Integrating Pre-test Probability and Point-of-Care Ultrasound (POCUS) in the Emergency Department (ED) Diagnosis of Small Bowel Obstruction (SBO).

Introduction A computed tomography (CT) scan and point-of-care ultrasound (POCUS) are commonly employed for diagnosing small bowel obstructions (SBOs). Prior studies demonstrated that POCUS has 90-95% sensitivity and specificity compared with CT scanning, which is the gold standard. Unlike other imaging modalities (in which the ordering and performing clinician are not the same), POCUS-performing/interpreting sonologists must recognize the risk of confirmation bias in the POCUS application. Per Bayesian analysis, the likelihood of a diagnosis being true following a diagnostic test is based on the ordering clinician's pre-test probability and the test characteristics (sensitivity and specificity, from which positive and negative likelihood ratios can be calculated). Consequently, establishing pre-test probability is important in informing downstream diagnostic or therapeutic interventions, as pre-test probability influences post-test odds. Little research has been done on the role of POCUS sonologist's pre-test probability and actual POCUS results regarding SBO. This study assessed the role of POCUS, integrating pre-test probability and POCUS results to determine post-test odds. Methods One hundred six patients were recruited on a convenience basis and underwent POCUS and CT between April 2017 and December 2022. All sonographers were credentialed in POCUS. POCUS sonologists' pre-test probabilities and POCUS and CT results were captured, which were compared. Sensitivity, specificity, LR+, and LR- were calculated, and correlations were made between pre-test probability and POCUS and CT results.  Results POCUS exhibited a sensitivity of 92% and specificity of 90%, with a corresponding positive likelihood ratio (LR+) of 9.3 and a negative likelihood ratio (LR-) of 0.09 for diagnosing SBO. Among patients with a high pre-test probability of SBO, a negative ultrasound yielded post-test odds of 0.4%, whereas a positive POCUS yielded post-test odds of 39.6%. Among patients with a low pre-test probability, a negative POCUS resulted in post-test odds of 0%, while a positive POCUS led to post-test odds of 2.1%, yielding a number needed to scan (NNS) of ~50 to identify a patient with an SBO on CT. Conclusion This study confirmed POCUS's sensitivity and specificity of ~90-95% and a corresponding LR+ of 9.2 and LR- of 0.9. Pre-test probability substantially affected post-test odds. Patients with a high pre-test probability and a positive POCUS had post-test odds of 39.6 and should have a confirmatory CT, while those with a negative POCUS have very low post-test odds and very likely will not benefit from CT. Patients with low pre-test probability and a positive POCUS have post-test odds of 2.1%, similar to the Wells Score and HEART score; such patients may not benefit from a CT, though clinicians should use their judgment/discretion. Patients with a low pre-test probability and a negative POCUS have post-test odds of 0% and should not have a CT. Among low pre-test probability patients, the NNS was ~50 to identify patients with an SBO on CT.

Deep Sedation in Pediatric Patients With Single Ventricle Physiology Outside of the Operating Room.

Background: Advancements in palliative surgery of patients with single ventricle physiology have led to an increase in the need for deep sedation protocols for painful procedures. However, positive pressure ventilation during anesthesia can result in unfavorable cardiopulmonary interactions. This patient population may benefit from sedation from these painful procedures. Methods: This study aims to demonstrate the safety and efficacy of deep sedation by pediatric intensivists outside the operating room for children with single ventricle physiology. This is a single-center, retrospective chart review on consecutive pediatric patients with single ventricle physiology who received deep sedation performed by pediatric intensivists between 2013 and 2020. Results: Thirty-three sedations were performed on 27 unique patients. The median age was 3.7 years (25th%-75th%: 2.1-15.6). The majority of the sedations, 88% (29/33), were done on children with Fontan physiology and 12% (4/33) were status-post superior cavopulmonary anastomosis. The primary cardiac defect was hypoplastic left heart in 63% (17/27) of all sedation procedures. There were 24 chest tube placements and 9 cardioversions. Ketamine alone [median dose 1.5 mg/kg (range 0.8-3.7)], ketamine [median dose 1 mg/kg (range 0.1-2.1)] with propofol [median dose 2.3 mg/kg (range 0.7-3.8)], and ketamine [median dose 1.5 mg/kg (range 0.4-3.0)] with morphine [median dose 0.06 mg/kg (range 0.03-0.20)] were the most common sedation regimens used. Adverse events (AEs) occurred in 4 patients (15%), three of which were transient AEs. All sedation encounters were successfully completed. Conclusion: Procedural deep sedation can be safely and effectively administered to single ventricle patients by intensivist-led sedation teams in selective case.

