Leveraging A Digital Pill System to Understand Prevention-Effective Adherence to Oral Hiv Pre-Exposure Prophylaxis Among Men Who Have Sex with Men with Substance Use.

Daily oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, though efficacy depends on adherence. Digital pill systems (DPS) can enable direct, real-time adherence measurement. HIV-negative men who have sex with men (MSM) with substance use (excluding alcohol) utilized a DPS over 90 days and completed weekly surveys reporting sexual activity, condom use, and substance use. Responses indicating (1) any sexual activity and substance use or (2) condomless anal intercourse (CAI) in the prior week were categorized as high risk for HIV acquisition. PrEP adherence data for the 7-day period preceding each response was dichotomized as ≤ 3 and ≥ 4 doses/week, indicating prevention-effective adherence, and compared by HIV risk level. Thirteen MSM were analyzed (median age: 32). Of 113 surveys, 48.7% indicated high HIV risk, with 12.4% reporting CAI alone, 16.8% any sexual activity and substance use, and 19.5% both CAI and substance use. Weekly mean PrEP adherence was 90.3% (6.3 of 7 doses/week), with ≥ 4 doses/week recorded during 92.0% of weeks. The proportion of participants with ≥ 4 recorded doses/week was 88.9% during weeks with CAI alone, 89.5% during weeks with any sexual activity and substance use, 92.0% during weeks with both CAI and substance use, and 92.8% during lower risk weeks. Participants ingested ≥ 4 doses/week during 89.1% of all high-risk weeks and 94.8% of low-risk weeks. Overall, participants maintained high levels of PrEP adherence while engaging in HIV risk behaviors. DPS can be deployed concurrently with data collection tools to assess ingestion patterns during periods of elevated risk.

Supporting the Art: Medication Adherence Patterns in Persons Prescribed Ingestible Sensor-enabled Oral Pre-Exposure Prophylaxis to Prevent Human Immunodeficiency Virus Infection.

BACKGROUND: Timely, accurate adherence data may support oral pre-exposure prophylaxis (PrEP) success and inform prophylaxis choice. We evaluated a Food and Drug Administration (FDA)-approved digital health feedback system (DHFS) with ingestible-sensor-enabled (IS) tenofovir-disoproxil-fumarate plus emtricitabine (Truvada®) in persons starting oral PrEP. METHODS: Human immunodeficiency virus (HIV)-negative adults were prescribed IS-Truvada® with DHFS for 12 weeks to observe medication taking behavior. Baseline demographics, urine toxicology, and self-report questionnaires were obtained. Positive detection accuracy and adverse events were computed as percentages, with Kaplan Meier Estimate for persistence-of-use. In participants persisting ≥28 days, adherence patterns (taking and timing) were analyzed, and mixed-effects logistic regression modeled characteristics associated with treatment adherence. RESULTS: Seventy-one participants were enrolled, mean age 37.6 years (range 18-69), 90.1% male, 77.5% White, 33.8% Hispanic, 95.8% housed, and 74.6% employed. Sixty-three participants (88.7%) persisted ≥28 days, generating 4987 observation days, average 79.2 (29-105). Total confirmed doses were 86.2% (95% confidence interval [CI] 82.5, 89.4), decreasing over time, odds ratio (OR) 0.899 (95% CI .876, .923) per week, P < .001; 79.4% (95% CI 66.7%, 87.3%) of participants had ≥80% adherence. Pattern analysis showed days without confirmed doses clustered (P = .003); regular dose timing was higher among participants with ≥80% confirmed doses (0.828, 95% CI .796 to .859) than among those with <80% (0.542, 95% CI95 .405 to .679) P < .001. In multi-predictor models, better adherence was associated with older age, OR 1.060 (95% CI 1.033, 1.091) per year, P < .001; negative vs positive methamphetamine screen, OR 5.051 (95% CI 2.252, 11.494), P < .001. CONCLUSIONS: DHFS with IS-Truvada® distinguished adherent persons from those potentially at risk of prophylactic failure. Ongoing methamphetamine substance use may impact oral PrEP success.

Adherence to Antiretrovirals and HIV Viral Suppression Under COVID-19 Pandemic Interruption - Findings from a Randomized Clinical Trial Using Ingestible Sensors to Monitor Adherence.

