Clinical Trials Studying Suicide Risk Reduction: Who is Excluded From Participation.

OBJECTIVE: The use of exclusion criteria in clinical trials can cause research participants to differ markedly from clinical populations, which negatively impacts generalizability of results. This study identifies and quantifies common and recurring exclusion criteria in clinical trials studying suicide risk reduction, and estimates their impact on eligibility among a clinical sample of adults in an emergency department with high suicide risk. METHOD: Recent trials were identified by searching PubMed (terms suicide, efficacy, effectiveness, limited to clinical trials in prior 5 years). Common exclusion criteria were identified using Qualitative Content Analysis. A retrospective chart review examined a one-month sample of all adults receiving psychiatric evaluation in a large urban academic emergency department. RESULTS: The search yielded 27 unique clinical trials studying suicide risk reduction as a primary or secondary outcome. After research fundamentals (e.g. informed consent, language fluency), the most common exclusion criteria involved psychosis (77.8%), cognitive problems (66.7%), and substance use (63.0%). In the clinical sample of adults with high suicide risk (N = 232), psychosis exclusions would exclude 53.0% of patients and substance use exclusions would exclude 67.2% of patients. Overall, 5.6% of emergency psychiatry patients would be eligible for clinical trials that use common exclusion criteria. CONCLUSIONS: Recent clinical trials studying suicide risk reduction have low generalizability to emergency psychiatry patients with high suicide risk. Trials enrolling persons with psychosis and substance use in particular are needed to improve generalizability to this clinical population.

Exclusion criteria limit who can enroll in trials studying suicide risk reduction.Trials most frequently exclude psychosis, cognitive problems, and substance use.Trials have poor generalizability to emergency psychiatry patients.

Ethics in placebo-controlled, acute treatment trials in schizophrenia: Two rival ethical frameworks.

Placebo-controlled, acute treatment trials in schizophrenia enroll acutely symptomatic persons, randomize them to receive placebo or antipsychotic medication for several weeks, and evaluate whether symptoms improve. These trials can have scientific benefits, especially when they test drugs with novel mechanisms of action. However, the use of placebo is ethically problematic inasmuch as standard treatment is withheld and participants are subjected to prolonged psychotic symptoms and associated risks. We propose that both deontological (duty-based) and utilitarian analyses are relevant, that it may be impossible to satisfy the ideals of both frameworks, and that researchers who conduct these trials will unavoidably encounter ethical tension and criticism even when they give careful attention to ethical aspects of study design.

Intramuscular ketamine vs. midazolam for rapid risk-reduction in suicidal, depressed emergency patients: Clinical trial design and rationale.

Emergency department (ED) visits for suicidal ideation or behavior have been increasing in all age groups, particularly younger adults. A rapid-acting treatment to reduce suicidal thinking, adapted for ED use, is needed. Previous studies have shown a single dose of ketamine can improve depression and suicidal ideation within hours. However, most studies used 40 min intravenous infusions which can be impractical in a psychiatric ED. The ER-Ketamine study we describe here is a randomized midazolam-controlled clinical trial (RCT; NCT04640636) testing intramuscular (IM) ketamine's feasibility, safety, and effectiveness to rapidly reduce suicidal ideation and depression in a psychiatric ED. A pre-injection phase involves screening, informed consent, eligibility confirmation, and baseline assessment of suicidal ideation, depression, and comorbidities. The randomized double-blind IM injection is administered in the ED under research staff supervision, vital sign monitoring, pharmacokinetic blood sampling, and clinical assessments. The post-injection phase occurs on a psychiatric inpatient unit with follow-up research assessments through four weeks post-discharge. Outcome measures are feasibility, safety, and effects on suicidal ideation and depression at 24 h post-injection, and through follow-up. The target sample is N = 90 adults in a major depressive episode, assessed by ED clinicians as warranting hospitalization for suicide risk. Here we report design, rationale, and preliminary feasibility and safety for this ongoing study. Demographics of the 53 participants (ages 18 to 65 years) randomized to date suggest a diverse sample tending towards younger adults.

