Mechanism-based organization of neural networks to emulate systems biology and pharmacology models.

Deep learning neural networks are often described as black boxes, as it is difficult to trace model outputs back to model inputs due to a lack of clarity over the internal mechanisms. This is even true for those neural networks designed to emulate mechanistic models, which simply learn a mapping between the inputs and outputs of mechanistic models, ignoring the underlying processes. Using a mechanistic model studying the pharmacological interaction between opioids and naloxone as a proof-of-concept example, we demonstrated that by reorganizing the neural networks' layers to mimic the structure of the mechanistic model, it is possible to achieve better training rates and prediction accuracy relative to the previously proposed black-box neural networks, while maintaining the interpretability of the mechanistic simulations. Our framework can be used to emulate mechanistic models in a large parameter space and offers an example on the utility of increasing the interpretability of deep learning networks.

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial.

Importance: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl). Objective: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose. Design, Setting, and Participants: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023. Intervention: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference). Main Outcomes and Measures: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics. Results: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes. Conclusions and Relevance: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04764630.

Deep learning-enabled natural language processing to identify directional pharmacokinetic drug-drug interactions.

BACKGROUND: During drug development, it is essential to gather information about the change of clinical exposure of a drug (object) due to the pharmacokinetic (PK) drug-drug interactions (DDIs) with another drug (precipitant). While many natural language processing (NLP) methods for DDI have been published, most were designed to evaluate if (and what kind of) DDI relationships exist in the text, without identifying the direction of DDI (object vs. precipitant drug). Here we present a method for the automatic identification of the directionality of a PK DDI from literature or drug labels. METHODS: We reannotated the Text Analysis Conference (TAC) DDI track 2019 corpus for identifying the direction of a PK DDI and evaluated the performance of a fine-tuned BioBERT model on this task by following the training and validation steps prespecified by TAC. RESULTS: This initial attempt showed the model achieved an F-score of 0.82 in identifying sentences as containing PK DDI and an F-score of 0.97 in identifying object versus precipitant drugs in those sentences. DISCUSSION AND CONCLUSION: Despite a growing list of NLP methods for DDI extraction, most of them use a common set of corpora to perform general purpose tasks (e.g., classifying a sentence into one of several fixed DDI categories). There is a lack of coordination between the drug development and biomedical informatics method development community to develop corpora and methods to perform specific tasks (e.g., extract clinical exposure changes due to PK DDI). We hope that our effort can encourage such a coordination so that more "fit for purpose" NLP methods could be developed and used to facilitate the drug development process.

Effect of Tibial Slope on Coronal Alignment in Total Knee Arthroplasty.

Malalignment of total knee arthroplasty (TKA) components affects function and survivorship. Common practice is to set coronal alignment prior to adjusting slope. With improper jig placement, adjustment of the slope may alter coronal alignment. The purpose of this study was to quantify the change in coronal alignment with increasing posterior tibial slope while comparing two methods of jig fixation. A prospective consecutive series of 100 patients underwent TKA using computer navigation. Fifty patients had the extramedullary cutting jig secured proximally with one pin and 50 patients had the jig secured proximally with two pins. Coronal alignment (CA) was recorded with each increasing degree of posterior slope (PS) from 0 to 7 degrees. Mean CA and change in CA were compared between cohorts. Utilizing one pin, osteotomies drifted into varus with an average change in CA of 0.34 degrees per degree PS. At 4 degrees PS, patients started to have >3 degrees of varus with 12.0% having >3 degrees of varus at 7 degrees PS. Utilizing two pins, osteotomies drifted into valgus with an average change of 0.04 degrees in CA per degree PS. No patients in the two-pin cohort fell outside 3 degrees varus/valgus CA. CA was significantly different at all degrees of PS between the cohorts. Changes in PS influenced CA making verification of tibial cut intraoperative critical. Use of >1 pin and computer navigation were beneficial to prevent coronal plane malalignment. This relationship may explain why computer navigation has been shown to improve alignment as well as survivorship and outcomes in some patients, especially those <65 years.

Comorbidity and healthcare utilization in patients with treatment resistant depression: A large-scale retrospective cohort analysis using electronic health records.