Pediatric Highlights From the Extracorporeal Life Support Organization Registry: 2017-2022.

The Extracorporeal Life Support Organization (ELSO) registry which collects data from hundreds of participating centers supports research in ECMO to help improve patient outcomes. The ELSO Scientific Oversight Committee, an international and diverse group of ECMOlogists ( https://www.elso.org/registry/socmembers.aspx ), selected the most impactful and innovative research articles on pediatric ECMO emerging from ELSO data. Here they present brief highlights of these publications.

Adult Highlights From the Extracorporeal Life Support Organization Registry: 2017-2022.

The Extracorporeal Life Support Organization (ELSO) registry captures clinical data and outcomes on patients receiving extracorporeal membrane oxygenation (ECMO) support across the globe at participating centers. It provides a very unique opportunity to benchmark outcomes and analyze the clinical course to help identify ways of improving patient outcomes. In this review, we summarize select adult ECMO articles published using the ELSO registry over the past 5 years. These articles highlight innovative utilization of the registry data in generating hypotheses for future clinical trials. Members of the ELSO Scientific Oversight Committee can be found here: https://www.elso.org/registry/socmembers.aspx .

An empirical investigation of definitions of subthreshold posttraumatic stress disorder.

Subthreshold posttraumatic stress disorder (PTSD) has long been recognized as an important construct that identifies a subgroup of individuals who report significant PTSD symptoms and associated disability but do not endorse enough symptoms to meet the criteria for a full PTSD diagnosis. Different investigators have defined subthreshold PTSD in various ways, making it difficult to interpret findings across studies. To address this problem, we systematically compared individuals who met criteria for nine different subthreshold PTSD definitions with individuals diagnosed with either full PTSD or no PTSD (i.e., failed to meet the criteria for a subthreshold definition) with respect to prevalence and associated clinical outcomes of interest. Participants were 1,082 veterans enrolled in the Veterans After Discharge Longitudinal Registry. PTSD and subthreshold PTSD diagnostic status were determined using the Structured Clinical Interview for DSM-5 (SCID-5) and validated self-report instruments were used to assess clinical outcomes. Across outcomes, subthreshold definitions generally identified a group of participants that was distinguishable from participants in both the PTSD and no PTSD groups, rs = .02-.47. We discuss the benefits and drawbacks of various subthreshold definitions and highlight the need for additional work evaluating these definitions across additional outcomes and samples. In the interim, we propose a working case definition of subthreshold PTSD as meeting any three of the four DSM-5 symptom criteria (i.e., Criteria B, C, D, and E) along with Criterion A and Criteria F-H. The results suggest subthreshold PTSD is a clinically meaningful construct.

The PTSD Criterion A debate: A brief history, current status, and recommendations for moving forward.

Posttraumatic stress disorder (PTSD) Criterion A, also known as the "stressor criterion," has been a major source of debate ever since PTSD was added to the third edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM) in 1980. Since then, the traumatic stress field has held an ongoing debate about how to best define Criterion A and the events that it covers. Because of the COVID-19 pandemic and recent race-based incidents, the Criterion A debate has been reinvigorated. In this paper, we review briefly the history of Criterion A and changes in its language across different editions of the DSM. We then describe the four main positions held by scholars involved in the Criterion A debate and carefully examine the support for those positions. We conclude by offering recommendations for moving forward.

Severity of posttraumatic stress disorder, type 2 diabetes outcomes and all-cause mortality: A retrospective cohort study.

