The Impact of a Digital Intervention (Happify) on Loneliness During COVID-19: Qualitative Focus Group.

BACKGROUND: Loneliness is a growing area of concern, attracting attention as a public health concern due to its association with a variety of psychological and physical health problems. However, interventions targeting loneliness are less common than interventions for other mental health problems, such as depression and anxiety, and existing interventions focus primarily on building social skills and increasing opportunities for social interaction despite research suggesting these techniques are not the most effective. Furthermore, although there is an increasing need for scalable and convenient interventions, digital interventions for loneliness are even less common. OBJECTIVE: Using a qualitative approach, we explore how adults (18-64 years of age) who express wanting to be more connected to others experience loneliness and react to a digital mental health intervention targeting loneliness. METHODS: A total of 11 participants were recruited from a pilot randomized controlled trial exploring the impact of a digital mental health intervention, Happify Health, on loneliness among adults aged 18-64 years who indicated wanting to feel more connected to others when signing up for the platform. Participants were invited to participate in a 3-day asynchronous focus group about their experiences with loneliness, with Happify Health, and with social distancing during the COVID-19 pandemic. All 11 participants completed the focus group in May 2020. RESULTS: Participants' responses were coded using thematic analysis, which led to identifying five themes, each with separate subthemes, that could be applied across the 3-day focus group: loneliness, relationships, social distancing, skill acquisition, and coping. Overall, we observed variability across participants in terms of the source of their loneliness, their perceptions of their social connections, and their motivation to reduce feelings of loneliness; however, participants commonly referred to negative self-perceptions as a cause or consequence of loneliness. Participants also varied in the extent to which they felt social distancing increased or decreased feelings of loneliness. In regard to the intervention, participants showed evidence of adopting skills they used to address their loneliness, particularly mindfulness and gratitude, and then using these skills to shift toward more active coping strategies following the intervention, including during the COVID-19 pandemic. CONCLUSIONS: The heterogeneity in participants' experiences with loneliness described during this focus group emphasizes the subjective and complex nature of loneliness. This highlights the importance of developing loneliness interventions that use a variety of strategies, including both direct and indirect strategies for reducing loneliness. However, based on our data, a key component to loneliness interventions is incorporating strategies for addressing underlying negative self-perceptions that stem from, but also contribute to, loneliness. This data also provides preliminary evidence that digital platforms may be an effective tool for disseminating loneliness interventions while providing the added benefit of offering a productive distraction when feeling lonely.

The Geshiyaro Project: a study protocol for developing a scalable model of interventions for moving towards the interruption of the transmission of soil-transmitted helminths and schistosome infections in the Wolaita zone of Ethiopia.

BACKGROUND: National deworming programmes rely almost exclusively on mass drug administration (MDA) to children to control morbidity caused by these parasitic infections. The provision of other interventions, consisting of preventive chemotherapy at high population level coverage together with water, sanitation and hygiene (WaSH) and changes in risk behaviour, should enable sustainable control of soil-transmitted helminths (STH) and schistosomiasis and ultimately interrupt transmission. METHODS/DESIGN: Two interventions will be implemented by the project: (i) community-wide biannual albendazole and annual praziquantel treatment with a target of 80-90% treatment coverage ("expanded MDA"); and (ii) provision of WaSH with behaviour change communication (BCC), within the Wolaita zone, Ethiopia. The project has three study arms: (i) expanded community-wide MDA, WaSH and BCC; (ii) expanded community-wide MDA only; and (iii) annual school-based MDA (the current National STH/schistosomiasis Control Programme). The impact of these interventions will be evaluated through prevalence mapping at baseline and endline (after four rounds of MDA), combined with annual longitudinal parasitological surveillance in defined cohorts of people to monitor trends in prevalence and reinfection throughout the project. Treatment coverage and individual compliance to treatment will be monitored by employing fingerprint biometric technology and barcoded identification cards at treatment. WaSH utilisation will be evaluated through school and household level observations and annual WaSH assessment survey. Complementary qualitative surveys will explore practices, cultural and social drivers of risk behaviours, uptake of WaSH and treatment, and assessing the impact of the BCC. DISCUSSION: The study has the potential to define an 'End Game' for STH and schistosomiasis programmes through provision of multiple interventions. Interrupting transmission of these infections would eliminate the need for long-term repeated MDA, lead to sustained health improvements in children and adults, thereby allowing health systems to focus on other disease control priorities.

Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a "gray zone"?

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

Soluble syndecan-3 binds chemokines, reduces leukocyte migration in vitro and ameliorates disease severity in models of rheumatoid arthritis.

BACKGROUND: Syndecans are heparan sulfate proteoglycans that occur in membrane-bound or soluble forms. Syndecan-3, the least well-characterised of the syndecan family, is highly expressed on synovial endothelial cells in rheumatoid arthritis patients. Here, it binds pro-inflammatory chemokines with evidence for a role in chemokine presentation and leukocyte trafficking into the joint, promoting the inflammatory response. In this study, we explored the role of soluble syndecan-3 as a binder of chemokines and as an anti-inflammatory and therapeutic molecule. METHODS: A human monocytic cell line and CD14+ PBMCs were utilised in both Boyden chamber and trans-endothelial migration assays. Soluble syndecan-3 was tested in antigen-induced and collagen-induced in vivo arthritis models in mice. ELISA and isothermal fluorescence titration assays assessed the binding affinities. Syndecan-3 expression was identified by flow cytometry and PCR, and levels of shedding by ELISA. RESULTS: Using in vitro and in vivo models, soluble syndecan-3 inhibited leukocyte migration in vitro in response to CCL7 and its administration in murine models of rheumatoid arthritis reduced histological disease severity. Using isothermal fluorescence titration, the binding affinity of soluble syndecan-3 to inflammatory chemokines CCL2, CCL7 and CXCL8 was determined, revealing little difference, with Kds in the low nM range. TNFα increased cell surface expression and shedding of syndecan-3 from cultured human endothelial cells. Furthermore, soluble syndecan-3 occurred naturally in the sera of patients with rheumatoid arthritis and periodontitis, and its levels correlated with syndecan-1. CONCLUSIONS: This study shows that the addition of soluble syndecan-3 may represent an alternative therapeutic approach in inflammatory disease.

Patient attitudes toward and goals for MDD treatment: a survey study.

Background/Objectives: Major depressive disorder (MDD) is a highly prevalent disorder, frequently diagnosed and treated in a primary care setting; however, little information is available about the treatment decision-making process between MDD patients and their providers. A shared decision-making and goal attainment approach to establishing and tracking progress toward treatment goals that are meaningful to individual patients is explored in this survey study. In addition, information about patient perspectives on setting treatment goals, medication selection/switching, and engaging patients with their health care professionals was also collected and evaluated. Methods: A 50-question online survey was administered to members of the PatientsLikeMe community who indicated an MDD diagnosis and a switch in antidepressant medications within the past 2 years. Follow-up interviews were also conducted with a small subset of these participants. Results: Of the 200 participants who completed the survey, 42% reported currently having goals for MDD treatment. These goals were typically in the areas of physical health (62.7%), cognitive functioning (60.2%), and social aspects of life (57.8%). A majority of survey participants (61%) believed the goal attainment approach would be helpful to set and evaluate treatment goals. Conclusions: The data provide important insights into patient perspectives on the development of formal treatment plans and goals for MDD. In addition, the data also support the use of a patient-centric approach to shared decision-making by using a goal attainment scale to establish and track progress toward treatment goals that are meaningful to MDD patients in real-world clinical practice. The results of this study can be used to inform best practices in patient-clinician communication when developing an MDD treatment plan and goals.

Novel Anti-Inflammatory Peptides Based on Chemokine-Glycosaminoglycan Interactions Reduce Leukocyte Migration and Disease Severity in a Model of Rheumatoid Arthritis.