BACKGROUND: Medical comorbidity and healthcare utilization in patients with treatment resistant depression (TRD) is usually reported in convenience samples, making estimates unreliable. There is only limited large-scale clinical research on comorbidities and healthcare utilization in TRD patients. METHODS: Electronic Health Record data from over 3.3 million patients from the INSIGHT Clinical Research Network in New York City was used to define TRD as initiation of a third antidepressant regimen in a 12-month period among patients diagnosed with major depressive disorder (MDD). Age and sex matched TRD and non-TRD MDD patients were compared for anxiety disorder, 27 comorbid medical conditions, and healthcare utilization. RESULTS: Out of 30,218 individuals diagnosed with MDD, 15.2 % of patients met the criteria for TRD (n = 4605). Compared to MDD patients without TRD, the TRD patients had higher rates of anxiety disorder and physical comorbidities. They also had higher odds of ischemic heart disease (OR = 1.38), stroke/transient ischemic attack (OR = 1.57), chronic kidney diseases (OR = 1.53), arthritis (OR = 1.52), hip/pelvic fractures (OR = 2.14), and cancers (OR = 1.41). As compared to non-TRD MDD, TRD patients had higher rates of emergency room visits, and inpatient stays. In relation to patients without MDD, both TRD and non-TRD MDD patients had significantly higher levels of anxiety disorder and physical comorbidities. LIMITATIONS: The INSIGHT-CRN data lack information on depression severity and medication adherence. CONCLUSIONS: TRD patients compared to non-TRD MDD patients have a substantially higher prevalence of various psychiatric and medical comorbidities and higher health care utilization. These findings highlight the challenges of developing interventions and care coordination strategies to meet the complex clinical needs of TRD patients.

Leukocyte inflammatory phenotype and function in migraine patients compared with matched non-migraine volunteers: a pilot study.

BACKGROUND: Migraine is a neurological condition characterized by chronic inflammation. However, not much is known about the potential role of peripheral blood immune cells in the pathophysiology of migraine. METHODS: We investigated the status of peripheral blood immune cells of 15 adults with frequent episodic or chronic migraine recruited chronologically from a randomized clinical trial (RCT) on Nutrition for Migraine (NCCIH 5R01AT007813-05) and 15 non-migraine, healthy volunteers (control) matched by age, gender, and Body Mass Index (BMI). Continuous variables were presented as means ± standard deviationas well as medians, and comparisons between patients and healthy volunteers were performed with non-parametric Wilcoxon signed rank tests. Statistical analysis was performed using Stata (StataCorp. 2019. Stata Statistical Software). Fluorescence-Activated Cell Sorting (FACS) data were processed using FlowJo software (Ashland, OR: Becton, Dickenson and Company; 2019). RESULTS: We observed that migraineurs had a significantly lower percentage of non-classical monocytes (CD14+CD16++) in blood circulation, compared to the control group. In addition, Migraineurs also showed a significantly lower percentage of blood CD3+CD4+ helper T cells and CD4+CD25+ regulatory T cells, compared to controls. Differences in leukocyte surface markers between chronic migraine patients and their matched controls were more prominent than those between episodic migraine patients and their matched controls. CONCLUSIONS: Our results suggest that migraine is associated with dysregulated peripheral immune homeostasis and that inflammation and autoimmunity may play a role in its pathophysiology.

Calibration and Validation of a Mechanistic COVID-19 Model for Translational Quantitative Systems Pharmacology - A Proof-of-Concept Model Development for Remdesivir.

With the ongoing global pandemic of coronavirus disease 2019 (COVID-19), there is an urgent need to accelerate the traditional drug development process. Many studies identified potential COVID-19 therapies based on promising nonclinical data. However, the poor translatability from nonclinical to clinical settings has led to failures of many of these drug candidates in the clinical phase. In this study, we propose a mechanism-based, quantitative framework to translate nonclinical findings to clinical outcome. Adopting a modularized approach, this framework includes an in silico disease model for COVID-19 (virus infection and human immune responses) and a pharmacological component for COVID-19 therapies. The disease model was able to reproduce important longitudinal clinical data for patients with mild and severe COVID-19, including viral titer, key immunological cytokines, antibody responses, and time courses of lymphopenia. Using remdesivir as a proof-of-concept example of model development for the pharmacological component, we developed a pharmacological model that describes the conversion of intravenously administered remdesivir as a prodrug to its active metabolite nucleoside triphosphate through intracellular metabolism and connected it to the COVID-19 disease model. After being calibrated with the placebo arm data, our model was independently and quantitatively able to predict the primary endpoint (time to recovery) of the remdesivir clinical study, Adaptive Covid-19 Clinical Trial (ACTT). Our work demonstrates the possibility of quantitatively predicting clinical outcome based on nonclinical data and mechanistic understanding of the disease and provides a modularized framework to aid in candidate drug selection and clinical trial design for COVID-19 therapeutics.