BACKGROUND: Some evidence suggests patients with comorbid PTSD and type 2 diabetes (T2D) have worse T2D outcomes than those with T2D alone. However, there is no evidence regarding PTSD severity and risk for starting insulin, hyperglycemia, microvascular complications, and all-cause mortality. METHODS: In this retrospective cohort study, Veterans Health Affairs (VHA) medical record data from fiscal year (FY) 2012 to FY2022 were used to identify eligible patients (n = 23,161) who had a PTSD diagnosis, ≥1 PTSD Checklist score, controlled T2D (HbA1c ≤ 7.5) without microvascular complications at baseline. PTSD Checklist for DSM-5 (PCL-5) scores defined mild, moderate, and severe PTSD. Competing risk and survival models estimated the association between PTSD severity and T2D outcomes before and after controlling for confounding. RESULTS: Most (70%) patients were ≥ 50 years of age, 88% were male, 64.2% were of white race and 17.1% had mild, 67.4% moderate and 15.5% severe PTSD. After control for confounding, as compared to mild PTSD, moderate (HR = 1.05; 95% CI:1.01-1.11) and severe PTSD (HR = 1.15; 95%CI:1.07-1.23) were significantly associated with increased risk for microvascular complication. Hyperarousal was associated with a 42% lower risk of starting insulin. Negative mood was associated with a 16% increased risk for any microvascular complication. Severe PTSD was associated with a lower risk for all-cause mortality (HR = 0.76; 95%CI:0.63-0.91). CONCLUSIONS: Patients with comorbid PTSD and T2D have an increased risk for microvascular complications. However, they have lower mortality risk perhaps due to more health care use and earlier chronic disease detection. PTSD screening among patients with T2D may be warranted.

Neurological and Psychological Sequelae Associated With Multisystem Inflammatory Syndrome in Children.

Importance: Acute neurological involvement occurs in some patients with multisystem inflammatory syndrome in children (MIS-C), but few data report neurological and psychological sequelae, and no investigations include direct assessments of cognitive function 6 to 12 months after discharge. Objective: To characterize neurological, psychological, and quality of life sequelae after MIS-C. Design, Setting, and Participants: This cross-sectional cohort study was conducted in the US and Canada. Participants included children with MIS-C diagnosed from November 2020 through November 2021, 6 to 12 months after hospital discharge, and their sibling or community controls, when available. Data analysis was performed from August 2022 to May 2023. Exposure: Diagnosis of MIS-C. Main Outcomes and Measures: A central study site remotely administered a onetime neurological examination and in-depth neuropsychological assessment including measures of cognition, behavior, quality of life, and daily function. Generalized estimating equations, accounting for matching, assessed for group differences. Results: Sixty-four patients with MIS-C (mean [SD] age, 11.5 [3.9] years; 20 girls [31%]) and 44 control participants (mean [SD] age, 12.6 [3.7] years; 20 girls [45%]) were enrolled. The MIS-C group exhibited abnormalities on neurological examination more frequently than controls (15 of 61 children [25%] vs 3 of 43 children [7%]; odds ratio, 4.7; 95% CI, 1.3-16.7). Although the 2 groups performed similarly on most cognitive measures, the MIS-C group scored lower on the National Institutes of Health Cognition Toolbox List Sort Working Memory Test, a measure of executive functioning (mean [SD] scores, 96.1 [14.3] vs 103.1 [10.5]). Parents reported worse psychological outcomes in cases compared with controls, particularly higher scores for depression symptoms (mean [SD] scores, 52.6 [13.1] vs 47.8 [9.4]) and somatization (mean [SD] scores, 55.5 [15.5] vs 47.0 [7.6]). Self-reported (mean [SD] scores, 79.6 [13.1] vs 85.5 [12.3]) and parent-reported (mean [SD] scores, 80.3 [15.5] vs 88.6 [13.0]) quality of life scores were also lower in cases than controls. Conclusions and Relevance: In this cohort study, compared with contemporaneous sibling or community controls, patients with MIS-C had more abnormal neurologic examinations, worse working memory scores, more somatization and depression symptoms, and lower quality of life 6 to 12 months after hospital discharge. Although these findings need to be confirmed in larger studies, enhanced monitoring may be warranted for early identification and treatment of neurological and psychological symptoms.

The New Hampshire Hospital Screening and Referral Algorithm (NHHSRA) for Substance Use in People With Serious Mental Illness.

