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Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, intensity and specifics of the conditioning regimens, degree of HLA matching, and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third-party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all International Society for Cellular Therapy criteria in any study. MSCs were harvested from cell culture at passage 1 to 7 and the dosage of MSCs ranged from 0.3 to 10 × 10(6)/kg, using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD.

Cell-based therapy using umbilical cord blood (UCB) is being used increasingly in novel applications. To balance heightened public expectations and ensure appropriateness of emerging cell-based treatment choices, regular evidence-based assessment of novel UCB-derived therapies is needed. We performed a systematic search of the literature and identified 57 studies (814 patients) for analysis. Sixteen of these studies (353 patients) included a control group for comparison. The most commonly reported novel indication for therapy was neurologic diseases (25 studies, 476 patients), including studies of cerebral palsy (12 studies, 276 patients). Other indications included diabetes mellitus (9 studies, 149 patients), cardiac and vascular diseases (7 studies, 24 patients), and hepatic diseases (4 studies, 106 patients). Most studies administered total nucleated cells, mononuclear cells, or CD34-selected cells (31 studies, 513 patients), whereas 20 studies described the use of UCB-derived mesenchymal stromal cells. The majority of reports (46 studies, 627 patients) described cellular products obtained from allogeneic sources, whereas 11 studies (187 patients) used autologous products. We identified 3 indications where multiple prospective controlled studies have been published: 4 of 4 studies reported clinical benefit in cerebral palsy, 1 of 3 studies reported benefit for cirrhosis, and 1 of 3 studies reported biochemical response in type 1 diabetes), although heterogeneity among the studies precluded meaningful pooled analysis of results. We anticipate a more clear understanding of the clinical benefit for specific indications once more controlled studies are reported. Patients should continue to be enrolled on registered clinical trials for novel therapies. Blood establishments, transplantation centers, and regulatory bodies need to prepare for greater clinical demand.

Objective: Suicidal ideation (SI) is heterogeneous with different patterns and risk factors. SI can be persistent with stable severity but may also fluctuate rapidly over a short period of time. The latter pattern is likely associated with affective instability and may consist of activation of SI at times of stress, that then subside. Although affective instability is a hallmark of borderline personality disorder (BPD), little is known about SI variability in BPD. We hypothesized that SI variability would be associated with affective instability in BPD suicide attempters. Method: Sample included 38 females with BPD and history of suicidal behavior. SI was assessed over one week using ecological momentary assessment (EMA) at 6 epochs daily. The relationship between SI variability (i.e., change of SI from one epoch to another) and SI severity (i.e., average scores across epochs), and affective instability, assessed using the Affective Lability Scale (ALS), were examined. Possible confounding effects of depression severity and impulsiveness were tested. Results: Participants demonstrated high ALS scores and wide range of SI variability. ALS scores predicted SI variability, even after controlling for depression severity. Although ALS also predicted SI severity, this association was driven by depression severity. ALS did not correlate with impulsiveness score. Conclusions: Affective instability may predict SI variability in BPD suicide attempters independent of depression severity. This supports our model of suicidal subgroups with different

Background Major depressive disorder (MDD) is associated with impaired attention control and alterations in frontal-subcortical connectivity. We hypothesized that attention control as assessed by Stroop task interference depends on white matter integrity in fronto-cingulate regions and assessed this relationship using diffusion tensor imaging (DTI) in MDD and healthy volunteers (HV). Methods DTI images and Stroop task were acquired in 29 unmedicated MDD patients and 16 HVs, aged 18–65 years. The relationship between Stroop interference and fractional anisotropy (FA) was examined using region-of-interest (ROI) and tract-based spatial statistics (TBSS) analyses. Results ROI analysis revealed that Stroop interference correlated positively with FA in left caudal anterior cingulate cortex (cACC) in HVs (r= 0.62, p= 0.01), but not in MDD (r= −0.05, p= 0.79) even after controlling for depression severity. The left cACC was among 4 ROIs in fronto-cingulate network where FA was lower in MDD relative to HVs (F(1,41)= 8.87, p= 0.005). Additionally, TBSS showed the same group interaction of differences and correlations, although only at a statistical trend level. Limitations The modest sample size limits the generalizability of the findings. Conclusions Structural connectivity of white matter network of cACC correlated with magnitude of Stroop interference in HVs, but not MDD. The cACC-frontal network, sub-serving attention control, may be disrupted in MDD. Less cognitive control may include enhanced effects of salience in HVs, or less effective response inhibition in MDD. Further studies of salience and inhibition components of executive function may better elucidate the relationship between brain white matter changes and executive dysfunction in MDD.

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Purpose of Review Suicide is a major public health concern and a leading cause of death in the US. Alcohol and opioid use disorders (AUD/OUD) significantly increase risk for suicidal ideation, attempts, and death, and are the two most frequently implicated substances in suicide risk. We provide a brief overview of shared risk factors and pathways in the pathogenesis of AUD/OUD and suicidal thoughts and behaviors. We also review clinical recommendations on inpatient care, pharmacotherapy, and psychotherapeutic interventions for people with AUD/OUD and co-occurring suicidal ideation and behavior. Recent Findings Among people with an underlying vulnerability to risk-taking and impulsive behaviors, chronic alcohol intoxication can increase maladaptive coping behaviors and hinder self-regulation, thereby increasing the risk of suicide. Additionally, chronic opioid use can result in neurobiological changes that lead to increases in negative affective states, jointly contributing to suicide risk and continued opioid use. Despite significantly elevated suicide risk in individuals with AUD/OUD, there is a dearth of research on pharmacological and psychosocial interventions for co-occurring AUD/OUD and suicidal ideation and behavior. Summary Further research is needed to understand the effects of alcohol and opioid use on suicide risk, as well as address notable gaps in the literature on psychosocial and pharmacological interventions to lower risk for suicide among individuals with AUD/OUD.

While prominent models of suicidal behavior emphasize the hypothalamic-pituitary-adrenal (HPA) axis dysregulation, studies examining its role have yielded contradictory results. One possible explanation is that suicide attempters are a heterogeneous group and HPA axis dysregulation plays a more important role only in a subset of suicidal individuals. HPA axis dysregulation also plays a role in impulsivity and aggression. We hypothesize subgroups of attempters, based on levels of impulsivity and aggression, will differ in HPA axis dysregulation. We examined baseline cortisol, total cortisol output, and cortisol reactivity in mood disordered suicide attempters (N = 35) and non-attempters (N = 37) during the Trier Social Stress Test. Suicide attempters were divided into four subgroups: low aggression/low impulsivity, high aggression/low impulsivity, low aggression/high impulsivity, and high aggression/high impulsivity. As hypothesized, attempters and non-attempters did not differ in any cortisol measures while stress response differed based on impulsivity/aggression levels in suicide attempters, and when compared to non-attempters. Specifically, attempters with high impulsive aggression had a more pronounced cortisol response compared with other groups. This is the first study to examine the relationship between cortisol response and suicidal behavior in impulsive aggressive subgroups of attempters. These findings may help to identify a stress responsive suicidal subtype of individuals.