Evolution and Impact of a Diagnostic Point-of-Care Ultrasound Program in a PICU.

OBJECTIVES: To evaluate the impact of point-of-care ultrasound (POCUS) use on clinicians within a PICU and to assess infrastructural elements of our POCUS program development. DESIGN: Retrospective observational study. SETTING: Large academic, noncardiac PICU in the United States. SUBJECTS: Patients in a PICU who had diagnostic POCUS performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between January 1, 2017, and December 31, 2022, 7201 diagnostic POCUS studies were ordered; 1930 (26.8%) had a quality assurance (QA) record generated in an independent POCUS QA database. The cardiac domain was most frequently imaged (81.0% of ordered studies, 81.2% of reviewed studies). POCUS images changed clinician understanding of pathophysiology in 563 of 1930 cases (29.2%); when this occurred, management was changed in 318 of 563 cases (56.5%). Cardiac POCUS studies altered clinician suspected pathophysiology in 30.1% of cases (472/1568), compared with 21.5% (91/362) in noncardiac studies (p = 0.06). Among cases where POCUS changed clinician understanding, management changed more often following cardiac than noncardiac POCUS (p = 0.02). Clinicians identified a need for cardiology consultation or complete echocardiograms in 294 of 1568 cardiac POCUS studies (18.8%). Orders for POCUS imaging increased by 94.9%, and revenue increased by 159.4%, from initial to final study year. QA database use by both clinicians and reviewers decreased annually as QA processes evolved in the setting of technologic growth and unit expansion. CONCLUSIONS: Diagnostic POCUS imaging in the PICU frequently yields information that alters diagnosis and changes management. As PICU POCUS use increased, QA processes evolved resulting in decreased use of our initial QA database. Modifications to QA processes are likely necessary as clinical contexts change over time.

Safety and Efficacy of Ethanol for Catheter Salvage and Central Line-Associated Bloodstream Infection Prophylaxis in Polyurethane Catheters in the PICU.

OBJECTIVES: Ethanol lock therapy (ELT) is a potential method of central catheter salvage following central line-associated bloodstream infection (CLABSI) although there is potential risk of catheter damage in polyurethane catheters. Further, there is limited efficacy data across the spectrum of common pediatric catheters, and published ELT protocols describe dwell times that are not feasible for critically ill children. We sought to evaluate the safety and efficacy of ELT in polyurethane catheters using brief (30 min to 2 hr) dwell times in our PICU. DESIGN: Investigational pilot study using historical control data. SETTING: PICU in quaternary care, free-standing children's hospital. INTERVENTIONS: ELT in polyurethane central venous catheters for catheter salvage. RESULTS: ELT with brief dwell times was used in 25 patients, 22 of whom were bacteremic. Ultimately 11 patients, comprising 14 catheters, were diagnosed with a primary CLABSI. The catheter salvage rate in primary CLABSI patients receiving ELT was 92% (13/14) and significantly higher than the salvage rate in patients receiving antibiotics alone (non-ELT) (62%, 39/64; mean difference 0.32, 95% CI [0.14-0.50], p = 0.03). The rate of catheter fracture in all patients receiving ELT was 8% (2/25) while the rate of fracture in the non-ELT group was 13% (8/64; mean difference -0.05, 95% CI [-0.18 to 0.09], p = 0.72). The rate of tissue plasminogen activator (tPA) use in the ELT group was 8% (2/25), whereas the rate of tPA use in the non-ELT group was significantly higher at 42% (26/64; mean difference -0.34, 95% CI [-0.49 to -0.17], p = 0.002). CONCLUSIONS: The use of ELT for catheter salvage and prophylaxis in the PICU is safe in a variety of polyurethane catheters. Dwell times ranging from 30 minutes to 2 hours were effective in sterilizing the catheters while allowing other therapies to continue. This approach may decrease the need for frequent line changes in a medically fragile pediatric population.

Effects of task type on spontaneous alternations of attentional states.