Inflammation is characterized by the infiltration of leukocytes from the circulation and into the inflamed area. Leukocytes are guided throughout this process by chemokines. These are basic proteins that interact with leukocytes to initiate their activation and extravasation via chemokine receptors. This is enabled through chemokine immobilization by glycosaminoglycans (GAGs) at the luminal endothelial surface of blood vessels. A specific stretch of basic amino acids on the chemokine, often at the C terminus, interacts with the negatively charged GAGs, which is considered an essential interaction for the chemokine function. Short-chain peptides based on this GAG-binding region of the chemokines CCL5, CXCL8, and CXCL12γ were synthesized using standard Fmoc chemistry. These peptides were found to bind to GAGs with high affinity, which translated into a reduction of leukocyte migration across a cultured human endothelial monolayer in response to chemokines. The leukocyte migration was inhibited upon removal of heparan sulfate from the endothelial surface and was found to reduce the ability of the chemokine and peptide to bind to endothelial cells in binding assays and to human rheumatoid arthritis tissue. The data suggest that the peptide competes with the wild-type chemokine for binding to GAGs such as HS and thereby reduces chemokine presentation and subsequent leukocyte migration. Furthermore, the lead peptide based on CXCL8 could reduce the disease severity and serum levels of the proinflammatory cytokine TNF-α in a murine Ag-induced arthritis model. Taken together, evidence is provided for interfering with the chemokine-GAG interaction as a relevant therapeutic approach.

Evaluation of the Relative Abuse of an OROS Extended-release Hydromorphone HCI Product: Results From 3 Postmarket Surveillance Studies.

OBJECTIVE: Formulating prescription opioids to limit abuse remains a priority. OROS extended-release (ER) hydromorphone HCl (EXALGO) may have lower abuse potential than many other opioid products. Three postmarketing studies of the relative abuse liability of OROS hydromorphone ER were conducted. METHODS: Estimates of abuse, unadjusted, and adjusted for prescription volume, were generated for OROS hydromorphone ER and comparators from Q2 2010 through Q2 2014 for a high-risk, substance abuse treatment population and the general population using poison control center data. Comparators were selected for compound, market penetration, and route of administration (ROA) profile. ROA comparisons were made among the substance abuse treatment population. Internet discussion was examined to determine abusers' interest in and desire for the OROS formulation. RESULTS: Examination of abuse prevalence among adults within substance abuse treatment, intentional poison exposures, and Internet discussion levels generally support the hypothesis that OROS hydromorphone ER may have lower abuse potential than many other opioid products. OROS hydromorphone ER also seems to be abused less often by alternate ROAs (eg, snorting and injection). Lower levels of online discussion were observed along with relatively low endorsement for abuse. DISCUSSION: Abuse of OROS hydromorphone ER was observed in high-risk substance abuse and general population samples but at a very low relative prevalence compared to comparators. Evidence suggests it may be less often abused by alternate ROAs than some comparators. Online data did not find evidence of high levels of desire for OROS hydromorphone ER by recreational abusers. Continued monitoring of this product's abuse liability is warranted.

Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment.

OBJECTIVE: Abuse of prescription opioid pain relievers continues to be a serious public health concern. In contrast to opioids such as oxycodone or morphine, tapentadol, a prescription analgesic, has two mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. As a result of differences in its receptor pharmacology, there may be differences in its abuse profile. As an initial step toward testing this hypothesis, we present a postmarketing examination of tapentadol's abuse liability relative to comparators. METHODS: A sentinel sample of 113,914 individuals assessed for substance abuse treatment as part of the NAVIPPRO ASI-MV(®) surveillance system at 624 facilities in 38 states from January 2011 to September 2012 was examined for prevalence and prescription-adjusted prevalence of past 30-day abuse of tapentadol as a compound and its immediate-release (IR) and extended-release (ER) formulations with oxymorphone, hydromorphone, hydrocodone, morphine, fentanyl, oxycodone, tramadol, and buprenorphine as comparators. RESULTS: Tapentadol abuse was reported significantly less often (P < 0.001) than all comparator compounds. Tapentadol IR abuse prevalence was significantly lower than all comparators except fentanyl IR, which had the next lowest unadjusted abuse prevalence. Prevalence of tapentadol ER abuse was lower than comparators except hydromorphone ER. Low prescription-adjusted estimates were observed for tapentadol as a compound as well as its IR and ER formulations, which were among the lowest observed and the lowest of the Schedule II comparators. Prescription-adjusted risk for tapentadol ER was less than comparators except hydromorphone ER (P = 0.06). CONCLUSIONS: Tapentadol abuse was seen infrequently in this study and, on a prescription basis, was less likely to be abused than most of the examined Schedule II analgesics.

