A Canadian Simulation Model for Major Depressive Disorder: Study Protocol.

BACKGROUND: Major depressive disorder (MDD) is a common, often recurrent condition and a significant driver of healthcare costs. People with MDD often receive pharmacological therapy as the first-line treatment, but the majority of people require more than one medication trial to find one that relieves symptoms without causing intolerable side effects. There is an acute need for more effective interventions to improve patients' remission and quality of life and reduce the condition's economic burden on the healthcare system. Pharmacogenomic (PGx) testing could deliver these objectives, using genomic information to guide prescribing decisions. With an already complex and multifaceted care pathway for MDD, future evaluations of new treatment options require a flexible analytic infrastructure encompassing the entire care pathway. Individual-level simulation models are ideally suited for this purpose. We sought to develop an economic simulation model to assess the effectiveness and cost effectiveness of PGx testing for individuals with major depression. Additionally, the model serves as an analytic infrastructure, simulating the entire patient pathway for those with MDD. METHODS AND ANALYSIS: Key stakeholders, including patient partners, clinical experts, researchers, and modelers, designed and developed a discrete-time microsimulation model of the clinical pathways of adults with MDD in British Columbia (BC), including all publicly-funded treatment options and multiple treatment steps. The Simulation Model of Major Depression (SiMMDep) was coded with a modular approach to enhance flexibility. The model was populated using multiple original data analyses conducted with BC administrative data, a systematic review, and an expert panel. The model accommodates newly diagnosed and prevalent adult patients with MDD in BC, with and without PGx-guided treatment. SiMMDep comprises over 1500 parameters in eight modules: entry cohort, demographics, disease progression, treatment, adverse events, hospitalization, costs and quality-adjusted life-years (payoff), and mortality. The model predicts health outcomes and estimates costs from a health system perspective. In addition, the model can incorporate interactive decision nodes to address different implementation strategies for PGx testing (or other interventions) along the clinical pathway. We conducted various forms of model validation (face, internal, and cross-validity) to ensure the correct functioning and expected results of SiMMDep. CONCLUSION: SiMMDep is Canada's first medication-specific, discrete-time microsimulation model for the treatment of MDD. With patient partner collaboration guiding its development, it incorporates realistic care journeys. SiMMDep synthesizes existing information and incorporates provincially-specific data to predict the benefits and costs associated with PGx testing. These predictions estimate the effectiveness, cost-effectiveness, resource utilization, and health gains of PGx testing compared with the current standard of care. However, the flexible analytic infrastructure can be adapted to support other policy questions and facilitate the rapid synthesis of new data for a broader search for efficiency improvements in the clinical field of depression.

Cost-effectiveness of pharmacogenomic-guided treatment for major depression.

BACKGROUND: Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants. METHODS: We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC. RESULTS: Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation. INTERPRETATION: Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.

Visible colorimetric growth indicators of Neisseria gonorrhoeae for low-cost diagnostic applications.

N. gonorrhoeae is one of the most pressing antibiotic resistant threats of our time and low-cost diagnostics that can easily identify antibiotic resistance are desperately needed. However, N. gonorrhoeae responds so uniquely to growth conditions that it cannot be assumed gonorrhea will respond to common microbiological methods used for other pathogenic organisms. In this paper, we explore visual colorimetric indicators of N. gonorrhoeae growth that can be seen without a microscope or spectrophotometer. We evaluate growth media, pH indicators, resazurin-based dyes, and tetrazolium-based dyes for their use in simple colorimetric system. Overall, we identified Graver Wade media as the best at supporting robust gonococcal growth while also providing the least background when analyzing results of colorimetric tests. XTT, a tetrazolium-based dye, proved to show to brightest color change over time and not negatively impact the natural growth of N. gonorrhoeae. However, other dyes including PrestoBlue, MTT, and NBT are less expensive than XTT and work well when added after bacterial growth has already occurred. By identifying the specific use cases of these dyes, this research lays the groundwork for future development of a color-based antibiotic susceptibility low-cost test for N. gonorrhoeae.

Author Correction: Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making.

