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Jessica L Norman, Sarah L Anderson Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA Abstract: Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia. Keywords: insomnia, orexin antagonist, suvorexant

Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1 -wild-type glioblastoma multi-regional samples ( n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4 + T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8 + T cells in the invasive margins but not in the tumour core ( P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas ( P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8 + T-cell infiltration in the leading edge ( P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8 + /CD4 + T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335 + ) correlated with CD8 + T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4 + /CD8 + /programmed death-ligand 1 RNA expression were validated ( P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8 + T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Mild traumatic brain injury (mTBI) poses risk to the neurocognitive, emotional, and financial well-being of affected individuals. While aggression and impulsivity have been examined in relation to mTBI, little work has been done to evaluate the relationship between history of mTBI and personality disorder (PD). The authors examined the associations between history of mTBI and PD in a control group without history of mTBI (N = 1189) and individuals with history of mTBI (N = 267). Results demonstrated that any PD diagnosis is a significant risk factor for mTBI (p < 0.001). Cluster B diagnoses, particularly borderline and antisocial PD, were independently significant risk factors for mTBI. These data suggest a role for screening for a history of mTBI in patients with PDs and associated traits., (© 2022 The Authors Personality and Mental Health Published by John Wiley & Sons Ltd.)

Mitochondrial (mt) DNA can be classified into haplogroups, which represent populations with different geographic origins. Individuals of maternal African backgrounds (L haplogroup) are more prone to develop specific diseases compared those with maternal European-H haplogroups. Using a cybrid model, effects of amyloid-β (Amyβ), sub-lethal ultraviolet (UV) radiation, and 5-Aza-2'-deoxycytidine (5-aza-dC), a methylation inhibitor, were investigated. Amyβ treatment decreased cell metabolism and increased levels of reactive oxygen species in European-H and African-L cybrids, but lower mitochondrial membrane potential (ΔΨM) was found only in African-L cybrids. Sub-lethal UV radiation induced higher expression levels of CFH , EFEMP1 , BBC3 , and BCL2L13 in European-H cybrids compared to African-L cybrids. With respect to epigenetic status, the African-L cybrids had ( a ) 4.7-fold higher total global methylation levels ( p = 0.005); ( b ) lower expression patterns for DNMT3B ; and ( c ) elevated levels for HIST1H3F . The European-H and African-L cybrids showed different transcription levels for CFH , EFEMP1 , CXCL1 , CXCL8 , USP25 , and VEGF after treatment with 5-aza-dC. In conclusion, compared to European-H haplogroup cybrids, the African-L cybrids have different ( i ) responses to exogenous stressors (Amyβ and UV radiation), ( ii ) epigenetic status, and ( iii ) modulation profiles of methylation-mediated downstream complement, inflammation, and angiogenesis genes, commonly associated with various human diseases.