Objective: Substance use is a common co-occurrence among psychiatrically hospitalized adults, yet it is especially difficult to identify in those with serious mental illness. Existing screening instruments are not feasible for individuals with serious mental illness, as they rely heavily on subjective self-report. This study aimed to develop and validate an objective substance use screening instrument for use in seriously mentally ill patient populations.Methods: Objective elements were extracted from existing substance use screening instruments and used to develop a new, data-driven referral tool, the New Hampshire Hospital screening and referral algorithm (NHHSRA). Descriptive statistics were employed to compare NHHSRA summed score and individual patient data elements in a convenience sample of patients who were referred to the Addiction Services by expert addiction psychiatrist evaluation to those who were not referred. Pearson correlation coefficients and logistic regression models assessed the association between patient referral and the overall NHHSRA score and individual items. The NHHSRA was then piloted in a smaller convenience sample of patients against the standard clinical-based identification for substance use treatment needs.Results: The instrument consists of 5 objective items. These were tested in a sample of 302 sequentially admitted adults with serious mental illness. Three of the items were significantly associated with likelihood of benefitting from referral for substance use interventions (maximum likelihood estimate and standard deviation [SD] for positive non-tetrahydrocannabinol [non-THC] toxicology screen or > 0% blood alcohol level = 3.61 [0.6]; diagnosis of a substance use disorder = 4.89 [0.73]; and medication-assisted treatment or relapse prevention = 2.78 [0.67]), and these were prioritized in building a decision tree algorithm. The area under the receiver operating characteristic (ROC) curve for the NHHSRA was 0.96, indicating that the NHHSRA has high overall sensitivity and the algorithm was capable of distinguishing between patients needing substance use intervention versus those who do not with 96% accuracy. In the pilot implementation study of another 20 patient admissions, the NHHSRA accurately identified 100% (n = 6) of patients deemed to benefit from substance use interventions by expert addiction psychiatric evaluation. The standard clinical-based referral process identified only 33% (n = 2) and erroneously identified another 4 for referral to substance use intervention that would not have been warranted.Conclusions: The NHHSRA holds promise in its ability to improve objective and timely identification of substance use in a seriously mentally ill inpatient population, helping to facilitate treatment.

Decision-Making and Ethical Considerations of Tracheostomy and Chronic Mechanical Ventilation in Children With Acute Neurological Injury.

The decisions around whether or not to provide tracheostomy and chronic mechanical ventilation to children with acute neurologic injury are difficult for medical providers and surrogate decision makers. Consideration of the 4 primary principles of medical ethics-autonomy, beneficence, non-maleficence, and justice-can provide a framework from which constructive discussions can form. Determination of the goals of care is a good first step in navigating these complex decisions. A shared decision model should be used, including education of decision-makers by medical providers and appropriate recommendations based on the stated goals of care. In this paper, 2 illustrative cases are discussed highlighting the utility of this decision-making framework.

Early-Onset Ventilator-Associated Pneumonia in Pediatric Severe Traumatic Brain Injury.

BACKGROUND: Early-onset ventilator-associated pneumonia (VAP) is associated with poor outcomes in patients with severe traumatic brain injury (TBI). The primary aim of this study was to describe VAP, including the microbiology of VAP and differences in frequency of VAP when various definitions are applied. The secondary aim was to determine the clinical variables associated with the development of VAP in children with severe TBI. METHODS: This is a retrospective cohort study at a quaternary referral children's hospital with a level I trauma center designation. Inclusion criteria were patients aged 0-18 years admitted to the pediatric intensive care unit between 2015 and 2020 with severe TBI requiring at least 2 days of invasive ventilation. VAP was defined by using Center of Disease Control (CDC) definition or clinical VAP, based on physician diagnosis. We compared general demographics, reviewed trauma and injury data, and outcomes to assess any differences between patients with VAP and non-VAP patients. Associations were tested with regression models. RESULTS: After applying all inclusion and exclusion criteria, 90 patients were included in the analysis. Patients with VAP were older (8.5 vs. 5.6 years, P = 0.03). Patients with VAP were less likely to have suffered from abusive head trauma (P = 0.01). Patients who received continuous neuromuscular blockade or targeted temperature management did not have different frequencies of VAP. CDC-defined VAP was diagnosed in 27% of patients. Number of patients with VAP increased to 41% for physician-diagnosed or clinical VAP. Methicillin-sensitive Staphylococcus aureus was the most common isolate grown, followed by Hemophilus influenza, with most VAP occurring on days 2-5 of intubation. VAP was not associated with mortality but was associated with worse functional status scale in patients who survived to discharge (8 vs. 7.5, P = 0.048). Over a cumulative period of days, nebulized 3% and albuterol were associated with decreased incidence of VAP. CONCLUSIONS: Ventilator-associated pneumonia occurs commonly in children with severe TBI, with rates of 27-41%, depending on CDC-defined VAP or clinical VAP. The discrepancy between clinical VAP and CDC-defined VAP further illustrates the need for a standardized definition for VAP. Although most interventions were not associated with VAP, nebulized 3% saline and albuterol were associated with reduced incidence of VAP; future investigation is needed to determine whether mucolytic agents can decrease the rate of VAP in children with severe TBI.