The COVID-19 pandemic had a significant impact on vulnerable populations, including people living with HIV. California implemented a coronavirus lockdown (stay-at-home order) in March 2020, which ended in January 2021. We evaluated the pandemic's impact on both clinical outcomes of HIV RNA viral load (VL) and retention rate in a randomized clinical trial conducted from May 2018 to October 2020. The intervention group took co-encapsulated antiretrovirals (ARVs) with ingestible sensor (IS) pills from baseline through week 16. The IS system has the capacity to monitor adherence in real-time using a sensor patch, a mobile device, and supporting software. Both the IS and usual care (UC) groups were followed monthly for 28 weeks. Longitudinal mixed-effects models with random intercept and slope (RIAS) were used to fit log VL and self-reported adherence. The sample size of the study was 112 (54 in IS). Overall, the retention rate at week 28 was 86%, with 90% before the lockdown and 83% after the lockdown. The lockdown strengthened the associations between adherence and VL. Before the lockdown, a 10% increase in adherence was associated with a 0.2 unit decrease in log VL (ß = -1.88, p = 0.004), while during the lockdown, the association was a 0.41-unit decrease (ß = -2.27, p = 0.03). The pandemic did not have a significant impact on our adherence-focused intervention. Our findings regarding the intervention effect remain valid. TRIAL REGISTRATION NUMBER: NCT02797262. Date registration: September 2015.

Acceptability of and Willingness to Take Digital Pills by Patients, the Public, and Health Care Professionals: Qualitative Content Analysis of a Large Online Survey.

BACKGROUND: Digital pills are pills combined with a sensor, which sends a signal to a patch connected to a smartphone when the pills are ingested. Health care professionals can access patient data from digital pills online via their own interface, thus allowing them to check whether a patient took the drug. Digital pills were developed for the stated goal of improving treatment adherence. The US Food and Drug Administration approved the first digital pills in November 2017, but the manufacturer withdrew its application to the European Medicines Agency in July 2020 because of insufficient evaluation. OBJECTIVE: As recommended for the evaluation of health technologies, this study assesses the prospective acceptability of and willingness to take digital pills among patients, the public, and health care professionals. METHODS: Participants were patients who were receiving long-term treatment for a chronic condition, public participants (both groups recruited from a representative sample), and health care professionals. Participants answered 5 open-ended questions regarding the acceptability of digital pills and 1 close-ended question regarding the willingness to take digital pills, which were developed in a preliminary qualitative study. We explored the 5 theoretical dimensions of acceptability by performing an abductive qualitative content analysis of all free-text responses. We assessed data saturation with mathematical models. We fitted a multivariate logistic regression model to identify the sociodemographic and health characteristics associated with the willingness to take digital pills. RESULTS: Between January 29, 2020, and April 18, 2020, 767 patients, 1238 public participants, and 246 health care professionals provided 11,451 free-text responses. We identified 98 codes related to the acceptability of digital pills: 29 codes on perceived clinical effectiveness (eg, sensor safety cited by 66/2251 participants, 29.5%), 6 on perceived burden (eg, increased doctors' workload, 164/2251 participants, 7.3%), 25 on perceived ethicality (eg, policing, 345/2251 participants, 15.3%), 30 codes on perceived opportunity (eg, exclusively negative perception, 690/2251 participants, 30.7%), and 8 on affective attitude (eg, anger, 541/2251, 24%). Overall, 271/767 (35.3%) patients, 376/1238 (30.4%) public participants, and 39/246 (15.8%) health care professionals reported willingness to take digital pills. This willingness was associated with male sex (odds ratio 1.98, 95% CI 1.62-2.43) and current use of a connected device to record health settings (with a dose-response relationship). CONCLUSIONS: The prospective acceptability of and willingness to take digital pills were limited by clinical and ethical concerns both at the individual and societal level. Our results suggest that digital pills should not be considered a mere change in the form of drug administration but a complex intervention requiring specific evaluation before extended use in clinical routine practice as well as an ethical and legal framework to ensure safe and ethical collection and use of health data through a patient-centered approach.

Long-Term Stability of the Electronic Sensor Component of a Digital Pill System in Real-World Storage Settings.

