Genetic Characteristics of Salmonella Isolates Recovered From Reused Broiler Litter Over Three Successive Flocks.

Salmonella infections are a leading cause of bacterial food-borne illness worldwide. Infections are highly associated with the consumption of contaminated food, and in particular, chicken meat. The severity of Salmonella infections depends on the presence of antimicrobial resistance genes and virulence factors. While there are many studies which have investigated Salmonella strains isolated from postharvest chicken samples, there is a gap in our understanding of the genetic properties that influence the persistence of Salmonella in preharvest and in particular their makeup of antimicrobial resistance genes and virulence factors. We used whole genome sequencing and hierarchical clustering to characterize and classify the genetic diversity of Salmonella enterica isolates (n = 55) recovered from the litter of commercial broiler chicken raised in four colocated broiler houses of one integrated farm over three consecutive flocks. The chicken were raised under a newly adopted "No Antibiotics Ever" program, and copper sulfate was administered via drinking water. In-silico serovar prediction identified three S. enterica serovars: Enteritidis (n = 12), Kentucky (n = 40), and Senftenberg (n = 3). Antimicrobial susceptibility testing revealed that only one S. Kentucky isolate was resistant to streptomycin, while the remaining isolates were susceptible to all antibiotics tested. Metal resistance operons, including copper and silver, were identified chromosomally and on plasmids in serovar Senftenberg and Kentucky isolates, respectively, while serovar Enteritidis carried several virulence factors on plasmids. Serovar Kentucky isolates harboring metal resistance operons were the only Salmonella isolates recovered from the litter of third flock cohort. These results suggest that there might be environmental selection for Salmonella strains carrying plasmid-associated metal resistance and virulence genes, which could play a role in their persistence in litter.

Virulence factors and antimicrobial resistance profiles of Campylobacter isolates recovered from consecutively reused broiler litter.

IMPORTANCE: Campylobacter is a leading cause of foodborne illness in the United States due to consumption of contaminated or mishandled food products, often associated with chicken meat. Campylobacter is common in the microbiota of avian and mammalian gut; however, acquisition of antimicrobial resistance genes (ARGs) and virulence factors (VFs) may result in strains that pose significant threat to public health. Although there are studies investigating the genetic diversity of Campylobacter strains isolated from post-harvest chicken samples, there are limited data on the genome characteristics of isolates recovered from preharvest broiler production. Here, we show that Campylobacter jejuni and Campylobacter coli differ in their carriage of antimicrobial resistance and virulence factors may also differ in their ability to persist in litter during consecutive grow-out of broiler flocks. We found that presence/absence of virulence factors needed for evasion of host defense mechanisms and gut colonization played an integral role in differentiating Campylobacter strains.

Broiler house environment and litter management practices impose selective pressures on antimicrobial resistance genes and virulence factors of Campylobacter.

Campylobacter infections are a leading cause of bacterial diarrhea in humans globally. Infections are due to consumption of contaminated food products and are highly associated with chicken meat, with chickens being an important reservoir for Campylobacter. Here, we characterized the genetic diversity of Campylobacter species detected in broiler chicken litter over three consecutive flocks and determined their antimicrobial resistance and virulence factor profiles. Antimicrobial susceptibility testing and whole genome sequencing were performed on Campylobacter jejuni (n = 39) and Campylobacter coli (n = 5) isolates. All C. jejuni isolates were susceptible to all antibiotics tested while C. coli (n =4) were resistant to only tetracycline and harbored the tetracycline-resistant ribosomal protection protein (TetO). Virulence factors differed within and across grow houses but were explained by the isolates' flock cohort, species and multilocus sequence type. Virulence factors involved in the ability to invade and colonize host tissues and evade host defenses were absent from flock cohort 3 C. jejuni isolates as compared to flock 1 and 2 isolates. Our results show that virulence factors and antimicrobial resistance genes differed by the isolates' multilocus sequence type and by the flock cohort they were present in. These data suggest that the house environment and litter management practices performed imposed selective pressures on antimicrobial resistance genes and virulence factors. In particular, the absence of key virulence factors within the final flock cohort 3 isolates suggests litter reuse selected for Campylobacter strains that are less likely to colonize the chicken host.

