Returning Individual Research Results from Digital Phenotyping in Psychiatry.

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants' locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant's real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas.

Should Medical Insurance Review Serve the Patient's Best Interests? Examples and Considerations Illustrated by Behavioral Health Cases.

ABSTRACT: Physician medical directors working for health care insurance companies conduct utilization reviews, participate in quality-of-care reviews, and adjudicate appeals. As a result, they have access to substantial and important clinical information. The medical director may have both current and historical information that can assist the treatment team in providing care. Sharing this information with a patient's current health care provider(s) is problematic due to concerns about patient privacy and the insurer's goal of not assuming legal liability for patient care. While this paper considers legal issues, it predominantly addresses the ethical responsibilities of medical directors who have valuable information unavailable to or unrecognized by the treatment team. Although it is important to consider sharing general medical information, this paper emphasizes the sharing of behavioral health information, which can be highly sensitive but also pertinent to psychiatric and other medical treatment choices. We suggest that clinical information should flow from insurer to provider when the insurer has information that will benefit the patient or prove crucial to optimal care rather than just flow from provider to insurer for the purposes of claims payments. To support and secure that flow, the paper outlines procedures for determining the need to share information, the means of providing that information, ways to separate liability, and processes for protecting privacy.

Monitoring of SARS-CoV-2 RNA in wastewater: A surveillance tool to foresee infection's evolution in the Mexican Caribbean.

The study aims to determine SARS-CoV-2 RNA in sewage of Cancun wastewater treatment plants, the main touristic destination of Mexico, and to estimate the infected persons during the sampling period. SARS-CoV-2 RNA traces were detected in the inlet of the five plants during almost all the sampling months. However, there is no presence of SARS-CoV-2 RNA traces in the effluent of the five WWTPs during the study period. ANOVA analysis showed differences in the concentrations of RNA traces of SARS-CoV-2 between the sample dates, but no differences were found from one WWTP to another. Estimated infected individuals by Markov chain Monte Carlo simulation are higher (between 77% and 91%) than the cases reported by the health authority. Wastewater monitoring and the estimation of infected individuals are a helpful tool, because estimation provides early warning signs on how broadly SARS-CoV-2 is circulating in the city, and led to the authorities to take measures wisely. PRACTITIONER POINTS: There is no presence of SARS-CoV-2 RNA traces in the effluent of the facilities, suggesting the effectiveness of treatment. Surveillance of viral RNA concentrations at treatment plants revealed presence in the influent of five plants Estimated infected individuals by MCMC simulation are higher than cases reported by health authority Environmental surveillance approach in wastewater influent is helpful to identify the clusters and to take informed decisions.

Practical Research Ethics in Psychiatric Clinical Trials: A Guide for Investigators.

The conduct of clinical psychiatric research is critical to advance the science and efficacy of treatment while also safeguarding the interests of participants. This article emerges from the authors' experience, providing practical guidance to colleagues seeking input on how to design and implement clinical research protocols in accordance with key ethical considerations. Thus, the intent of this article is to provide (1) an overview of common ethical considerations when conducting psychiatric clinical research along with (2) practical advice for preparing Institutional Review Board applications and associated materials in the ethical conduct of psychiatric clinical research.

Consensus Statement on Ethical & Safety Practices for Conducting Digital Monitoring Studies with People at Risk of Suicide and Related Behaviors.

OBJECTIVE: Digital monitoring technologies (e.g., smart-phones and wearable devices) provide unprecedented opportunities to study potentially harmful behaviors such as suicide, violence, and alcohol/substance use in real-time. The use of these new technologies has the potential to significantly advance the understanding, prediction, and prevention of these behaviors. However, such technologies also introduce myriad ethical and safety concerns, such as deciding when and how to intervene if a participant's responses indicate elevated risk during the study? METHODS: We used a modified Delphi process to develop a consensus among a diverse panel of experts on the ethical and safety practices for conducting digital monitoring studies with those at risk for suicide and related behaviors. Twenty-four experts including scientists, clinicians, ethicists, legal experts, and those with lived experience provided input into an iterative, multi-stage survey, and discussion process. RESULTS: Consensus was reached on multiple aspects of such studies, including: inclusion criteria, informed consent elements, technical and safety procedures, data review practices during the study, responding to various levels of participant risk in real-time, and data and safety monitoring. CONCLUSIONS: This consensus statement provides guidance for researchers, funding agencies, and institutional review boards regarding expert views on current best practices for conducting digital monitoring studies with those at risk for suicide-with relevance to the study of a range of other potentially harmful behaviors (e.g., alcohol/substance use and violence). This statement also highlights areas in which more data are needed before consensus can be reached regarding best ethical and safety practices for digital monitoring studies.

