Hospitalization and help-seeking among first episode psychosis patients.

PURPOSE: To examine hospitalization as part of a complex pathway to care in first episode psychosis (FEP), exploring help-seeking episodes (HSE) and their relationship to hospitalization. METHODS: Data from 66 patients at the Early Psychosis Intervention Clinic New Orleans (EPIC-NOLA), a coordinated specialty care (CSC) clinic, was obtained from Pathways to Care (PTC) assessments, which documents elements of help seeking. A chart review was performed identifying hospitalizations. RESULTS: Most patients were hospitalized multiple times (n = 37, M = 2.98, SD = 2.14). On average, patients had more hospitalizations prior to starting treatment at EPIC-NOLA (M = 1.72, SD = 1.35) than after (M = 1.27, SD = 1.79). Patients whose first HSE resulted in intake at EPIC-NOLA were significantly less likely to be hospitalized after intake than patients with multiple HSE (F(1,52.3) = 12.9, p < .001). There was a significant correlation (N = 42) between HSE and hospitalizations after intake (τb = .327 p < .05); patients seeking help more often were more likely to be hospitalized after intake. No significant correlations were found between duration of untreated psychosis (DUP) and hospitalization. CONCLUSION: While results are correlational, several key relationships were noted. Fewer hospitalizations occurred after intake into EPIC-NOLA. Starting treatment after the first HSE was related to fewer future hospitalizations, compared to intake after multiple HSEs. Intake into a CSC clinic after a single HSE may reduce hospitalization. Additionally, increased HSE, not DUP, impacted patients' likelihood of hospitalization. This prompts treatment engagement during a first HSE to reduce hospitalization.

BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen.

Metabolism of haem by-products such as bilirubin by humans and their gut microbiota is essential to human health, as excess serum bilirubin can cause jaundice and even neurological damage. The bacterial enzymes that reduce bilirubin to urobilinogen, a key step in this pathway, have remained unidentified. Here we used biochemical analyses and comparative genomics to identify BilR as a gut-microbiota-derived bilirubin reductase that reduces bilirubin to urobilinogen. We delineated the BilR sequences from similar reductases through the identification of key residues critical for bilirubin reduction and found that BilR is predominantly encoded by Firmicutes species. Analysis of human gut metagenomes revealed that BilR is nearly ubiquitous in healthy adults, but prevalence is decreased in neonates and individuals with inflammatory bowel disease. This discovery sheds light on the role of the gut microbiome in bilirubin metabolism and highlights the significance of the gut-liver axis in maintaining bilirubin homeostasis.

Discovery of the gut microbial enzyme responsible for bilirubin reduction to urobilinogen.

The degradation of heme and the interplay of its catabolic derivative, bilirubin, between humans and their gut microbiota is an essential facet of human health. However, the hypothesized bacterial enzyme that reduces bilirubin to urobilinogen, a key step that produces the excretable waste products of this pathway, has remained unidentified. In this study, we used a combination of biochemical analyses and comparative genomics to identify a novel enzyme, BilR, that can reduce bilirubin to urobilinogen. We delineated the BilR sequences from other members of the Old Yellow Enzyme family through the identification of key residues in the active site that are critical for bilirubin reduction and found that BilR is predominantly encoded by Firmicutes in the gut microbiome. Our analysis of human gut metagenomes showed that BilR is a common feature of a healthy adult human microbiome but has a decreased prevalence in neonates and IBD patients. This discovery sheds new light on the role of the gut microbiome in bilirubin metabolism and highlights the significance of the gut-liver axis in maintaining bilirubin homeostasis.

Gut Microbiome-Wide Search for Bacterial Azoreductases Reveals Potentially Uncharacterized Azoreductases Encoded in the Human Gut Microbiome.