A causal relationship between immune dysregulation and schizophrenia has been supported by genome-wide association studies and epidemiological evidence. It remains unclear to what extent the brain immune environment is implicated in this hypothesis. We investigated the immunophenotype of microglia and the presence of perivascular macrophages and T lymphocytes in post-mortem brain tissue. Dorsal prefrontal cortex of 40 controls (22F:18M) and 37 (10F:27M) schizophrenia cases, of whom 16 had active psychotic symptoms at the time of death, was immunostained for seven markers of microglia (CD16, CD32a, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers for perivascular macrophages (CD163 and CD206) and T-lymphocytes (CD3). Automated quantification was blinded to the case designation and performed separately on the grey and white matter. 3D reconstruction of Iba1-positive microglia was performed in selected cases. An increased cortical expression of microglial Fcγ receptors (CD64 F = 7.92, p = 0.007; CD64/HLA-DR ratio F = 5.02, p = 0.029) highlights the importance of communication between the central and peripheral immune systems in schizophrenia. Patients in whom psychotic symptoms were present at death demonstrated an age-dependent increase of Iba1 and increased CD64/HLA-DR ratios relative to patients without psychotic symptoms. Microglia in schizophrenia demonstrated a primed/reactive morphology. A potential role for T-lymphocytes was observed, but we did not confirm the presence of recruited macrophages in the brains of schizophrenia patients. Taking in account the limitations of a post-mortem study, our findings support the hypothesis of an alteration of the brain immune environment in schizophrenia, with symptomatic state- and age-dependent effects., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: A pharmacist-managed chronic pain clinic (PMCPC) in a primary care setting is described., Summary: As primary care providers (PCPs) may be unprepared or lack time to manage high-risk patients receiving opioids for chronic nonmalignant pain, alternative models of care are needed. The University of Colorado PMCPC is integrated into an internal medicine outpatient clinic. The PMCPC is staffed by 1 clinical pharmacist, with pharmacy students and residents also performing clinic duties. The pharmacy team reviews health records to determine eligibility for PMCPC services and documents referral requests in the electronic health record (EHR); on PCP acceptance of a referral, the pharmacy team assumes primary responsibility for the patient's pain management under a collaborative practice agreement. Using a collaborative drug therapy management (CDTM) protocol, the pharmacy team conducts patient assessments, including an assessment for signs of aberrant drug-taking behaviors; provides initial and ongoing counseling and education; and makes recommendations to the PCP for opioid dosage adjustments and regimen additions and discontinuations. Experience at the clinic to date indicates that the PMCPC model is feasible and accepted by PCPs and patients., Conclusion: A PMCPC based in a primary care setting was established to improve the care of patients with chronic nonmalignant pain who are prescribed opioid therapy for a period of 3 months or longer. Clinic patients are referred to the clinic through the EHR and managed by a pharmacist under a CDTM protocol., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Background: Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women., Objectives: The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem., Methods: Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients' records was also evaluated., Results: A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%-50%, p = 0.23), elderly men (34%-40%, p = 0.53), and elderly women (60%-74%, p = 0.14), but the change was only significant in young women (42%-70%, p = 0.0045)., Conclusion: After Food and Drug Administration-mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In 2009, an intestinal rehabilitation team implemented feeding guidelines for infants following gastrointestinal surgery at our institution. The purpose of this study was to determine the effect of enteral feeding guidelines on the incidence of parenteral nutrition (PN)-associated liver disease (PNALD) in infants with surgically managed necrotizing enterocolitis (NEC)., Methods: This retrospective study included infants treated during 18-month time periods before and after the implementation of feeding guidelines. PNALD diagnosis was based on serum direct bilirubin >2 mg/dL after ≥14 days of PN exposure., Results: Of the 140 infants identified, 64 were surgically managed and included in the analysis. The duration of PN and the time nil per os (NPO) were significantly reduced after guideline implementation from a median of 106 days to 65 days (P = .03) and from 29 days to 16 days (P = .02), respectively. The incidence of PNALD decreased from 73% before guideline implementation to 42% after guideline implementation (P = .01)., Conclusions: Implementation of feeding guidelines resulted in decreased time NPO and duration of PN support. Significantly fewer infants developed PNALD after guideline implementation. These data suggest that feeding guidelines may expedite the transition from PN to enteral nutrition and may improve outcomes.

Angiotensin-converting enzyme inhibitors (ACE-Is) are the primary medication class implicated in drug-associated angioedema. Angioedema is most common early in ACE-I therapy, yet episodes can occur late in therapy and have been reported even as late as 10 years after single treatment initiation. We present a case of a 65-year-old African American woman who experienced 2 episodes of angioedema, with the second being life threatening after receiving several concomitant agents known to cause angioedema, most notably lisinopril for 11 years.

Parenteral nutrition (PN) is commonly used in pediatric institutions in patients who either cannot be fed enterally or are unable to tolerate sufficient enteral calories to provide their nutrition requirements. Many pediatric patients, particularly those with short bowel syndrome or intestinal failure, will eventually require home PN (HPN) therapy. Although discharge to HPN is complex and can be associated with both immediate and long-term complications, it can be successfully achieved through collaboration between healthcare providers within the institution and the home care company and HPN education of the patient and caregivers. This review describes the processes that clinicians and institutions should consider when preparing for HPN discharge and serves as a guide for the effective transition to HPN in pediatric patients.

Boneless pork loins (N=95) divided into three groupings based on National Pork Producers Council color standards were utilized to characterize changes in color and pH throughout the loin. CIE L(∗), CIE a(∗), CIE b(∗), saturation, and hue angle differed (P<0.05) for color category and chop position. A color category by position interaction (P<0.05) existed only for pH values. These differences in color and pH measures throughout the loin indicate that one measurement may not characterize the entire boneless loin. For all color and pH measures significant orthogonal and polynomial contrasts existed, therefore, separate regression equations were developed for each color category to predict position response. Multiple regression equations were significant for most objective measures of color and pH, but the low R(2) values indicate that these models provide little information as to changes in color and pH throughout the boneless pork loin.

