Gaseous nitric oxide failed to inhibit the replication cycle of SARS-CoV-2 in vitro.

Nitric oxide (NO) has been shown to have antimicrobial activity in vitro and in some in vivo models, while the virucidal activity of NO remains elusive. Some studies using NO donors have suggested that NO could be a potential candidate to treat SARS-CoV infection. The Covid-19 pandemic raised the hypothesis that NO gas might have an impact on Sars-CoV-2 replication cycle and might be considered as a candidate therapy to treat COVID-19. To our knowledge, there are no in vitro preclinical studies demonstrating a virucidal effect of gaseous NO on SARS-CoV-2. This study aims to determine whether gaseous NO has an impact on the replication cycle of SARS-CoV-2 in vitro. To that end, SARS-CoV-2 infected epithelial (VeroE6) and pulmonary (A549-hACE2) cells were treated with repeated doses of gaseous NO at different concentrations known to be efficient against bacteria. Our results show that exposing SARS-CoV-2 infected-cells to NO gas even at high doses (160 ppm, 6 h) does not influence the replication cycle of the virus in vitro. We report here that NO gas has no antiviral properties in vitro on SARS-COV-2. Therefore, there is no rationale for its usage in clinical settings to treat COVID-19 patients for direct antiviral purposes, which does not exclude other potential physiological benefits of this gas.

Method for the Identification of Potentially Bioactive Argon Binding Sites in Protein Families.

Argon belongs to the group of chemically inert noble gases, which display a remarkable spectrum of clinically useful biological properties. In an attempt to better understand noble gases, notably argon's mechanism of action, we mined a massive noble gas modeling database which lists all possible noble gas binding sites in the proteins from the Protein Data Bank. We developed a method of analysis to identify among all predicted noble gas binding sites the potentially relevant ones within protein families which are likely to be modulated by Ar. Our method consists in determining within structurally aligned proteins the conserved binding sites whose shape, localization, hydrophobicity, and binding energies are to be further examined. This method was applied to the analysis of two protein families where crystallographic noble gas binding sites have been experimentally determined. Our findings indicate that among the most conserved binding sites, either the most hydrophobic one and/or the site which has the best binding energy corresponds to the crystallographic noble gas binding sites with the best occupancies, therefore the best affinity for the gas. This method will allow us to predict relevant noble gas binding sites that have potential pharmacological interest and thus potential Ar targets that will be prioritized for further studies including in vitro validation.

Neuroprotection of dopamine neurons by xenon against low-level excitotoxic insults is not reproduced by other noble gases.

Using midbrain cultures, we previously demonstrated that the noble gas xenon is robustly protective for dopamine (DA) neurons exposed to L-trans-pyrrolidine-2,4-dicarboxylate (PDC), an inhibitor of glutamate uptake used to generate sustained, low-level excitotoxic insults. DA cell rescue was observed in conditions where the control atmosphere for cell culture was substituted with a gas mix, comprising the same amount of oxygen (20%) and carbon dioxide (5%) but 75% of xenon instead of nitrogen. In the present study, we first aimed to determine whether DA cell rescue against PDC remains detectable when concentrations of xenon are progressively reduced in the cell culture atmosphere. Besides, we also sought to compare the effect of xenon to that of other noble gases, including helium, neon and krypton. Our results show that the protective effect of xenon for DA neurons was concentration-dependent with an IC50 estimated at about 44%. We also established that none of the other noble gases tested in this study protected DA neurons from PDC-mediated insults. Xenon's effectiveness was most probably due to its unique capacity to block NMDA glutamate receptors. Besides, mathematical modeling of gas diffusion in the culture medium revealed that the concentration reached by xenon at the cell layer level is the highest of all noble gases when neurodegeneration is underway. Altogether, our data suggest that xenon may be of potential therapeutic value in Parkinson disease, a chronic neurodegenerative condition where DA neurons appear vulnerable to slow excitotoxicity.

Brief Report: Opioid-Involved Overdose Mortality in United States Veterans.

