A comprehensive assessment of selective amino acid 15N-labeling in human embryonic kidney 293 cells for NMR spectroscopy.

A large proportion of human proteins contain post-translational modifications that cannot be synthesized by prokaryotes. Thus, mammalian expression systems are often employed to characterize structure/function relationships using NMR spectroscopy. Here we define the selective isotope labeling of secreted, post-translationally modified proteins using human embryonic kidney (HEK)293 cells. We determined that alpha-[15N]- atoms from 10 amino acids experience minimal metabolic scrambling (C, F, H, K, M, N, R, T, W, Y). Two more interconvert to each other (G, S). Six others experience significant scrambling (A, D, E, I, L, V). We also demonstrate that tuning culture conditions suppressed V and I scrambling. These results define expectations for 15N-labeling in HEK293 cells.

Using implementation science frameworks to translate and adapt a pregnancy app for an emerging Latino community.

BACKGROUND: Digital mobile health (mHealth) applications are a popular form of prenatal education and care delivery in the U.S.; yet there are few Spanish language options for native speakers. Furthermore, existing applications do not consider cultural differences and disparities in healthcare access, including those specific to emerging Latino communities. OBJECTIVE: To adapt and translate an English-language pregnancy mobile health app to meet the language and cultural needs of Spanish-speaking Latino immigrants living in the United States. METHODS: We use a multi-step process, grounded in implementation science frameworks, to adapt and translate the contents of an existing pregnancy app. Interviews with stakeholders (n = 12) who advocate for the needs of pregnant individuals in an emerging Latino community were used to identify domains of possible disparities in access to prenatal care. We then conducted semi-structured interviews with peripartum Spanish-speaking Latino users (n = 14) to understand their perspectives within those domains. We identified a list of topics to create educational material for the modified app and implemented a systematic translation approach to ensure that the new version was acceptable for immigrants from different countries in Latin America. RESULTS: The interviews with stakeholders revealed seven critical domains that need to be addressed in an adapted prenatal app: language and communication, financial concerns, social support, immigration status, cultural differences, healthcare navigation, and connection to population-specific community resources that offer Spanish language services. The interviews with peripartum Spanish-speaking Latino women informed how the existing content in the app could be adjusted or built upon to address these issues, including providing information on accessing care offered in their native language and community support. Finally, we used a systematic approach to translate the existing application and create new content. CONCLUSION: This work illustrates a process to adapt an mHealth pregnancy app to the needs of an emerging Latino community, by incorporating culturally sensitive Spanish language content while focusing on addressing existing health disparities.

The Clinical Utility of the MOCA in iNPH Assessment.

Objectives: We sought to estimate reliable change thresholds for the Montreal Cognitive Assessment (MoCA) for older adults with suspected Idiopathic Normal Pressure Hydrocephalus (iNPH). Furthermore, we aimed to determine the likelihood that shunted patients will demonstrate significant improvement on the MoCA, and to identify possible predictors of this improvement. Methods: Patients (N = 224) presenting with symptoms of iNPH were given a MoCA assessment at their first clinic visit, and also before and after tap test (TT) or extended lumbar drainage (ELD). Patients who were determined to be good candidates for shunts (N = 71, 31.7%) took another MoCA assessment following shunt insertion. Reliable change thresholds for MoCA were derived using baseline visit to pre-TT/ELD assessment using nine different methodologies. Baseline characteristics of patients whose post-shunt MoCA did and did not exceed the reliable change threshold were compared. Results: All nine of reliable change methods indicated that a 5-point increase in MoCA would be reliable for patients with a baseline MoCA from 16 to 22 (38.4% of patients). Furthermore, a majority of reliable change methods indicated that a 5-point increase in MoCA would be reliable for patients with a baseline MoCA from 14 to 25. Reliable change thresholds varied across methods from 4 to 7 points for patients outside of this range. 10.1% had at least a 5-point increase from baseline to post-TT/ELD. Compared to patients who did not receive a shunt, patients who received a shunt did not have lower average MoCA at baseline (p = 0.88) or have better improvement in MoCA scores after the tap test (p = 0.17). Among shunted patients, 23.4% improved by at least 5 points on the MoCA from baseline to post-shunt. Time since onset of memory problems and post-TT/ELD gait function were the only clinical factors significantly associated with having a reliable change in MoCA after shunt insertion (p = 0.019; p = 0.03, respectively). Conclusions: In patients with iNPH, clinicians could consider using a threshold of 5 points for determining whether iNPH-symptomatic patients have experienced cognitive benefits from cerebrospinal fluid drainage at an individual level. However, a reliable change cannot be detected for patients with a baseline MoCA of 26 or greater, necessitating a different cognitive assessment tool for these patients.