Neuromonitoring During ECMO Support in Children.

Extracorporeal membrane oxygenation is a potentially lifesaving intervention for children with severe cardiac or respiratory failure. It is used with increasing frequency and in increasingly more complex and severe diseases. Neurological injuries are important causes of morbidity and mortality in children treated with extracorporeal membrane oxygenation and include ischemic stroke, intracranial hemorrhage, hypoxic-ischemic injury, and seizures. In this review, we discuss the epidemiology and pathophysiology of neurological injury in patients supported with extracorporeal membrane oxygenation, and we review the current state of knowledge for available modalities of monitoring neurological function in these children. These include structural imaging with computed tomography and ultrasound, cerebral blood flow monitoring with near-infrared spectroscopy and transcranial Doppler ultrasound, and physiological monitoring with electroencephalography and plasma biomarkers. We highlight areas of need and emerging advances that will improve our understanding of neurological injury related to extracorporeal membrane oxygenation and help to reduce the burden of neurological sequelae in these children.

Low Intensity Noise Exposure Enhanced Auditory Loudness and Temporal Processing by Increasing Excitability of DCN.

Sound stimulation is generally used for tinnitus and hyperacusis treatment. Recent studies found that long-term noise exposure can change synaptic and firing properties in the central auditory system, which will be detected by the acoustic startle reflex. However, the perceptual consequences of long-term low-intensity sound exposure are indistinct. This study will detect the effects of moderate-level noise exposure (83 dB SPL) on auditory loudness, and temporal processing was evaluated using CBA/CaJ mice. C-Fos staining was used to detect neural activity changes in the central auditory pathway. With two weeks of 83 dB SPL noise exposure (8 hours per day), no persistent threshold shift of the auditory brainstem response (ABR) was identified. On the other hand, noise exposure enhanced the acoustic startle response (ASR) and gap-induced prepulse inhibition significantly (gap-PPI). Low-level noise exposure, according to the findings, can alter temporal acuity. Noise exposure increased the number of c-Fos labeled neurons in the dorsal cochlear nucleus (DCN) and caudal pontine reticular nucleus (PnC) but not at a higher level in the central auditory nuclei. Our results suggested that noise stimulation can change acoustical temporal processing presumably by increasing the excitability of auditory brainstem neurons.

Multi-Lobar Atelectasis in Children Receiving Venoarterial Extracorporeal Membrane Oxygenation for Cardiac Indications.

BACKGROUND: Respiratory complications are common in patients who require venoarterial (VA) extracorporeal membrane oxygenation (ECMO) for cardiac indications. We aimed to examine the frequency and characteristics of patients who develop multi-lobar atelectasis early in the course of VA ECMO and to identify factors associated with its occurrence. METHODS: We performed a single-center retrospective review of consecutive pediatric subjects on VA ECMO in the cardiovascular ICU from 2014 to 2019. Chest radiographs before VA ECMO initiation and daily for up to 5 d of VA ECMO support were reviewed. Multi-lobar atelectasis was defined as the collapse of ≥2 lobes of the same lung. Patients with multi-lobar atelectasis before or immediately after VA ECMO cannulation were excluded. Bivariate comparisons and multivariable logistic regression analyses were performed to identify factors independently associated with lung collapse. Results of the multivariable analysis are provided as odds ratio (OR) with 95% CI. RESULTS: We reviewed 119 VA ECMO runs in 101 unique subjects. Multi-lobar atelectasis occurred in 36 runs (30%), with an isolated collapse of the left lung occurring most frequently (no. runs = 20). VA ECMO runs complicated by multi-lobar atelectasis were significantly longer and associated with lower hospital survival (51% vs 77%, survival in subjects without multi-lobar atelectasis; P = .01). Multivariable logistic regression analysis identified a subsequent ECMO run during the same admission to be independently associated with multi-lobar atelectasis (OR 5.4, 95% CI 1.2-21.5). Subanalysis of the subjects with isolated left lung collapse revealed male sex (OR 8.9, 95% CI 1.6-48.2) and subsequent ECMO run during the same admission (OR 4.0, 95% CI 1.2-13.6) to be independently associated with this complication, and mechanical ventilation at least 12 h before ECMO may be protective (OR 0.22, 95% CI 0.07-0.76). CONCLUSIONS: Multi-lobar atelectasis commonly occurred in children who were receiving VA ECMO for cardiac failure and was associated with worse outcomes. Male patients, a subsequent VA ECMO run during the same hospitalization, and patients in whom mechanical ventilation was initiated shortly before ECMO cannulation may be at increased risk for this complication.