BACKGROUND AND OBJECTIVES: The purpose of this study is to assess trends in opioid-involved overdose mortality among US Veterans. METHODS: Age-adjusted drug overdose mortality rates, overall and by opioid subtype, were assessed from National Death Index data for US Veterans; statistical significance of trends was assessed for 2010 to 2015 and 2015 to 2016. RESULTS: Veteran age-adjusted overdose mortality rates increased 23.7% from 2010 to 2015 (19.7-24.4 of 100 000) and a further 20.4% through 2016 (29.3 of 100 000). Opioid involvement increased from 51.3% in 2010 to 62.1% in 2016, as opioid overdose rates increased from 10.9 to 19.5 of 100 000. Overdose mortality varied substantially by opioid subtype and demographics. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This report provides the first-ever description of trends and characteristics of overdose mortality and opioid-involved deaths among US Veterans of military service for the period 2010 to 2016. With the exception of female Veterans and Veterans in Western States, it has been found that trends in Veteran overdose mortality paralleled rising rates of drug overdose observed in the United States more broadly. Published 2020. This article is a U.S. Government work and is in the public domain in the USA. (Am J Addict 2020;00:00-00).

Dose variability of supplemental oxygen therapy with open patient interfaces based on in vitro measurements using a physiologically realistic upper airway model.

BACKGROUND: Supplemental oxygen therapy is widely used in hospitals and in the home for chronic care. However, there are several fundamental problems with the application of this therapy such that patients are often exposed to arterial oxygen concentrations outside of the intended target range. This paper reports volume-averaged tracheal oxygen concentration measurements (FtO2) from in vitro experiments conducted using a physiologically realistic upper airway model. The goal is to provide data to inform a detailed discussion of the delivered oxygen dose. METHODS: A baseline FtO2 dataset using a standard, straight adult nasal cannula was established by varying tidal volume (Vt), breathing frequency (f), and continuous oxygen flow rate (QO2) between the following levels to create a factorial design: Vt = 500, 640, or 800 ml; f = 12, 17, or 22 min- 1; QO2 = 2, 4, or 6 l/min. Further experiments were performed to investigate the influence on FtO2 of variation in inspiratory/expiratory ratio, inclusion of an inspiratory or expiratory pause, patient interface selection (e.g. nasal cannula versus a facemask), and rapid breathing patterns in comparison with the baseline measurements. RESULTS: Oxygen concentration measured at the trachea varied by as much as 60% (i.e. from 30.2 to 48.0% of absolute oxygen concentration) for the same oxygen supply flow rate due to variation in simulated breathing pattern. Among the baseline cases, the chief reasons for variation were 1) the influence of variation in tidal volume leading to variable FiO2 and 2) variation in breathing frequency affecting volume of supplemental oxygen delivered through the breath. CONCLUSION: For oxygen administration using open patient interfaces there was variability in the concentration and quantity of oxygen delivered to the trachea over the large range of scenarios studied. Of primary importance in evaluating the oxygen dose is knowledge of the breathing parameters that determine the average inhalation flow rate relative to the oxygen flow rate. Otherwise, the oxygen dose cannot be determined.

Argon and xenon ventilation during prolonged ex vivo lung perfusion.

BACKGROUND: Evidence supports the use of ex vivo lung perfusion (EVLP) as a platform for active reconditioning before transplantation to increase the potential donor pool and to reduce the incidence of primary graft dysfunction. A promising reconditioning strategy is the administration of inhaled noble gases based on their organoprotective effects. Our aim was to validate a porcine warm ischemic lung injury model and investigate postconditioning with argon (Ar) or xenon (Xe) during prolonged EVLP. METHODS: Domestic pigs were divided in four groups (n = 5 per group). In the negative control group, lungs were flushed immediately. In the positive control (PC) and treatment (Ar, Xe) groups, lungs were flushed after a warm ischemic interval of 2-h in situ. All grafts were evaluated and treated during normothermic EVLP for 6 h. In the control groups, lungs were ventilated with 70% N2/30% O2 and in the treatment groups with 70% Ar/30% O2 or 70% Xe/30% O2, respectively. Outcome parameters were physiological variables (pulmonary vascular resistance, peak airway pressures, and PaO2/FiO2), histology, wet-to-dry weight ratio, bronchoalveolar lavage, and computed tomography scan. RESULTS: A significant difference between negative control and PC for pulmonary vascular resistance, peak airway pressures, PaO2/FiO2, wet-to-dry weight ratio, histology, and computed tomography-imaging was observed. No significant differences between the injury group (PC) and the treatment groups (Ar, Xe) were found. CONCLUSIONS: We validated a reproducible prolonged 6-h EVLP model with 2 h of warm ischemia and described the physiological changes over time. In this model, ventilation during EVLP with Ar or Xe administered postinjury did not improve graft function.