Brachioradial Pruritus: An Etiologic Review and Treatment Summary.

Brachioradial pruritus (BRP) is a relatively uncommon neuropathic dysesthesia localized to the dorsolateral arms that causes unrelenting itching, burning, tingling, or stinging sensations. There is no identifiable cause of BRP to date, though it is thought to be secondary to either cervical spine pathology or exposure to UV radiation (UVR). Gold-standard treatment of BRP remains unknown. This article reviews previously trialed conservative management options, including chiropractic manipulation, acupuncture, physiotherapy, and photoprotection, as well as medical management options that have been utilized to treat BRP, such as medications, interventional pain management procedures, and surgery. We compiled an updated comprehensive list of possible treatment strategies to be utilized by future providers.

Eligibility of emergency psychiatry patients for clinical trials studying depression.

BACKGROUND: Differences often exist between people with depression who are eligible for clinical trials and those seen in clinical practice. The impact of exclusion criteria on eligibility has been previously reported for inpatients and outpatients, but has not been assessed for emergency psychiatry patients; a group that overlaps with inpatients and outpatients but also has important distinctives. Understanding the frequencies of commonly used exclusion criteria in this population could inform interpretation of existing data (generalizability) and highlight opportunities/needs for future trials. METHODS: We reviewed 67 clinical trials studying depression using Qualitative Content Analysis to identify common and recurring exclusion criteria. We examined the frequency of these exclusion criteria among a clinical sample of emergency psychiatry patients. RESULTS: Most clinical trials had exclusions for basic research requirements, age, symptom severity, psychosis, and substance use. Applying 9 commonly used exclusion criteria to the clinical population resulted in a 3.3 % eligibility rate (95 % CI 1.2 %-7.0 %). Exclusions for psychosis (85.1 % of trials), substance use (83.6 % of trials), and suicide risk (65.7 % of trials) would likely exclude 93 % of emergency psychiatry patients. The prevalence of psychosis, substance use, and suicide risk was much higher among emergency psychiatry patients than among previously studied populations. LIMITATIONS: Some eligibility criteria could not be measured. The Qualitative Content Analysis consolidated similar exclusion criteria, losing potentially important nuances in wordings. CONCLUSIONS: Exclusion criteria commonly used in contemporary clinical trials of depression limit generalizability to emergency psychiatry patients, due in large part to exclusions for psychosis, substance use, and suicide risk.

Physical Assault in the Psychiatry Emergency Room.

Previous studies of physical assaults in hospitals focused primarily on inpatient psychiatric units, leaving unanswered questions about the extent to which findings generalize to psychiatric emergency rooms. Assault incident reports and electronic medical records from one psychiatric emergency room and two inpatient psychiatric units were reviewed. Qualitative methods were used to identify precipitants. Quantitative methods were used to describe characteristics of each event, as well as demographic and symptom profiles associated with incidents. During the five-year study period, there were 60 incidents in the psychiatric emergency room and 124 incidents on the inpatient units. Precipitating factors, incident severity, means of assault, and interventions were similar in both settings. Among patients in the psychiatric emergency room, a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with manic symptoms (Adjusted Odds Ratio (AOR) 27.86) and presenting with thoughts to harm others (AOR 10.94) were associated with an increased likelihood of having an assault incident report. Similarities between assaults in the psychiatric emergency room and inpatient psychiatric units suggest that the broader literature from inpatient psychiatry can be generalized to the psychiatric emergency room setting, although some differences exist. Reprinted from J Am Acad Psychiatry Law 2020; 48:484-495, with permission from The American Academy of Psychiatry and the Law. Copyright © 2020.

Structural mass spectrometry approaches to understand multidrug efflux systems.