Management and environmental factors influence the prevalence and abundance of food-borne pathogens and commensal bacteria in peanut hull-based broiler litter.

In this study, we conducted a longitudinal sampling of peanut hull-based litter from a farm under a "no antibiotics ever" program. Our objective was to determine broiler management practices and environmental factors that are associated with the occurrence of food-borne pathogens (Salmonella and Campylobacter) and the abundance of commensal bacteria (Escherichia coli, Enterococcus spp., and Staphylococcus spp.). Litter (n = 288) was collected from 4 broiler houses over three consecutive flocks, starting with a complete house cleanout and fresh peanut hull. Litter was sampled at the beginning of each grow-out cycle and at the end of the cycle. Logistic and linear regression models were used to model the relationships between pathogen prevalence, commensal abundance and management practices, and environmental factors. The number of flocks raised on litter, grow-out period, broiler house, litter pH, litter moisture, and house temperature were associated with the prevalence of pathogens and the abundance of commensal bacteria in litter. The final logistic model for pathogens showed that a higher probability of detecting Salmonella in litter was associated with the number of flocks raised on litter and the grow-out period. A higher probability of detecting Campylobacter in litter was associated with the number of flocks raised on litter, broiler house and the sections of the house, and the pH of litter. Our results suggest that management practices and environmental factors affect Salmonella and Campylobacter differently and suggest that each pathogen will require its own tailored intervention to stop their persistence in broiler litter.

Participant Engagement and Symptom Improvement: Aripiprazole Tablets with Sensor for the Treatment of Schizophrenia.

Purpose: A recent, phase 3b, mirror-image clinical trial of outpatients with schizophrenia found that use of aripiprazole tablets with sensor (AS; Abilify MyCite®, comprising an ingestible event-marker sensor embedded in aripiprazole tablets, wearable sensor patches, and a smartphone application) reduced the incidence of psychiatric hospitalizations relative to oral standard-of-care antipsychotics. This analysis explored the relationship between AS engagement by participants and changes in participant performance and symptom-severity measures assessed by clinical raters. Participants and Methods: This post hoc analysis used prospectively collected clinical data from a phase 3b clinical trial (NCT03892889). Outpatients had schizophrenia, were aged 18-65 years, and had ≥ 1 psychiatric hospitalization in the previous 48 months. Participants were grouped by study completion status and a k-means clustering algorithm based on AS utilization, resulting in 3 groups: discontinued (discontinued AS before month 3 of the study); moderate engagement (completed 3 months, used AS intermittently); and high engagement (completed 3 months, used AS regularly). Baseline to end-of-study differences for the Clinical Global Impression Scale (Severity of Illness and Improvement of Illness scales), Personal and Social Performance Scale, and Positive and Negative Syndrome Scale were calculated. Results: A total of 277 outpatients were enrolled (discontinued, n = 164; moderate engagement, n = 63; high engagement, n = 50). All groups experienced symptom improvement from baseline to end-of-study, with significant changes in the more-engaged groups. Highly engaged participants showed significant improvement for all clinical scores and subscores (all P < 0.05) and demonstrated significantly more improvement in symptoms than participants with less engagement. Conclusion: Participants who completed 3 months of the study and had higher AS engagement experienced significantly greater improvement in their end-of-study clinical assessments versus participants who did not complete 3 months. Improvement may be related to more-consistent medication intake and better engagement with a digital health system.

Phase 3b Multicenter, Prospective, Open-label Trial to Evaluate the Effects of a Digital Medicine System on Inpatient Psychiatric Hospitalization Rates for Adults With Schizophrenia.