An injection and mixing element for delivery and monitoring of inhaled nitric oxide.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator used primarily in the critical care setting for patients concurrently supported by invasive or noninvasive positive pressure ventilation. NO delivery devices interface with ventilator breathing circuits to inject NO in proportion with the flow of air/oxygen through the circuit, in order to maintain a constant, target concentration of inhaled NO. METHODS: In the present article, a NO injection and mixing element is presented. The device borrows from the design of static elements to promote rapid mixing of injected NO-containing gas with breathing circuit gases. Bench experiments are reported to demonstrate the improved mixing afforded by the injection and mixing element, as compared with conventional breathing circuit adapters, for NO injection into breathing circuits. Computational fluid dynamics simulations are also presented to illustrate mixing patterns and nitrogen dioxide production within the element. RESULTS: Over the range of air flow rates and target NO concentrations investigated, mixing length, defined as the downstream distance required for NO concentration to reach within ±5 % of the target concentration, was as high as 47 cm for the conventional breathing circuit adapters, but did not exceed 7.8 cm for the injection and mixing element. CONCLUSION: The injection and mixing element has potential to improve ease of use, compatibility and safety of inhaled NO administration with mechanical ventilators and gas delivery devices.

Fear conditioning leads to alteration in specific genes expression in cortical and thalamic neurons that project to the lateral amygdala.

RNA transcription is needed for memory formation. However, the ability to identify genes whose expression is altered by learning is greatly impaired because of methodological difficulties in profiling gene expression in specific neurons involved in memory formation. Here, we report a novel approach to monitor the expression of genes after learning in neurons in specific brain pathways needed for memory formation. In this study, we aimed to monitor gene expression after fear learning. We retrogradely labeled discrete thalamic neurons that project to the lateral amygdala (LA) of rats. The labeled neurons were dissected, using laser microdissection microscopy, after fear conditioning learning or unpaired training. The RNAs from the dissected neurons were subjected to microarray analysis. The levels of selected RNAs detected by the microarray analysis to be altered by fear conditioning were also assessed by nanostring analysis. We observed that the expression of genes involved in the regulation of translation, maturation and degradation of proteins was increased 6 h after fear conditioning compared to unpaired or naïve trained rats. These genes were not expressed 24 h after training or in cortical neurons that project to the LA. The expression of genes involved in transcription regulation and neuronal development was altered after fear conditioning learning in the cortical-LA pathway. The present study provides key information on the identity of genes expressed in discrete thalamic and cortical neurons that project to the LA after fear conditioning. Such an approach could also serve to identify gene products as targets for the development of a new generation of therapeutic agents that could be aimed to functionally identified brain circuits to treat memory-related disorders.

Predictive Modeling and Concentration of the Risk of Suicide: Implications for Preventive Interventions in the US Department of Veterans Affairs.

OBJECTIVES: The Veterans Health Administration (VHA) evaluated the use of predictive modeling to identify patients at risk for suicide and to supplement ongoing care with risk-stratified interventions. METHODS: Suicide data came from the National Death Index. Predictors were measures from VHA clinical records incorporating patient-months from October 1, 2008, to September 30, 2011, for all suicide decedents and 1% of living patients, divided randomly into development and validation samples. We used data on all patients alive on September 30, 2010, to evaluate predictions of suicide risk over 1 year. RESULTS: Modeling demonstrated that suicide rates were 82 and 60 times greater than the rate in the overall sample in the highest 0.01% stratum for calculated risk for the development and validation samples, respectively; 39 and 30 times greater in the highest 0.10%; 14 and 12 times greater in the highest 1.00%; and 6.3 and 5.7 times greater in the highest 5.00%. CONCLUSIONS: Predictive modeling can identify high-risk patients who were not identified on clinical grounds. VHA is developing modeling to enhance clinical care and to guide the delivery of preventive interventions.

Determination of regional lung air volume distribution at mid-tidal breathing from computed tomography: a retrospective study of normal variability and reproducibility.

