Impact of the 99DOTS digital adherence technology on tuberculosis treatment outcomes in North India: a pre-post study.

BACKGROUND: 99DOTS is a cellphone-based digital adherence technology. The state of Himachal Pradesh, India, made 99DOTS available to all adults being treated for drug-sensitive tuberculosis (TB) in the public sector in May 2018. While 99DOTS has engaged over 500,000 people across India, few studies have evaluated its effectiveness in improving TB treatment outcomes. METHODS: We compared treatment outcomes of adults with drug-sensitive TB before and after Himachal Pradesh's 99DOTS launch using data from India's national TB database. The pre-intervention group initiated treatment between February and October 2017 (N = 7722), and the post-intervention group between July 2018 and March 2019 (N = 8322). We analyzed engagement with 99DOTS and used multivariable logistic regression to estimate impact on favorable treatment outcomes (those marked as cured or treatment complete). RESULTS: In the post-intervention group, 2746 (33.0%) people called 99DOTS at least once. Those who called did so with a wide variation in frequency (< 25% of treatment days: 24.6% of callers; 25-50% of days: 15.1% of callers, 50-75% of days: 15.7% of callers; 75-100% of days: 44.6% of callers). In the pre-intervention group, 7186 (93.1%) had favorable treatment outcomes, compared to 7734 (92.9%) in the post-intervention group. This difference was not statistically significant (OR = 0.981, 95% CI [0.869, 1.108], p = 0.758), including after controlling for individual characteristics (adjusted OR = 0.970, 95% CI [0.854, 1.102]). CONCLUSIONS: We found no statistically significant difference in treatment outcomes before and after a large-scale implementation of 99DOTS. Additional work could help to elucidate factors mediating site-wise variations in uptake of the intervention.

Measuring Tuberculosis Medication Adherence: A Comparison of Multiple Approaches in Relation to Urine Isoniazid Metabolite Testing Within a Cohort Study in India.

Background: Nonadherence to tuberculosis medications is associated with poor outcomes. However, measuring adherence in practice is challenging. In this study, we evaluated the accuracy of multiple tuberculosis adherence measures. Methods: We enrolled adult Indians with drug-susceptible tuberculosis who were monitored using 99DOTS, a cellphone-based technology. During an unannounced home visit with each participant, we assessed adherence using a pill estimate, 4-day dose recall, a last missed dose question, and urine isoniazid metabolite testing. We estimated the area under the receiver operating characteristic curve (AUC) for each alternate measure in comparison to urine testing. 99DOTS data were analyzed using patient-reported doses alone and patient- and provider-reported doses, the latter reflecting how 99DOTS is implemented in practice. We assessed each measure's operating characteristics, with particular interest in specificity-that is, the percentage of participants detected as being nonadherent by each alternate measure, among those who were nonadherent by urine testing. Results: Compared with urine testing, alternate measures had the following characteristics: 99DOTS patient-reported doses alone (area under the curve [AUC], 0.65; specificity, 70%; 95% CI, 58%-81%), 99DOTS patient- and provider-reported doses (AUC, 0.61; specificity, 33%; 95% CI, 22%-45%), pill estimate (AUC, 0.55; specificity, 21%; 95% CI, 12%-32%), 4-day recall (AUC, 0.60; specificity, 23%; 95% CI, 14%-34%), and last missed dose question (AUC, 0.65; specificity, 52%; 95% CI, 40%-63%). Conclusions: Alternate measures missed detecting at least 30% of people who were nonadherent by urine testing. The last missed dose question performed similarly to 99DOTS using patient-reported doses alone. Tuberculosis programs should evaluate the feasibility of integrating more accurate, objective measures, such as urine testing, into routine care.

Innovation in care for individuals with cognitive impairment: Can reimbursement policy spread best practices?

There is now an unprecedented opportunity to improve the care of the over 5 million people who are living with Alzheimer's disease and related dementias and many more with cognitive impairment due to brain injury, systemic diseases, and other causes. The introduction of a new Medicare care planning benefit-long sought openly by advocacy organizations and clinicians and badly needed by patients and families-could greatly improve health care quality, but only if widely and fully implemented. We describe the components of this new benefit and its promise of better clinical care, as well as its potential to create a new platform for clinical and health outcomes research. We highlight external factors-and some that are internal to the benefit structure itself-that challenge the full realization of its value, and we call for broad public and professional engagement to ensure that it will not fail.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Imaging markers for Alzheimer disease: which vs how.

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹8F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹8F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association.

Positron emission tomography (PET) of brain amyloid ß is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. To provide guidance to dementia care practitioners, patients, and caregivers, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be used appropriately. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific appropriate use criteria (AUC) were agreed on that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes.

Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association.

Positron emission tomography (PET) of brain amyloid b is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. To provide guidance to dementia care practitioners, patients, and caregivers, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be used appropriately. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific appropriate use criteria (AUC) were agreed on that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated,and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes.

Alzheimer's Association recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting.

The Patient Protection and Affordable Care Act added a new Medicare benefit, the Annual Wellness Visit (AWV), effective January 1, 2011. The AWV requires an assessment to detect cognitive impairment. The Centers for Medicare and Medicaid Services (CMS) elected not to recommend a specific assessment tool because there is no single, universally accepted screen that satisfies all needs in the detection of cognitive impairment. To provide primary care physicians with guidance on cognitive assessment during the AWV, and when referral or further testing is needed, the Alzheimer's Association convened a group of experts to develop recommendations. The resulting Alzheimer's Association Medicare Annual Wellness Visit Algorithm for Assessment of Cognition includes review of patient Health Risk Assessment (HRA) information, patient observation, unstructured queries during the AWV, and use of structured cognitive assessment tools for both patients and informants. Widespread implementation of this algorithm could be the first step in reducing the prevalence of missed or delayed dementia diagnosis, thus allowing for better healthcare management and more favorable outcomes for affected patients and their families and caregivers.