Development of a Translational Model to Assess the Impact of Opioid Overdose and Naloxone Dosing on Respiratory Depression and Cardiac Arrest.

In response to a surge of deaths from synthetic opioid overdoses, there have been increased efforts to distribute naloxone products in community settings. Prior research has assessed the effectiveness of naloxone in the hospital setting; however, it is challenging to assess naloxone dosing regimens in the community/first-responder setting, including reversal of respiratory depression effects of fentanyl and its derivatives (fentanyls). Here, we describe the development and validation of a mechanistic model that combines opioid mu receptor binding kinetics, opioid agonist and antagonist pharmacokinetics, and human respiratory and circulatory physiology, to evaluate naloxone dosing to reverse respiratory depression. Validation supports our model, which can quantitatively predict displacement of opioids by naloxone from opioid mu receptors in vitro, hypoxia-induced cardiac arrest in vivo, and opioid-induced respiratory depression in humans from different fentanyls. After validation, overdose simulations were performed with fentanyl and carfentanil followed by administration of different intramuscular naloxone products. Carfentanil induced more cardiac arrest events and was more difficult to reverse than fentanyl. Opioid receptor binding data indicated that carfentanil has substantially slower dissociation kinetics from the opioid receptor compared with nine other fentanyls tested, which likely contributes to the difficulty in reversing carfentanil. Administration of the same dose of naloxone intramuscularly from two different naloxone products with different formulations resulted in differences in the number of virtual patients experiencing cardiac arrest. This work provides a robust framework to evaluate dosing regimens of opioid receptor antagonists to reverse opioid-induced respiratory depression, including those caused by newly emerging synthetic opioids.

Symmetric bis-benzimidazoles as DNA minor groove-binding agents with anti-tumour and antibacterial activity, and the evolution of the drug ridinilazole for the treatment of Clostridium difficile infections.

We report the synthesis of a range of symmetrical bis-benzimidazoles (BBZ) which possess anticancer and antibacterial activities. One of these BBZs has specific activity against Clostridium difficile and is currently in a phase 3 clinical evaluation as the drug ridinilazole. X-ray and computer modelling studies showed that BBZs typically exhibit high specificity for oligonucleotide sequences that occur in the minor groove of DNA.

Ultrasound-Guided Adductor Canal Block Versus Intraoperative Transarticular Saphenous Nerve Block: A Retrospective Analysis.

BACKGROUND: The ultrasound-guided adductor canal block (High-ACB) is an effective option for pain control in total knee arthroplasty (TKA), but its use can add substantial cost and preparatory time to a TKA procedure. An intraoperative adductor canal block (Low-ACB) performed by the operative surgeon has been described as an alternative. The hypothesis of this study is that the Low-ACB would achieve noninferior pain control and opioid utilization postoperatively when compared to the High-ACB. METHODS: This is a retrospective study of a prospectively maintained database comparing the High-ACB vs the Low-ACB. The primary outcome measure was morphine milligram equivalents consumed. Secondary outcome measures included Visual Analog Scale pain scores, postoperative outcomes (Patient-Reported Outcome Measurement Information System, Knee Injury and Osteoarthritis Outcome Score, knee range of motion), length of stay, postoperative speed of mobilization, and complications related to the type of block. RESULTS: There were 139 patients in the study. There was lower opioid use in the first 24 hours in the Low-ACB compared to the High-ACB group respectively (26.3 vs 30, P = .29) but this did not reach statistical significance. There was a statistically significant difference in Visual Analog Scale score on postoperative day 1 in the Low-ACB vs High-ACB groups respectively (4.6 vs 3.7, P = .02) but this did not reach the level of clinical significance. There was no statistical difference in the Patient-Reported Outcome Measurement Information System, Knee Injury and Osteoarthritis Outcome Score, or postoperative range of motion. There were no block-related complications in either group. CONCLUSION: The Low-ACB is a safe, effective, and cost-saving alternative to the traditional High-ACB for pain control in TKA.