BACKGROUND: Determination of regional lung air volume has several clinical applications. This study investigates the use of mid-tidal breathing CT scans to provide regional lung volume data. METHODS: Low resolution CT scans of the thorax were obtained during tidal breathing in 11 healthy control male subjects, each on two separate occasions. A 3D map of air volume was derived, and total lung volume calculated. The regional distribution of air volume from centre to periphery of the lung was analysed using a radial transform and also using one dimensional profiles in three orthogonal directions. RESULTS: The total air volumes for the right and left lungs were 1035 +/- 280 ml and 864 +/- 315 ml, respectively (mean and SD). The corresponding fractional air volume concentrations (FAVC) were 0.680 +/- 0.044 and 0.658 +/- 0.062. All differences between the right and left lung were highly significant (p < 0.0001). The coefficients of variation of repeated measurement of right and left lung air volumes and FAVC were 6.5% and 6.9% and 2.5% and 3.6%, respectively. FAVC correlated significantly with lung space volume (r = 0.78) (p < 0.005). FAVC increased from the centre towards the periphery of the lung. Central to peripheral ratios were significantly higher for the right (0.100 +/- 0.007 SD) than the left (0.089 +/- 0.013 SD) (p < 0.0001). CONCLUSION: A technique for measuring the distribution of air volume in the lung at mid-tidal breathing is described. Mean values and reproducibility are described for healthy male control subjects. Fractional air volume concentration is shown to increase with lung size.

Argon pharmacokinetics: measurements in pigs and analysis in humans using a physiologically based pharmacokinetics model.

The primary objective of this study was to investigate the pharmacokinetics of inhaled argon in young pigs using mechanical ventilation. Also a physiologically based model of argon pharmacokinetics (PBPK) is validated with human data for xenon from the literature and the new data from juvenile pigs. The inherent difficulty in performing pharmacokinetics studies of argon makes the use of the PBPK model especially relevant. The model is used to investigate argon pharmacokinetics for adult and neonate applications. Juvenile pigs (n = 4) were anesthetized, submitted to endotracheal intubation, and mechanical ventilation using a conventional ventilator. Argon inhalation was achieved by switching the animal from the first mechanical ventilator (with air/oxygen) to a second one that was supplied with 75% argon and 25% oxygen from premixed gas cylinders. This administration yielded blood samples that were analyzed using a quadrupole based technique for determining argon concentration. The range of blood:gas partition coefficient corresponding to the average measured Cmax of 190-872 µM is 0.005-0.022. Based on the average curve, T1/2= 75 seconds. The PBPK is shown to be in general agreement with the experimental data in pigs. Inhaled argon administration exhibited an on-off nature such that AUC was proportional to administration time. Confidence in the PBPK model and the remarkably robust and stable on-off nature of argon pharmacokinetics, notwithstanding intersubject variability and comorbidity, suggests that inhaled argon could readily be applied to any treatment regime.

Validated respiratory drug deposition predictions from 2D and 3D medical images with statistical shape models and convolutional neural networks.

For the one billion sufferers of respiratory disease, managing their disease with inhalers crucially influences their quality of life. Generic treatment plans could be improved with the aid of computational models that account for patient-specific features such as breathing pattern, lung pathology and morphology. Therefore, we aim to develop and validate an automated computational framework for patient-specific deposition modelling. To that end, an image processing approach is proposed that could produce 3D patient respiratory geometries from 2D chest X-rays and 3D CT images. We evaluated the airway and lung morphology produced by our image processing framework, and assessed deposition compared to in vivo data. The 2D-to-3D image processing reproduces airway diameter to 9% median error compared to ground truth segmentations, but is sensitive to outliers of up to 33% due to lung outline noise. Predicted regional deposition gave 5% median error compared to in vivo measurements. The proposed framework is capable of providing patient-specific deposition measurements for varying treatments, to determine which treatment would best satisfy the needs imposed by each patient (such as disease and lung/airway morphology). Integration of patient-specific modelling into clinical practice as an additional decision-making tool could optimise treatment plans and lower the burden of respiratory diseases.

Impact of Implementation Facilitation on the REACH VET Clinical Program for Veterans at Risk for Suicide.