Assessing abuse potential of new analgesic medications following market release: an evaluation of Internet discussion of tapentadol abuse.

OBJECTIVE: Research on substance abusers in treatment suggests that tapentadol, a prescription analgesic, may have relatively low abuse potential. Messages posted by recreational drug abusers on online forums were examined for amount of discussion and endorsement for abuse of tapentadol and comparator drugs. METHODS: Internet messages posted between January 1, 2011 and September 30, 2012 on seven drug-abuse web forums were evaluated. Proportions of posts and unique authors discussing tapentadol were compared with eight comparator compounds. Postcontent was coded to compare endorsement for abuse of tapentadol with two comparators, one drug with high desirability for abuse and one with low desirability for abuse. RESULTS: A total of 1,940,121 messages posted during the study period were copied from selected web forums. The proportion of all posts discussing tapentadol (proportion = 0.0003) was significantly lower than any of the comparator compounds (range of odds ratios from 16.6 to 104.3; P < 0.001). The proportion of unique authors was also lower. Posts coded for endorsement (N = 2,117) yielded an endorsement ratio (Ero) of 2.14 for tapentadol, which was significantly lower than the highly desirable for abuse oxymorphone (ERo = 5.08; P = 0.0011) and was as low as tramadol (ERo = 1.66), which has a long-established profile of low abuse and desirability for abuse. CONCLUSIONS: Recreational abusers posting on web forums appear to be less interested in abusing tapentadol when compared with other, selected prescription analgesics based on the amount of discussion (i.e., fewer posts and authors mentioning tapentadol). Endorsement of the product for abuse was also low.

Nonmedical use of prescription ADHD stimulant medications among adults in a substance abuse treatment population: early findings from the NAVIPPRO surveillance system.

OBJECTIVE: To examine nonmedical use (NMU) of prescription ADHD stimulants among adults evaluated for substance abuse treatment. METHOD: 147,816 assessments from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) system (10/01/2009 through 03/31/2012) examined NMU prevalence, routes of administration (ROA), and diversion sources. RESULTS: Past 30-day NMU for prescription stimulants (1.29%) was significantly lower than that of prescription opioids (19.79%) or sedatives (10.62%). For stimulant products, NMU for Adderall was 0.62, followed by Adderall XR (0.42), Ritalin (0.16), Vyvanse (0.12), and Concerta (0.08); product differences likely have limited clinical relevance given the low estimates (<1%). Higher NMU per prescriptions was for Adderall (4.92), Ritalin (4.68), and Adderall XR (3.18) compared with newer formulations (Vyvanse 1.26, Concerta 0.89). Diversion source was mainly family/friends with no differences between products; swallowing whole was the most frequent ROA. CONCLUSION: Prescription stimulant NMU was low compared with other prescription medications among individuals assessed for substance abuse problems, with little difference among specific products.

Monitoring of internet forums to evaluate reactions to the introduction of reformulated OxyContin to deter abuse.