Multidrug efflux pumps are ubiquitous across both eukaryotes and prokaryotes, and have major implications in antimicrobial and multidrug resistance. They reside within cellular membranes and have proven difficult to study owing to their hydrophobic character and relationship with their compositionally complex lipid environment. Advances in structural mass spectrometry (MS) techniques have made it possible to study these systems to elucidate critical information on their structure-function relationships. For example, MS techniques can report on protein structural dynamics, stoichiometry, connectivity, solvent accessibility, and binding interactions with ligands, lipids, and other proteins. This information proving powerful when used in conjunction with complementary structural biology methods and molecular dynamics (MD) simulations. In the present review, aimed at those not experts in MS techniques, we report on the current uses of MS in studying multidrug efflux systems, practical considerations to consider, and the future direction of the field. In the first section, we highlight the importance of studying multidrug efflux proteins, and introduce a range of different MS techniques and explain what information they yield. In the second section, we review recent studies that have utilised MS techniques to study and characterise a range of different multidrug efflux systems.

Persons Who Engage in Self-Harm While in the Emergency Department: A Case-Control Analysis.

ABSTRACT: Some patients engage in self-harm behaviors while in the emergency department. Risk factors for self-harm have been described for inpatient and outpatient/community settings, but not among emergency department patients. Authors conducted case-control, retrospective reviews of medical records and incident reports for emergency department patients in two academic medical centers. Variables were analyzed using conditional logistic regression. There were 113 individuals who engaged in self-harm while in the emergency department and 226 individuals who did not. Four variables were significant in the final model: a history of nonsuicidal self-harm (odds ratio [OR], 4.28; 95% confidence interval [CI], 1.95-9.41), opioid use in the prior 2 weeks (OR, 2.89; CI, 1.19-7.02), current manic episode (OR, 3.59; CI, 1.33-9.70), and a history of seizures (OR, 4.19; CI, 1.16-15.14). Risk of self-harm while in the emergency department may be mitigated with interventions that support adaptive coping skills, promptly address pain and withdrawal symptoms, and treat mania.

Aberrant Nuclear Translocation of E2F1 and Its Association in Cushing's Disease.

Nonsurgical medical treatments are often performed for Cushing's disease due to high recurrence rates. However, current medical treatment that targets corticotroph adenomas are limited. To develop a treatment that specifically targets corticotrophs in Cushing's disease, it is necessary to identify corticotroph lineage-specific proteins, which are involved in the Cushing's tumor phenotype. We have previously reported that the expression of E2F transcription factor 1 (E2F1), one of the cell cycle regulatory proteins, was increased in corticotrophs in Cushing's disease model mice and was involved in the regulation of POMC gene expression. Phosphorylation of Ser337 of E2F1 (pS337-E2F1) facilitates its binding to the POMC promoter, which was suggested to contribute to elevated POMC expression in corticotrophs. Here, we report that E2F1 expression is specific to the corticotroph lineage in normal human pituitaries and that the E2F1 protein is localized in the cytosol in normal corticotrophs. We show that pS337-E2F1 is localized in the nucleus specifically in Cushing's tumors, while it is localized in the perinuclear cytoplasm in the normal pituitary. This observation demonstrates that pS337 is a marker for Cushing's tumors and suggests that phosphorylation of E2F1 may be a target for developing a novel pharmacological treatment for tumorigenesis and hormone dysregulation of Cushing's disease.

Coupling plant litter quantity to a novel metric for litter quality explains C storage changes in a thawing permafrost peatland.