The value of adherence information during clinical pharmaceutical trials.

BACKGROUND/AIMS: The quality of the evidence used to evaluate a drug's safety and efficacy depends, in part, on how well participants adhere to the prescribed drug-taking regime. There are multiple approaches to measure adherence in clinical trials, varying in their cost and accuracy. We demonstrate a method for evaluating the cost-effectiveness of common adherence monitoring methods, considering the costs and data quality for drugs that differ in how forgiving they are of nonadherence. METHODS: We propose a simulation approach to estimate the value of evidence about adherence, considering both costs of collection and potential errors in interpreting clinical trial results. We demonstrate the approach with a simulated clinical trial of nitrendipine, a common calcium channel blocker. We consider two trial designs, one using pretrial adherence to "enrich" the trial sample and one without an enrichment strategy. We use scenarios combining high and low values of two key properties of a clinical trial: participant adherence and drug forgiveness. RESULTS: Under the conditions of these simulations, the most cost-effective adherence monitoring approach depends on both trial participant adherence and drug forgiveness. For example, the enrichment strategy is not cost-effective for the base scenario (high forgiveness and high adherence), but is for other scenarios. We also estimate the effects of evaluable patient analysis, a controversial procedure that excludes nonadherent participants from the analyses, after a trial is completed. CONCLUSIONS: Our proposed approach can guide drug regulators and developers in designing efficient clinical trials and assessing the impact of nonadherence on trial results. It can identify cost-effective adherence-monitoring methods, given available knowledge about the methods, drug, and patients' expected adherence.

Asbestos-related lung cancer: Clinical characteristics and survival outcomes in an Australian cohort seeking workers compensation.

BACKGROUND AND OBJECTIVES: Due to difficulties in identifying sufficient-sized cohorts there remains uncertainty about prognostic and clinical differences that may be unique to asbestos-related lung cancer (ARLC). In this study, we use the Helsinki Criteria to define a group of ex-workers with lung cancer attributable to asbestos exposure and investigate differences that may exist. METHODS: A total of 529 patients seeking workers' compensation for their lung cancer were assigned to either ARLC or the non-ARLC based on parameters defined in the Helsinki Criteria. Clinical and survival details were collected and analyzed. RESULTS: In our study population, ARLC patients were on average older (72.1 ± 7.8) than non-ARLC patients (66.5 ± 10.2, P < 0.001) and were more likely to be diagnosed as a result of incidental findings or screening program (P < 0.001). The groups were similar in terms of clinical characteristics with the only difference being that plaques were more prevalent among ARLC patients (P < 0.001). Differences were observed for median overall survival (OS), ARLC (9 months) and non-ARLC (13 months, P = 0.005), as well for treatment (P = 0.01). After adjusting for age, however, these differences disappeared. CONCLUSIONS: Age at diagnosis, pleural plaques, and asymptomatic presentation were the attributes that we identified as significantly different between asbestos-related cancer and other lung cancers. In this cohort, ARLC patients were older diagnosis and with worse overall survival.

Evaluation of the effect comorbid Parkinson syndrome on normal pressure hydrocephalus assessment.

OBJECTIVE: The primary aim of the study was to assess the effect comorbid Parkinson syndromes have on results of CSF tap test (TT) and shunt outcomes for patients presenting with Normal Pressure Hydrocephalus (NPH). We hypothesized that patients with possible NPH and comorbid Parkinson syndromes with Positive DaT scans will not respond to CSF TT at the same rate as patients without comorbid Parkinson syndromes. Additionally, we followed a small number of patients with positive DaT scans who were shunted to assess long term outcome of comorbid Parkinson syndromes. METHODS: Medical records and neurological exams of 251 patients were reviewed. In our analysis 101 patients with no parkinsonian symptoms and no DaT scans were included as a control group, there were 52 patients with DaT scans, 31 patients were positive (DaT-P). Gait measures were assessed before and after CSF TT using the Wilcoxon matched-pairs signed-rank test or paired t-tests were used. To compare the effect of DaT-P and Control, we used an ANCOVA controlling for age, sex, assistive device used, and past medical history effecting gait. RESULTS: There was not a significant difference in response between Control and DaT-P group. The Control group improved on timed up and go (TUG) by 14.82%, DualTUG 16.35%, 10-meter Walk Test (10MWT) 18.13%, MiniBEST 15.91%, and 6-minute Walk Test (6MWT) 13.96%, while the DaT-P group improved on TUG by 14.93%, DualTUG 17.24%, 10MWT 22.68%, MiniBEST 18.07%, and 6MWT 16.06%. CONCLUSION: Our findings suggest that patients with possible NPH and suspected comorbid movement disorder, showed similar improvement after diagnostic CSF TT compared to participants with no parkinsonian symptoms present on exam. DATA AVAILABILITY STATEMENT: Data relevant to the study will be made available from the corresponding author upon a reasonable request.