Mind wandering is a common occurrence that can have serious consequences, but estimating when mind wandering occurs is a challenging research question. Previous research has shown that during meditation, people may spontaneously alternate between task-oriented and mind-wandering states without awareness (Zukosky & Wang, 2021, Cognition, 212, Article 104689). However, under what conditions such alternations occur is not clear. The present study examined the effects of task type on spontaneous alternations between task focus and mind wandering. In addition to a meditation task, participants performed either a scene-categorization-based CPT or a visual detection task while attentional orientation was assessed via self-monitoring and intermittent probes. The three tasks differ in the extent of their reliance on continuous monitoring (less required in the detection than meditation and CPT tasks) and attentional orientation (oriented internally in meditation task and externally in CPT and detection tasks). To overcome prior methodological challenges, we applied a technique designed to detect spontaneous alternations between focused and mind-wandering states without awareness, based on how the proportion of "focused" responses/ratings to intermittent probes changes during a focus-to-mind-wandering interval (i.e., the period from one self-report of mind wandering to the subsequent self-report). Our results showed that the proportion of "focused" responses to intermittent probes remained constant with increasing interprobe interval during meditation (consistent with previous work), but declined significantly in the CPT and detection tasks. These findings support the hypothesis that spontaneous alternations of attentional states without self-awareness occur during tasks emphasizing internally but not externally oriented attention.

Bedside placement of tunneled femorally inserted central catheters in pediatric patients on extracorporeal life support: A case series and discussion.

BACKGROUND: Pediatric patients requiring extracorporeal life support (ECLS) often need central venous access for extended periods of time. In this population, the placement of an upper extremity peripherally inserted central catheter (PICC) can be challenging due to the location and size of the venous ECLS cannula. Bedside placement of a tunneled femorally inserted central catheters (T-FICC) can be a viable alternative to a traditional PICC. METHODS: In this case series we present five children who were on ECLS and had a T-FICC placed at the bedside. RESULTS: In this series of five patients we successfully placed T-FICCs while the patients were on ECLS. The T-FICCs dwelled from 15 to 182 days. There were no events of central line associated blood stream infections or deep vein thrombosis. There was only one unintentional line dislodgement noted. CONCLUSION: The use of T-FICCs placed at the bedside is a safe and reliable alternative for secure long-term venous access in children who are on ECLS.

Fluorescence-Based Detection of Fatty Acid ß-Oxidation in Cells and Tissues Using Quinone Methide-Releasing Probes.

Detection of metabolic activity enables us to reveal the inherent metabolic state of cells and elucidate mechanisms underlying cellular homeostasis and growth. However, a fluorescence approach for the study of metabolic pathways is still largely unexplored. Herein, we have developed a new chemical probe for the fluorescence-based detection of fatty acid ß-oxidation (FAO), a key process in lipid catabolism, in cells and tissues. This probe serves as a substrate of FAO and forms a reactive quinone methide (QM) as a result of metabolic reactions. The liberated QM is covalently captured by intracellular proteins, and subsequent bio-orthogonal ligation with a fluorophore enables fluorescence analysis. This reaction-based sensing allowed us to detect FAO activity in cells at a desired emission wavelength using diverse analytical techniques including fluorescence imaging, in-gel fluorescence activity-based protein profiling (ABPP), and fluorescence-activated cell sorting (FACS). The probe was able to detect changes in FAO activity induced by chemical modulators in cultured cells. The probe was further employed for fluorescence imaging of FAO in mouse liver tissues and revealed the metabolic heterogeneity of FAO activity in hepatocytes by the combination of FACS and gene expression analysis, highlighting the utility of our probe as a chemical tool for fatty acid metabolism research.

Translating Guidelines into Practical Practice: Point-of-Care Ultrasound for Pediatric Critical Care Clinicians.

Point-of-care ultrasound (POCUS) is now transitioning from an emerging technology to a standard of care for critically ill children. POCUS can provide immediate answers to clinical questions impacting management and outcomes within this fragile population. Recently published international guidelines specific to POCUS use in neonatal and pediatric critical care populations now complement previous Society of Critical Care Medicine guidelines. The authors review consensus statements within guidelines, identify important limitations to statements, and provide considerations for the successful implementation of POCUS in the pediatric critical care setting.

Effectiveness of Spinal Stabilization Exercises on Dynamic Balance in Adults with Chronic Low Back Pain.