Background: Digital pill systems comprise an ingestible sensor integrated into a gelatin capsule that overencapsulates medication allowing real-time measures of medication ingestion. These systems may improve the manner in which medication adherence can be assessed and supported. Objective: In this investigation, we tested the durability of the ingestible sensor as part of a clinical trial to measure the feasibility and acceptability of the system to measure adherence to once daily tenofovir disoproxil fumarate/emtricitabine (NCT03842436). Methods: Digital pills not dispensed during the study were stored in a pharmacy. Seventeen sensors were selected from digital pills stored for at least 12 months and activated in a simulated gastric environment. A radiofrequency spectrum analyzer and the reader device used in the clinical trial to capture ingestion events were used to measure activation of emitters. A passing evaluation was defined as an energized emitter within 30 minutes of immersion, ability to broadcast a signal for 10 minutes, and successful acquisition by the reader. Results: All ingestible sensors passed the stability test. Mean activation time in simulated gastric fluid was 3.33 minutes (SD = 1.47); emitters remained active for a mean of 47.72 minutes (SD = 1.78). These parameters matched guidelines defined in the ID-Cap system requirements for use in patients. Conclusions: Ingestible sensor components of the ID-Cap system were therefore stable after long-term storage.

User Experience of Persons Using Ingestible Sensor-Enabled Pre-Exposure Prophylaxis to Prevent HIV Infection: Cross-Sectional Survey Study.

Background: A digital health technology's success or failure depends on how it is received by users. objectives: We conducted a user experience (UX) evaluation among persons who used the Food and Drug Administration-approved Digital Health Feedback System incorporating ingestible sensors (ISs) to capture medication adherence, after they were prescribed oral pre-exposure prophylaxis (PrEP) to prevent HIV infection. We performed an association analysis with baseline participant characteristics, to see if "personas" associated with positive or negative UX emerged. Methods: UX data were collected upon exit from a prospective intervention study of adults who were HIV negative, prescribed oral PrEP, and used the Digital Health Feedback System with IS-enabled tenofovir disoproxil fumarate plus emtricitabine (IS-Truvada). Baseline demographics; urine toxicology; and self-report questionnaires evaluating sleep (Pittsburgh Sleep Quality Index), self-efficacy, habitual self-control, HIV risk perception (Perceived Risk of HIV Scale 8-item), and depressive symptoms (Patient Health Questionnaire-8) were collected. Participants with ≥28 days in the study completed a Likert-scale UX questionnaire of 27 questions grouped into 4 domain categories: overall experience, ease of use, intention of future use, and perceived utility. Means and IQRs were computed for participant total and domain subscores, and linear regressions modeled baseline participant characteristics associated with UX responses. Demographic characteristics of responders versus nonresponders were compared using the Fisher exact and Wilcoxon rank-sum tests. Results: Overall, 71 participants were enrolled (age: mean 37.6, range 18-69 years; n=64, 90% male; n=55, 77% White; n=24, 34% Hispanic; n=68, 96% housed; and n=53, 75% employed). No demographic differences were observed in the 63 participants who used the intervention for ≥28 days. Participants who completed the questionnaire were more likely to be housed (52/53, 98% vs 8/10, 80%; P=.06) and less likely to have a positive urine toxicology (18/51, 35% vs 7/10, 70%; P=.08), particularly methamphetamine (4/51, 8% vs 4/10, 40%; P=.02), than noncompleters. Based on IQR values, ≥75% of participants had a favorable UX based on the total score (median 3.78, IQR 3.17-4.20), overall experience (median 4.00, IQR 3.50-4.50), ease of use (median 3.72, IQR 3.33-4.22), and perceived utility (median 3.72, IQR 3.22-4.25), and ≥50% had favorable intention of future use (median 3.80, IQR 2.80-4.40). Following multipredictor modeling, self-efficacy was significantly associated with the total score (0.822, 95% CI 0.405-1.240; P<.001) and all subscores (all P<.05). Persons with more depressive symptoms reported better perceived utility (P=.01). Poor sleep was associated with a worse overall experience (-0.07, 95% CI -0.133 to -0.006; P=.03). Conclusions: The UX among persons using IS-enabled PrEP (IS-Truvada) to prevent HIV infection was positive. Association analysis of baseline participant characteristics linked higher self-efficacy with positive UX, more depressive symptoms with higher perceived utility, and poor sleep with negative UX.