1H, 13C, and 15N backbone chemical shift assignments of m7GTP cap-bound Leishmania initiation factor 4E-1.

Most of the translational control of gene expression in higher eukaryotes occurs during the initiation step of protein synthesis. While this process is well characterized in mammalian cells, it is less defined in parasites, including the ones that cause human Leishmaniasis. The Leishmania cap-binding isoform 1 (LeishIF4E-1) is the only isoform that binds the specific trypanosomatids-specific hypermethylated 5' cap, called cap-4, in the human stage of the parasite life cycle. We report here the extensive NMR resonance assignment of LeishIF4E-1 bound to a cap analog, m7GTP. The chemical shift data constitute a prerequisite to understanding specific translation initiation mechanisms used in Leishmania parasites and to developing antiparasitic drugs targeting their translation initiation factors.

A newly identified Leishmania IF4E-interacting protein, Leish4E-IP2, modulates the activity of cap-binding protein paralogs.

Translation of most cellular mRNAs in eukaryotes proceeds through a cap-dependent pathway, whereby the cap-binding complex, eIF4F, anchors the preinitiation complex at the 5' end of mRNAs and regulates translation initiation. The requirement of Leishmania to survive in changing environments can explain why they encode multiple eIF4E (LeishIF4Es) and eIF4G (LeishIF4Gs) paralogs, as each could be assigned a discrete role during their life cycle. Here we show that the expression and activity of different LeishIF4Es change during the growth of cultured promastigotes, urging a search for regulatory proteins. We describe a novel LeishIF4E-interacting protein, Leish4E-IP2, which contains a conserved Y(X)4LΦ IF4E-binding-motif. Despite its capacity to bind several LeishIF4Es, Leish4E-IP2 was not detected in m7GTP-eluted cap-binding complexes, suggesting that it could inhibit the cap-binding activity of LeishIF4Es. Using a functional assay, we show that a recombinant form of Leish4E-IP2 inhibits the cap-binding activity of LeishIF4E-1 and LeishIF4E-3. Furthermore, we show that transgenic parasites expressing a tagged version of Leish4E-IP2 also display reduced cap-binding activities of tested LeishIF4Es, and decreased global translation. Given its ability to bind more than a single LeishIF4E, we suggest that Leish4E-IP2 could serve as a broad-range repressor of Leishmania protein synthesis.

IRB Oversight of Patient-Centered Outcomes Research: A National Survey of IRB Chairpersons.

Patient-centered outcomes research (PCOR) is becoming increasingly common. However, there is little evidence regarding what novel ethical challenges, if any, are posed by PCOR with relevance to institutional review board (IRB) oversight and human subjects protections. This article reports the results of a national survey of all IRB chairpersons from research-intensive institutions in the United States. Findings address the responsibilities of IRBs and the challenges associated with PCOR review and oversight. IRB chairpersons varied in their judgment of PCOR's overall value to the scientific enterprise and to research at their institution. Furthermore, 27% of respondents considered patients serving in nontraditional roles to be research subjects even when they are not enrolled in research. There was also variation in the training and safeguards their IRBs require for patient partners. Our results suggest that guidance should be developed around ethical and regulatory issues associated with PCOR oversight.

Structural basis for LeishIF4E-1 modulation by an interacting protein in the human parasite Leishmania major.

Leishmania parasites are unicellular pathogens that are transmitted to humans through the bite of infected sandflies. Most of the regulation of their gene expression occurs post-transcriptionally, and the different patterns of gene expression required throughout the parasites' life cycle are regulated at the level of translation. Here, we report the X-ray crystal structure of the Leishmania cap-binding isoform 1, LeishIF4E-1, bound to a protein fragment of previously unknown function, Leish4E-IP1, that binds tightly to LeishIF4E-1. The molecular structure, coupled to NMR spectroscopy experiments and in vitro cap-binding assays, reveal that Leish4E-IP1 allosterically destabilizes the binding of LeishIF4E-1 to the 5' mRNA cap. We propose mechanisms through which Leish4E-IP1-mediated LeishIF4E-1 inhibition could regulate translation initiation in the human parasite.

1H, 13C, and 15N backbone chemical shift assignments of 4E-BP144-87 and 4E-BP144-87 bound to eIF4E.