Background: Dynamic balance is a vital aspect of everyday life. It is important to incorporate an exercise program that is useful for maintaining and improving balance in patients with chronic low back pain (CLBP). However, there is a lack of evidence supporting the effectiveness of spinal stabilization exercises (SSEs) on improving dynamic balance. Purpose: To determine the effectiveness of SSEs on dynamic balance in adults with CLBP. Study Design: A double-blind randomized clinical trial. Methods: Forty participants with CLBP were assigned randomly into either an SSE group or a general exercise (GE) group, which consisted of flexibility and range-of-motion exercises. Participants attended a total of four to eight supervised physical therapy (PT) sessions and performed their assigned exercises at home in the first four weeks of the eight-week intervention. In the last four weeks, the participants performed their exercises at home with no supervised PT sessions. Participants' dynamic balance was measured using the Y-Balance Test (YBT) and the normalized composite scores, Numeric Pain Rating Scale and Modified Oswestry Low Back Pain Disability Questionnaire scores were collected at baseline, two weeks, four weeks, and eight weeks. Results: A significant difference between groups from two weeks to four weeks (p = 0.002) was found, with the SSE group demonstrating higher YBT composite scores than the GE group. However, there were no significant between-group differences from baseline to two weeks (p =0.098), and from four weeks to eight weeks (p = 0.413). Conclusions: Supervised SSEs were superior to GEs in improving dynamic balance for the first four weeks after initiating intervention in adults with CLBP. However, GEs appeared to have an effect equivalent to that of SSEs after 8-week intervention. Levels of Evidence: 1b.

Effectiveness of Spinal Stabilization Exercises on Movement Performance in Adults with Chronic Low Back Pain.

Introduction: Low back pain (LBP) is a musculoskeletal disorder that affects more than 80% of people in the United States at least once in their lifetime. LBP is one of the most common complaints prompting individuals to seek medical care. The purpose of this study was to determine the effects of spinal stabilization exercises (SSEs) on movement performance, pain intensity, and disability level in adults with chronic low back pain (CLBP). Methods: Forty participants, 20 in each group, with CLBP were recruited and randomly allocated into one of two interventions: SSEs and general exercises (GEs). All participants received their assigned intervention under supervision one to two times per week for the first four weeks and then were asked to continue their program at home for another four weeks. Outcome measures were collected at baseline, two weeks, four weeks, and eight weeks, including the Functional Movement ScreenTM (FMSTM), Numeric Pain Rating Scale (NPRS), and Modified Oswestry Low Back Pain Disability Questionnaire (OSW) scores. Results: There was a significant interaction for the FMSTM scores (p = 0.016), but not for the NPRS and OSW scores. Post hoc analysis showed significant between-group differences between baseline and four weeks (p = 0.005) and between baseline and eight weeks (p = 0.026) favor SSEs over GEs. Further, the results demonstrated that all participants, regardless of group, had significant improvements in movement performance, pain intensity, and disability level over time. Conclusion: The results of the study favor SSEs over GEs in improving movement performance for individuals with CLBP, specifically after four weeks of the supervised SSE program.

Comparisons of Clinical Competency and Job Responsibilities of Physical Therapists With and Without Postprofessional Training.

INTRODUCTION: Understanding how educational pathways may influence clinical competence and work responsibilities is important in providing guidance to academic and clinic stakeholders and physical therapists (PTs) on PT career development. The purpose of this paper was to compare perceived clinical competency and job duties between PTs with formal mentored postprofessional clinical education with PTs without formal postprofessional clinical education. REVIEW OF LITERATURE: The understanding of self-perceived clinical competence of PTs overall in the United States is limited, especially as related to the impact of postprofessional education. Furthermore, there is limited understanding of the career pathways and development of job duties of PTs in the United States. SUBJECTS: Two thousand three hundred thirty-four PTs in the United States. METHODS: An online survey was sent to licensed PTs. This survey included items measuring self-perceived clinical competency and questions related to weekly job responsibilities. Participants were categorized as residency trained, fellowship trained, or non-residency/fellowship trained. Frequency analyses and Kruskal-Wallis tests with pairwise post hoc tests were performed comparing the 3 groups. RESULTS: Residency-trained (P < .007) and fellowship-trained (P < .001) groups demonstrated elements of higher self-perceived clinical competency compared with the non-residency-/fellowship-trained group. Both the residency- and fellowship-trained groups spent less time with patient care and more time with other responsibilities (e.g., teaching, mentoring, and research) (P < .02) during an average workweek. Fellowship-trained PTs (P < .001) spent more time with administrative duties compared with the non-residency-/fellowship-trained group. DISCUSSION AND CONCLUSION: Results from this paper demonstrate that residency- and fellowship-trained PTs have elements of higher self-perceived clinical competency and spend more of their job duties outside of direct patient care compared with PTs who were not residency or fellowship trained. These results may help guide PTs, academic institutions, and employers in planning and achieving specific career paths.