Objective: Inpatient psychiatric admissions drive the financial burden of schizophrenia, and medication adherence remains challenging. We assessed whether aripiprazole tablets with sensor (AS; system includes ingestible event-marker sensor, wearable sensor patches, and smartphone application) could reduce psychiatric hospitalizations compared with oral standard-of-care (SOC) antipsychotics.Methods: This phase 3b, mirror-image clinical trial was conducted from April 29, 2019-August 11, 2020, in adults with schizophrenia with ≥ 1 hospitalization in the previous 48 months who had been prescribed oral SOC for the preceding 6 months (retrospective phase). All participants used AS for at least 3 months and up to 6 months. Primary endpoint was the inpatient psychiatric hospitalization rate in the modified intent-to-treat (mITT; n = 113) population during prospective months 1-3 versus retrospective phase. Proportion of days covered by medication was the secondary endpoint. Safety endpoints included adverse events related to the medication or patch and suicidality.Results: AS significantly reduced hospitalizations during prospective months 1-3 (-9.7%) and months 1-6 (-21.3% [P ≤ .001 for all comparisons]) in the mITT population versus the corresponding retrospective phase. AS use improved confirmed medication ingestion by 26.5 percentage points in prospective months 1-3 (P ≤ .001) and reduced PANSS scores. Patches were well-tolerated, and no participant reported changes in suicide risk.Conclusions: Compared with oral SOC, AS reduced inpatient psychiatric hospitalization rates for adults with mild-to-moderate schizophrenia. The AS system may aid medication ingestion and is associated with improvements in symptoms, potentially reducing acute-care needs among patients with schizophrenia.Trial Registration: ClinicalTrials.gov identifier: NCT03892889.

Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania.

BACKGROUND: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). AIMS: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). METHODS: ST studies were three-week randomized, double-blind, flexible dose (2-4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2-4 mg/day) study for patients completing the ST studies. RESULTS: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (-1.74, 2.03), p = 0.8797; study 081: -1.62 (-3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). CONCLUSIONS: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

A Rest Quality Metric Using a Cluster-Based Analysis of Accelerometer Data and Correlation With Digital Medicine Ingestion Data: Algorithm Development.

BACKGROUND: Adherence to medication regimens and patient rest are two important factors in the well-being of patients with serious mental illness. Both of these behaviors are traditionally difficult to record objectively in unsupervised populations. OBJECTIVE: A digital medicine system that provides objective time-stamped medication ingestion records was used by patients with serious mental illness. Accelerometer data from the digital medicine system was used to assess rest quality and thus allow for investigation into correlations between rest and medication ingestion. METHODS: Longest daily rest periods were identified and then evaluated using a k-means clustering algorithm and distance metric to quantify the relative quality of patient rest during these periods. This accelerometer-derived quality-of-rest metric, along with other accepted metrics of rest quality, such as duration and start time of the longest rest periods, was compared to the objective medication ingestion records. Overall medication adherence classification based on rest features was not performed due to a lack of patients with poor adherence in the sample population. RESULTS: Explorations of the relationship between these rest metrics and ingestion did seem to indicate that patients with poor adherence experienced relatively low quality of rest; however, patients with better adherence did not necessarily exhibit consistent rest quality. This sample did not contain sufficient patients with poor adherence to draw more robust correlations between rest quality and ingestion behavior. The correlation of temporal outliers in these rest metrics with daily outliers in ingestion time was also explored. CONCLUSIONS: This result demonstrates the ability of digital medicine systems to quantify patient rest quality, providing a framework for further work to expand the participant population, compare these rest metrics to gold-standard sleep measurements, and correlate these digital medicine biomarkers with objective medication ingestion data.

Hummingbird Study: Results from an Exploratory Trial Assessing the Performance and Acceptance of a Digital Medicine System in Adults with Schizophrenia, Schizoaffective Disorder, or First-Episode Psychosis.

PURPOSE: Symptoms of psychotic disorders can complicate efforts to accurately evaluate patients' medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders. METHODS: This was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs). RESULTS: From May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported. CONCLUSION: The DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.

Responses to environmental variability by herbivorous insects and their natural enemies within a bioenergy crop, Miscanthus x giganteus.