The human gut is home to trillions of microorganisms that are responsible for the modification of many orally administered drugs, leading to a wide range of therapeutic outcomes. Prodrugs bearing an azo bond are designed to treat inflammatory bowel disease and colorectal cancer via microbial azo reduction, allowing for topical application of therapeutic moieties to the diseased tissue in the intestines. Despite the inextricable link between microbial azo reduction and the efficacy of azo prodrugs, the prevalence, abundance, and distribution of azoreductases have not been systematically examined across the gut microbiome. Here, we curated and clustered amino acid sequences of experimentally confirmed bacterial azoreductases and conducted a hidden Markov model-driven homolog search for these enzymes across 4644 genome sequences present in the representative Unified Human Gastrointestinal Genomes collection. We identified 1958 putative azo-reducing species, corroborating previous findings that azo reduction appears to be a ubiquitous function of the gut microbiome. However, through a systematic comparison of predicted and confirmed azo-reducing strains, we hypothesize the presence of uncharacterized azoreductases in 25 prominent strains of the human gut microbiome. Finally, we confirmed the azo reduction of Acid Orange 7 by multiple strains of Fusobacterium nucleatum, Bacteroides fragilis, and Clostridium clostridioforme Together, these results suggest the presence and activity of many uncharacterized azoreductases in the human gut microbiome and motivate future studies aimed at characterizing azoreductase genes in prominent members of the human gut microbiome. SIGNIFICANCE STATEMENT: This work systematically examined the prevalence, abundance, and distribution of azoreductases across the healthy and inflammatory bowel disease human gut microbiome, revealing potentially uncharacterized azoreductase genes. It also confirmed the reduction of Acid Orange 7 by strains of Fusobacterium nucleatum, Bacteroides fragilis, and Clostridium clostridioforme.

Capgras Syndrome: In the Conscious and the Unconscious Mind: A Case Report.

ABSTRACT: We report the successful psychotherapy and medical treatment of a patient with an atypical presentation of Capgras syndrome, in which the patient not only believed that his parents were impostors but also believed that the entirety of what others would consider consensual reality was in fact an impostor. He insisted that a complex delusional world in which he wished to reside was authentic reality. His delusions of misidentification waxed and waned in response to discernable social stressors, and at times, he seemed to have conscious insight into the delusional nature of his beliefs. This case raises questions about whether Capgras should be considered a stand-alone diagnosis or whether it should be placed within a wider spectrum of psychotic disorders. Excepting our current report, although there are numerous reports of the resolution of Capgras after treatment with neuroleptics, we are unaware of descriptions in the literature of the successful treatment of medication-resistant Capgras with a combination of individual psychotherapy and pharmacological management.

The safety of rapid infusion levetiracetam: A systematic review.

Epilepsy is a common diagnosis and can quickly progress to status epilepticus which requires rapid treatment. Levetiracetam is a frequent treatment choice in these situations. The approved administration of intravenous levetiracetam is an infusion over 15 min. In recent years, studies have been published on faster infusion rates of levetiracetam. The objective of this review is to discuss the safety of levetiracetam as an intravenous push at a rate quicker than recommended. A literature search using PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar resulted in 192 articles. Inclusion criteria consisted of English language, human studies, use of levetiracetam administered intravenously at a rate faster than 15 min, discussion of safety, and full-text availability. After screening, nine articles remained for inclusion. Of the nine articles, one was a prospective, open-label study, six were retrospective studies, and two were open-label, randomized controlled trials. The most common rapid infusion speed was 5 min and doses ranged from 280 to 4500 mg. Some of these trials used undiluted levetiracetam and many reported that peripheral access was used for a portion or all of the administrations. There were few adverse effects, including specific adverse effects relating to medication concentration and speed of infusion, in all the studies. Administration of intravenous levetiracetam at a rate faster than recommended in the labeling information appears to be safe and tolerable and can be given via a peripheral line. Rapid infusion of levetiracetam is a beneficial method of administration in an acute care setting where patients need rapid attainment of therapeutic levels of antiepileptic medications. Additional research is needed to ensure that rapid administration of intravenous levetiracetam is as efficacious as the traditional dosing method.

Impact of timing and dosing of four-factor prothrombin complex concentrate administration on outcomes in warfarin-associated intracranial hemorrhage.