Methodology for altering omega-3 EPA+DHA and omega-6 linoleic acid as controlled variables in a dietary trial.

BACKGROUND & AIMS: Increasing dietary intake of n-3 EPA+DHA and lowering dietary n-6 LA is under investigation as a therapeutic diet for improving chronic pain syndromes as well as other health outcomes. Herein we describe the diet methodology used to modulate intake of n-3 and n-6 PUFA in a free living migraine headache population and report on nutrient intake, BMI and diet acceptability achieved at week 16 of the intensive diet intervention and week 22 follow-up time-point. METHODS: A total of 178 participants were randomized and began one of three diet interventions: 1) a high n-3 PUFA, average n-6 PUFA (H3) diet targeting 1500 mg EPA+DHA/day and 7% of energy (en%) from n-6 linoleic acid (LA), 2) a high-n-3 PUFA, low-n-6 PUFA (H3L6) targeting 1500 mg EPA+DHA/day and <1.8 en% n-6 LA or 3) a Control diet with typical American intakes of both EPA+DHA (<150 mg/day) and 7 en% from n-6 LA. Methods used to achieve diet change to week 16 include diet education, diet counseling, supply of specially prepared foods, self-monitoring and access to online diet materials. Only study oils and website materials were provided for the follow-up week 16 to week 22 periods. Diet adherence was assessed by multiple 24 h recalls administered throughout the trial. Diet acceptability was assessed in a subset of participants at 4 time points by questionnaire. RESULTS: At week 16 H3 and H3L6 diet groups significantly increased median n-3 EPA+DHA intake from 48 mg/2000 kcals at baseline to 1484 mg/2000 kcals (p < 0.0001) and from 44 mg/2000 kcals to 1341 mg/2000 kcals (p < 0.0001), respectively. In the Control group, EPA+DHA intake remained below the typical American intake with baseline median at 60 mg/2000 kcals and 80 mg/2000 kcals (p = 0.6) at week 16. As desired, LA intake was maintained in the H3 and Control group with baseline median of 6.5 en% to 7.1 en% (p = 0.4) at week 16 and from 6.5 en% to 6.8 en% (p = 1.0) at week 16, respectively. In the H3L6 group, n-6 LA decreased from 6.3 en% at baseline to 3.2 en% (p < 0.0001) at week 16. There were no significant changes in BMI or diet acceptability throughout the trial or between diet groups. CONCLUSIONS: We find this diet method to be acceptable to research participants and successful in altering dietary n-3 EPA+DHA with and without concurrent decreases in n-6 LA. If n-6 LA of less than 3 en% is desired, additional techniques to limit LA may need to be employed.

A broadband integrated time series (BITS) for longitudinal analyses of the digital divide.

To evaluate actions taken to implement the Telecommunications Act of 1996, the primary goal of which was to foster competition in the industry, the FCC created a standardized form (Form 477) to collect information about broadband deployment and competition in local telephone service. These data represent the best publicly available record of broadband provision in the United States. Despite the potential benefits offered by this database, there are several nuances to these data related to shifting geographies and reporting requirements that uncorrected, prevent them from being used as an uninterrupted time series for longitudinal analyses. Given the analytical challenges associated with the FCC Form 477 data, the purpose of this paper is to present a solution to the fragmented nature of these data which prevents meaningful longitudinal analyses of the digital divide. Specifically, this paper develops and describes a procedure for producing an integrated broadband time series (BITS) for the last decade (2008-2018). This includes the procedures for using these data, their value to social and economic analysis, and their underlying limitations. The core contribution of this paper is the creation of data infrastructure for investigating the evolution of the digital divide.

International study of definitions of English-language terms for suicidal behaviours: a survey exploring preferred terminology.