Iron-containing metal-organic framework thin film as a drug delivery system.

Selective bulk metal-organic frameworks (MOFs) have exhibited great potential in biomedical applications. However, topical treatments and drug elution coatings will require uniform films as drug delivery systems. This work studies the use of surface supportive MOF thin films for drug loading and releasing. More specifically, we focus on an iron-containing MOF, MIL-88B(Fe), on a COOH-terminated self-assembled monolayer (SAM) modified Au surface for encapsulating ibuprofen as a model drug. A combined experimental and computational approach was employed to study the fabrication of MIL-88B(Fe) film on functionalized Au surfaces. We used several surface characterization techniques, including infrared spectroscopy and scanning electron microscopy, to confirm the chemical composition and morphological changes of the surface after each modification step. The resulting MIL-88B(Fe) thin film was found capable of loading 8.7 wt% of ibuprofen using quartz crystal microbalance analysis. Moreover, we applied cluster simulations to study the binding mechanisms of MIL-88B(Fe) and its interactions with ibuprofen based on the density functional theory (DFT). The unsaturated Fe site was confirmed kinetically more favorable to bind to the COOH-end group on the SAM. Hydrogen bonding and π-CH interactions between ibuprofen and MIL-88B(Fe) promote ibuprofen being retained inside of the cages of MIL-88B(Fe).

Utilization of lateral exit sites for femorally inserted central catheters in pediatric patients: A case report and review of the literature.

Tunneled femorally inserted central catheters (FICCs) are frequently required for central access in children when upper extremity vessels cannot or should not be cannulated. A recently published decision tool for tunneled FICCs identifies the medial thigh as the preferred exit site. In pediatric patients, this medial exit site may remain at risk of contamination from stool due to anatomic size, and there are no tools developed for FICC exit site decisions specific to children. We present our approach for the placement of the exit site in the far lateral region of the thigh and review previous FICC literature relevant to the pediatric population. In select patients, a lateral approach has the potential to decrease the risk of exit site contamination to prolong catheter viability and reduce patient harm.

Creating the HHS COVID-19 Public Education Media Campaign: Applying Systems Change Learnings.

The COVID-19 Public Education Media Campaign was initiated in July 2020 by the US Department of Health and Human Services (HHS). The process by which the Campaign was developed and operated by the HHS Office of the Assistant Secretary for Public Affairs (ASPA) was different than for other HHS campaigns. Nine learnings from recent ASPA systems change efforts were employed to guide development and implementation of the Campaign. The learnings, based in communication science as well as experience, have not been applied or have been inconsistently applied in other HHS campaigns. In this case, their application kept the Campaign's work focused on public health needs and not on political diversions. Separable from content and media aspects of the Campaign, the development and operational process guided by the nine learnings resulted in accomplishments such as: (1) advisory input and operation by a team of Federal employees from across the US Government; (2) award of large Federal contracts in a much shorter time than is typical, (3) proactive response to concerns from Congress, largely driven by the news media, (4) ability to make Campaign revisions in the context of the rapidly evolving science about the pandemic, and (5) ability to transcend the unusual political realities of a Presidential election season and the transition of administrations. Ways the nine learnings were applied to the Campaign's creation and operation may provide useful guidance to U.S. Government officials and others planning and conducting similar efforts in politically charged environments.

Retrospective Assessment of Patient and Catheter Characteristics Associated With Malpositioned Central Venous Catheters in Pediatric Patients.