STUDY OBJECTIVE: The objective of this study was to evaluate clinical outcomes associated with time to administration and dose of four-factor prothrombin complex concentrate (4F-PCC) in patients with ICH on warfarin. DESIGN: This was a single-center retrospective analysis of patients with ICH on warfarin who received 4F-PCC. SETTING: The site of the study was a large, Level I trauma, academic medical center with a dedicated neurologic intensive care unit and an emergency department (ED) that has approximately 72,000 visits annually. PATIENTS: Patients were included if they were ≥18 years of age, diagnosed with ICH, had an INR >1 due to warfarin use, and received both 4F-PCC and IV vitamin K for anticoagulation reversal. Exclusion criteria included patients who were less than 18 years of age, were not currently taking warfarin, had a bleeding site other than ICH, were pregnant or incarcerated, had an inadequate medical record, had a left ventricular assist device, had known liver disease with Child-Pugh Class C, received anticoagulation with heparin therapy within 24 h of anticoagulation reversal, or did not receive vitamin K within 24 h of hospital admission. INTERVENTION: Our primary outcome was a composite of hematoma expansion or death due to neurologic injury. Treatment groups were defined as receipt of 4F-PCC within 0-30, 31-60, 61-90, 91-120 min, or greater than 120 min. Hematoma expansion was defined as any increase in hematoma size as assessed by a radiologist via standard 6-h CT. Death due to neurologic injury was defined as death prior to a repeat CT being performed or documentation of a neurologic cause of death. Adequate INR reversal (INR ≤1.3 on repeat INR) vs. inadequate INR reversal and weight-based vs. fixed-dose 4F-PCC were also assessed. MEASUREMENTS AND MAIN RESULTS: A total of 94 patients met the inclusion criteria. Forty-one patients (43.6%) met the composite endpoint, including 60% of the 31-60 min group, 47.6% of the 61-90 min group, 71.4% of the 91-120 min group, and 30.6% of the >120-min group. A significant difference in primary outcome occurred between the 91-120 min and >120-min groups (71.4% vs. 30.6%; p= 0.005), but this difference was not observed when accounting for disparities in Glasgow Coma Scale (GCS). Patients with adequate INR reversal were less likely to meet the primary endpoint than those with inadequate INR reversal (28.1% vs. 58.6%; p= 0.0059). There was less failure of anticoagulation reversal with weight-based dosing compared with fixed dosing (24.2% vs. 65.0%; p< 0.001). CONCLUSIONS: No difference in clinical outcomes among 4F-PCC dosing strategies or time windows to administration was observed in patients with GCS <15. Rates of repeat INR ≤1.3 were higher with weight-based dosing, suggesting investigation of populations in which fixed dosing may be inappropriate is warranted.

Psychosis, Telehealth, and COVID-19: Successes and Lessons Learned From the First Wave of the Pandemic.

OBJECTIVE: This brief report analyzes a first-episode psychosis (FEP) clinic's shift from in-person treatment to the provision of services through telemental health during the 2019 coronavirus disease (COVID-19) pandemic. The feasibility of using this technology was examined by assessing client engagement. METHODS: The authors created and implemented procedures for the clinic's transition to telemental health. Once clients' consents were obtained, the Health Insurance Portability and Accountability Act (HIPAA) compliant platform was used to continue service provision. RESULTS: Client engagement during this period improved compared to that of the same quarter in the previous year. Telemental health was also practical for providing groups and other supportive services to meet clients' needs. CONCLUSION: Telemental health is an effective approach to providing care at an FEP clinic during a pandemic. Successes and lessons learned from the first wave of the pandemic can be used to prevent an uptick in symptoms and sustain engagement for this vulnerable population during the anticipated second wave.

Pathways to Care: How Help-Seeking Behaviors Relate to Duration of Untreated Psychosis and Treatment Engagement.

While much research has focused on the relationship between duration of untreated psychosis (DUP) and clinical outcomes in the first episode psychosis (FEP) patient population, little is known about the individual help-seeking episodes (HSE) that patients undergo before receiving appropriate care. The purpose of this project is to better understand how early referral to FEP-specific care and support system differences affect patients' DUP and engagement with treatment. Data from 50 patients was analyzed at the Early Psychosis Intervention Clinic of New Orleans (EPIC-NOLA) using a modified version of the Pathways to Care Assessments and data captured during clinical care. Patients with their first HSE leading to a referral to EPIC-NOLA (M = 13.3, SD = 11.17) had shorter DUP compared to patients referred after two or more HSEs (M = 29.7, SD = 36. 7), t (38.6) = 2.31, p = .026, 95%CI = 2.0-30.7. One chi-square test revealed a significantly greater proportion of patients referred after one HSE stayed in treatment for 12 months or more. Cluster analysis and independent t-test analyses revealed that patients with hospital pathways (M = 35.00, SD = 39.36) had significantly longer DUP compared to those with self, other and hospital (M = 15.21, SD = 19.07) care pathways. This study supports existing literature that suggest early FEP treatment leads to shortened DUP and longer treatment engagement. Additionally, patients with support systems (people or services) assisting them with help-seeking reach EPIC-NOLA faster, have shorter DUP, and have better treatment engagement.

Abnormal B-cell development in TIMP-deficient bone marrow.

