Search

• Post-COVID-19 restrictions, driving days per week decreased 37 % among adolescents. • Vehicle miles driven in past two weeks decreased 35 % among adolescents. • Decrease was lower among ethnic minorities, older and employed adolescents. • Those with greater dire prosocial tendencies showed greater driving decline. Understanding who heeds the driving-related COVID-19 restrictions is critical for assisting public health professionals improve response to this and future pandemic events. The purpose of the current study was to characterize driving behavior changes among adolescents as a function of COVID-19 restrictions. It was hypothesized that adolescent driving would be reduced by COVID-19 restrictions, especially for younger teens, non-minorities, females, non-working teens, and those with higher prosocial tendencies. Participants were licensed drivers in "REACT," a longitudinal study of adolescent driving attention. Upon enrollment in REACT, drivers were required to be age 16 or 18, have been issued a driver's license within the last two weeks, and be fluent in written/spoken English. The current observational cohort study was of drivers reporting driving exposure between February 8 and April 22, 2020. Linear mixed-effects models estimated differences in driving changes between COVID-19 periods. Results indicated a decrease across pre-COVID-19 period (February 8 – March 13, 2020) in days driven per week and vehicle miles driven (VMD) was explained by the change of slope post-COVID-19 restrictions (March 14 – April 22, 2020). Post-COVID-19, driving days per week decreased by 37 % and VMD decreased by 35 %. This decrease was lower in ethnic minorities, older adolescents, and employed adolescents. Those with greater dire prosocial tendencies showed greater post-COVID-19 driving decline. Findings provide early evidence of COVID-19 restriction-related adolescent driving changes suggesting older, employed, minority teens and teens with lower prosocial tendencies are less likely to reduce driving behavior. These observations provide a foundation for more extensive studies of adolescent drivers during various driving and contact restrictions and inform future public health campaigns for social distancing. [ABSTRACT FROM AUTHOR]

Pain Coping Skills Training (PCST) is a first-line cognitive-behavioral, non-pharmacological treatment for chronic pain and comorbid symptoms. PCST has been shown to be effective in racially and ethnically diverse cohorts across several chronic medical conditions. However, PCST has not been evaluated in those with end stage kidney disease (ESKD) receiving in-center maintenance hemodialysis. Due to the high rates of morbidity associated with ESKD, and time-intensive treatment, an adaptation of PCST was warranted to address the unique challenges experienced by people living with ESKD. Using current guidelines developed by Card and colleagues for intervention adaptation, PCST was adapted so that it could be implemented among people living with ESKD in a national multisite trial. The objective of this paper was to describe the adaption process outlined by Card and colleagues including how the team selected an effective intervention to adapt, developed a program model, identified mismatches in the original intervention and study population, and then adapted the intervention for those with ESKD treated with in-center maintenance hemodialysis. Finally, we briefly describe future directions for clinical practice and research with the adapted PCST intervention for those with ESKD.Trial registration: ClinicalTrials.gov #NCT04571619., Competing Interests: Declarations. Conflict of interest: No conflict of interest was reported by the authors of this paper. Human and animal rights and informed consent: No humans or animals were used to write this paper - no data presented, (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: S.C. is supported by the Australian National Health and Medical Research Council Emerging Leadership Scholarship and the Royal Australasian College of Physicians Research Establishment Fellowship. C.H. is the recipient of research grants paid to her institution from Baxter Health and Fresenius Medical Care and from Otsuka, Janssen, and GlaxoSmithKline for trial steering committee activities, paid to her institution. D.J. has received consultancy fees, research grants, speaker’s honoraria, and travel sponsorships from Baxter Health and Fresenius Medical Care. He has received consultancy fees from AstraZeneca, Bayer, and AWAK; speaker’s honoraria from Ono and BI and Lilly; and travel sponsorships from Amgen. He is a current recipient of an Australian National Health and Medical Research Council (NHMRC) Leadership Investigator Grant. A.J. is supported by the NHMRC Research Fellowship. A.V. receives grant support from the Royal Australasian College of Physicians (Jacquot Research Establishment Award) and the Princess Alexandra Research Foundation. D.C.B. receives institutional research grant funding from CareDx and is a consultant for CareDx, Medeor, Sanofi, and Vera Therapeutics and is supported by National Institute of Diabetes and Digestive and Kidney Diseases U01 DK116042, U01AI063594, and R44DK123978. E.B. receives research support from Merck, Takeda and Hologix, and DSMB for Amplyx and is an unpaid consultant for Merck and Takeda. Y.C. has received research grants and speaker’s honoraria from Baxter Health and Fresenius Medical Care and is a current recipient of an Australian NHMRC Emerging Leadership Investigator Grant and Queensland Health Advancing Care Fellowship (mid-career). The other authors declare no conflicts of interest.