Precision agriculture (PA) is the application of management decisions based on identifying, quantifying, and responding to space-time variability. However, knowledge of crop pest responses to within-field environmental variability, and the spatial distribution of their natural enemies, is limited. Quantitative methods providing insights on how pest-predator relationships vary within fields are potentially important tools. In this study, phloem feeders and their natural enemies, were observed over two years across 81 locations within a field of the perennial feedstock grass in Georgia, USA. Geographically weighted regression (GWR) was used to spatially correlate their abundance with environmental factors. Variables included distance to forest edge, Normalized Difference of Vegetation Index (NDVI), slope, aspect, elevation, soil particle size distribution, and weather values. GWR methods were compared with generalized linear regression methods that do not account for spatial information. Non-spatial models indicated positive relationships between phloem-feeder abundance and wind speed, but negative relationships between elevation, proportions of silt and sand, and NDVI. With data partitioned into three seasonal groups, terrain and soil variables remained significant, and natural enemies and spiders became relevant. Results from GWR indicated that magnitudes and directions of responses varied within the field, and that relationships differed among seasons. Strong negative relationships between response and explanatory factors occurred: with NDVI during mid-season; with percent silt, during mid-, and late seasons; and with spider abundance during early and late seasons. In GWR models, slope, elevation, and aspect were mostly positive indicating further that associations with elevation depended on whether models incorporated spatial information or not. By using spatially explicit models, the analysis provided a complex, nuanced understanding of within-field relationships between phloem feeders and environmental covariates. This approach provides an opportunity to learn about the variability within agricultural fields and, with further analysis, has potential to inform and improve PA and habitat management decisions.

Riparian land cover and hydrology influence stream dissolved organic matter composition in an agricultural watershed.

Dissolved organic matter (DOM) represents an essential component of the carbon cycle and controls biogeochemical and ecological processes in aquatic systems. The composition and reactivity of DOM are determined by the spatial distribution of its sources and its residence time in a watershed. While the effects of agricultural land cover on DOM quality have been reported across spatial and temporal scales, the influence of riparian land cover on stream DOM composition has received little attention. Furthermore, the combined effects of riparian land cover and streamflow rates on DOM composition require investigation. To this end, a multi-year (2016-2018) DOM characterization study was conducted using bi-weekly water samples collected from seven sub-watersheds nested within the Little River Experimental Watershed (LREW) near Tifton, Georgia, USA. DOM optical properties were determined to assess compositional variations using UV-Vis and excitation-emission matrix (EEM) fluorescence spectroscopy coupled with parallel factor (PARAFAC) analysis. PARAFAC analysis indicated that DOM in the LREW was dominated by three humic-like fluorescing components of terrestrial, microbial, and anthropogenic origin and a protein-like component. DOM composition was influenced by riparian land cover and hydrology, and shifted towards recently produced, low molecular weight DOM with low aromaticity as the percentage of agricultural land within riparian wetlands increased. During periods of high discharge and high baseflow, the DOM pool was dominated by recalcitrant and terrestrial-derived material but shifted towards protein-like and microbial-derived with increasing cropland in the riparian area. The results of this two-year study indicate that the replacement of forested riparian buffers with agricultural land can result in altered DOM composition which may affect carbon cycling and downstream water quality in agricultural watersheds.

Method to Evaluate the Age of Groundwater Inputs to Surface Waters by Determining the Chirality Change of Metolachlor Ethanesulfonic Acid (MESA) Captured on a Polar Organic Chemical Integrative Sampler (POCIS).

We previously discovered a method to estimate the groundwater mean residence time using the changes in the enantiomeric ratio of metolachlor ethanesulfonic acid (MESA), (2-[(2-ethyl-6-methylphenyl)(2-methoxy-1-methylethyl)amino]-2-oxoethanesulfonic acid), a metabolite of the herbicide metolachlor. However, many grab samples would be needed for each watershed over an extended period, and this is not practical. Thus, we examined the use of a polar organic chemical integrative sampler (POCIS) deployed for 28 days combined with a modified liquid chromatography-mass spectrometry LC-MS/MS method to provide a time-weighted average of the MESA enantiomeric ratio. POCISs equipped with hydrophilic-lipophilic-balanced (HLB) discs were deployed at five sites across the United States where metolachlor was used before and after 1999 and compared the effectiveness of the POCIS to capture MESA versus grab samples. In addition, an in situ POCIS sampling rate (Rs) for MESA was calculated (0.15 L/day), the precision of MESA extraction from stored POCIS discs was determined, and the effectiveness of HLB to extract MESA was examined. Finally, using molecular modeling, the influence of the asymmetric carbon of metolachlor degradation on the MESA enantiomeric ratio was predicted to be negligible. Results of this work will be used in projects to discern the groundwater mean residence times, to evaluate the delivery of nitrate-N from groundwater to surface waters under various soil, agronomic, and land use conditions, and to examine the effectiveness of conservation practices.