OBJECTIVES: The primary objective was to determine the prevalence and characteristics associated with malpositioned temporary, nontunneled central venous catheters (CVCs) placed via the internal jugular (IJ) and subclavian (SC) veins in pediatric patients. DESIGN: Single-center retrospective cohort study. SETTING: Quaternary academic PICU. PATIENTS: Children greater than 1 month to less than 18 years who had a CVC placed between January 2014 and December 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the CVC tip position located on the first postprocedural radiograph. CVC tip was defined as follows: "recommended" (tip location between the carina and two vertebral bodies inferior to the carina), "high" (tip location between one and four vertebral bodies superior to the carina), "low" (tip position three or more vertebral bodies inferior to the carina), and "other" (tip grossly malpositioned). Seven hundred eighty-one CVCs were included: 481 (61.6%) were in "recommended" position, 157 (20.1%) were "high," 131 (16.8%) were "low," and 12 (1.5%) were "other." Multiple multinomial regression (referenced to "recommended" position) showed that left-sided catheters (adjusted odds ratio [aOR], 2.00, 95% CI 1.17-3.40) were associated with "high" CVC tip positions, whereas weight greater than or equal to 40 kg had decreased odds of having a "high" CVC tip compared with the reference (aOR, 0.45; 95% CI, 0.24-0.83). Further, weight category 20-40 kg (aOR, 2.42; 95% CI, 1.38-4.23) and females (aOR, 1.51; 95% CI, 1.01-2.26) were associated with "low" CVC tip positions. There was no difference in rates of central line-associated blood stream infection, venous thromboembolism, or tissue plasminogen activator usage or dose between the CVCs with tips outside and those within the recommended location. CONCLUSIONS: The prevalence of IJ and SC CVC tips outside of the recommended location was high. Left-sided catheters, patient weight, and sex were associated with malposition. Malpositioned catheters were not associated with increased harm.

Use of intracavitary-ECG for tip location of femorally inserted central catheters.

Femorally inserted central catheters (FICCs) are frequently required for central access in children. Ultrasound can accurately locate the catheter tip in most cases and its use is increasing in clinical vascular access practice. In patients with poor acoustic windows, intracavitary electrocardiogram (IC-ECG) is an alternative to ultrasound-guidance for FICC positioning. A case series of three patients demonstrate methods of FICC positioning in children. The first patient had excellent acoustic windows and ultrasound-guided FICC positioning is described in conjunction with IC-ECG measurements. The following two patients had poor acoustic windows, thus IC-ECG guided FICC tip position. The use of FICCs in children has increased in recent years. Ultrasound has emerged as a reliable method of assessing FICC tip location. IC-ECG is an accurate and complementary method of assessing FICC tip location, but can be a primary method when ultrasound is not available or cannot directly visualize the catheter. IC-ECG P-wave characteristics identify optimal tip position at the inferior cavoatrial junction and are different from characteristics at the superior cavoatrial junction.

A narrative review of diaphragmatic ultrasound in pediatric critical care.

The use of point of care ultrasound (POCUS) at the bedside has increased dramatically within emergency medicine and in critical care. Applications of POCUS have spread to include diaphragmatic assessments in both adults and children. Diaphragm POCUS can be used to assess for diaphragm dysfunction (DD) and atrophy or to guide ventilator titration and weaning. Quantitative, semi-quantitative and qualitative measurements of diaphragm thickness, diaphragm excursion, and diaphragm thickening fraction provide objective data related to DD and atrophy. The potential for quick, noninvasive, and repeatable bedside diaphragm assessments has led to a growing amount of literature on diaphragm POCUS. To date, there are no reviews of the current state of diaphragm POCUS in pediatric critical care. The aims of this narrative review are to summarize the current literature regarding techniques, reference values, applications, and future innovations of diaphragm POCUS in critically ill children. A summary of current practice and future directions will be discussed.

Reliability and Validity of the Y-balance Test in Young Adults with Chronic Low Back Pain.