Preliminary feasibility of a wrist-worn receiver to measure medication adherence via an ingestible radiofrequency sensor.

Adherence to medications is a complex task that requires complex biobehavioral support. To better provide tools to assist with medication adherence, digital pills provide an option to directly measure medication taking behaviors. These systems comprise a gelatin capsule with radiofrequency emitter, a wearable Reader that collects the radio signal and a smartphone app that collects ingestion data displays it for patients and clinicians. These systems are feasible in measuring adherence in the real-world, even in stigmatized diseases like HIV treatment adherence. While the current iteration of the digital pill system utilizes a wearable Reader worn like a necklace, preliminary feedback demonstrated that a miniaturized system that was worn on the wrist could be more functional in the real-world. This paper therefore describes the development and preliminary field testing of a wrist-borne wearable Reader to facilitate acquisition of oral HIV pre-exposure prophylaxis (PrEP) adherence data among individual prescribed PrEP.

Bibliometric analysis and evidence of clinical efficacy and safety of digital pills.

Objectives: Digital pills are new technologies that aim to improve healthcare by increasing medication adherence. The aim of the work was a bibliometric analysis of clinical studies of digital pills and an assessment of the level of evidence of their effectiveness, safety, and prospects for the future. Materials and Methods: The studies were conducted using online databases such as ClinicalTrials.gov, Dimensions, and Web of Science for the period January 2012 to July 2022. The VOSviewer tool for building and visualizing bibliometric networks was used. Results: Bibliometric analysis of the scientific literature revealed that over the past 10 years, the number of publications about digital pills has noticeably increased, which indicates the increasing importance of this field of knowledge. The leading positions in this area are occupied by scientists from the United States, the United Kingdom, and India. Sources of financial support for authors of publications in the field of digital pills are funds from leading developer companies, budget allocations, and funds from non-commercial organizations. Public-private partnerships are an important path to develop and implement digital pills. The four main clusters of digital pill studies were highlighted and visualized: efficacy and safety analysis for serious mental disorders; treatment and costs of tuberculosis therapy; features of the treatment of diabetes, cardiovascular diseases, and AIDS; and usage monitoring. Available publications demonstrate the efficacy potential and safety of digital pills. Nevertheless, the effects of digital pills have not yet been fully studied. Conclusion: Priority areas for future research are further randomized controlled clinical trials and meta-analyses, which are necessary for a high level (I level) of evidence for therapeutic applications of digital pills, as well as pharmacoeconomic studies.

Design considerations of aptasensors for continuous monitoring of biomarkers in digestive tract fluids.

We present a porous Si (PSi)-based label-free optical biosensor for sensitive and continuous detection of a model target protein biomarker in gastrointestinal (GI) tract fluids. The biosensing platform is designed to continuously monitor its target protein within the complex GI fluids without sample preparation and washing steps. An oxidized PSi Fabry-Pérot thin films are functionalized with aptamers, which are used as the capture probes. The optical response of the aptamer-conjugated PSi is studied upon exposure to unprocessed GI fluids, originated from domestic pigs, spiked with the target protein. We investigate biological and chemical surface passivation methods to stabilize the surface and reduce non-specific adsorption of interfering proteins and molecules within the GI fluids. For the passivated PSi aptasensor we simulate continuous in vivo biosensing conditions, demonstrating that the aptasensor could successfully detect the target in a continuous manner without any need for surface washing after the target protein binding events, at a clinically relevant range. Furthermore, we simulate biosensing conditions within a smart capsule, in which the aptasensor is occasionally exposed to GI fluids in flow or via repeated cycles of injection and static incubation events. Such biosensor can be implemented within ingestible capsule devices and used for in situ biomarker detection in the GI tract.

Ingestible sensor system for measuring, monitoring and enhancing adherence to antiretroviral therapy: An open-label, usual care-controlled, randomised trial.