Evaluation of miscanthus productivity and water use efficiency in southeastern United States.

Second generation biofuels, such as perennial grasses, have potential to provide biofuel feedstock while growing on degraded land with minimal inputs. Perennial grasses have been reported to sequester large amounts of soil organic carbon (SOC) in the Midwestern United States (USA). However, there has been little work on biofuel and carbon sequestration potential of perennial grasses in the Southeastern US. Biofuel productivity for dryland Miscanthus × gigantus and irrigated maize in Georgia, USA were quantified using eddy covariance observations of evapotranspiration (ET) and net ecosystem exchange (NEE) of carbon. Miscanthus biomass yield was 15.54 Mg ha-1 in 2015 and 11.80 Mg ha-1 in 2016, while maize produced 30.20 Mg ha-1 of biomass in 2016. Carbon budgets indicated that both miscanthus and maize fields lost carbon over the experiment. The miscanthus field lost 5 Mg C ha-1 in both 2015 and 2016 while the maize field lost 1.37 Mg C ha-1 for the single year of study. Eddy covariance measurement indicated that for 2016 the miscanthus crop evapotranspired 598 mm and harvest water use efficiencies ranged from 6.95 to 13.84 kg C ha-1 mm-1. Maize evapotranspired 659 mm with a harvest water use efficiency of 19.12 kg C ha-1 mm-1. While biomass yields and gross primary production were relatively high, high ecosystem respiration rates resulted in a loss of ecosystem carbon. Relatively low biomass production, low water use efficiency and high respiration for Miscanthus × gigantus in this experiment suggest that this strain of miscanthus may not be well-suited for dryland production under the environmental conditions found in South Georgia USA.

Evaluating digital medicine ingestion data from seriously mentally ill patients with a Bayesian Hybrid Model.

The objective of this work was to adapt and evaluate the performance of a Bayesian hybrid model to characterize objective temporal medication ingestion parameters from two clinical studies in patients with serious mental illness (SMI) receiving treatment with a digital medicine system. This system provides a signal from an ingested sensor contained in the dosage form to a patient-worn patch and transmits this signal via the patient's mobile device. A previously developed hybrid Markov-von Mises model was used to obtain maximum-likelihood estimates for medication ingestion behavior parameters for individual patients. The individual parameter estimates were modeled to obtain distribution parameters of priors implemented in a Markov chain-Monte Carlo framework. Clinical and demographic covariates associated with model ingestion parameters were also assessed. We obtained individual estimates of overall observed ingestion percent (median:75.9%, range:18.2-98.3%, IQR:32.9%), rate of excess dosing events (median:0%, range:0-14.3%, IQR:3.0%) and observed ingestion duration. The modeling also provided estimates of the Markov-dependence probabilities of dosing success following a dosing success or failure. The ingestion-timing deviations were modeled with the von Mises distribution. A subset of 17 patients (22.1%) were identified as prompt correctors based on Markov-dependence probability of a dosing failure followed by a dosing success of unity. The prompt corrector sub-group had a better overall digital medicine ingestion parameter profile compared to those who were not prompt correctors. Our results demonstrate the potential utility of a Bayesian Hybrid Markov-von Mises model for characterizing digital medicine ingestion patterns in patients with SMI.

The effect of aripiprazole once-monthly on personal and social functioning: post hoc analyses of acute and long-term studies.