The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained, for the primary analysis, at 12 weeks. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619., Competing Interests: Declaration of Competing Interest L.M. Dember receives compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases, consulting fees from AstraZeneca, Cara Therapeutics, and Merck, and compensation for serving on Data and Safety Monitoring Boards for the National Institute of Diabetes and Digestive and Kidney Diseases, CSL Behring, and Vertex Pharmaceuticals. D.M. Charytan reports consulting fees from Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Allena Pharmaceuticals (DSMB), Fresenius, Gilead, Novo Nordisk, GSK, Medtronic, Merck, Amgen, CSL Behring, Zogenix, and Renalytix; research funding from Medtronic, clinical trial support from Gilead, NovoNordisk, Amgen, and Boehringer Ingelheim; royalties from UpToDate.com for authorship or editorial activities; and expert witness fees related to proton pump inhibitors. D. Esserman serves on data monitoring boards for Ablative Solutions and PhaseBio. M. Jhamb reports research funding from Bayer LLC, Dialysis Clinic Inc. and Pfizer, and advisory board fees from Xcenda LLC, Boehringer Ingelheim, Lilly, and CKD Networks of Excellence. S. Joffe reports compensation for service on a Data and Safety Monitoring Board for CSL Behring. K.L. Johansen reports consultancy for GlaxoSmithKline, Akebia, and Vifor; advisory or leadership role for GSK; and role as an Associate Editor of Journal of the American Society of Nephrology. S. Kalim reports receiving speaking fees and consulting fees from Fresenius Kabi. P.L. Kimmel reports compensation from Elsevier for his roles as Co-Editor of Chronic Renal Disease, and Co-Editor of Psychosocial Aspects of Chronic Kidney Disease. E.J. Krebs receives research funding from the US Department of Veterans Affairs (VA), National Institutes of Health (NIH), and the Patient Centered Outcomes Research Institute (PCORI), has received support (paid to her institution) from Origin Editorial for serving as Associate Editor for PCORI research reports, travel expense reimbursement from the American College of Physicians, and has provided unpaid expert service as a member of the Foundation for Opioid Response Efforts Scientific Advisory Council, temporary member (ad hoc) for the Food and Drug Administration (FDA) Drug Safety and Risk Management Advisory Committee, panel member for FDA Public Workshop on Reconsidering Mandatory Opioid Prescriber Education, member of Society of General Internal Medicine (SGIM) program and award committees, and chair or member of data safety monitoring boards for VA, NIH, and PCORI studies. R. Mehrotra serves as the Editor-in-Chief of the Clinical Journal of the American Society of Nephrology. J.L. Steel reports compensation for serving on a Data and Safety Monitoring Board for the National Institute of Diabetes and Digestive and Kidney Diseases and for her role as an editor for the Journal of Gastrointestinal Cancers, and royalties from Springer. L. Bernardo, K.L. Cavanaugh, S.T. Crowley, D. Cukor A.Z. Doorenbos, D.A. Edwards, M.J. Fischer, N. Kuzla, P. Mishra, B. Pellegrino, D.M. White, and J.G. Yabes have no disclosures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials., Methods: In an international online survey, participants rated the absolute importance of 16 infections and eight severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated., Results: 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, eight who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5, respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1), and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top three most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top three severity dimensions. Relative importance (best-worst) scores were consistent., Conclusions: Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections, and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recent innovations have the potential to disrupt the current paradigm for kidney failure treatment. The US Food and Drug Administration is committed to incorporating valid scientific evidence about how patients weigh the benefits and risks of new devices into their decision making, but to date, premarket submission of patient preference information (PPI) has been limited for kidney devices. With input from stakeholders, we developed a survey intended to yield valid PPI, capturing how patients trade off the potential benefits and risks of wearable dialysis devices and in-center hemodialysis., Methods: We conducted concept elicitation interviews with individuals receiving dialysis to inform instrument content. After instrument drafting, we conducted two rounds of pretest interviews to evaluate survey face validity, comprehensibility, and perceived relevance. We pilot tested the survey with in-center hemodialysis patients to assess comprehensibility and usability further. Throughout, we used participant input to guide survey refinements., Results: Thirty-six individuals receiving in-center or home dialysis participated in concept elicitation ( N =20) and pretest ( N =16) interviews. Participants identified reduced fatigue, lower treatment burden, and enhanced freedom as important benefits of a wearable device, and many expressed concerns about risks related to device disconnection-specifically bleeding and infection. We drafted a survey that included descriptions of the risks of serious bleeding and serious infection and an assessment of respondent willingness to wait for a safer device. Input from pretest interviewees led to various instrument modifications, including treatment descriptions, item wording, and risk-level explanations. Pilot testing of the updated survey among 24 in-center hemodialysis patients demonstrated acceptable survey comprehensibility and usability, although 50% of patients required some assistance., Conclusions: The final survey is a 54-item web-based instrument that will yield estimates of the maximal acceptable risk for the described wearable device and willingness to wait for wearable devices with lower risk., Competing Interests: K.L. Cavanaugh reports consultancy for the Kidney Health Initiative, REATA Pharmaceuticals, and Responsum Health; ownership interest in HCA Healthcare; and an advisory or leadership role for the National Kidney Foundation (KDQOI education committee), Clinical Journal of American Society of Nephrology (editorial board), American Journal of Kidney Diseases (editorial board), Kidney360 (associate editor), and Medical Decision Making (editorial board). J.E. Flythe reports consultancy for AstraZeneca and Fresenius Medical Care Medical Advisory Board; research funding from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Patient-Centered Outcomes Research Institute, Renal Research Institute (subsidiary of Fresenius Medical Care, North America), and Robert Wood Johnson Foundation; honoraria from the American Society of Nephrology, National Kidney Foundation, and numerous universities; and an advisory or leadership role for the American Journal of Kidney Diseases (editorial board 2017–2021), Clinical Journal of American Society of Nephrology (editorial board 2017–), Hemodialysis (theme editor 2018–), KDIGO Executive Committee (2020–), Kidney Health Initiative (board of directors 2019–), Kidney Health Initiative (Patient Preferences Project chairperson 2019–), Kidney Medicine (editorial board 2019–), Kidney360 (associate editor 2019–), and Nephrology Dialysis and Transplantation (editorial board). D. Forfang reports employment by the American Society of Nephrology Kidney Health Initiative; consultancy for Ardelyx, Inc., Scientific Advisory Board, the American Society of Nephrology and Responsum, CareDX, HSAG, and University of North Carolina Kidney Center; honoraria from the American Society of Nephrology, European Association for Dialysis, HSAG ESRD Network #17, National Kidney Foundation; an advisory or leadership role for Arbor Research, HSAG ESRD Network #17 (board member), Kidney Health Initiative (Patient Advisory Committee), National Forum of ESRD Networks (board member), National Forum of ESRD Networks Kidney Patient Advisory Council (chair); National Kidney Foundation, SONG Group, and Unity Health Toronto OPPUS, UCSF Kidney Project (patient advisor); and other interests or relationships as a volunteer for the Forum of ESRD Networks as Kidney Patient