Permafrost thaw is a major potential feedback source to climate change as it can drive the increased release of greenhouse gases carbon dioxide (CO2 ) and methane (CH4 ). This carbon release from the decomposition of thawing soil organic material can be mitigated by increased net primary productivity (NPP) caused by warming, increasing atmospheric CO2 , and plant community transition. However, the net effect on C storage also depends on how these plant community changes alter plant litter quantity, quality, and decomposition rates. Predicting decomposition rates based on litter quality remains challenging, but a promising new way forward is to incorporate measures of the energetic favorability to soil microbes of plant biomass decomposition. We asked how the variation in one such measure, the nominal oxidation state of carbon (NOSC), interacts with changing quantities of plant material inputs to influence the net C balance of a thawing permafrost peatland. We found: (1) Plant productivity (NPP) increased post-thaw, but instead of contributing to increased standing biomass, it increased plant biomass turnover via increased litter inputs to soil; (2) Plant litter thermodynamic favorability (NOSC) and decomposition rate both increased post-thaw, despite limited changes in bulk C:N ratios; (3) these increases caused the higher NPP to cycle more rapidly through both plants and soil, contributing to higher CO2 and CH4  fluxes from decomposition. Thus, the increased C-storage expected from higher productivity was limited and the high global warming potential of CH4 contributed a net positive warming effect. Although post-thaw peatlands are currently C sinks due to high NPP offsetting high CO2 release, this status is very sensitive to the plant community's litter input rate and quality. Integration of novel bioavailability metrics based on litter chemistry, including NOSC, into studies of ecosystem dynamics, is needed to improve the understanding of controls on arctic C stocks under continued ecosystem transition.

Self-harm During Visits to the Emergency Department: A Qualitative Content Analysis.

BACKGROUND: Some patients engage in self-harm behaviors while in the emergency department, both suicidal and nonsuicidal self-harm. Little is known about what motivates these behaviors. This gap in the empirical literature limits efforts to develop early identification and risk mitigation strategies. OBJECTIVE: To describe methods and motivations when patients self-harm in the emergency department. METHOD: Authors reviewed self-harm incident reports and medical records from two urban academic emergency departments. Event timing and self-harm methods were extracted. Authors performed a qualitative content analysis of self-harm narratives to examine the question, "Which factors motivate patients to engage in deliberate (nonaccidental) self-harm in the emergency department?" RESULTS: The sample included 184 self-harm incidents involving 118 unique patients. A wide variety of self-harm methods were present in the data. Suicidal intent was present in a minority of incidents. Other motives included psychosis, intoxication, aggression, managing distress, communication, and manipulation. CONCLUSIONS: Self-harm behaviors in the emergency department encompassed a variety of methods and motivations. These findings suggest risk mitigation strategies that emphasize suicide screening, reducing environmental hazards, and increasing observation are unlikely to achieve the goal of zero harm. Strategies focusing on engagement may create more fruitful opportunities to improve patient safety.

The NERSH Questionnaire and Pool of Data from 12 Countries: Development and Description.

Modern healthcare research has only in recent years investigated the impact of health care workers' religious and other values on medical practice, interaction with patients, and ethically complex decision making. So far, only limited international data exist on the way such values vary across different countries. We therefore established the NERSH International Collaboration on Values in Medicine with datasets on physician religious characteristics and values based on the same questionnaire. The present article provides (a) an overview of the development of the original and optimized questionnaire, (b) an overview of the content of the NERSH data pool at this stage and (c) a brief review of insights gained from articles published with the questionnaire. The pool at this stage consists of data from 17 studies from research units in 12 different countries representing six continents with responses from more than 6000 health professionals. The joint data pool suggests that there are large differences in religious and other moral values across nations and cultures, and that these values contribute to the observed differences in health professionals' clinical practices-across nations and cultures!

Medication Use and Physical Assaults in the Psychiatric Emergency Department.