OBJECTIVE: To evaluate the effect of aripiprazole once-monthly 400 mg (AOM 400; Abilify Maintena®) on personal and social functioning in patients with schizophrenia in both the acute treatment and maintenance therapy settings. METHODS: Post hoc analyses were conducted on data from Study 291 (NCT01663532), a 12-week, randomized, double-blind, placebo-controlled trial conducted in patients who were experiencing an acute psychotic episode, and Study 248 (NCT00731549), a 52-week open-label extension of two randomized, controlled trials of AOM 400 as maintenance therapy. Assessment of functioning was made using the Personal and Social Performance (PSP) scale. In Study 291, results were stratified by age (≤35 years or >35 years). RESULTS: In Study 291, 340 patients were included in the analysis (n=168 randomized to AOM 400 [n=49 aged ≤35 years, n=119 aged >35 years]; n=172 randomized to placebo [n=54 aged ≤35 years, n=118 aged >35 years]). In Study 248, 1,081 patients entered the open-label maintenance phase and 858 completed the study. In Study 291, AOM 400, compared with placebo, resulted in a significant increase (improvement) in PSP scores based on LSM (SE) changes from baseline to Week 12 in patients aged ≤35 years (20.6 [1.9] for AOM 400 vs 9.5 [2.4] for placebo; P=0.001) and a numerically (but not significantly) larger increase in PSP scores in patients aged >35 years (16.1 [1.7] for AOM 400 vs 12.5 [1.9] for placebo; P=0.093). Improvements in both age groups met criteria for a minimally important clinical difference (7-10 points). In Study 248, AOM 400 resulted in either numerical improvements (increases) from baseline in PSP total score or maintenance of stable baseline values throughout the study. CONCLUSION: AOM 400 was effective in improving personal and social functioning during acute treatment and maintaining function during long-term treatment.

Effectiveness Evaluation of Additional Risk Minimization Measures for Adolescent Use of Aripiprazole in the European Union: Results from a Post-Authorization Safety Study.

INTRODUCTION: Two risk minimization (RM) tools-a healthcare professional frequently asked questions (HCP-FAQs) brochure and a patient/caregiver information brochure (PCIB)-were developed for HCPs and for adolescents (aged ≥ 13 years) receiving aripiprazole for bipolar I mania and their caregivers. OBJECTIVES: This study evaluated the effectiveness of these RM tools in improving the awareness and education of HCPs and patients/caregivers. METHOD: The RM tools were distributed to HCPs (identified in agreement with the marketing authorization holder [MAH] and local regulatory authorities), who in turn distributed the PCIBs to patients/caregivers. A web-based survey was then conducted targeting HCPs and patients/caregivers. RESULTS: The response rate was low: 118 of 23,282 invited HCPs and 16 patients/caregivers completed the survey. Overall, 42% (49/118) of HCP respondents were aware of aripiprazole RM tools; of these, 59% (29/49) of HCPs read them at least once and 66% (19/29) of these used the RM tools while discussing the benefit-risk profile of aripiprazole with patients/caregivers. In total, 30 of the 118 HCPs (25%) were aware of the PCIB, and 26 distributed it to their patients/caregivers, whereas seven HCPs advised them to read the brochure. Overall, 15 of the 16 patients/caregivers were aware of the PCIB, and 13 read/referred to it. Of these, 12 found the PCIB useful, and five monitored their weight while receiving aripiprazole and reported potential risks immediately to their HCP. CONCLUSION: The response rate to the survey was low, and the tools displayed limited utility and effectiveness in improving awareness and education in a small number of responders. Therefore, the aripiprazole risk management plan was amended, and the tools were discontinued.

Human factors evaluation of a novel digital medicine system in psychiatry.

BACKGROUND: The digital medicine system (DMS), a drug-device combination developed for patients with serious mental illness, integrates adherence measurement with pharmacologic treatment by embedding an ingestible sensor in a pill, allowing for information sharing among patients, health care providers (HCPs), and caregivers via a mobile interface. Studies conducted during the DMS development process aimed to minimize cognitive burden and use-related risks and demonstrated effective use of the technology. METHODS: Human factors (HF) studies assessed the system's safe and effective use by the intended users for the intended uses. The patient interface was tested in six formative HF studies followed by a validation study. The HCP/caregiver interface was tested in one study before validation. All tasks critical to safety or necessary for effective use were included. Formative studies identified use-related risks and the causes of use problems to guide design modification. Validation of the patient and HCP/caregiver interfaces assessed risks of the final product. RESULTS: During the patient formative studies, design improvements were made to address problems and mitigate risks thought to be associated with a suboptimal system design or patient understanding of the system. In the validation study of the patient interface, 35 patients attempted 23 performance tasks, for a total of 805 attempts; 783/805 attempts were completed with success. One close call, 15 failures, and 6 difficulties occurred on these user tasks; only 3 of these were on a critical task. Residual risks resistant to mitigation were found to be of low severity based on the US Food and Drug Administration 2016 guidance. CONCLUSION: The final design of the DMS reflects input by the intended user populations through a comprehensive development methodology. In alignment with the US Food and Drug Administration goals for HF studies, the system was found to be safe and effective for the intended users, uses, and use environments.