BACKGROUND: Co-encapsulated antiretrovirals (ARVs) with ingestible sensor (IS) has the capacity to monitor adherence in real-time using a sensor patch, a mobile device, and supporting software. We evaluated the acceptability, effectiveness, and sustainability of the IS system with real-time text reminders. METHODS: Participants were recruited from HIV clinics in Los Angeles and were randomised 1:1 to IS or usual care (UC) group. Adherence to ARVs (primary outcome) was measured by IS system (IS group only), plasma ARV concentration, and self-report. IS-measured adherence was clustered by group-based trajectory model and was validated by ARV concentration summarized by integrated pharmacokinetic adherence measure (IPAM) score. HIV RNA viral load (VL) was compared between IS and UC group. FINDINGS: A total of 112 (IS = 54, UC = 58) participants who completed baseline with at least one follow-up data collection were included in analyses. Overall satisfaction rate for the IS system was >90%. The IPAM score was higher (0.018, 95% CI: -0.098-0.134, p = 0.75) and VL decayed faster (-0.020, 95% CI: -0.042-0.002, p = 0.08) in the IS group compared with the UC group. The ingestible sensor system was well tolerated by study participants. INTERPRETATION: The IS system was well accepted by participants and its use was associated with improved adherence and lower HIV RNA VL. The findings provide a potentially effective strategy for improving adherence. FUNDING: This work was supported by grant R01-MH110056 from the National Institute of Mental Health (NIMH)/National Institutes of Health (NIH). Y. Wang was in part supported by the NIMH/NIH award T32MH080634. E. Daar was in part supported by the National Center for Advancing Translational Sciences through UCLACTSI Grant UL1TR001881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Digital Pills with Ingestible Sensors: Patent Landscape Analysis.

The modern healthcare system is directly related to the development of digital health tools and solutions. Pills with digital sensors represent a highly innovative class of new pharmaceuticals. The aim of this work was to analyze the patent landscape and to systematize the main trends in patent protection of digital pills with ingestible sensors worldwide; accordingly, to identify the patenting leaders as well as the main prevailing areas of therapy for patent protection, and the future perspectives in the field. In July 2022, a search was conducted using Internet databases, such as the EPO, USPTO, FDA and the Lens database. The patent landscape analysis shows an increase in the number of patents related to digital pills with ingestible sensors for mobile clinical monitoring, smart drug delivery, and endoscopy diagnostics. The leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China. The following main areas of patenting digital pills with ingestible sensors were identified: treatment in the field of mental health; HIV/AIDS; pain control; cardiovascular diseases; diabetes; gastroenterology (including hepatitis C); oncology; tuberculosis; and transplantology. The development of scientific and practical approaches towards the implementation of effective and safe digital pills will improve treatment outcomes, increase compliance, reduce hospital stays, provide mobile clinical monitoring, have a positive impact on treatment costs and will contribute to increased patient safety.

A better understanding of daily life abdominal wall mechanical solicitation: Investigation of intra-abdominal pressure variations by intragastric wireless sensor in humans.

Intra-abdominal pressure (IAP), as the main mechanical load applied to the abdominal wall, is decisive in the occurrence of ventral hernia. The objective of the study was to propose a comprehensive evaluation of IAP based on a limited risk and discomfort method. A prospective study was carried out in 20 healthy volunteers. The intragastric pressure, validated for estimating IAP, was assessed by an ingestible pressure sensor. Volunteers realized a set of supervised exercises, then resumed their daily activities with the pressure continuously recorded until gastric emptying. Coughing and jumping exercises resulted in the highest IAP levels with maximum peaks of 65 ± 35 and 67 ± 31 mmHg and pressure rates of 121 and 114 mmHg.s-1 respectively. The position did not affect the IAP variation. Men had significantly higher pressure values for pushing against a wall (P < 0.01), Valsalva maneuver and legs raising (P<0.05) exercises. During daily life, IAP greater than 50, 100, and 150 mmHg occurred on average five times, twice, and once per hour, respectively. This study provides a real-life characterization of the IAP allowing the quantification of mechanical solicitation applied to the abdominal wall and the identification of risk situations for the occurrence of ventral hernias.

Feeding Our Microbiota: Stimulation of the Immune/Semiochemical System and the Potential Amelioration of Non-Communicable Diseases.