The draft "National Plan" to address Alzheimer's disease - National Alzheimer's Project Act (NAPA).

This perspective updates the status of the "National Plan to Address Alzheimer's Disease" and the recommendations of the NAPA Advisory Council's Sub-committee on Research. Here, we identify some of the critical issues the future reiterations of the National Plan should consider during implementation phase of the plan. The Journal invites the scientific community to contribute additional ideas and suggestions towards a national research initiative.

Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-ß burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.

Biocoder: A programming language for standardizing and automating biology protocols.

BACKGROUND: Published descriptions of biology protocols are often ambiguous and incomplete, making them difficult to replicate in other laboratories. However, there is increasing benefit to formalizing the descriptions of protocols, as laboratory automation systems (such as microfluidic chips) are becoming increasingly capable of executing them. Our goal in this paper is to improve both the reproducibility and automation of biology experiments by using a programming language to express the precise series of steps taken. RESULTS: We have developed BioCoder, a C++ library that enables biologists to express the exact steps needed to execute a protocol. In addition to being suitable for automation, BioCoder converts the code into a readable, English-language description for use by biologists. We have implemented over 65 protocols in BioCoder; the most complex of these was successfully executed by a biologist in the laboratory using BioCoder as the only reference. We argue that BioCoder exposes and resolves ambiguities in existing protocols, and could provide the software foundations for future automation platforms. BioCoder is freely available for download at http://research.microsoft.com/en-us/um/india/projects/biocoder/. CONCLUSIONS: BioCoder represents the first practical programming system for standardizing and automating biology protocols. Our vision is to change the way that experimental methods are communicated: rather than publishing a written account of the protocols used, researchers will simply publish the code. Our experience suggests that this practice is tractable and offers many benefits. We invite other researchers to leverage BioCoder to improve the precision and completeness of their protocols, and also to adapt and extend BioCoder to new domains.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Learning biophysically-motivated parameters for alpha helix prediction.

BACKGROUND: Our goal is to develop a state-of-the-art protein secondary structure predictor, with an intuitive and biophysically-motivated energy model. We treat structure prediction as an optimization problem, using parameterizable cost functions representing biological "pseudo-energies". Machine learning methods are applied to estimate the values of the parameters to correctly predict known protein structures. RESULTS: Focusing on the prediction of alpha helices in proteins, we show that a model with 302 parameters can achieve a Qalpha value of 77.6% and an SOValpha value of 73.4%. Such performance numbers are among the best for techniques that do not rely on external databases (such as multiple sequence alignments). Further, it is easier to extract biological significance from a model with so few parameters. CONCLUSION: The method presented shows promise for the prediction of protein secondary structure. Biophysically-motivated elementary free-energies can be learned using SVM techniques to construct an energy cost function whose predictive performance rivals state-of-the-art. This method is general and can be extended beyond the all-alpha case described here.

Digital microfluidics using soft lithography.

Although microfluidic chips have demonstrated basic functionality for single applications, performing varied and complex experiments on a single device is still technically challenging. While many groups have implemented control software to drive the pumps, valves, and electrodes used to manipulate fluids in microfluidic devices, a new level of programmability is needed for end users to orchestrate their own unique experiments on a given device. This paper presents an approach for programmable and scalable control of discrete fluid samples in a polydimethylsiloxane (PDMS) microfluidic system using multiphase flows. An immiscible fluid phase is utilized to separate aqueous samples from one another, and a novel "microfluidic latch" is used to precisely align a sample after it has been transported a long distance through the flow channels. To demonstrate the scalability of the approach, this paper introduces a "general-purpose" microfluidic chip containing a rotary mixer and addressable storage cells. The system is general purpose in that all operations on the chip operate in terms of unit-sized aqueous samples; using the underlying mechanisms for sample transport and storage, additional sensors and actuators can be integrated in a scalable manner. A novel high-level software library allows users to specify experiments in terms of variables (i.e., fluids) and operations (i.e., mixes) without the need for detailed knowledge about the underlying device architecture. This research represents a first step to provide a programmable interface to the microfluidic realm, with the aim of enabling a new level of scalability and flexibility for lab-on-a-chip experiments.

Alzheimer's Association Research Roundtable Meeting on Mild Cognitive Impairment: what have we learned?

The biological changes that occur in the brains of Alzheimer's disease (AD) patients are thought to begin long before the onset of clinical symptoms. Although current therapeutic agents have been approved only for patients with mild to moderate AD, Alzheimer-type pathology in patients with mild to moderate AD is already quite advanced. One impetus for the development of the concept of mild cognitive impairment (MCI) was the attempt to recognize AD early in its clinical expression and to determine whether it is possible through therapeutic interventions to improve the memory impairment at this stage or delay further progression to dementia. To this end, several clinical trials have been conducted in patients with MCI. On September 8 and 9, 2004 a meeting of the Alzheimer's Association Research Roundtable was held at which experts in the field of MCI convened to review the collective experience from these trials and to consider potential approaches that might improve MCI clinical trials in the future. This article summarizes the presentations and discussions of that meeting.