The eukaryotic translational initiation factor 4G (eIF4G) interacts with the cap-binding protein eIF4E through a consensus binding motif, Y(X)4LΦ (where X is any amino acid and Φ is a hydrophobic residue). 4E binding proteins (4E-BPs), which also contain a Y(X)4LΦ motif, regulate the eIF4E/eIF4G interaction. The non- or minimally-phosphorylated form of 4E-BP1 binds eIF4E, preventing eIF4E from interacting with eIF4G, thus inhibiting translation initiation. 4EGI-1, a small molecule inhibitor of the eIF4E/eIF4G interaction that is under investigation as a novel anti-cancer drug, has a dual activity; it disrupts the eIF4E/eIF4G interaction and stabilizes the binding of 4E-BP1 to eIF4E. Here, we report the complete backbone NMR resonance assignment of an unliganded 4E-BP1 fragment (4E-BP144-87). We also report the near complete backbone assignment of the same fragment in complex to eIF4E/m7GTP (excluding the assignment of the last C-terminus residue, D87). The chemical shift data constitute a prerequisite to understanding the mechanism of action of translation initiation inhibitors, including 4EGI-1, that modulate the eIF4E/4E-BP1 interaction.

Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1.

The eIF4E-binding protein (4E-BP) is a phosphorylation-dependent regulator of protein synthesis. The nonphosphorylated or minimally phosphorylated form binds translation initiation factor 4E (eIF4E), preventing binding of eIF4G and the recruitment of the small ribosomal subunit. Signaling events stimulate serial phosphorylation of 4E-BP, primarily by mammalian target of rapamycin complex 1 (mTORC1) at residues T37/T46, followed by T70 and S65. Hyperphosphorylated 4E-BP dissociates from eIF4E, allowing eIF4E to interact with eIF4G and translation initiation to resume. Because overexpression of eIF4E is linked to cellular transformation, 4E-BP is a tumor suppressor, and up-regulation of its activity is a goal of interest for cancer therapy. A recently discovered small molecule, eIF4E/eIF4G interaction inhibitor 1 (4EGI-1), disrupts the eIF4E/eIF4G interaction and promotes binding of 4E-BP1 to eIF4E. Structures of 14- to 16-residue 4E-BP fragments bound to eIF4E contain the eIF4E consensus binding motif, (54)YXXXXLΦ(60) (motif 1) but lack known phosphorylation sites. We report here a 2.1-Å crystal structure of mouse eIF4E in complex with m(7)GTP and with a fragment of human 4E-BP1, extended C-terminally from the consensus-binding motif (4E-BP150-84). The extension, which includes a proline-turn-helix segment (motif 2) followed by a loop of irregular structure, reveals the location of two phosphorylation sites (S65 and T70). Our major finding is that the C-terminal extension (motif 3) is critical to 4E-BP1-mediated cell cycle arrest and that it partially overlaps with the binding site of 4EGI-1. The binding of 4E-BP1 and 4EGI-1 to eIF4E is therefore not mutually exclusive, and both ligands contribute to shift the equilibrium toward the inhibition of translation initiation.

Industry Relationships Among Academic Institutional Review Board Members: Changes From 2005 Through 2014.

IMPORTANCE: For the past decade, more attention and concern has been directed toward financial relationships between the life science industry and physicians. Relationships between industry and institutional review board (IRB) members represent an important subclass that has the potential to broadly influence decisions regarding medical research. OBJECTIVES: To study the nature, extent, and perceived consequences of industry relationships among IRB members in academic health centers and to compare our results with findings from 2005. DESIGN, SETTING, AND PARTICIPANTS: A survey mailed to IRB members from the 115 most research-intensive medical schools and teaching hospitals in the United States from January 16 through May 16, 2014. The survey included questions identical to those used in 2005. Data analysis was conducted from June through October 2014. MAIN OUTCOMES AND MEASURES: The frequency of industry relationships among IRB members and the perceived effect of those relationships on IRB-related activities. RESULTS: We found no significant change in the percentage of IRB members with an industry relationship from 2005 through 2014 (2005: 37.2%; 95% CI, 32.7%-42.0%; 2014: 32.1%; 95% CI, 28.0%-36.4%; P = .09). However, since 2005, the percentage of members who felt another member did not properly disclose a financial relationship decreased from 10.8% (95% CI, 8.0%-14.4%) to 6.7% (95% CI, 4.7%-9.4%) (P = .04), as did the percentage who felt pressure from their institution or department to approve a protocol (2005: 18.6%; 95% CI, 15.0%-22.9%; 2014: 10.0%; 95% CI, 7.6%-13.0%; P < .001). The percentage of members with a conflict of interest who voted on protocols with which they have a conflict has not changed, although the percentage who said they always disclose relationships increased significantly from 54.9% in 2005 (95% CI, 42.2%-66.9%) to 80.0% in 2014 (95% CI, 65.3%-89.4%) (P = .01). We also found evidence of anti-industry bias in the presentation of protocols to the IRB. CONCLUSIONS AND RELEVANCE: The results show significant positive progress in the reporting and management of conflicts of interest among IRB members in academic health centers since 2005 after adjusting for other factors. Additional attention should be focused on deterring IRB members from inappropriately voting on or presenting protocols in a biased manner.