Prevalence of Depression and Posttraumatic Stress Disorder in Flint, Michigan, 5 Years After the Onset of the Water Crisis.

Importance: Environmental disasters, such as the Flint, Michigan, water crisis, are potentially traumatic events (PTEs) that may precipitate long-term psychiatric disorders. The water crisis was associated with acute elevations in mental health problems in the Flint community, but long-term psychiatric sequelae have not yet been evaluated using standardized diagnostic measures. Objective: To investigate the prevalence of and factors associated with current presumptive diagnostic-level major depression and posttraumatic stress disorder (PTSD) among Flint residents 5 years after the onset of the crisis. Design, Setting, and Participants: In this cross-sectional study, a household probability sample of 1970 adults living in Flint, Michigan, during the crisis were surveyed about their crisis experiences, their psychological symptoms 5 years later, and their access to and use of mental health services in the intervening years. Analyses were weighted to produce population-representative estimates. Main Outcomes and Measures: Presumptive Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) diagnostic-level past-year major depression and PTSD. Results: Among 1970 respondents, 1061 of 1946 reporting sex (54.5%) were women; 1043 of 1951 reporting race (53.5%) were Black or African American and 829 (42.5%) were White; and 1895 of 1946 reporting ethnicity (97.4%) were non-Hispanic. Overall, 435 (22.1%) met DSM-5 criteria for presumptive past-year depression, 480 (24.4%) for presumptive past-year PTSD, and 276 (14.0%) for both disorders. Residents who believed that their or their family's health was harmed by contaminated water (eg, risk ratio [RR] for depression: 2.23; 95% CI, 1.80-2.76), who had low confidence in public-official information (eg, RR for PTSD, 1.44; 95% CI, 1.16-1.78), who had previous exposure to PTEs (eg, RR for both disorders: 5.06; 95% CI, 2.99-8.58), or who reported low social support (eg, RR for PTSD, 2.58; 95% CI, 1.94-3.43) had significantly higher risk for depression, PTSD, and comorbidity. PTEs involving prior physical or sexual assault were especially potent risk factors (eg, both disorders: RR, 7.30; 95% CI, 4.30-12.42). Only 685 respondents (34.8%) were ever offered mental health services to assist with water-crisis-related psychiatric symptoms; most (543 [79.3%]) who were offered services utilized them. Conclusions and Relevance: In this cross-sectional study of psychiatric disorder in Flint, Michigan, presumptive depression and PTSD were highly prevalent 5 years after the onset of the water crisis. These findings suggest that public-works environmental disasters have large-scale, long-term psychological sequelae. The Flint community may require expanded mental health services to meet continued psychiatric need. National disaster preparedness and response programs should consider psychiatric outcomes.

Deimplementation of Benzodiazepine Prescribing in Posttraumatic Stress Disorder in the Veterans Health Administration.