OBJECTIVE: In 2017, the Veterans Health Administration (VHA) implemented a national suicide prevention program, called Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET), that uses a predictive algorithm to identify, attempt to reach, assess, and care for patients at the highest risk for suicide. The authors aimed to evaluate whether facilitation enhanced implementation of REACH VET at VHA facilities not meeting target completion rates. METHODS: In this hybrid effectiveness-implementation type 2 program evaluation, a quasi-experimental pre-post design was used to assess changes in implementation outcome measures evaluated 6 months before and 6 months after onset of facilitation of REACH VET implementation at 23 VHA facilities. Measures included percentages of patients with documented coordinator and provider acknowledgment of receipt, care evaluation, and outreach attempt. Generalized estimating equations were used to compare differences in REACH VET outcome measures before and after facilitation. Qualitative interviews were conducted with personnel and were explored via template analysis. RESULTS: Time had a significant effect in all outcomes models (p<0.001). An effect of facilitation was significant only for the outcome of attempted outreach. Patients identified by REACH VET had significantly higher odds of having a documented outreach attempt after facilitation of REACH VET implementation, compared with before facilitation. Site personnel felt supported and reported that the external facilitators were helpful and responsive. CONCLUSIONS: Facilitation of REACH VET implementation was associated with an improvement in outreach attempts to veterans identified as being at increased risk for suicide. Outreach is critical for engaging veterans in care.

Suicide mortality following nursing home discharge in the Department of Veterans Affairs health system.

OBJECTIVES: We assessed suicide rates up to 6 months following discharge from US Department of Veterans Affairs (VA) nursing homes. METHODS: In VA Minimum Data Set (MDS) records, we identified 281 066 live discharges from the 137 VA nursing homes during fiscal years 2002 to 2008. We used MDS and administrative data to assess resident age, gender, behaviors, pain, and indications of psychoses, bipolar disorder, dementia, and depression. We identified vital status and suicide mortality within 6 months of discharge through National Death Index searches. RESULTS: Suicide rates within 6 months of discharge were 88.0 per 100 000 person-years for men and 89.4 overall. Standardized mortality ratios relative to age- and gender-matched individuals in the VA patient population were 2.3 for men (95% confidence interval [CI] = 1.9, 2.8) and 2.4 overall (95% CI = 2.0, 2.9). In multivariable proportional hazards regression analyses, resident characteristics, diagnoses, behaviors, and pain were not significantly associated with suicide risk. CONCLUSIONS: Suicide risk was elevated following nursing home discharge. This underscores the importance of ongoing VA efforts to enhance discharge planning and timely postdischarge follow-up.

Identifying medically relevant xenon protein targets by in silico screening of the structural proteome.

In a previous study, in silico screening of the binding of almost all proteins in the Protein Data Bank to each of the five noble gases xenon, krypton, argon, neon, and helium was reported. This massive and rich data set requires analysis to identify the gas-protein interactions that have the best binding strengths, those where the binding of the noble gas occurs at a site that can modulate the function of the protein, and where this modulation might generate clinically relevant effects. Here, we report a preliminary analysis of this data set using a rational, heuristic score based on binding strength and location. We report a partial prioritized list of xenon protein targets and describe how these data can be analyzed, using arginase and carbonic anhydrase as examples. Our aim is to make the scientific community aware of this massive, rich data set and how it can be analyzed to accelerate future discoveries of xenon-induced biological activity and, ultimately, the development of new "atomic" drugs.

Outcomes for treatment of depression in the Veterans Health Administration: Rates of response and remission calculated from clinical and survey data.

Healthcare Effectiveness Data and Information Set (HEDIS) quality measures for depression treatment aggregate Patient Health Questionnaire (PHQ)-9 data from routine clinical assessments recorded in electronic health records (EHR). To determine whether aggregated PHQ-9 data in US Veterans Health Administration (VHA) EHRs should be used to characterize the organization's performance, we compared rates for depression response and remission calculated from EHRs with rates calculated with data representing the underlying Veteran patient population estimated using Veterans Outcome Assessment (VOA) survey data. We analyzed data from initial assessments and 3-month follow-up for Veterans beginning treatment for depression. EHR data were available for only a minority of Veteran patients, and the group of Veterans with EHR data differed from the underlying Veteran patient population with respect to demographic and clinical characteristics. Aggregated rates of response and remission from EHR data were significantly different from estimates based on representative VOA data. The findings suggest that until patient-reported outcome from EHRs are available for a substantial majority of patients receiving care, aggregated measures of patient outcomes derived from these data cannot be assumed to be representative of the outcomes for the overall population, and they should not be used as outcome-based measures of quality or performance.

Suicide risk following a new cancer diagnosis among Veterans in Veterans Health Administration care.