BACKGROUND: Individuals with chronic low back pain (CLBP) may demonstrate reduced ability to perform dynamic tasks due to fear of additional pain and injury in response to the movement. The Y-balance test (YBT) is a functional and inexpensive test used with various populations. However, the reliability and validity of the YBT used for assessing dynamic balance in young adults with CLBP have not yet been examined. PURPOSE: To determine the inter-rater reliability of the YBT and to compare dynamic balance between young adults with CLBP and an asymptomatic group. STUDY DESIGN: Reliability and validity study. METHODS: Fifteen individuals with CLBP (≥ 12 weeks) and 15 age- and gender-matched asymptomatic adults completed the study. Each group consisted of 6 males and 9 females who were 21-38 years of age (27.47 ± 5.0 years). The YBT was used to measure participant's dynamic balance in the anterior (ANT), posteromedial (PM) and posterolateral (PL) reach directions. The scores for each participant were independently determined and recorded to the nearest centimeter by two raters. Both the YBT reach distances and composite scores were collected from the dominant leg of asymptomatic individuals and the involved side of participants with CLBP and were used for statistical analysis. RESULTS: The YBT demonstrated excellent inter-rater reliability, with intraclass correlation coefficients ranging from 0.99 to 1.0 for the YBT scores of both asymptomatic and CLBP groups. The CLBP group had lower scores than those of the asymptomatic group in the reach distances of the ANT (p = 0.023), PM (p < 0.001), and PL (p = 0.001) directions, and the composite scores (p < 0.001). CONCLUSIONS: The results demonstrated excellent inter-rater reliability and validity of the YBT for assessing dynamic balance in the CLBP population. The YBT may be a useful tool for clinicians to assess dynamic balance deficits in patients with CLBP. LEVEL OF EVIDENCE: 2b.

Left Ventricular Diastolic Dysfunction in Pediatric Sepsis: Outcomes in a Single-Center Retrospective Cohort Study.

OBJECTIVES: Left ventricular diastolic dysfunction is associated with difficulty in ventilator weaning and increased mortality in septic adults. We evaluated the association of left ventricular diastolic dysfunction with outcomes in a cohort of children with severe sepsis and septic shock. DESIGN: Retrospective cohort study. SETTING: Single-center noncardiac PICU. PATIENTS: Age greater than 1 month to less than 18 years old with severe sepsis or septic shock from January 2011 to June 2017 with echocardiogram within 48 hours of sepsis onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Echocardiograms were retrospectively assessed for mitral inflow E (early) and A (atrial) velocity and e' (early mitral annular motion) septal and lateral velocity. Left ventricular diastolic dysfunction was defined as E/e' greater than 10, E/A less than 0.8, or E/A greater than 1.5. Left ventricular diastolic dysfunction was present in 109 of 204 patients (53%). The data did not demonstrate an association between the presence of left ventricular diastolic dysfunction and the proportion of children requiring invasive mechanical ventilation at the time of echocardiogram (difference in proportion, +5% [72% vs 67%; 95% CI, -8% to 17%]; p = 0.52). The duration of mechanical ventilation was median 192.9 hours (interquartile range, 65.0-378.4 hr) in the left ventricular diastolic dysfunction group versus 151.0 hours (interquartile range, 45.7-244.3 hr) in the group without left ventricular diastolic dysfunction. The presence of left ventricular diastolic dysfunction was not significantly associated with ICU length of stay or mortality. Exploratory analyses revealed that an alternative definition of left ventricular diastolic dysfunction, solely defined by E/e' greater than 10, was found to have an association with mechanical ventilation requirement at the time of echocardiogram (difference in proportion, +15%; 95% CI, 3-28%; p = 0.02) and duration of mechanical ventilation (median, 207.3 vs 146.9 hr). CONCLUSIONS: The data failed to show an association between the presence of left ventricular diastolic dysfunction defined by both E/e' and E/A and the primary and secondary outcomes. When an alternative definition of left ventricular diastolic dysfunction with E/e' alone was used, there was a significant association with respiratory outcomes.

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.

Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1ß protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.

GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons.

Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type. In acute murine mPFC slices the GluN2C/D selective positive allosteric modulator (PAM), CIQ(+), increased the intrinsic excitability as well as enhanced NMDAR-mediated EPSCs onto FSINs. This increase in intrinsic excitability with GluN2C/D PAM was also observed in the Dlx 5/6+/- FSIN developmental deficit model with reported FSIN hypoexcitability. Together these data speak to selective modulation of FSINs by a GluN2D PAM, providing a potential mechanism to counter the FSIN-deficit seen in schizophrenia.