Illustration of a Method to Incorporate Preference Uncertainty in Benefit-Cost Analysis.

Benefit-cost analysis is widely used to evaluate alternative courses of action that are designed to achieve policy objectives. Although many analyses take uncertainty into account, they typically only consider uncertainty about cost estimates and physical states of the world, whereas uncertainty about individual preferences, thus the benefit of policy intervention, is ignored. Here, we propose a strategy to integrate individual uncertainty about preferences into benefit-cost analysis using societal preference intervals, which are ranges of values over which it is unclear whether society as a whole should accept or reject an option. To illustrate the method, we use preferences for implementing a smart grid technology to sustain critical electricity demand during a 24-hour regional power blackout on a hot summer weekend. Preferences were elicited from a convenience sample of residents in Allegheny County, Pennsylvania. This illustrative example shows that uncertainty in individual preferences, when aggregated to form societal preference intervals, can substantially change society's decision. We conclude with a discussion of where preference uncertainty comes from, how it might be reduced, and why incorporating unresolved preference uncertainty into benefit-cost analyses can be important.

Vendor of choice and the effectiveness of policies to promote health information exchange.

BACKGROUND: As more hospitals adopt Electronic Health Records (EHR), focus has shifted to how these records can be used to improve patient care. One barrier to this improvement is limited information exchange between providers. In this work we examine the role of EHR vendors, hypothesizing that vendors strategically control the exchange of clinical care summaries. Their strategy may involve the creation of networks that easily exchange information between providers with the same vendor but frustrate exchange between providers with different vendors, even as both Federal and State policies attempt to incentivize exchange through a common format. METHODS: Using data from the 2013 American Hospital Association's Information Technology Supplement, we examine the relationship between a hospital's decision to share clinical care summaries outside of their network and EHR vendor market share, measured by the percentage of hospitals that have the same vendor in a Hospital Referral Region. RESULTS: Our findings show that the likelihood of a hospital exchanging clinical summaries with hospitals outside its health system increases as the percentage of hospitals with the same EHR vendor in the region increases. The estimated odds of a hospital sharing clinical care summaries outside their system is 5.4 (95% CI, 3.29-8.80) times greater if all hospitals in the Hospital Referral Region use the same EHR Vendor than the corresponding odds for a hospital in an area with no hospitals using the same EHR Vendor. When reviewing the relationship of vendor market concentration at the state level we find a positive significant relationship with the percentage of hospitals that share clinical care summaries within a state. We find no significant impact from state policies designed to incentivize information exchange through the State Health Information Exchange Cooperative Program. CONCLUSION: There are benefits to exchanging using proprietary methods that are strengthened when the vendors are more concentrated. In order to avoid closed networks that foreclose some hospitals, it is important that future regulation attempt to be more inclusive of hospitals that do not use large vendors and are therefore unable to use proprietary methods for exchange.

Providing Limited Local Electric Service During a Major Grid Outage: A First Assessment Based on Customer Willingness to Pay.

While they are rare, widespread blackouts of the bulk power system can result in large costs to individuals and society. If local distribution circuits remain intact, it is possible to use new technologies including smart meters, intelligent switches that can change the topology of distribution circuits, and distributed generation owned by customers and the power company, to provide limited local electric power service. Many utilities are already making investments that would make this possible. We use customers' measured willingness to pay to explore when the incremental investments needed to implement these capabilities would be justified. Under many circumstances, upgrades in advanced distribution systems could be justified for a customer charge of less than a dollar a month (plus the cost of electricity used during outages), and would be less expensive and safer than the proliferation of small portable backup generators. We also discuss issues of social equity, extreme events, and various sources of underlying uncertainty.