BACKGROUND: Cancer diagnoses are associated with an increased risk for suicide. The aim of this study was to evaluate this association among Veterans receiving Veterans Health Administration (VHA) care, a population that has an especially high suicide risk. METHODS: Among 4,926,373 Veterans with VHA use in 2011 and in 2012 or 2013, and without VHA cancer diagnoses in 2011, we assessed suicide risk following incident cancer diagnoses. Risk time was from initial VHA use in 2012-2013 to 12/31/2018 or death, whichever came first. Cox proportional hazards regression models evaluated associations between new cancer diagnoses and suicide risk, adjusting for age, sex, VHA regional network, and mental health comorbidities. Suicide rates were calculated among Veterans with new cancer diagnoses through 84 months following diagnosis. RESULTS: A new cancer diagnosis corresponded to a 47% higher suicide risk (Adjusted Hazard Ratio [aHR] = 1.47, 95% CI: 1.33-1.63). The cancer subtype associated with the highest suicide risk was esophageal cancer (aHR = 6.01, 95% CI: 3.73-9.68), and other significant subtypes included head and neck (aHR = 3.55, 95% CI: 2.74-4.62) and lung cancer (aHR = 2.35, 95% CI: 1.85-3.00). Cancer stages 3 (aHR = 2.36, 95% CI: 1.80-3.11) and 4 (aHR = 3.53, 95% CI: 2.81-4.43) at diagnosis were positively associated with suicide risk. Suicide rates were highest within 3 months following diagnosis and remained elevated in the 3-6- and 6-12-month periods following diagnosis. CONCLUSION: Among Veteran VHA users, suicide risk was elevated following new cancer diagnoses. Risk was particularly high in the first 3 months. Additional screening and suicide prevention efforts may be warranted for VHA Veterans newly diagnosed with cancer.

Argon pharmacokinetics: a solubility measurement technique.

The noble gas argon has demonstrated biological activity that may prove useful as a medical intervention. Pharmacokinetics, the disposition of the drug molecule in the body through time, is fundamental necessary knowledge to drug discovery, development and even post-marketing. The fundamental measurement in pharmacokinetic studies is blood concentration of the molecule (and its metabolites) of interest. While a physiologically based model of argon pharmacokinetics has appeared in the literature, no experimental data have been published. Thus, argon pharmaceutical development requires measurement of argon solubility in blood. This paper reports on the development of a technique based on mass spectrometry for measuring argon solubility in liquids, including blood, to be further employed in pharmacokinetics testing of argon. Based on a prototype, results are reported from sensitivity experiments using ambient air, water and rabbit blood. The key takeaway is that the system was sensitive to argon during all of the testing. We believe the technique and prototype of the quadrupole mass spectrometer gas analyzer will be capable of inferring argon pharmacokinetics through the analysis of blood samples.

Estimating the per-protocol effect of lithium on suicidality in a randomized trial of individuals with depression or bipolar disorder.

BACKGROUND: The CSP590 randomized trial was designed to estimate the effect of lithium on suicidality. After a third of the intended number of participants were enrolled, the hazard ratio of suicidality was 1.10 (95% CI: 0.77, 1.55). Based on this, the trial was stopped for futility. However, only 17% of patients adhered to the specified protocol. AIMS: The objective was to estimate the per-protocol effect of lithium on suicidality, that is, the effect of adhering to the treatment strategies as specified in the protocol. METHODS: We stopped individuals' follow-up if/when they showed evidence of nonadherence. We then conducted the analysis in the restricted sample, adjusting for prognostic factors that predict adherence via inverse probability weighting. The primary outcome was the 12-month risk of suicidality (including death from suicide, suicide attempt, interrupted attempt, hospitalization specifically to prevent suicide). RESULTS: The estimated 12-month risk of suicidality was 18.8% for lithium, and 24.3% for placebo. The risk ratio was 0.78 (95% CI: 0.43, 1.37) and the risk difference -5.5 percentage points (95% CI: -17.5, 5.5). Results were consistent across sensitivity analyses. CONCLUSIONS: With one-third of the targeted sample size, lithium effects (compared with placebo) ranging between a 17.5% reduction and a 5.5% increase in the risk of suicidality were highly compatible with the data. Thus, a protective effect of lithium on suicidality among patients with bipolar disorder or major depressive disorder cannot be ruled out. Trials should incorporate adequate per-protocol analyses into the decision-making processes for stopping trials for futility.