Cell migration during the invasion-metastasis cascade requires cancer cells to navigate a spatially complex microenvironment that presents directional choices to migrating cells. Here, we investigate cellular energetics during migration decision-making in confined spaces. Theoretical and experimental data show that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance as well as the degree of spatial confinement to direct decision-making. Energetic costs, driven by the cellular work needed to generate force for matrix displacement, increase with increasing cell stiffness, matrix stiffness, and degree of spatial confinement, limiting migration. By assessing energetic costs between possible migration paths, we can predict the probability of migration choice. Our findings indicate that motility in confined spaces imposes high energetic demands on migrating cells, and cells migrate in the direction of least confinement to minimize energetic costs. Therefore, therapeutically targeting metabolism may limit cancer cell migration and metastasis.

Fluorescence lateral flow competitive protein binding assay for the assessment of serum folate concentrations.

Folate is a micronutrient required for the production of new cells, making it a key factor in early fetal development and ensuring normal growth and maintenance of health. The increase in consumption of folate due to increased periconceptional supplementation and fortification of grains in many countries has led to a decrease in occurrence of folate deficiency and a class of birth defects called neural tube defects. However, an opportunity remains to further improve folate status of populations in areas with limited access to fortified foods and supplementation. Screening of women of reproductive age and other vulnerable populations for folate status would increase our understanding of the magnitude of the burden of folate deficiency and inform monitoring of public health programs. Current gold standard methods for folate assessment are time-intensive and require cold chain, sophisticated laboratory infrastructure, and highly-trained personnel. Our lateral flow assay is low-cost, easy to use, and allows a user to assess folate insufficiency at the point of care in less than 40 minutes. We evaluated the sensitivity and specificity of our assay in 24 human serum samples, including 8 samples with folate concentrations less than 10.0 nmol/L and 14 samples less than 13.4 nmol/L using the Immulite 2000 commercial assay as a reference standard. The sensitivity and specificity were found to be 93% (95% CI: 54.7-100.0) and 91% (95% CI: 80.0-100.0), respectively, when using our test to determine folate insufficiency based on a cutoff of 13.4 nmol/L. Our point-of-care diagnostic test for folate concentrations could inform screening and public health programs in at-risk populations.

ironPhone: Mobile device-coupled point-of-care diagnostics for assessment of iron status by quantification of serum ferritin.

Iron deficiency (ID) is an urgent public health problem that has devastating effects on maternal and child health. However, due to poor access and affordability, screening and diagnosis for ID is often limited to proxy hemoglobin measurements alone. Here, we report the development and validation of ironPhone, a mobile-device coupled portable diagnostics for quantification of serum ferritin concentrations, an iron status biomarker, within a few minutes, from a drop of fingerprick blood. The ironPhone diagnostic platform comprises of a smartphone accessory, an app, and a disposable lateral flow immunoassay test strip to quantify serum ferritin. For initial validation in the lab, we optimized and evaluated the performance of ironPhone with known ferritin concentrations in spiked buffer and serum samples. Following lab validation, we performed a human validation by collecting fingerprick whole blood samples from 20 participants to assess iron status using ironPhone and compared the results with the laboratory standard IMMULITE 2000 analyzer. Findings from the ironPhone for the buffer and spiked serum samples provided a calibration curve with R2 values of 0.97 (n=27) and 0.93 (n=12), respectively. On comparison with the laboratory standard IMMULITE analyzer in whole blood samples, a correlation of 0.92 (P<0.0001) was observed with a sensitivity of over 90% for predicting ID (ferritin<15.0µg/L) via the ironPhone, demonstrating its promise for iron status assessment at the point-of-care.

Rainer Gross Award Lecture 2016: A Laboratory in Your Pocket: Enabling Precision Nutrition.

The need for improving methods of nutritional assessment and delivering primary health care globally cannot be overemphasized. While advances in medical technology typically create more disparities because of access being limited to resource-rich settings, a transition of health care to a mobile platform is increasingly leveling the field. Technological advances offer opportunities to scale laboratory procedures down to mobile devices, such as smartphones and tablets. Globalization also provides the required infrastructure and network capacity to support the use of mobile health devices in developing settings where nutritional deficiencies are most prevalent. Here, we discuss some of the applications and advantages provided by expanding markets of biomarker measurement coupled with primary health care and public health systems and how this is enhancing access and delivery of health services with significant global impact.

Precision nutrition - review of methods for point-of-care assessment of nutritional status.