Advisory Council chair and board member, a volunteer for ESRD Network #17 as Patient Advisory Committee Chair and Network board member, a volunteer for the National Kidney Foundation as a member of their Public Policy Committee, and a volunteer for the National Kidney Foundation as a Regional Leader of their Kidney Advocacy Committee, Kidney Health Initiative PFPC member. N. Gedney reports honoraria from the American Society of Nephrology, IDEAs, and the University of Washington. R.C. Harris reports consultancy for Bayer, Fibrocor, and Nicoya; ownership interest in Apple; research funding from Bayer; patents or royalties from eNOS db/db mouse; an advisory or leadership role for the Kidney Health Initiative (paid); and other interests or relationships with the Kidney Health Initiative (co-chair, board of directors). F.P. Hurst reports employment by the Food and Drug Administration/Center for Drug Evaluation and Research, and other interests or relationships with a US government employee. C. Mansfield reports the employment by RTI Health Solutions, which receives funding from for-profit pharmaceutical companies to conduct research. C.Y. Neuland reports being a member of the board of directors for the Kidney Health Initiative, representing the Food and Drug Administration/Center for Devices and Radiological Health during this time period. A. Saha reports employment by the Food and Drug Administration. C.S. Soloe reports employment by RTI International. G. Squillaci reports consultancy for The Griff Group. M.E. Tarver reports employment by the Food and Drug Administration/Center for Devices and Radiological Health. K. Treiman reports employment by RTI International. M.L. Unruh reports consultancy for Cara Therapeutics to chair of Data Monitoring Committee; a consulting agreement between Cara and the University of New Mexico; research funding from DCI; and honoraria related to lectures from the American Society of Nephrology, National Kidney Foundation, and Renal Research Institute. M. West reports employment by the American Society of Nephrology. D.M. White reports employment by Debevoise & Plimpton; consultancy for the Kidney Transplant Collaborative, the National Committee for Quality Assurance, and Responsum Health; ownership interest in Amgen, Inc.; honoraria from AstraZeneca, Hennepin Healthcare, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, New York Academy of Medicine, and PFCC partners; and other interests or relationships with the American Association of Kidney Patients, American Society of Transplantation, Kidney Health Initiative, National Kidney Foundation, National Patient Advocate Foundation, Patient Advocate Foundation, and Quality Insights. C. Wilkie reports employment by Kuhns Law Firm, PLLC; consultancy for the University of North Carolina, University of Pennsylvania, and University of Pittsburg; ownership interest in Kuhns Law Firm, PLLC; an advisory or leadership role for the Kidney Health Initiative, University of Pennsylvania with the HOPE Consortium, and University of Pittsburgh; and other interests or relationships with the Kidney Health Initiative, National Kidney Foundation, University of Pennsylvania with the HOPE Consortium, University of North Carolina at Chapel Hill, and University of Pittsburgh. D. Wood reports employment by RTI International. The remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background: Infection remains a leading cause of death in kidney transplant recipients. This study aimed to assess the scope and consistency of infection outcomes reported in contemporary trials conducted in kidney transplant recipients., Methods: A literature review of all randomized trials and trial protocols reporting infection outcomes in adult kidney transplant recipients was identified in the Cochrane Kidney and Transplant Specialized Register from January 2014 to July 2019. Characteristics and infection outcomes from the trials were analyzed., Results: From 102 included trials, 772 outcome measures were extracted and categorized into 216 unique measures with a median of 3.2 outcome measures per trial (range: 1-9). Measures were further grouped into 32 outcomes based on site of infection (14 outcomes) and organism (18 outcomes). The most commonly reported site-specific outcome and organism-specific outcome were systemic infection (71% trials) and cytomegalovirus infection (62% trials), respectively. Outcome metric and methods of aggregation included mean, median, proportion, proportional change, and number of patients with at least 1 episode. Across all trials, measures were assessed at 55 different time points with a range of 1-11 time points per trial., Conclusions: Infection outcomes in kidney transplant recipients were frequently reported by site and organism but varied widely in terms of outcome, metrics, method of aggregation, and time point of measurement. Establishment of core outcomes for infection based on the shared priorities of patients/caregivers and health professionals may improve the consistency, comparability, and usefulness of trial evidence., Competing Interests: S.C. is supported by the Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship, the Microba recipient grant, the Metro South Research Support Scheme, and the Royal Australasian College of Physicians (RACP) Jacquot NHMRC Research Excellence top-up award. E.A. is supported by a NHMRC Postgraduate Scholarship and RACP Jacquot NHMRC Award for Excellence. C.M.H. is the recipient of research grants paid to her institution from Baxter Healthcare and Fresenius Medical Care and from Otsuka, Janssen, and GlaxoSmithKline for trial steering committee activities, paid to her institution. D.W.J. has received consultancy fees, research grants, speaker’s honoraria, and travel sponsorships from Baxter Healthcare and Fresenius Medical Care. He has received consultancy fees from Astra Zeneca and AWAK, speaker’s honoraria from Ono, and travel sponsorships from Amgen. He is a current recipient of an Australian NHMRC Practitioner Fellowship. N.M.I. has received consultancy fees and speakers honoraria from Alexion Pharmaceuticals, Novo Nordisk, and Amgen. A.T. is supported by the NHMRC Research Fellowship. A.K.V. receives grant support from the Royal Australasian College of Physicians (Jacquot Research Establishment Award) and the Princess Alexandra Research Foundation. D.B. receives institutional research grant funding from CareDx, speaking honoraria from CareDx and Veloxis and is a consultant for AlloVir, Amplyx, Argenyx, CareDx, Medeor, Natera, Sanofi, and Veloxis. D.B. is supported by NIDDK U01 DK116042-01 and R01DK102981. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: The language used to communicate important aspects of kidney health is inconsistent and may be conceptualized differently by patients and health professionals. These problems may impair the quality of communication, care, and patient outcomes. We aimed to describe the perspectives of patients on terms used to describe kidney health., Design, Setting, Participants, & Measurements: Patients with CKD ( n =54) and caregivers ( n =13) from the United States, United Kingdom, and Australia participated in ten focus groups to discuss terms for kidney health (including kidney, renal, CKD, ESKD, kidney failure, and descriptors for kidney function). We analyzed the data using thematic analysis., Results: We identified four themes: provoking and exacerbating undue trauma (fear of the unknown, denoting impending death, despair in having incurable or untreatable disease, premature labeling and assumptions, judgment, stigma, and failure of self); frustrated by ambiguity (confused by medicalized language, lacking personal relevance, baffled by imprecision in meaning, and/or opposed to obsolete terms); making sense of the prognostic enigma (conceptualizing level of kidney function, correlating with symptoms and effect on life, predicting progression, and need for intervention); and mobilizing self-management (confronting reality, enabling planning and preparation, taking ownership for change, learning medical terms for self-advocacy, and educating others)., Conclusions: The obscurity and imprecision of terms in CKD can be unduly distressing and traumatizing for patients, which can impair decision making and self-management. Consistent and meaningful patient-centered terminology may improve patient autonomy, satisfaction, and outcomes., (Copyright © 2020 by the American Society of Nephrology.)

