on the path followed in tracing the hysteresis loop--positive (p) or negative (n)--as well as the maximum field applied, the exchange bias (H(E)) varies significantly with | - H(Ep) | > | H(En) |. The temperature dependence of H(E) is nonmonotonic. It increases, initially, till ~150 K and then decreases as the blocking temperature T(B) is approached. All these rich features appear to be originating from the spontaneous symmetry breaking and consequent onset of unidirectional anisotropy driven by "superinteraction bias coupling" between the ferromagnetic core of Bi(2)Fe(4)O(9) (of average size ~19 nm) and the canted antiferromagnetic structure of BiFeO(3) (of average size ~112 nm) via superspin glass moments at the shell.

Exploring the sequence-function relationship in transcriptional regulation by the lac O1 operator.

Understanding how binding of a transcription factor to an operator is influenced by the operator sequence is an ongoing quest. It facilitates discovery of alternative binding sites as well as tuning of transcriptional regulation. We investigated the behavior of the Escherichia coli Lac repressor (LacI) protein with a large set of lac O(1) operator variants. The 114 variants examined contained a mean of 2.9 (range 0-4) mutations at positions -4, -2, +2 and +4 in the minimally required 17 bp operator. The relative affinity of LacI for the operators was examined by quantifying expression of a GFP reporter gene and Rosetta structural modeling. The combinations of mutations in the operator sequence created a wide range of regulatory behaviors. We observed variations in the GFP fluorescent signal among the operator variants of more than an order of magnitude under both uninduced and induced conditions. We found that a single nucleotide change may result in changes of up to six- and 12-fold in uninduced and induced GFP signals, respectively. Among the four positions mutated, we found that nucleotide G at position -4 is strongly correlated with strong repression. By Rosetta modeling, we found a significant correlation between the calculated binding energy and the experimentally observed transcriptional repression strength for many operators. However, exceptions were also observed, underscoring the necessity for further improvement in biophysical models of protein-DNA interactions.

Large scale monodisperse hexagonal arrays of superparamagnetic iron oxides nanodots: a facile block copolymer inclusion method.

Highly dense hexagonal ordered arrays of superparamagnetic iron oxides nanodots are fabricated by a simple and cost-effective route. Spectroscopic, microscopic and magnetic measurements show that the nanodots have uniform size, shape and their placement mimics the original self-assembled block copolymer pattern. The nanodots show good thermal stability and strong adherence to the substrate surface, making them useful for practical device applications.

DNA binding site analysis of Burkholderia thailandensis response regulators.

Bacterial response regulators (RR) that function as transcription factors in two component signaling pathways are crucial for ensuring tight regulation and coordinated expression of the genome. Currently, consensus DNA binding sites in the promoter for very few bacterial RRs have been identified. A systematic method to characterize these DNA binding sites for RRs would enable prediction of specific gene expression patterns in response to extracellular stimuli. To identify RR DNA binding sites, we functionally activated RRs using beryllofluoride and applied them to a protein-binding microarray (PBM) to discover DNA binding motifs for RRs expressed in Burkholderia, a Gram-negative bacterial genus. We identified DNA binding motifs for conserved RRs in Burkholderia thailandensis, including KdpE, RisA, and NarL, as well as for a previously uncharacterized RR at locus BTH_II2335 and its ortholog in the human pathogen Burkholderia pseudomallei at locus BPSS2315. We further demonstrate RR binding of predicted genomic targets for the two orthologs using gel shift assays and reveal a pattern of RR regulation of expression of self and other two component systems. Our studies illustrate the use of PBMs to identify DNA binding specificities for bacterial RRs and enable prediction of gene regulatory networks in response to two component signaling.

Discovery of DNA operators for TetR and MarR family transcription factors from Burkholderia xenovorans.

Determining transcription factor (TF) recognition motifs or operator sites is central to understanding gene regulation, yet few operators have been characterized. In this study, we used a protein-binding microarray (PBM) to discover the DNA recognition sites and putative regulons for three TetR and one MarR family TFs derived from Burkholderia xenovorans, which are common to the genus Burkholderia. We also describe the development and application of a more streamlined version of the PBM technology that significantly reduced the experimental time. Despite the genus containing many pathogenically important species, only a handful of TF operator sites have been experimentally characterized for Burkholderia to date. Our study provides a significant addition to this knowledge base and illustrates some general challenges of discovering operators on a large scale for prokaryotes.