Bone marrow (BM) is the primary site of hematopoiesis and is responsible for a lifelong supply of all blood cell lineages. The process of hematopoiesis follows key intrinsic programs that also integrate instructive signals from the BM niche. First identified as an erythropoietin-potentiating factor, the tissue inhibitor of metalloproteinase (TIMP) protein family has expanded to 4 members and has widely come to be viewed as a classical regulator of tissue homeostasis. By virtue of metalloprotease inhibition, TIMPs not only regulate extracellular matrix turnover but also control growth factor bioavailability. The 4 mammalian TIMPs possess overlapping enzyme-inhibition profiles and have never been studied for their cumulative role in hematopoiesis. Here, we show that TIMPs are critical for postnatal B lymphopoiesis in the BM. TIMP-deficient mice have defective B-cell development arising at the pro-B-cell stage. Expression analysis of TIMPless hematopoietic cell subsets pointed to an altered B-cell program in the Lineage-Sca-1+c-Kit+ (LSK) cell fraction. Serial and competitive BM transplants identified a defect in TIMP-deficient hematopoietic stem and progenitor cells for B lymphopoiesis. In parallel, reverse BM transplants uncovered the extrinsic role of stromal TIMPs in pro- and pre-B-cell development. TIMP deficiency disrupted CXCL12 localization to LepR+ cells, and increased soluble CXCL12 within the BM niche. It also compromised the number and morphology of LepR+ cells. These data provide new evidence that TIMPs control the cellular and biochemical makeup of the BM niche and influence the LSK transcriptional program required for optimal B lymphopoiesis.

Comparison of Clinical Outcomes with Initial Norepinephrine or Epinephrine for Hemodynamic Support After Return of Spontaneous Circulation.

BACKGROUND: The optimal vasoactive agent for management of patients with return of spontaneous circulation (ROSC) after cardiac arrest has not yet been identified. The Advanced Cardiac Life Support guidelines recommend initiation of either norepinephrine (NE), epinephrine (EPI), or dopamine (DA) to maintain adequate hemodynamics after ROSC is achieved. The goal of this study is to retrospectively assess the impact of initial vasopressor agent on incidence rate of rearrest, death, or need for additional vasopressor in post-cardiac arrest emergency department (ED) patients. METHODS: A retrospective review of electronic medical records was conducted at a tertiary care, academic medical center over a 32-month period. Inclusion criteria were any patient who received vasopressors in the ED after achieving ROSC from out-of-hospital cardiac arrest, or in ED cardiac arrest. The incidence of the primary outcome was assessed during care within the ED, at 6 h regardless of location (early resuscitation period), and throughout the entire hospitalization. Secondary outcomes included incidence of tachyarrhythmia while on vasopressor, type of additional therapy needed for refractory shock, and functional status at discharge as determined by discharge location (discharged home without assistance, or discharged to long-term care facility, subacute rehabilitation, or assisted living). RESULTS: A total of 93 patients were included for analysis; 45 received NE, 42 EPI, and six DA. Due to small sample size, DA was excluded from reporting post hoc. Significantly more EPI patients met the primary outcome of refractory hypotension, rearrest, or death in the emergency department (EPI 21/42, 50% vs. NE 10/45, 22.2%; P = 0.008). The incidence was no longer significantly different during the early resuscitation period of 6 h (EPI 30/42, 71.4% vs. NE 25/45, 55.6%; P = 0.182), or during the entire hospitalization (EPI 40/42, 95.2% vs. NE 36/45, 80.0%; P = 0.051). Notably, the EPI group had higher rates of rearrest prior to vasopressor initiation, potentially signaling more severe illness despite other prognostic variables being similarly distributed. In an adjusted regression model, which included adjustment for rearrest prior to vasopressor initiation, the odds of reaching the primary outcome in the ED were 3.94 [95%CI 1.38-12.2] (P = 0.013) times higher in the EPI group compared to NE treated patients. No difference in tachyarrhythmia or functional status at discharge was detected between groups. CONCLUSION: These data suggest prospective study of initial vasopressors used for hemodynamic support after ROSC may be warranted. Rates of intra-emergency department refractory shock, rearrest, or death were higher among epinephrine treated patients compared to norepinephrine treated patients in this population. However, inability to control for potential confounding variables in retrospective studies limits the findings. These results are hypothesis generating and further study is warranted.

Establishing the Early Psychosis Intervention Clinic, New Orleans (EPIC-NOLA): Sustainability Challenges Threaten Clinical Success.

This paper describes the implementation of the first coordinated specialty care clinic for first episode psychosis in New Orleans, Louisiana (Early Psychosis Intervention Clinic-New Orleans), a historically underserved area. Successes, lessons, and challenges will be explored in the context of a mission to provide highest quality clinical care in the current insurance reimbursement systems.