Background: Cortical thickness (CT) and gyrification are complementary indices that assess different aspects of gray matter structural integrity. Both neurodevelopment insults and acute tissue response to antipsychotic medication could underlie the known heterogeneity of treatment response and are well-suited for interrogation into the relationship between gray matter morphometry and clinical outcomes in schizophrenia (SZ)., Methods: Using a prospective design, we enrolled 34 unmedicated patients with SZ and 23 healthy controls. Patients were scanned at baseline and after a 6-week trial with risperidone. CT and local gyrification index (LGI) values were quantified from structural MRI scans using FreeSurfer 5.3., Results: We found reduced CT and LGI in patients compared to controls. Vertex-wise analyses demonstrated that hypogyrification was most prominent in the inferior frontal cortex, temporal cortex, insula, pre/postcentral gyri, temporoparietal junction, and the supramarginal gyrus. Baseline CT was predictive of subsequent response to antipsychotic treatment, and increase in CT after 6 weeks was correlated with greater symptom reductions., Conclusions: In summary, we report evidence of reduced CT and LGI in unmedicated patients compared to controls, suggesting involvement of different aspects of gray matter morphometry in the pathophysiology of SZ. Importantly, we found that lower CT at baseline and greater increase of CT following 6 weeks of treatment with risperidone were associated with better clinical response. Our results suggest that cortical thinning may normalize as a result of a good response to antipsychotic medication, possibly by alleviating potential neurotoxic processes underlying gray matter deterioration.