Non-communicable diseases are those conditions to which causative infectious agents cannot readily be assigned. It is increasingly likely that at least some of these conditions are due to the breakdown of the previously mutualistic intestinal microbiota under the influence of a polluted, biocide-rich, environment. Following the mid-20th century African studies of Denis Burkitt, the environmental cause of conditions such as obesity has been ascribed to the absence of sufficient fibre in the modern diet, however in itself that is insufficient to explain the parallel rise of problems with both the immune system and of mental health. Conversely, Burkitt himself noted that the Maasai, a cattle herding people, remained healthy even with their relatively low intake of dietary fibre. Interestingly, however, Burkitt also emphasised that levels of non-communicable disease within a population rose as faecal weight decreased significantly, to about one third of the levels found in healthy populations. Accordingly, a more cogent explanation for all the available facts is that the fully functioning, adequately diverse microbiome, communicating through what has been termed the microbiota-gut-brain axis, helps to control the passage of food through the digestive tract to provide itself with the nutrition it needs. The method of communication is via the production of semiochemicals, interkingdom signalling molecules, potentially including dopamine. In turn, the microbiome aids the immune system of both adult and, most importantly, the neonate. In this article we consider the role of probiotics and prebiotics, including fermented foods and dietary fibre, in the stimulation of the immune system and of semiochemical production in the gut lumen. Finally, we reprise our suggestion of an ingestible sensor, calibrated to the detection of such semiochemicals, to assess both the effectiveness of individual microbiomes and methods of amelioration of the associated non-communicable diseases.

Ingestible electronic sensors to measure instantaneous medication adherence: A narrative review.

OBJECTIVE: Medication nonadherence contributes to significant morbidity and mortality worldwide. While many techniques to measure adherence exist, digital pill systems represent a novel, direct method of measuring adherence and a means of providing instantaneous adherence supports. In this narrative review, we discuss digital pill system research based on clinical trials and qualitative investigations conducted to date and potential future applications of digital pill system in medication adherence measurement. METHODS: We conducted a literature search in PubMed of English language peer-reviewed articles describing the use of digital pill system for medication adherence measurement between 2000 and 2021. We included all articles that described the deployment of ingestible sensors and those involving qualitative investigations of digital pill system with human subjects. RESULTS: A total of 95 articles were found on initial search; 75 were removed based on exclusion criteria. Included articles were categorized as investigations that deployed an ingestible sensor in human populations (n = 18), or those that conducted qualitative work (n = 3). For pilot studies, the mean accuracy of the sensor to successfully detect a medication ingestion event ranged from 68% to 100%. When digital pill systems were deployed in real-world clinical settings, accuracy ranged from 68% to 90% with lower accuracy due to nonadherence to digital pill system technology. Qualitative studies demonstrated that providers and patients perceive the digital pill system as a facilitator for improving adherence and as a potential platform for delivering adherence interventions. Additionally, ingestion data from digital pill system was viewed as useful in facilitating adherence discussions between clinicians and patients. CONCLUSIONS: This narrative review demonstrates that the use of digital pill system is broadly feasible across multiple disease states including human immunodeficiency virus, hepatitis C infection, solid organ transplants, tuberculosis, schizophrenia, cardiovascular disease, and acute fractures, where adherence is closely linked to significant morbidity and mortality. It also highlights key areas of research that are still needed prior to broad-scale clinical deployment of such systems.

Use of an Ingestible, Sensor-Based Digital Adherence System to Strengthen the Therapeutic Relationship in Serious Mental Illness.

Serious mental illness is a chronic condition that requires long-term pharmacological treatment. Adherence to oral antipsychotic medication has specific nuances that affects patients and physicians alike. For patients with serious mental illness, nonadherence increases their risk of hospitalization and relapse. Nonadherence is a formidable barrier for physicians in accurately assessing medication efficacy and helping patients achieve their fullest potential. A digital adherence system approved by the Food and Drug Administration can provide near-real time aripiprazole ingestion information. The system records ingestions through an embedded ingestible sensor in oral aripiprazole, which sends a transient local signal to a patch worn on the patient's torso that is then stored on a paired smartphone app. With patient permission, these data can be viewed remotely by their physician, along with a patient's mood, activity, and time spent resting. Such data are able to do the following: reveal broad patterns of medication adherence behavior to the patient as well as their physician; help physicians and patients understand and create more realistic expectations for adherence; promote discussion of treatment options; and minimize therapeutic appointment time devoted to determining actual adherence, thereby maximizing the time available to address each patient's distinctive reasons for their adherence pattern. Crucially, extra time created during appointments can be used to strengthen the therapeutic relationship, which may translate into both improvements in adherence and patient attitude toward their medication. Future investigations are needed to examine how this technology impacts the development of training and best practice guidelines for its use. Otherwise, the potential benefits of this technology may be lost, or worse, inadequate and inappropriate use may harm the therapeutic relationship.