BACKGROUND: Reformulating opioid analgesics to deter abuse is one approach toward improving their benefit-risk balance. To assess sentiment and attempts to defeat these products among difficult-to-reach populations of prescription drug abusers, evaluation of posts on Internet forums regarding reformulated products may be useful. A reformulated version of OxyContin (extended-release oxycodone) with physicochemical properties to deter abuse presented an opportunity to evaluate posts about the reformulation in online discussions. OBJECTIVE: The objective of this study was to use messages on Internet forums to evaluate reactions to the introduction of reformulated OxyContin and to identify methods aimed to defeat the abuse-deterrent properties of the product. METHODS: Posts collected from 7 forums between January 1, 2008 and September 30, 2013 were evaluated before and after the introduction of reformulated OxyContin on August 9, 2010. A quantitative evaluation of discussion levels across the study period and a qualitative coding of post content for OxyContin and 2 comparators for the 26 month period before and after OxyContin reformulation were conducted. Product endorsement was estimated for each product before and after reformulation as the ratio of endorsing-to-discouraging posts (ERo). Post-to-preintroduction period changes in ERos (ie, ratio of ERos) for each product were also calculated. Additionally, post content related to recipes for defeating reformulated OxyContin were evaluated from August 9, 2010 through September 2013. RESULTS: Over the study period, 45,936 posts related to OxyContin, 18,685 to Vicodin (hydrocodone), and 23,863 to Dilaudid (hydromorphone) were identified. The proportion of OxyContin-related posts fluctuated between 6.35 and 8.25 posts per 1000 posts before the reformulation, increased to 10.76 in Q3 2010 when reformulated OxyContin was introduced, and decreased from 9.14 in Q4 2010 to 3.46 in Q3 2013 in the period following the reformulation. The sentiment profile for OxyContin changed following reformulation; the post-to-preintroduction change in the ERo indicated reformulated OxyContin was discouraged significantly more than the original formulation (ratio of ERos=0.43, P<.001). A total of 37 recipes for circumventing the abuse-deterrent characteristics of reformulated OxyContin were observed; 32 were deemed feasible (ie, able to abuse). The frequency of posts reporting abuse of reformulated OxyContin via these recipes was low and decreased over time. Among the 5677 posts mentioning reformulated OxyContin, 825 posts discussed recipes and 498 reported abuse of reformulated OxyContin by such recipes (41 reported injecting and 128 reported snorting). CONCLUSIONS: After introduction of physicochemical properties to deter abuse, changes in discussion of OxyContin on forums occurred reflected by a reduction in discussion levels and endorsing content. Despite discussion of recipes, there is a relatively small proportion of reported abuse of reformulated OxyContin via recipes, particularly by injecting or snorting routes. Analysis of Internet discussion is a valuable tool for monitoring the impact of abuse-deterrent formulations.

A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity.

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.

Measuring online endorsement of prescription opioids abuse: an integrative methodology.

PURPOSE: The ability to track prescription opioid abusers' endorsement of compounds may be valuable in forecasting abuser's preferences. We developed a metric, referred to as the Endorsement Ratio (ERo), to explore the feasibility of quantifying the sentiment expressed by opioid abusers who post online about prescription opioid products. METHODS: Internet posts written between April 1, 2010 and March 31, 2011 and related to six prescription opioid compounds (oxycodone ER, hydrocodone, hydromorphone, oxymorphone, morphine ER, and tramadol) were identified and qualitatively coded. A mixed effects multinomial logistic regression was employed to model the probability of observing endorsing, discouraging, mixed, or unclear messages per compound. Endorsement-to-discouragement ratio (ERo) and ratio of endorsement-to-discouragement ratios (RERo) were estimated for each compound. RESULTS: In the study sample of 12 838 Internet posts, a ranking of endorsement could be established, with oxymorphone as most endorsed (ERo = 7.39), followed by hydromorphone (ERo = 5.02), hydrocodone (ERo = 3.53), oxycodone ER (ERo = 3.23), morphine ER (ERo = 2.71), and tramadol (ERo = 1.76). Relative rankings of products required that route of administration be considered. CONCLUSIONS: This study expands existing Internet monitoring approaches by developing a metric to estimate the endorsement of specific prescription opioid compounds as viewed through the lens of Internet communities. Route of administration must be taken into account when examining preferences of drug abusers for various products. This study did not assess whether the novel metric is valid with respect to classification of abuse rates of different drugs. Further studies examining external validation studies are warranted.