Metalloproteases: On the Watch in the Hematopoietic Niche.

Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical features of the niche by altering protease-dependent bioavailability of local niche factors (e.g., CXCL12, SCF, TGFß, VEGF), matrix turnover, and cellular interactions. With over 40 examples of diverse metalloprotease substrates known to trigger fate-changing decisions, the spatially confined activity of this multi-member protease family is ideally positioned to constitute a higher order control over hematopoiesis. Comprehension of regulated proteolysis in the bone marrow may fuel innovative strategies to harness HSC fate and function.

Metalloprotease inhibitor TIMP proteins control FGF-2 bioavailability and regulate skeletal growth.

Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs have growth plate closure in long bones, precipitating limb shortening, epiphyseal distortion, and widespread chondrodysplasia. We identify TIMP/FGF-2/IHH as a novel nexus underlying bone lengthening where TIMPs negatively regulate the release of FGF-2 from chondrocytes to allow IHH expression. Using a knock-in approach that combines MMP-resistant or ADAMTS-resistant aggrecans with TIMP deficiency, we uncouple growth plate activity in axial and appendicular bones. Thus, natural metalloprotease inhibitors are crucial regulators of chondrocyte maturation program, growth plate integrity, and skeletal proportionality. Furthermore, individual and combinatorial TIMP-deficient mice demonstrate the redundancy of metalloprotease inhibitor function in embryonic and postnatal development.

TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass.

Deregulated proteolysis invariably underlies most human diseases including bone pathologies. Metalloproteinases constitute the largest of the five protease families, and the metzincin metalloproteinases are inhibited by the four tissue inhibitors of metalloproteinase called TIMPs. We hypothesized that Timp genes are essential for skeletal homeostasis. We bred individual Timp knockout mice to generate unique mouse models, the quadruple Timp null strain (QT) as well as mice harboring only a single Timp3 allele (QT3+/- ). QT mice are grossly smaller and exhibit a dramatic reduction of trabeculae in long bones by µCT imaging with a corresponding increase in metalloproteinase activity. At the cellular level, Timp deficiency compromised differentiation markers, matrix deposition and mineralization in neonatal osteoblasts from calvariae, as well as the fibroblastic colony-forming unit (CFU-F) capacity of bone marrow-derived stromal cells. In contrast, we observed that osteoclasts were overactive in the Timp null state, consistent with the noted excessive bone resorption of QT bones. Immunohistochemistry (IHC) and immunofluorescence (IF) analyses of bone sections revealed higher Cathepsin K and RANKL signals upon Timp loss. Seeking the molecular mechanism, we identified abnormal TNFα bioactivity to be a central event in Timp-deficient mice. Specifically, TNFα triggered induction of the Wnt signaling inhibitor Dkk1 in the osteoblasts at the mRNA and protein levels, with a simultaneous increase in RANKL. Neutralizing TNFα antibody was capable of rescuing the induction of Dkk1 as well as RANKL. Therefore, the generation of novel Timp-deficient systems allowed us to uncover the essential and collective function of TIMP proteins in mammalian long-bone homeostasis. Moreover, our study discovers a functional TIMP/metalloproteinase-TNFα-Dkk1/RANKL nexus for optimal control of the bone microenvironment, which dictates coexistence of the osteoblast and osteoclast lineages. © 2018 American Society for Bone and Mineral Research.

Timp3 deficient mice show resistance to developing breast cancer.

Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3-/- mice have delayed tumor onset and 36% of MMTV-Neu Timp3-/- mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1.

Psychopharmacological treatment of delirium: does earlier treatment and scheduled dosing improve outcomes?

PURPOSE: The goals of this study were to examine how dosing strategies and timeliness of antipsychotic medication initiation would affect delirium duration. METHODS: This is a retrospective paper and electronic record review of patients in an academic hospital who had been diagnosed with delirium. Forty-two patients met inclusion criteria. Quantitative and qualitative data on the course of delirium was gathered, as well as important demographic and medical variables. RESULTS: There were no significant differences in duration of delirium between the scheduled and PRN groups using survival analysis, although the test was marginally significant (log rank test, p<0.06). Those who received treatment within 24 hours of recognition had significantly shorter durations of delirium compared to those who began treatment after 24 hours (log rank test, p<0.006). CONCLUSION: These data suggest that early psychopharmacological treatment of delirium can reduce duration. Future research needs to investigate prompt and scheduled medication dosing strategies for treatment of delirium symptoms.