Assessing the Cost of Large-Scale Power Outages to Residential Customers.

Residents in developed economies depend heavily on electric services. While distributed resources and a variety of new smart technologies can increase the reliability of that service, adopting them involves costs, necessitating tradeoffs between cost and reliability. An important input to making such tradeoffs is an estimate of the value customers place on reliable electric services. We develop an elicitation framework that helps individuals think systematically about the value they attach to reliable electric service. Our approach employs a detailed and realistic blackout scenario, full or partial (20 A) backup service, questions about willingness to pay (WTP) using a multiple bounded discrete choice method, information regarding inconveniences and economic losses, and checks for bias and consistency. We applied this method to a convenience sample of residents in Allegheny County, Pennsylvania, finding that respondents valued a kWh for backup services they assessed to be high priority more than services that were seen as low priority ($0.75/kWh vs. $0.51/kWh). As more information about the consequences of a blackout was provided, this difference increased ($1.2/kWh vs. $0.35/kWh), and respondents' uncertainty about the backup services decreased (Full: $11 to $9.0, Partial: $13 to $11). There was no evidence that the respondents were anchored by their previous WTP statements, but they demonstrated only weak scope sensitivity. In sum, the consumer surplus associated with providing a partial electric backup service during a blackout may justify the costs of such service, but measurement of that surplus depends on the public having accurate information about blackouts and their consequences.

An Approach to Reconciling Competing Ethical Principles in Aggregating Heterogeneous Health Preferences.

BACKGROUND: Health-related quality of life (HRQL) scores are used extensively to quantify the effectiveness of medical interventions. Societal preference-based HRQL scores aim to produce societal valuations of health by aggregating valuations from individuals in the general population, where each aggregation procedure embodies different ethical principles, as explained in social choice theory. METHODS: Using the Health Utilities Index as an exemplar, we evaluate societal preference-based HRQL measures in the social choice theory framework. RESULTS: We find that current preference aggregation procedures are typically justified in terms of social choice theory. However, by convention, they use only one of many possible aggregation procedures (the mean). Central to the choice of aggregation procedure is how to treat preference heterogeneity, which can affect analyses that rely on HRQL scores, such as cost-effectiveness analyses. We propose an analytical-deliberative framework for choosing one (or a set of) aggregation procedure(s) in a socially credible way, which we believe to be analytically sound and empirically tractable, but leave open the institutional mechanism needed to implement it. CONCLUSIONS: Socially acceptable decisions about aggregating heterogeneous preferences require eliciting stakeholders' preferences among the set of analytically sound procedures, representing different ethical principles. We describe a framework for eliciting such preferences for the creation of HRQL scores, informed by social choice theory and behavioral decision research.

Computing tumor trees from single cells.

Computational methods have been developed to reconstruct evolutionary lineages from tumors using single-cell genomic data. The resulting tumor trees have important applications in cancer research and clinical oncology.Please see related Research articles: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0929-9 and http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0936-x .

Spend today, clean tomorrow: predicting methamphetamine abstinence in a randomized controlled trial.

OBJECTIVE: This secondary analysis of data from a randomized controlled trial tested two behavioral economics mechanisms (substitutability and delay discounting) to explain outcomes using contingency management (CM) for methamphetamine dependence. Frequency and purchase type (hedonic/utilitarian and consumable/durable) of CM payments were also examined. METHODS: A total of 82 methamphetamine-dependent gay/bisexual men randomly assigned to conditions delivering CM received monetary vouchers in exchange for stimulant-negative urine samples in a 16-week trial requiring thrice weekly visits (Shoptaw et al., 2005). At any visit participants could redeem vouchers for goods. A time-lagged counting process Cox Proportional Hazards model for recurrent event survival analysis examined aspects of the frequency and type of these CM purchases. RESULTS: After controlling for severity of baseline methamphetamine use and accumulated CM wealth, as measured by cumulative successful earning days, participants who redeemed CM earnings at any visit ("spenders") were significantly more likely to produce stimulant-negative urine samples in the subsequent visit, compared with those who did not redeem ("savers") 1.011* [1.005, 1.017], Z = 3.43, p < .001. CONCLUSIONS: Findings support the economic concept of substitutability of CM purchases and explain trial outcomes as a function of frequency of CM purchases rather than frequency or accumulated total CM earnings. Promotion of frequent purchases in incentive-based programs should facilitate substitution for the perceived value of methamphetamine and improve abstinence outcomes.