Background: In the perioperative context, benzodiazepines are widely used as anxiolytics. They affect cognition in general, but it is unclear whether the effects of a small dose of the short-acting benzodiazepine midazolam can be assessed objectively. To address this scientific question, we conducted a prospective observational study in adults 55-73 years of age. Using both validated psychometric and functional imaging techniques, we determined whether a 2-mg intravenous (IV) dose of midazolam affects cognitive function., Methods: We measured the effect of 2 mg IV of midazolam with both the well-established Repeatable Battery for the Assessment of Neuropsychological Status test and resting-state functional magnetic imaging (rs-fMRI) in older adults., Results: Midazolam reduces immediate and delayed memory and has a profound and robust effect on rs-fMRI. Baseline resting-state connectivity predicts memory decline after midazolam administration., Conclusions: Observed effects of midazolam on brain networks were statistically significant even in a small group of volunteers. If validated by other investigators, resting-state brain connectivity may have utility as a measure to predict sensitivity to midazolam in older adults.

Magnetic Resonance Spectroscopy is a popular approach to probe brain chemistry in schizophrenia (SZ), but no consensus exists as to the extent of alterations. This may be attributable to differential effects of populations studied, brain regions examined, or antipsychotic medication effects. Here, we measured neurometabolites in the anterior cingulate cortex (ACC) and hippocampus, two structurally dissimilar brain regions implicated in the SZ pathophysiology. We enrolled 61 SZ with the goal to scan them before and after six weeks of treatment with risperidone. We also scanned 31 matched healthy controls twice, six weeks apart. Using mixed effect repeated measures linear models to examine the effect of group and time on metabolite levels in each voxel, we report an increase in hippocampal glutamate + glutamine (Glx) in SZ compared to controls (p = 0.043), but no effect of antipsychotic medication (p = 0.330). In the ACC, we did not find metabolite alterations or antipsychotic medication related changes after six weeks of treatment with risperidone. The coefficients for the discriminant function (differentiating SZ from HC) in the ACC were greatest for NAA (-0.83), and in the hippocampus for Glx (0.76), the same metabolites were associated with greater treatment response in patients at trend level. Taken together, our data extends the existing literature by demonstrating regionally distinct metabolite alterations in the same patient group and suggests that antipsychotic medications may have limited effects on metabolite levels in these regions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To better understand cognitive control impairment in schizophrenia, it is vital to determine the extent of dysfunctional connectivity in the associated fronto-striatal brain network, with a focus on the connections with the anterior cingulate cortex (ACC), prior to the potential confounding effect of medication. It is also essential to determine the effects following antipsychotic medication and the relationship of those effects on psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 matched healthy controls (HC) performed a fMRI task twice, six weeks apart. We investigated group and longitudinal differences in ACC-related functional connectivity during performance of a Stroop color task as well as connectivity patterns associated with improvement in psychosis symptoms. Unmedicated patients with schizophrenia showed greater functional connectivity between ACC and bilateral caudate and midbrain and lower connectivity with left putamen compared to healthy controls. At baseline, greater functional connectivity between ACC and bilateral putamen predicted subsequent better treatment response. Change in functional connectivity between ACC and left putamen positively correlated with better treatment response. These results suggest that patterns of functional connectivity in fronto-striatal networks can be utilized to predict potential response to antipsychotic medication. Prior to treatment, brain function may be structured with a predisposition that favors or not treatment response., (Copyright © 2018. Published by Elsevier B.V.)