The Enclosed Intestinal Microbiome: Semiochemical Signals from the Precambrian and Their Disruption by Heavy Metal Pollution.

It is increasingly likely that many non-communicable diseases of humans and associated animals are due to the degradation of their intestinal microbiomes, a situation often referred to as dysbiosis. An analysis of the resultant diseases offers an opportunity to probe the function of these microbial partners of multicellular animals. In our view, it now seems likely that vertebrate animals and their microbiomes have coevolved throughout the Ediacaran-Cambrian transition and beyond, operating by semiochemical messaging between the multicellular host and its microbial community guest. A consideration of the overall role of the mutualistic intestinal microbiome as an enclosed bioreactor throws up a variety of challenging concepts. In particular: the significance of the microbiome with respect to the immune system suggests that microeukaryotes could act as microbial sentinel cells; the ubiquity of bacteriophage viruses implies the rapid turnover of microbial composition by a viral-shunt mechanism; and high microbial diversity is needed to ensure that horizontal gene transfer allows valuable genetic functions to be expressed. We have previously postulated that microbes of sufficient diversity must be transferred from mother to infant by seemingly accidental contamination during the process of natural birth. We termed this maternal microbial inheritance and suggested that it operates alongside parental genetic inheritance to modify gene expression. In this way, the adjustment of the neonate immune system by the microbiome may represent one of the ways in which the genome of a vertebrate animal interacts with its microbial environment. The absence of such critical functions in the neonate may help to explain the observation of persistent immune-system problems in affected adults. Equally, granted that the survival of the guest microbiome depends on the viability of its host, one function of microbiome-generated semiochemicals could be to facilitate the movement of food through the digestive tract, effectively partitioning nutrition between host and guest. In the event of famine, downregulation of microbial growth and therefore of semiochemical production would allow all available food to be consumed by the host. Although it is often thought that non-communicable diseases, such as type 2 diabetes, are caused by consumption of food containing insufficient dietary fibre, our hypothesis suggests that poor-quality food is not the prime cause but that the tendency for disease follows the degradation of the intestinal microbiome, when fat build-up occurs because the relevant semiochemicals can no longer be produced. It is the purpose of this paper to highlight the possibility that the origins of the microbiome lie in the Precambrian and that the disconnection of body and microbiome gives rise to non-communicable disease through the loss of semiochemical signalling. We further surmise that this disconnect has been largely brought about by heavy metal poisoning, potentially illuminating a facet of the exposome, the sum total of environmental insults that influence the expression of the genetic inheritance of an animal.

A Novel Digital Pill System for Medication Adherence Measurement and Reporting: Usability Validation Study.

BACKGROUND: Medication nonadherence is a costly problem that is common in clinical use and clinical trials alike, with significant adverse consequences. Digital pill systems have proved to be effective and safe solutions to the challenges of nonadherence, with documented success in improving adherence and health outcomes. OBJECTIVE: The aim of this human factors validation study is to evaluate a novel digital pill system, the ID-Cap System from etectRx, for usability among patient users in a simulated real-world use environment. METHODS: A total of 17 patients with diverse backgrounds who regularly take oral prescription medications were recruited. After training and a period of training decay, the participants were asked to complete 12 patient-use scenarios during which errors or difficulties were logged. The participants were also interviewed about their experiences with the ID-Cap System. RESULTS: The participants ranged in age from 27 to 74 years (mean 51 years, SD 13.8 years), and they were heterogeneous in other demographic factors as well, such as education level, handedness, and sex. In this human factors validation study, the patient users completed 97.5% (196/201) of the total use scenarios successfully; 75.1% (151/201) were completed without any failures or errors. The participants found the ID-Cap System easy to use, and they were able to accurately and proficiently record ingestion events using the device. CONCLUSIONS: The participants demonstrated the ability to safely and effectively use the ID-Cap System for its intended use. The ID-Cap System has great potential as a useful tool for encouraging medication adherence and can be easily implemented by patient users.