Long-term effectiveness of aripiprazole once-monthly for schizophrenia is maintained in the QUALIFY extension study.

OBJECTIVE: To evaluate long-term safety and effectiveness of continued treatment with aripiprazole once-monthly 400mg (AOM 400) in patients with schizophrenia. METHODS: Patients who completed the QUALIFY study (NCT01795547) in the AOM 400 arm were eligible for 6 additional once-monthly injections of AOM 400 during an open-label, 24-week extension (NCT01959035). Safety data were collected at each visit. Effectiveness measures included change from baseline in health-related qualify of life and functioning on the Heinrichs-Carpenter Quality of Life scale (QLS) and Clinical Global Impression - Severity (CGI-S) scale. RESULTS: Of the 88 patients enrolled, 77 (88%) completed the extension study. Most common treatment-emergent adverse events (incidence ≥2%) were weight increased (6/88, 7%), toothache (3/88, 3%) and headache (3/88, 3%). Effectiveness was maintained during the extension study, with small but continued improvements from baseline: the least squares mean (LSM) change (95% CI) from baseline to week 24 was 2.32 (-1.21 to 5.85) for the QLS total score and -0.10 (-0.26 to 0.06) for the CGI-S score. The aggregated LSM change (95% CI) from baseline of the lead-in study to week 24 of the extension study was 11.54 (7.45 to 15.64) for the QLS total score and -0.98 (-1.18 to -0.79) for the CGI-S score. CONCLUSIONS: AOM 400 was well tolerated in patients continuing AOM treatment during the extension phase of the QUALIFY study. Robust and clinically meaningful improvements in health-related quality of life and functioning were maintained, further supporting the long-term clinical benefits of AOM 400 for the treatment of patients with schizophrenia.

A multicenter, open-label, pilot study evaluating the functionality of an integrated call center for a digital medicine system to optimize monitoring of adherence to oral aripiprazole in adult patients with serious mental illness.

BACKGROUND: Medication nonadherence is common in the treatment of serious mental illness (SMI) and leads to poor outcomes. The digital medicine system (DMS) objectively measures adherence with oral aripiprazole in near-real time, allowing recognition of adherence issues. This pilot study evaluated the functionality of an integrated call center in optimizing the use of the DMS. MATERIALS AND METHODS: An 8-week, open-label, single-arm trial at four US sites enrolled adults with bipolar I disorder, major depressive disorder, and schizophrenia on stable oral aripiprazole doses and willing to use the DMS (oral aripiprazole + ingestible event marker [IEM], IEM-detecting skin patch, and software application). Integrated call-center functionality was assessed based on numbers and types of calls. Ingestion adherence with prescribed treatment (aripiprazole + IEM) during good patch wear and proportion of time with good patch wear (days with ≥80% patch data or detected IEM) were also assessed. RESULTS: All enrolled patients (n=49) used the DMS and were included in analyses; disease duration overall approached 10 years. For a duration of 8 weeks, 136 calls were made by patients, and a comparable 160 calls were made to patients, demonstrating interactive communication. The mean (SD) number of calls made by patients was 2.8 (3.5). Approximately half of the inbound calls made by patients occurred during the first 2 weeks and were software application- or patch-related. Mean ingestion adherence was 88.6%, and corresponding good patch wear occurred on 80.1% of study days. CONCLUSION: In this pilot study, the integrated call center facilitated DMS implementation in patients with SMI on stable doses of oral aripiprazole. In clinical practice, the call center and the DMS will facilitate objective measurement of adherence and potentially improve rates of adherence in patients with SMI.