Objective: To evaluate the relationship between medications used to treat acute agitation (antipsychotics, mood stabilizers, and benzodiazepines) and subsequent assault incidence in the psychiatric emergency department.Methods: Medication orders and assault incident reports were obtained from electronic health records for 17,056 visits to an urban psychiatric emergency department from 2014 to 2019. Assault risk was modeled longitudinally using Poisson mixed-effects regression.Results: Assaults were reported during 0.5% of visits. Intramuscular (IM) medications were ordered in 23.3% of visits overall and predominantly were ordered within the first 4 hours of a visit. IM medication orders were correlated with assault (incident rate ratio [IRR] = 24.2; 95% CI, 5.33-110.0), often because IM medications were ordered immediately subsequent to reported assaults. Interacted with time, IM medications were not significantly associated with reduction in subsequent assaults (IRR = 0.700; 95% CI, 0.467-1.04). Neither benzodiazepines nor mood stabilizers were associated with subsequent changes to the risk of reported assault. By contrast, antipsychotic medications were associated with decreased assault risk across time (IRR = 0.583; 95% CI, 0.360-0.942).Conclusions: Although assault prevention is not the sole reason for ordering IM medications, IM medication order rates are high relative to overall assault incident risk. Of the 3 major categories of medications ordered commonly in the psychiatric emergency setting, only antipsychotic medications were associated with measurable decreases in subsequent assault risk. As antipsychotic medication can have a significant side effect burden, careful weighing of the risks and benefits of medications is encouraged.

The Impact of the COVID-19 Pandemic on Psychiatric Emergency Service Volume and Hospital Admissions.

BACKGROUND: During the COVID-19 pandemic, there have been an increasing number of emergency department visits for behavioral health reasons, even as overall emergency department volumes have decreased. The impact of the pandemic and related public health interventions on specialized psychiatric emergency services has not been described. These services provide high-intensity care for severely ill patients who are likely to be homeless and underserved. OBJECTIVE: We describe the change in total volume and psychiatric hospitalization rates among three psychiatric emergency services across the United States. METHODS: Changes in volumes and hospitalization were assessed for statistical significance using a seasonal autoregressive integrated moving average with exogenous factors model from January 2018 to December 2020. RESULTS: The pandemic's impact on volumes and hospitalization varied by site. In Denver (CO), there was a statistically significant 9% decrease in overall volumes, although an 18% increase in hospitalizations was not significant. In New York City (NY), there was a significant 7% decrease in volumes as well as a significant 6% decrease in hospitalizations. In Portland (OR), volumes decreased by 4% and hospitalizations increased by 6% although differences did not reach statistical significance. CONCLUSIONS: There has been a decrease in volume at these services after the pandemic, but there are substantial variations in the magnitude of change and demand for hospitalization by region. These findings suggest a need to understand where patients in crisis are seeking care and how systems of care must adapt to changing utilization in the pandemic era.

Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A.

The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays an important role in suppressing the invasion and metastasis of tumour cells. The nucleoside diphosphate kinase (NDPK) activity of NME1 is well recognized in balancing the intracellular pools of nucleotide diphosphates and triphosphates to regulate cytoskeletal rearrangement and cell motility, endocytosis, intracellular trafficking, and metastasis. In addition, NME1 was found to function as a protein-histidine kinase, 3'-5' exonuclease and geranyl/farnesyl pyrophosphate kinase. These diverse cellular functions are regulated at the level of expression, post-translational modifications, and regulatory interactions. The NDPK activity of NME1 has been shown to be inhibited in vitro and in vivo under oxidative stress, and the inhibitory effect mediated via redox-sensitive cysteine residues. In this study, affinity purification followed by mass spectrometric analysis revealed NME1 to be a major coenzyme A (CoA) binding protein in cultured cells and rat tissues. NME1 is also found covalently modified by CoA (CoAlation) at Cys109 in the CoAlome analysis of HEK293/Pank1ß cells treated with the disulfide-stress inducer, diamide. Further analysis showed that recombinant NME1 is efficiently CoAlated in vitro and in cellular response to oxidising agents and metabolic stress. In vitro CoAlation of recombinant wild type NME1, but not the C109A mutant, results in the inhibition of its NDPK activity. Moreover, CoA also functions as a competitive inhibitor of the NME1 NDPK activity by binding non-covalently to the nucleotide binding site. Taken together, our data reveal metastasis suppressor protein NME1 as a novel binding partner of the key metabolic regulator CoA, which inhibits its nucleoside diphosphate kinase activity via non-covalent and covalent interactions.