Ingestible Sensors and Medication Adherence: Focus on Use in Serious Mental Illness.

BACKGROUND: Poor medication adherence is a major public health concern. Patients living with a serious mental illness (SMI) commonly present with non-adherence to their medication regimen, which can lead to relapse and hospitalizations. The high rates of antipsychotic non-adherence continue to persist despite several interventions and medication advances. This review evaluates the possible role of the ingestible sensor technology for medication adherence in different conditions, with a focus on use in the SMI schizophrenia. METHODS: Literature searches were conducted in July 2019 in the PubMed database. RESULTS: In small studies of ingestible sensor use, the average adherence ranged from 73.9% to 88.6% for SMI and ≥ 80% for cardiac and transplant (99.4%) patients. In SMI studies, patients were clinically stable, and the majority had a clinical global impression severity of "mild disease". Patients generally experienced relatively minor dermatological adverse effects related to wearable sensor use. CONCLUSIONS: A medication with an ingestible sensor may help provide real-time objective medication-taking adherence information for clinicians. However, further studies are needed to understand the impact of use on adherence and improvement on treatment outcomes with the ingestible sensor technology.

Pharmacokinetics of Coencapsulated Antiretrovirals with Ingestible Sensors.

We investigated the use of a system with an ingestible sensor (Proteus Digital Health Feedback system) coencapsulated with antiretrovirals (ARVs) to measure real-time adherence. To assess the safety and impact, if any, coencapsulation might have on ARV concentrations, we evaluated the pharmacokinetics of ARVs coencapsulated with an ingestible sensor for eight commonly used fixed-dose combination ARVs: emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF); FTC/tenofovir alafenamide (TAF); efavirenz (EFV)/FTC/TDF; abacavir (ABC)/lamivudine (3TC); dolutegravir (DTG)/ABC/3TC; rilpivirine (RPV)/TAF/FTC; elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF; and bictegravir (BIC)/FTC/TAF. The steady-state apparent peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were determined from plasma concentrations measured at predose, 1, 2, 4, and 6 h postdose, and compared with literature values. A total of 49 unique patients on stable regimens for at least 12 weeks with undetectable viral loads were recruited. Cmax and AUC values were not statistically significantly different from literature values for all of the formulations except the Cmax of FTC/TDF, Cmax of BIC, and the Cmax of RPV. In a subsequent evaluation of FTC/TDF and BIC/FTC/TAF using a crossover design, the geometric mean ratio (GMR) between the coencapsulated and the unencapsulated formulations for FTC/TDF were the following: FTC, 84.6% (90% confidence interval [CI] 66.6-107.4) for AUC and 77.5% (60.1-99.9) for Cmax. For tenofovir (TFV), the GMR was 96.2% (90% CI 89.2-103.8) for AUC and 87.3% (64.2-118.7) for Cmax. The GMR for BIC (from the BIC/FTC/TAF formulation) was 98.0% (90% CI 84.5-113.5) for AUC and 89.9% (84.5-95.7) for Cmax. The observed deviation in FTC/TDF (Truvada) may be due to participant characteristics, fasted/fed conditions, and/or random variation and may warrant further investigations with a larger sample size. These findings provide assurance for use of coencapsulated ARVs for future HIV treatment-adherence research.

'Digital pills' for mental diseases: an ethical and social analysis of the issues behind the concept.

Recently, the US Food and Drug Administration has given a landmark approval to the very first digital pill with a sensor embedded in the inside. These are complex systems that include a drug and an electronic tracker that is activated when the patient takes the pill. Accordingly, they might be an excellent tool for monitoring and potentially improving patients' adherence to prescriptions. This would serve well to avoid unnecessary healthcare costs and reduce the anxiety of patients and their relatives. However, digital pills might also diminish patient autonomy, reduce privacy, or promote inadequate use of pharmaceutical resources. This article is aimed at contributing to adequate use of this new tool by showing the main ethical and social issues they involve and proposing measures meant to address them. Finally, we conclude by defending the idea that these new systems should be seen as means of complementing traditional strategies to promote adherence to treatment, and not as substitutes.