Precision nutrition encompasses prevention and treatment strategies for optimizing health that consider individual variability in diet, lifestyle, environment and genes by accurately determining an individual's nutritional status. This is particularly important as malnutrition now affects a third of the global population, with most of those affected or their care providers having limited means of determining their nutritional status. Similarly, program implementers often have no way of determining the impact or success of their interventions, thus hindering their scale-up. Exciting new developments in the area of point-of-care diagnostics promise to provide improved access to nutritional status assessment, as a first step towards enabling precision nutrition and tailored interventions at both the individual and community levels. In this review, we focus on the current advances in developing portable diagnostics for assessment of nutritional status at point-of-care, along with the numerous design challenges in this process and potential solutions.

NutriPhone: a mobile platform for low-cost point-of-care quantification of vitamin B12 concentrations.

Vitamin B12 is necessary for formation of red blood cells, DNA synthesis, neural myelination, brain development, and growth. Vitamin B12 deficiency is often asymptomatic early in its course; however, once it manifests, particularly with neurological symptoms, reversal by dietary changes or supplementation becomes less effective. Access to easy, low cost, and personalized nutritional diagnostics could enable individuals to better understand their own deficiencies as well as track the effects of dietary changes. In this work, we present the NutriPhone, a mobile platform for the analysis of blood vitamin B12 levels in 15 minutes. The NutriPhone technology comprises of a smartphone accessory, an app, and a competitive-type lateral flow test strip that quantifies vitamin B12 levels. To achieve the detection of sub-nmol/L physiological levels of vitamin B12, our assay incorporates an innovative "spacer pad" for increasing the duration of the key competitive binding reaction and uses silver amplification of the initial signal. We demonstrate the efficacy of our NutriPhone system by quantifying physiologically relevant levels of vitamin B12 and performing human trials where it was used to accurately evaluate blood vitamin B12 status of 12 participants from just a drop (~40 µl) of finger prick blood.

Neighborhood adversity, child health, and the role for community development.

Despite medical advances, childhood health and well-being have not been broadly achieved due to rising chronic diseases and conditions related to child poverty. Family and neighborhood living conditions can have lasting consequences for health, with community adversity affecting health outcomes in significant part through stress response and increased allostatic load. Exposure to this "toxic stress" influences gene expression and brain development with direct and indirect negative consequences for health. Ensuring healthy child development requires improving conditions in distressed, high-poverty neighborhoods by reducing children's exposure to neighborhood stressors and supporting good family and caregiver functioning. The community development industry invests more than $200 billion annually in low-income neighborhoods, with the goal of improving living conditions for residents. The most impactful investments have transformed neighborhoods by integrating across sectors to address both the built environment and the social and service environment. By addressing many facets of the social determinants of health at once, these efforts suggest substantial results for children, but health outcomes generally have not been considered or evaluated. Increased partnership between the health sector and community development can bring health outcomes explicitly into focus for community development investments, help optimize intervention strategies for health, and provide natural experiments to build the evidence base for holistic interventions for disadvantaged children. The problems and potential solutions are beyond the scope of practicing pediatricians, but the community development sector stands ready to engage in shared efforts to improve the health and development of our most at-risk children.

Quantitative proteomic analysis reveals a simple strategy of global resource allocation in bacteria.

A central aim of cell biology was to understand the strategy of gene expression in response to the environment. Here, we study gene expression response to metabolic challenges in exponentially growing Escherichia coli using mass spectrometry. Despite enormous complexity in the details of the underlying regulatory network, we find that the proteome partitions into several coarse-grained sectors, with each sector's total mass abundance exhibiting positive or negative linear relations with the growth rate. The growth rate-dependent components of the proteome fractions comprise about half of the proteome by mass, and their mutual dependencies can be characterized by a simple flux model involving only two effective parameters. The success and apparent generality of this model arises from tight coordination between proteome partition and metabolism, suggesting a principle for resource allocation in proteome economy of the cell. This strategy of global gene regulation should serve as a basis for future studies on gene expression and constructing synthetic biological circuits. Coarse graining may be an effective approach to derive predictive phenomenological models for other 'omics' studies.

Mechanical decision trees for investigating and modulating single-cell cancer invasion dynamics.