Pork loin color categories were established with the intent of demonstrating differences in eating quality between them. Center-cut boneless pork loins (n=64) were divided into three color classifications. Category A included National Pork Producers Council color standards 1 and 2; category B, 3 and 4; and category C, 5 and 6. L* means for categories A, B, and C were 57.00, 50.24, and 45.54, respectively. Warner-Bratzler shear force values were not affected by category (P>0.05), but were negatively correlated with a* and b* values (P<0.05). The "in-home" portion of this study consisted of 47 households that prepared and evaluated chops randomly distributed by category. Consumers reported differences in liking of juiciness and liking of tenderness (P<0.05) due to color category. Eighty-nine percent of the households participated in a simulated retail display where, 20.8% chose chops from category A, 26.4% from category B, and 52.8% from category C. A trained panel evaluated the cooked chops and perceived category C to be more tender, more juicy, and less dry than both A and B (P<0.05). Consumers responded similarly to the trained panel in their perceptions of tenderness and juiciness.

1. In the lateral geniculate nucleus (LGN) of 18 kittens whose ages ranged from 6 to 40 days, 445 cells were studied. 2. LGN cells of kittens younger than 21 days are characterized by very low maintained rates, long latencies to full-field flash, response fatigue, large receptive field, absence of surround responses and surround inhibition, poor responses to fast-moving stimuli, and low-amplitude responses to flashing spots. 3. Cells were characterized as sustained or transient, and on, off, or on-off by their responses to flashing spots of light, and as X-like of Y-like by their responses to contrast reversal. Prior to 21 days, cells are hard to classify as X or Y. 4. A large proportion of cells in kitten LGN have both on- and off-responses to small and center-sized spots of light. This proportion decreases with development. 5. A small number of cells develop mature receptive-field properties very early (14--20 days). These are cells with X-type responses (linear summation) to contrast reversal and tend to have sustained responses to flashing spots. 6. Y-like cells, with nonlinear summation, develop mature receptive-field properties later than 34 days of age and later than all X-cells. 7. We conclude that there are different developmental patterns for cells of the kitten LGN. These different patterns may be important in determining the visual responses of cortical cells and their degree of susceptibility to environmental modification.

The basic indication for Baker tube plication is widespread enteric serosal injury. The prediction of subsequent small bowel obstruction remains difficult. Consequently, the benefits of Baker tube plication cannot be clearly defined. A therapeutic decision must be made by weighing the known facts. In this series of 160 Baker tube plications, the incidence of tube complications was 7 percent. Witzel tunnel construction of the jejunostomy was judged important in reducing the complications of this procedure. The incidence of recurrent obstruction was 9 percent with an average follow-up period of 3.9 years.

Visual receptive fields of 42 LGN cells from normal cats and 110 cells from striped cylinder-reared kittens were studied with the aid of a computer controlled optical system. In the normal cats, ten of the 42 cells were weakly biased for orientation of the visual stimulus when tested with bars swept through the receptive field. Of those ten, eight were classified as transient. The orientation preferences of the ten biased units appeared randomly distributed around the clock. Of the LGN cells from the cylinder-reared group, about half of the transient cells had weak biases for orientation; only 7% of the sustained cells had biases. The orientation preferences of the biased LGN cells in the stripe-reared animals were either parallel to or orthogonal to the stripes each animal saw during its time in the conditioning cylinder. In 16 out of 18 of the biased LGN cells it was found that increasing the velocity of the test target reduced or eliminated the bias apparent at the lower velocity. For some LGN cells special techniques, such as inhibition of activated discharge, were needed to reveal orientation biases. The results described here, considered with data from others, suggest a role for the corticofugal projection in modulating the responses of some LGN cells.

Lateral geniculate nucleus cells of the kitten were classified as X-cells or Y-cells with a contrast reversal test and their latencies to optic chiasm shock were measured. X-cells with mature latencies were found as early as 21 days. Y-cells did not have adult latencies at 40 days. The early development of some X-cells may be due to differential rates of fiber myelination and synaptic maturation within the lateral geniculate nucleus.