Factors associated with extended length of stay for patients presenting to an urban psychiatric emergency service: a case-control study.

This study assessed factors associated with extended length of stay (ELOS) for patients presenting to a psychiatric emergency service (PES). Two hundred six subjects with a length of stay of 24 h or longer were compared with time-matched controls (patients that presented directly after the ELOS patient). Binary logistic regression was used to identify risk factors for ELOS. ELOS was associated with suicidal ideation, disposition to an inpatient unit, homicidal ideation, lack of insurance, homelessness, male gender, past history of psychiatric hospitalization, diagnosis of substance abuse, significant psychiatric co-morbidity (represented by three or more Axis I diagnoses), and diagnosis of a psychotic disorder. Lack of insurance, suicidal ideation, disposition to inpatient unit, and homicidal ideation all made nonredundant contributions to predicting stays of 24 h or longer.

Financial relationships between institutional review board members and industry.

BACKGROUND: Little is known about the nature, extent, and consequences of financial relationships between industry and institutional review board (IRB) members in academic institutions. We surveyed IRB members about such relationships. METHODS: We surveyed a random sample of 893 IRB members at 100 academic institutions (response rate, 67.2%). The questionnaire focused on the financial relationships that the members had with industry (e.g., employment, membership on boards, consulting, receipt of royalties, and paid speaking). RESULTS: We found that 36% of IRB members had had at least one relationship with industry in the past year. Of the respondents, 85.5% said they never thought that the relationships that another IRB member had with industry affected his or her IRB-related decisions in an inappropriate way, 11.9% said they thought this occurred rarely, 2.4% thought it occurred sometimes, and 0.2% thought it occurred often. Seventy-eight respondents (15.1%) reported that at least one protocol came before their IRB during the previous year that was sponsored either by a company with which they had a relationship or by a competitor of that company, both of which could be considered conflicts of interest. Of these 78 members (62 voting members and 16 nonvoting members), 57.7% reported that they always disclosed the relationship to an IRB official, 7.7% said they sometimes did, 11.5% said they rarely did, and 23.1% said they never did. Of the 62 voting members who reported conflicts, 64.5% reported that they never voted on the protocol, 4.8% said they rarely did, 11.3% said they sometimes did, and 19.4% said they always did. Most respondents reported that the views of IRB members who had experience working with industry were beneficial in reviewing industry-sponsored protocols. CONCLUSIONS: Relationships between IRB members and industry are common, and members sometimes participate in decisions about protocols sponsored by companies with which they have a financial relationship. Current regulations and policies should be examined to be sure that there is an appropriate way to handle conflicts of interest stemming from relationships with industry.

Prescription of antipsychotic drugs by office-based physicians in the United States, 1989-1997.

OBJECTIVE: This study examined trends in the prescription of antipsychotic drugs in a nationally representative sample of physicians in nonfederal office-based clinical practice during the 1990s. METHODS: The authors analyzed physician-reported data from annual National Ambulatory Medical Care Surveys between 1989 and 1997 using weighted national estimates of physician visits during which antipsychotic drugs were prescribed. Prescription rates for antipsychotic drugs were compared between periods and among demographic, organizational, and clinical subgroups. RESULTS: Prescription of antipsychotic drugs in office-based practice increased significantly between 1989 and 1997. In 1989 antipsychotics were prescribed during 3.2 million office visits (.46 percent of all visits), compared with 6.9 million visits in 1997 (.88 percent). The atypical antipsychotics risperidone and olanzapine were the most widely prescribed antipsychotics in 1997. Risperidone was prescribed during 22.8 percent of all visits that involved prescription of an antipsychotic, and olanzapine during 17.1 percent. Psychiatrists were more likely than other physicians to prescribe an atypical agent (37.1 percent of visits involving prescription of an antipsychotic compared with 14.2 percent). Psychiatrists were also more likely than other physicians to schedule a follow-up visit after prescribing an antipsychotic (96.6 percent of visits compared with 73 percent). No evidence was found of a broadening of diagnostic indications for use over time. CONCLUSIONS: The rate of prescription of antipsychotic drugs among office-based physicians increased sharply during the 1990s after a nine-year decline. The increase was accounted for by growth in the use of atypical antipsychotics; the overall prescription rate of conventional agents did not change. Psychiatrists were more likely to prescribe atypical agents and to monitor more closely patients who were taking antipsychotics.