OBJECTIVES: Explore international consensus on nomenclatures of suicidal behaviours and analyse differences in terminology between high-income countries (HICs) and low/middle-income countries (LMICs). DESIGN: An online survey of members of the International Organisation for Suicide Prevention (IASP) used multiple-choice questions and vignettes to assess the four dimensions of the definition of suicidal behaviour: outcome, intent, knowledge and agency. SETTING: International. PARTICIPANTS: Respondents included 126 individuals, 37 from 30 LMICs and 89 from 33 HICs. They included 40 IASP national representatives (65% response rate), IASP regular members (20% response rate) and six respondents from six additional countries identified by other organisations. OUTCOME MEASURES: Definitions of English-language terms for suicidal behaviours. RESULTS: The recommended definition of 'suicide' describes a fatal act initiated and carried out by the actors themselves. The definition of 'suicide attempt' was restricted to non-fatal acts with intent to die, whereas definition of 'self-harm' more broadly referred to acts with varying motives, including the wish to die. Almost all respondents agreed about the definitions of 'suicidal ideation', 'death wishes' and 'suicide plan'. 'Aborted suicide attempt' and 'interrupted suicide attempt' were not considered components of 'preparatory suicidal behaviour'. There were several differences between representatives from HICs and LMICs. CONCLUSION: This international opinion survey provided the basis for developing a transcultural nomenclature of suicidal behaviour. Future developments of this nomenclature should be tested in larger samples of professionals, including LMICs may be a challenge.

Cognitive enhancing drug use by students in the context of neoliberalism: cheating? Or, a legitimate expression of competitive entrepreneurialism?

A recurrent theme regarding drug policy and the use of cognitive enhancing drugs (CEDs) by students in higher education (HE), concerns the potential introduction of policy to prohibit the use of CEDs. One of the arguments put forward to support a prohibitive policy framework, is that the use of CEDs by students in HE is a form of academic misconduct; that the use of CEDs constitutes cheating. Now, given that it is widely documented that the use of CEDs by students in HE has been growing steadily over the past decade or more, there is surprisingly, a dearth of in-depth discussion on the topic of whether their use represents academic misconduct and is a form of cheating. Therefore, this commentary will summarise some examples of literature dedicated to the topic, before discussing whether the use of CEDs by students in HE constitutes cheating, when framed contextually, around neoliberalism and the key characteristics of competition and entrepreneurialism. The commentary will propose a potentially useful argument that, given the neoliberal context and those key characteristics, (HE) students could in theory, legitimise their use of CEDs. Consequently, students using CEDs for the purpose of hypothetically increasing academic excellence, would not consider their use of CEDs as a form of academic misconduct, of cheating. Thus, this paper, would in principle, support and endorse a legal, regulatory approach to CED policy and in addition, recommends that individual HE institutions do not prohibit the use of CEDs by students on the grounds of academic misconduct, but instead, advance harm reduction initiatives around their use.

A Mixed-Methods, Randomized Clinical Trial to Examine Feasibility of a Mindfulness-Based Stress Management and Diabetes Risk Reduction Intervention for African Americans with Prediabetes.

African Americans have disproportionately high rates of stress-related conditions, including diabetes and diabetes-related morbidity. Psychological stress may negatively influence engagement in risk-reducing lifestyle changes (physical activity and healthy eating) and stress-related physiology that increase diabetes risk. This study examined the feasibility of conducting a randomized trial comparing a novel mindfulness-based stress management program combined with diabetes risk-reduction education versus a conventional diabetes risk-reduction education program among African American adults with prediabetes and self-reported life stress. Participants were recruited in collaboration with community partners and randomized to the mindfulness-based diabetes risk-reduction education program for prediabetes (MPD; n = 38) or the conventional diabetes risk-reduction education program for prediabetes (CPD; n = 30). The mindfulness components were adapted from the Mindfulness-based Stress Reduction Program. The diabetes risk-reduction components were adapted from the Power to Prevent Program and the Diabetes Prevention Program. Groups met for eight weeks for 2.5 hours, with a half-day retreat and six-monthly boosters. Mixed-methods strategies were used to assess feasibility. Psychological, behavioral, and metabolic data were collected before the intervention and at three and six months postintervention to examine within-group change and feasibility of collecting such data in future clinical efficacy research. Participants reported acceptability, credibility, and cultural relevance of the intervention components. Enrollment of eligible participants (79%), intervention session attendance (76.5%), retention (90%), and postintervention data collection attendance (83%, 82%, and 78%, respectively) demonstrated feasibility, and qualitative data provided information to further enhance feasibility in future studies. Both groups exhibited an A1C reduction. MPD participants had reductions in perceived stress, BMI, calorie, carbohydrate and fat intake, and increases in spiritual well-being. Considering the high prevalence of diabetes and diabetes-related complications in African Americans, these novel findings provide promising guidance to develop a larger trial powered to examine efficacy of a mindfulness-based stress management and diabetes risk-reduction education program for African Americans with prediabetes.