Objective: Our objective was to characterize benzodiazepine prescribing changes among veterans with posttraumatic stress disorder (PTSD) and inform efforts to deimplement low-value prescribing practices.Methods: This retrospective observational study used national Veterans Health Administration (VHA) administrative databases to examine annual period prevalence and incidence of benzodiazepine prescribing from 2009 through 2019 in veterans with PTSD. International Classification of Diseases (ICD-9/10) codes were used to identify PTSD. Temporal trends in discontinuation rates, incidence rates, and prevalent prescribing among patients newly engaged in PTSD care were measured.Results: Benzodiazepine prevalence in veterans with PTSD declined from 31.3% in 2009 to 10.7% in 2019, and incidence decreased from 11.4% to 2.9%, along with a 30% decrease in daily doses. Increasing discontinuation rates accounted for 21.0% of the decline in prevalence, while decreasing incidence among existing patients accounted for 36.8%, and decreased prevalence among new PTSD cohort entrants accounted for 42.2%. Women received benzodiazepines more commonly than men (odds ratio [OR] = 1.67; 95% CI, 1.64-1.70). The proportion of older adults increased over time among both existing (2009: 14.5%; 2019: 46.5%) and new (2009: 8.6%; 2019: 24.3%) benzodiazepine recipients.Conclusions: Benzodiazepine prescribing in VHA among veterans with PTSD showed changes driven by decreases in prevalence among new PTSD cohort entrants, with smaller changes in discontinuation and decreased incidence among existing patients. Educational initiatives may have curtailed benzodiazepine prescribing through promotion of effective alternative treatment options and supporting discontinuation through various tapering strategies. These initiatives offer resources and lessons to other health care systems to deimplement inappropriate benzodiazepine prescribing and other potentially harmful practices through patient-centered approaches that promote viable treatment alternatives.

Induction of Activity-Dependent Plasticity at Auditory Nerve Synapses.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Decoding Shared Versus Divergent Transcriptomic Signatures Across Cortico-Amygdala Circuitry in PTSD and Depressive Disorders.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric disease that is highly comorbid with major depressive disorder (MDD) and bipolar disorder. The overlap in symptoms is hypothesized to stem from partially shared genetics and underlying neurobiological mechanisms. To delineate conservation between transcriptional patterns across PTSD and MDD, the authors examined gene expression in the human cortex and amygdala in these disorders. METHODS: RNA sequencing was performed in the postmortem brain of two prefrontal cortex regions and two amygdala regions from donors diagnosed with PTSD (N=107) or MDD (N=109) as well as from neurotypical donors (N=109). RESULTS: The authors identified a limited number of differentially expressed genes (DEGs) specific to PTSD, with nearly all mapping to cortical versus amygdala regions. PTSD-specific DEGs were enriched in gene sets associated with downregulated immune-related pathways and microglia as well as with subpopulations of GABAergic inhibitory neurons. While a greater number of DEGs associated with MDD were identified, most overlapped with PTSD, and only a few were MDD specific. The authors used weighted gene coexpression network analysis as an orthogonal approach to confirm the observed cellular and molecular associations. CONCLUSIONS: These findings provide supporting evidence for involvement of decreased immune signaling and neuroinflammation in MDD and PTSD pathophysiology, and extend evidence that GABAergic neurons have functional significance in PTSD.

Induction of synapse formation by de novo neurotransmitter synthesis.

A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.

Risk factors for suicide in the Vietnam-era twin registry.

BACKGROUND: The risk of suicide among Veterans is of major concern, particularly among those who experienced a combat deployment and/or have a history of PTSD. DESIGN AND METHODS: This was a retrospective cohort study of post-discharge suicide among Vietnam-era Veterans who are members of the Vietnam Era Twin (VET) Registry. The VET Registry is a national sample of male twins from all branches of the military, both of whom served on active duty between 1964 and 1975. Military service and demographic factors were available from the military records. Service in-theater was based on military records; combat exposure and PTSD symptoms were assessed in 1987 by questionnaire. Mortality follow-up, from discharge to 2016, is identified from Department of Veterans Affairs, Social Security Administration, and National Death Index records; suicide as a cause of death is based on the International Classification of Death diagnostic codes from the death certificate. Statistical analysis used Cox proportional hazards regression to estimate the association of Vietnam-theater service, combat exposure, and PTSD symptoms with suicide while adjusting for military service and demographic confounding factors. RESULTS: From the 14,401 twins in the VET Registry, there were 147 suicide deaths during follow-up. In adjusted analyses, twins who served in the Vietnam theater were at similar risk of post-discharge suicide compared with non-theater Veterans; there was no association between combat and suicide. An increase in severity of PTSD symptoms was significantly associated with an increased risk of suicide in adjusted analyses (hazard ratio = 1.13 per five-point increase in symptom score; 95% CI: 1.02-1.27). CONCLUSIONS: Service in the Vietnam theater is not associated with greater risk of suicide; however, PTSD symptom severity poses a degree of risk of suicide in Vietnam-era Veterans. Adequate screening for PTSD in Veterans may be promising to identify Veterans who are at increased risk of suicide.