Physical cues exist across all biological scales, from the geometries of molecules to the shapes of complex organisms. While their roles have been identified across a range of scales, i.e. the arrangements of biomolecules and the form and function of tissues, less is known in some intermediate lengths. Particularly, at the cell scale, there is emerging evidence demonstrating the impact of mechanical signals, such as substrate stiffness and confinement, on many critical biological processes and malignancies, especially cancer dissemination. In the context of cell invasion, it is currently unclear how cells select from accessible mechanical paths that result in migratory patterns observed in physiological environments. Here, we devise microchannel decision trees to explore how fundamental and ubiquitous mechanical factors, specifically dimensionality and directionality, affect migratory cell decision making. We then implement strategies based purely on mechanical asymmetries to induce repetitive, non-disseminating motions, in a phenomenon we call iteratio ad nauseam.

The coding region of the UFGT gene is a source of diagnostic SNP markers that allow single-locus DNA genotyping for the assessment of cultivar identity and ancestry in grapevine (Vitis vinifera L.).

BACKGROUND: Vitis vinifera L. is one of society's most important agricultural crops with a broad genetic variability. The difficulty in recognizing grapevine genotypes based on ampelographic traits and secondary metabolites prompted the development of molecular markers suitable for achieving variety genetic identification. FINDINGS: Here, we propose a comparison between a multi-locus barcoding approach based on six chloroplast markers and a single-copy nuclear gene sequencing method using five coding regions combined with a character-based system with the aim of reconstructing cultivar-specific haplotypes and genotypes to be exploited for the molecular characterization of 157 V. vinifera accessions. The analysis of the chloroplast target regions proved the inadequacy of the DNA barcoding approach at the subspecies level, and hence further DNA genotyping analyses were targeted on the sequences of five nuclear single-copy genes amplified across all of the accessions. The sequencing of the coding region of the UFGT nuclear gene (UDP-glucose: flavonoid 3-0-glucosyltransferase, the key enzyme for the accumulation of anthocyanins in berry skins) enabled the discovery of discriminant SNPs (1/34 bp) and the reconstruction of 130 V. vinifera distinct genotypes. Most of the genotypes proved to be cultivar-specific, and only few genotypes were shared by more, although strictly related, cultivars. CONCLUSION: On the whole, this technique was successful for inferring SNP-based genotypes of grapevine accessions suitable for assessing the genetic identity and ancestry of international cultivars and also useful for corroborating some hypotheses regarding the origin of local varieties, suggesting several issues of misidentification (synonymy/homonymy).

Partnerships among community development, public health, and health care could improve the well-being of low-income people.

Safe, vibrant neighborhoods are vital to health. The community development "industry"-a network of nonprofit service providers, real estate developers, financial institutions, foundations, and government-draws on public subsidies and other financing to transform impoverished neighborhoods into better-functioning communities. Although such activity positively affects the "upstream" causes of poor health, the community development industry rarely collaborates with the health sector or even considers health effects in its work. Examples of initiatives-such as the creation of affordable housing that avoids nursing home placement-suggest a strong potential for cross-sector collaborations to reduce health disparities and slow the growth of health care spending, while at the same time improving economic and social well-being in America's most disadvantaged communities. We propose a four-point plan to help ensure that these collaborations achieve positive outcomes and sustainable progress for residents and investors alike.

Trends of selected malformations in relation to folic acid recommendations and fortification: an international assessment.

BACKGROUND: Two crucial issues relative to the benefits and impact of folic acid in the prevention of birth defects are whether supplementation recommendations alone, without fortification, are effective in reducing the population-wide rates of neural tube defects (NTDs), and whether such policies can reduce the occurrence of other birth defects. Using data from 15 registries, we assessed rates and trends of 14 major defects, including NTDs, in areas with official recommendations or fortification to assess the effectiveness of recommendations and fortification on a wide range of major birth defects. METHODS: We evaluated surveillance data through 2003 on major birth defects from population-based registries from Europe, North America, and Australia. All included ascertainment of pregnancy terminations (where legal). Trends before and after policies or fortification were assessed via Poisson regression and were compared via rate ratios. RESULTS: Significant changes in trends were seen for NTDs in areas with fortification but not in areas with supplementation recommendations alone. For other major birth defects, there was an overall lack of major trend changes after recommendations or fortification. However, some significant declines were observed for select birth defects in individual areas. CONCLUSIONS: Recommendations alone remain an ineffective approach in translating the known protective effect of folic acid in population-wide decline in NTD rates. Fortification appears to be effective in reducing NTDs. The effect on other birth defects remains unclear.