Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors that block programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved outcomes for many cancer subtypes but do exhibit toxicity, in the form of immune-related adverse events. OBJECTIVE: The aim of this study was to investigate the emerging toxicities of PD-1 and PD-L1 inhibitors including acute or reactivation of tuberculosis (TB) and atypical mycobacterial infection (AMI). METHODS: This study was completed as a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS) for incidence of TB and AMI due to PD-1 and PD-L1 inhibitors compared with other FDA (Food and Drug Administration) approved drugs. The statistical methods included disproportionality signal analysis using the reporting OR (ROR) to compare cases. The 95% Wald CI was reported to assess the precision of the ROR. RESULTS: Out of the 10 146 481 adverse events (AEs) reported to FAERS for all drugs between 1 January 2015 and 31 March 2020, 73 886 AEs were due to the five FDA approved PD-1/PD-L1 inhibitors. Seventy-two cases of TB were due to PD-1/PD-L1 inhibitors. Specifically, 45 cases (62.5%) due to nivolumab, 18 (25%) due to pembrolizumab, 5 (7%) due to atezolizumab and 4 (5.5%) due to durvalumab. There were 13 cases of AMI: 9 (69.3%) due to nivolumab, 2 (15.3%) due to pembrolizumab and 1 (7.7%) each due to durvalumab and atezolizumab. Avelumab was not attributed to any AE of TB or AMI. From analysis of the FAERS database, the calculated ROR for TB due to PD-1/PD-L1 inhibitors was 1.79 (95% CI, 1.42 to 2.26) (p<0.0001) and for AMI was 5.49 (95% CI, 3.15 to 9.55) (p<0.0001). CONCLUSION: PD-1/PD-L1 inhibitors used in the treatment of cancer subtypes is associated with increased TB and AMI risk. Although this complication is rare, clinicians using PD-1/PD-L1 inhibitors should be aware of the risks.

Role of tissue plasminogen activator and plasminogen activator inhibitor as potential biomarkers in psychosis.

The identification of biological markers for psychosis has an impact on its diagnosis, prognosis, and likelihood of treatment response. Tissue plasminogen activator (tPA) is involved in important functions such as synaptic plasticity, long-term potentiation and neurogenesis. Plasminogen activator inhibitor (PAI-1) is the most important inhibitor of tPA. Preliminary studies have shown that schizophrenia patients have lower tPA and higher PAI-1 levels than the general population. The association of tPA and PAI-1 abnormalities with psychotic spectrum disorders, however, remains elusive. Our primary objective was to assess the plasma levels of tPA and PAI-1 in patients experiencing acute psychotic episodes as compared to those in healthy controls. In this prospective case-control study, we collected peripheral blood samples from psychiatric inpatients and healthy age, gender and race-matched subjects and determined plasma levels of tPA and PAI-1 by enzyme-linked immune-absorbent assays. Plasma levels of PAI-1 in patients with schizoaffective disorder were significantly lower as compared to those in control subjects (P = 0.03). tPA was lower in cases as compared to controls although it did not reach statistical significance. Asian patients and controls had lower PAI-1 levels. Further, Asian patients with schizoaffective disorder had significantly lower PAI-1 level compared to Asian patients with schizophrenia. Our results indicate that patients with schizoaffective disorder have lower PAI-1 levels than those with schizophrenia, affective psychosis, and healthy controls. Further studies are warranted to explore the potential of PAI-1 as a biomarker for diagnosing schizoaffective disorder.

Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature.

Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia.

Patterns of Restraint Utilization in a Community Hospital's Psychiatric Inpatient Units.

Restraint use in psychiatry has been a topic of clinical and ethical debate for years. As much as the medical community desires to attain the goal of a restraint-free environment, there are not many alternatives available when it comes to protecting the safety of violent patients and those around them. Our objective was to examine patterns of restraint use and analyze the factors leading to its use in adult psychiatric inpatient units. We conducted a retrospective review of restraint orders from January 2007 to December 2012, for inpatient units at a community mental health hospital, examining-unit, patient gender, number and duration of restraint episodes, time of day, and whether medications and/or verbal redirection were used. For the 6-year period studied, a total of 1753 restraint order-sheets were filed for 455 patients. Mixed-model regression found significant differences in duration of restraint episodes depending on: patient gender, unit, medication use, verbal redirection and AM/PM shifts. These differences were consistent over time with no significant interactions with years and remained significant when included together in an overall multivariate model. We elucidate variable patterns of restraint utilization correlating with elements such as patient gender, time of day and staff shift, medication use, and attempts at verbally redirecting the patient. Besides providing much needed data on the intricate dynamics influencing restraint use, we suggest steps to implement hospital-wide restraint-reduction initiatives including cultural changes related to restraint usage, enhanced staff-training in conflict de-escalation techniques and personalized treatment plans for foreseeable restraint episodes.