International Study of Definitions of English-Language Terms for Suicidal Behaviours: protocol of an opinion survey.

INTRODUCTION: The objective of present paper is to outline the methodology of the International Study of Definitions of English-Language Terms for Suicidal Behaviours (ISDELTSB). The aim of the study is to survey existing English language terms and definitions used around the world for suicidal behaviour. METHODS AND ANALYSIS: The ISDELTSB is a worldwide survey based on one 'designated expert' per each WHO-registered country. 'Experts' were contacted through the International Association for Suicide Prevention (IASP), the World Psychiatric Association and the World Organization of Family Doctors. Each individual was sent an invitation to participate and a link to an online questionnaire. A comparison sample was created by inviting all IASP members to respond to the questionnaire. The questionnaire was designed to assess respondents' preferences about a particular set of terms and definitions by using the four major criteria of the definition of suicide identified in the literature (outcome, intent, knowledge and agency). The questionnaire used a multiple-choice question format. Participants were asked to choose one term in the list for each of the proposed definitions. Statements and definitions in the questionnaire were elaborated using the four main features of the definition of suicide, starting by the definitions and terms for which there is already a certain degree of consensus and then progressing to definitions and terms less agreed on. ETHICS AND DISSEMINATION: The study protocol obtained approval of Griffith University's Ethics Committee (ethics reference number 2017/601) and in accordance with the Australian National Statement on Ethical Conduct in Human Research. Respondents are asked if they accept to be personally acknowledged in any output originating from this study, and if so to provide their full name, title and affiliations. If respondents do not accept, they are informed that the conduct of this research respects Griffith University's Privacy Plan and that identified personal information is confidential and that anonymity will at all times be safeguarded. As detailed in the questionnaire cover letter, by answering the online or paper version of the questionnaire, respondents express their consent to participate. Dissemination of results will be done through a peer-reviewed journal article publication. This study aims to map the international use of definitions and terms for suicidal behaviour and ideation and favour the future use of an internationally shared set of terms and definitions. This will hopefully avoid undue duplication of efforts and reliably permit meta-analysis of data produced in different countries.

Brain cytochrome-c-oxidase as a marker of mitochondrial function: A pilot study in major depression using NIRS.

BACKGROUND: Brain mitochondrial dysfunction is implicated in the pathophysiology of mood disorders. Brain cytochrome-c-oxidase (COX) activity is associated with the mitochondrial function. Near-infrared spectroscopy (NIRS) noninvasively measures oxidized COX (oxCOX) and tissue oxygenation index (TOI) reflecting cerebral blood flow and oxygenation. METHODS: oxCOX and TOI were assessed in prefrontal cortex (Fp1/2, Brodmann area 10) in patients in a major depressive episode (N = 13) with major depressive disorder (MDD; N = 7) and bipolar disorder (BD; N = 6) compared with the controls (N = 10). One patient with MDD and all the patients with BD were taking medications. Computational modeling estimated oxCOX and TOI related indices of mitochondrial function and cerebral blood flow, respectively. RESULTS: oxCOX was lower in patients than controls (p = .014) correlating inversely with depression severity (r = -.72; p = .006), driven primarily by lower oxCOX in BD compared with the controls. Computationally modeled mitochondrial parameters of the electron transport chain, such as the nicotinamide adenine dinucleotide ratio (NAD+ /NADH; p = .001) and the proton leak rate across the inner mitochondrial membrane (klk2 ; p = .008), were also lower in patients and correlated inversely with depression severity. No such effects were found for TOI. CONCLUSIONS: In this pilot study, oxCOX and related mitochondrial parameters assessed by NIRS indicate an abnormal cerebral metabolic state in mood disorders proportional to depression severity, potentially providing a biomarker of antidepressant effect. Because the effect was driven by the medicated BD group, findings need to be evaluated in a larger, medication-free population.