Background: Schizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used magnetic resonance spectroscopy and functional magnetic resonance imaging at 7T to investigate how measurements of glutamate and gamma-aminobutyric acid (GABA) relate to the blood oxygen level-dependent (BOLD) response during a cognitive task, and how these relationships are altered in schizophrenia., Methods: Usable functional magnetic resonance imaging data from 17 first-episode psychosis (FEP) patients (4 women, 13 men) and 21 matched healthy control subjects (HCs) (5 women, 16 men) were acquired during a Stroop task. Within- and between-group comparisons of the BOLD response were performed. Neurometabolite levels were measured in the dorsal anterior cingulate cortex. Two multiple regressions investigated how glutamate, glutamine, and GABA related to the BOLD response in HCs and FEP patients separately. A third investigated between-group differences in the relationships between the BOLD response and each of these neurometabolites., Results: Compared with HCs, FEP patients showed an increased BOLD response within regions of the executive and default mode networks. In FEP patients, the relationship between anterior cingulate cortex glutamate levels and the BOLD response in regions of the posterior default mode network was opposite to that of HCs. In FEP patients but not HCs, anterior cingulate cortex GABA levels correlated with the local BOLD response and with the Stroop reaction time., Conclusion: These results suggest a mechanism whereby alterations in the relationship between cortical glutamate/GABA and BOLD response is disrupting the dynamic of major neural networks, possibly affecting cognition., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Schizophrenia (SZ) is a d isease characterized by brain dysconnectivity and abnormal brain development. The study of cortical gyrification in schizophrenia may capture underlying alterations reflective of neurodevelopmental abnormalities more accurately than other imaging modalities. Graph-based connectomic approaches have been previously used in schizophrenia to study structural and functional brain covariance using a diversity of techniques. The goal of the present study was to evaluate morphological covariance using a measure of local gyrification index in patients with schizophrenia. The aims of this study were two-fold: (1) Evaluate the structural covariance of local gyrification index using graph theory measures of integration and segregation in unmedicated patients with schizophrenia compared to healthy controls and (2) investigate changes in these measures following a short antipsychotic drug (APD) treatment. Using a longitudinal prospective design, structural scans were obtained prior to treatment in 34 unmedicated patients with SZ and after 6 weeks of treatment with risperidone. To control for the effect of time, 23 matched healthy controls (HC) were also scanned twice, 6 weeks apart. The cortical surface of each structural image was reconstructed and local gyrification index values were computed using FreeSurfer. Local gyrification index values where then parcellated into atlas based regions and entered into a 68 × 68 correlation matrix to construct local gyrification index connectomes for each group at each time point. Longitudinal comparisons showed significant group by time interactions for measures of segregation (clustering, local efficiency) and modularity, but not for measures of integration (path length, global efficiency). Post-hoc tests showed increased clustering, local efficiency, and modularity connectomes in unmedicated patients with SZ at baseline compared to HC. Post-hoc tests did not show significant within group differences for HCs or patients with SZ. After 6 weeks of treatment, there were no significant differences between the groups on these measures. Abnormal cortical topography is detected in schizophrenia and is modified by short term APD treatment reflective of decreases in hyper-specialization in network connectivity. We speculate that changes in the structural organization of the brain is achieved through the neuroplastic effects that APDs have on brain tissue, thus promoting more efficient brain connections and, possibly, a therapeutic effect.

Schizophrenia is a chronic, often progressive, disorder. Understanding the underlying neurobiology present in the early stages of the illness is as a pivotal step in designing targeted interventions aimed at arresting disease progression. The aim of our study was to examine neurometabolic changes in the dopamine rich associative striatum in medication-naïve first episode psychosis (FEP). We quantified neurometabolites in 14 FEP and 18 healthy controls (HC) matched on key demographic characteristics. Spectra from the voxel in the left associative striatum were acquired using a PRESS sequence (TR/TE = 2000/80 ms; 512 averages). MRS data were quantified in the time domain with AMARES in jMRUI. Choline was significantly elevated in FEP compared to HC. No significant alterations in other metabolites were observed. We did not observe correlations between metabolite levels and clinical characteristics in FEP. Here, we demonstrated elevated choline and a disruption of the relationship between N-acetyl-aspartate and Glx (glutamate + glutamine) in medication-naïve FEP patients in the left striatum indicating possible mitochondrial, membrane and glial dysfunction as an underlying pathological phenomenon. In addition, striatal choline shows promise as a biomarker for FEP that may have utility in clinical trials investigating target engagement in experimental regimens., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To understand the mechanism of cognitive control dysfunction in schizophrenia, it is critical to characterize brain function without the confounding effect of medication. It is also important to establish the extent to which antipsychotic medication restores brain function and whether those changes are related to psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 healthy controls (HC) studied twice, 6 weeks apart, performed an fMRI task. We examined group and longitudinal differences in anterior cingulate cortex (ACC), striatum, and midbrain functional activity during performance of a Stroop color task as well as activity patterns associated with improvement in psychosis symptoms. Unmedicated patients showed reduced functional activity in the ACC, striatum, and midbrain compared to HC. Post hoc contrasts from significant group-by-time interactions indicated that, in patients, drug administration was associated with both activity increases and decreases. In unmedicated patients, greater baseline functional activity in the striatum and midbrain predicted subsequent better treatment response. Greater changes in functional activity in ACC and ventral putamen over the course of 6 weeks positively correlated with better treatment response. Unmedicated patients show reduced activity in brain networks pivotal for cognitive control and medication is associated with functional changes in these regions. These results suggest a mechanism by which antipsychotic medication has a beneficial effect on cognition. Our results also support the notion that treatment response is determined by a combination of the baseline pattern of brain function and by the pharmacological modulation of these regions.

Neuroimaging studies have uncovered structural and functional alterations in the cingulate cortex in individuals with autism spectrum disorders (ASD). Such abnormalities may underlie neurochemical imbalance. In order to characterize the neurochemical profile, the current study examined the concentration of brain metabolites in dorsal ACC (dACC) and posterior cingulate cortex (PCC) in high-functioning adults with ASD. Twenty high-functioning adults with ASD and 20 age-and-IQ-matched typically developing (TD) peers participated in this Proton magnetic resonance spectroscopy (1H-MRS) study. LCModel was used in analyzing the spectra to measure the levels of N-Acetyl aspartate (NAA), choline (Cho), creatine (Cr), and glutamate/glutamine (Glx) in dACC and PCC. Groups were compared using means for the ratio of each metabolite to their respective Cr levels as well as on absolute internal-water-referenced measures of each metabolite. There was a significant increase in Cho in PCC for ASD adults, with a marginal increase in dACC. A reduction in NAA/Cr in dACC was found in ASD participants, compared to their TD peers. No significant differences in Glx/Cr or Cho/Cr were found in dACC. There were no statistically significant group differences in the absolute concentration of NAA, Cr, Glx, or NAA/Cr, Cho/Cr, and Glx/Cr in the PCC. Differences in the metabolic properties of dACC compared to PCC were also found. Results of this study provide evidence for possible cellular and metabolic differences in the dACC and PCC in adults with ASD. This may suggest neuronal dysfunction in these regions and may contribute to the neuropathology of ASD. Autism Res 2016, 9: 643-657. © 2015 International Society for Autism Research, Wiley Periodicals, Inc., (© 2015 International Society for Autism Research, Wiley Periodicals, Inc.)

Diffusion tensor imaging (DTI) studies in schizophrenia consistently show global reductions in fractional anisotropy (FA), a putative marker of white matter integrity. The cingulum bundle, which facilitates communication between the anterior cingulate cortex (ACC) and hippocampus, is frequently implicated in schizophrenia. Magnetic resonance spectroscopy (MRS) studies report metabolic abnormalities in the ACC and hippocampus of patients. Combining DTI and MRS offers exploration of the relationship between cortical neuronal biochemistry and the integrity of white matter tracts connecting specific cortical regions; however, few studies have attempted this in schizophrenia. Twenty-nine schizophrenia patients and twenty controls participated in this 3 T imaging study in which we used DTI and tract-based spatial statistics (TBSS) to assess white matter integrity and MRS to quantify metabolites in the ACC and hippocampus. We found FA reductions with overlapping radial diffusivity (RD) elevations in patients in multiple tracts, suggesting white matter abnormalities in schizophrenia are driven by loss of myelin integrity. In controls, we found significant negative correlations between hippocampal N-acetylaspartate/creatine and RD and axial diffusivity (AD) as well as a significant negative correlation between FA and ACC glutamate+glutamine/creatine in the hippocampal part of the cingulum bundle. It is possible that the extent of myelin damage could have resulted in the absence of DTI-MRS correlations in our patient group. In conclusion, we demonstrate the potential utility of a multi-modal neuroimaging approach to help further our understanding of the relationship between white matter microstructure and neurochemistry in distinct cortical regions connected by white matter tracts., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto-temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication., Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1-week of antipsychotic treatment., Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto-temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1-week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions., Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto-temporal dysconnectivity. Patterns of fronto-temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits., (© 2014 Wiley Periodicals, Inc.)

We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of 6 weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness., (© 2013 Published by Elsevier Ireland Ltd.)

Importance: Alterations in glutamatergic neurotransmission have been postulated to be a key pathophysiologic mechanism in schizophrenia., Objective: To evaluate hippocampal volumetric measures and neurometabolites in unmedicated patients with schizophrenia and the correlations between these markers. Our a priori hypothesis was that glutamate levels would negatively correlate with hippocampal volume in schizophrenia., Design, Setting, and Participants: Combined 3-T structural magnetic resonance imaging and single-voxel proton magnetic resonance spectroscopy study at the Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, of 27 unmedicated patients with schizophrenia and 27 healthy controls., Main Outcomes and Measures: Hippocampal volumetric measures and neurometabolites, and the correlations between volumetric measurements and neurometabolites., Results: Hippocampal volumetric deficits, increased ratios of hippocampal glutamate and glutamine to creatine (Glx/Cr), and a loss of correlation between hippocampal N-acetylaspartate (NAA)/Cr and Glx/Cr in patients with schizophrenia were found. Significant correlations between hippocampal volumetric measures and Glx/Cr were also found in patients with schizophrenia but not healthy controls., Conclusions and Relevance: Our findings support the theory that alterations in hippocampal glutamate levels potentially account for structural deficits in the hippocampus observed in schizophrenia neuroimaging studies.

Background: Converging evidence in schizophrenia points to disruption of the dopamine and glutamate neurotransmitter systems in the pathophysiology of the disorder. Dopamine is produced in the substantia nigra, but few neuroimaging studies have specifically targeted this structure. In fact, no studies of the substantia nigra in schizophrenia have used proton magnetic resonance spectroscopy (MRS). We sought to demonstrate the feasibility of acquiring single-voxel MRS measurements at 3T from the substantia nigra and to determine which metabolites could be reliably quantified in schizophrenia patients and healthy controls., Methods: We used a turbo spin echo sequence with magnetization transfer contrast to visualize the substantia nigra and single-voxel proton MRS to quantify levels of N-acetylaspartate, glutamate and glutamine (Glx), and choline in the left substantia nigra of 35 people with schizophrenia and 22 healthy controls., Results: We obtained spectra from the substantia nigra and quantified neurometabolites in both groups. We found no differences in levels of N-acetylaspartate/creatine, Glx/creatine, or choline/creatine between the groups. We found a significant correlation between Glx/creatine and overall cognitive performance, measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), in controls but not patients, a difference that was statistically significant., Conclusions: Our study demonstrates the feasibility of obtaining single-voxel MRS data from the substantia nigra in schizophrenia. Such measurements may prove useful in understanding the biochemistry underlying cellular function in a region implicated in the pathophysiology of schizophrenia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia., Methods: We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC)., Results: The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr., Conclusions: We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cold pre-conditioning reduces subsequent brain injury in small animals but the underlying mechanisms remain undefined. As hypothermia triggers systemic macrophage tumor necrosis factor alpha (TNF-α) production and other neural pre-conditioning stimuli depend on this cytokine, we reasoned that microglia and TNF-α would be similarly involved with cold pre-conditioning neuroprotection. Also, as slice cultures closely approximate their in vivo counterpart and include quiescent microglia, we used rat hippocampal slice cultures to confirm this hypothesis. Furthermore, inflammatory cytokine gene screening with subsequent PCR and immunostaining confirmation of targeted mRNA and related protein changes showed that cold pre-conditioning triggered a significant rise in TNF-α that localized to microglia and a significant rise in interleukin (IL)-11 that localized mainly to hippocampal pyramidal neurons and, more rarely, astrocytes. Importantly, co-stimulation with cold and IL-11, an anti-inflammatory cytokine that inhibits TNF-α expression, abrogated the otherwise evident protection. Instead, cold pre-conditioning coupled with blockade of IL-11 signaling further enhanced neuroprotection from that seen with cold pre-conditioning alone. Thus, physiological activation of brain pro-inflammatory cytokine signaling, and its amplification by inhibition of coincident anti-inflammatory cytokine signaling, may be opportune targets for the development of novel therapeutics that can mimic the protection seen in cold pre-conditioning., (© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.)

Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.

Generating efficient antibody (Ab) responses against weak antigens remains challenging. Ab responses require antigen (Ag) uptake by antigen-presenting cells (APC), followed by presentation of processed Ag to T cells. Limited uptake of antigenic peptides by APC constrains Ab responses. Here we improve vaccine efficacy by targeting Ag to Fcgamma receptors (FcgammaR) using R4, a recombinant FcgammaR ligand. R4 has four repeats per chain of the hinge region and CH2 domain (HCH2) of human IgG1. HCH2 encompasses the FcgammaR binding site. The repeats are linked to the human IgG1 framework. To test R4 in augmenting Ag uptake, we expressed human serum albumin domain 1 (HSA1) at the N terminus of R4 to produce HSA1R4. HSA1R4 (50 microg) administered to mice in Ribi adjuvant induces up to 1100-fold higher HSA1-specific IgG titers than HSA1 (p<0.001). HSA1R4 (250 ng) induces up to 130 times more anti-HSA1 Ab than HSA1Fc, a protein with HSA1 linked to the IgG1 framework (p<0.001). HSA-reactive T cells proliferate more briskly to HSA1R4 than to HSA1Fc (p<0.008). Immunization with HSA1R4 yields greater T cell reactivity to HSA1 ex vivo than immunization with HSA1Fc (p<0.004). Linking antigenic peptides to linear HCH2 polymers may facilitate vaccine development.

Transportation officers at mass casualty incidents are faced with the daunting task of tracking large amounts of patients as they leave the disaster scene. Patients often leave under their own power without notifying any authorities, presenting a problem for personnel attempting to account for every patient they have treated. This paper describes a system of tracking patients at a disaster scene or en route to hospitals using electronic triage tags registered with an external database.