Efficacy of bortezomib desensitization among heart transplant candidates.

Allosensitization is prevalent in heart transplant candidates and is associated with prolonged waiting times and poor outcomes following transplantation. We analyzed the efficacy of a desensitization regimen consisting of plasma exchange, intravenous immunoglobulin, and bortezomib among 25 consecutive sensitized waitlisted candidates at our center from 2016 to 2021. Following desensitization therapies, all C1q negative antibodies were removed from a candidate's unacceptable antigen list. There was a significant decrease in the median number of human leukocyte antigen (HLA) class I (21-15, p = .001) but not class II antibodies (7-6.5, p = .07). There was a significant corresponding decrease in median calculated panel reactive antibodies for class I (90%-74%, p = .004) but not class II (74.5%-75.5%, p = .30). Following desensitization, 76% of patients were transplanted at a median of 91 days. One-year survival following transplant was 89% with a 33% rate of antibody-mediated rejection (AMR). In conclusion, a bortezomib desensitization protocol was modestly effective for class I antibodies and allowed successful transplant in most cases when combined with selective crossing of C1q negative antigens.

Effect of Statin Intensity on the Progression of Cardiac Allograft Vasculopathy.

Background: In the non-transplant population, hyperlipidaemia has shifted from targeting LDL goals to statin intensity-based treatment. It is unknown whether this strategy is also beneficial in cardiac transplantation. Methods: This single-centre retrospective study evaluated the effect of statin use and intensity on time to cardiac allograft vasculopathy (CAV) after cardiac transplantation. Kaplan-Meier and Cox proportional hazards regression survival methods were used to assess the association of statin intensity and median post-transplant LDL on CAV-free survival. Results: The study involved 143 adults (71% men, average follow-up of 25 ± 14 months) who underwent transplant between 2013 and 2017. Mean CAV-free survival was 47.5 months (95% CI [43.1-51.8]), with 29 patients having CAV grade 1 or greater. Median LDL was not associated with time to CAV (p=0.790). CAV-free survival did not differ between intensity groups (p=0.435). Conclusion: Given the non-statistically significant difference in time to CAV with higher intensity statins, the data suggest that advancing moderate- or high-intensity statin after cardiac transplantation may not provide additional long-term clinical benefit. Trial registration: Not applicable.

Assessing Autism Spectrum Disorder in Intellectually Able Adults with the Personality Assessment Inventory: Normative Data and a Novel Supplemental Indicator.

Differential diagnosis of autism spectrum disorder (ASD) among intellectually-able adults often presents a clinical challenge, particularly when individuals present in crisis without diagnostic history. The Personality Assessment Inventory (PAI) is a multiscale personality and psychopathology instrument utilized across clinical settings, but to date there are no published normative data for use of the PAI with adults with ASD. This study provides normative PAI data for adults diagnosed with ASD, with effect size comparisons to the PAI clinical standardization sample and an inpatient sample. Additionally, a discriminant function was developed and cross-validated for identification of ASD-like symptomatology in a clinical population, which demonstrates promise as a screening tool to aid in the identification of individuals in need of specialized ASD assessment.

A National Trial on Differences in Cerebral Perfusion Pressure Values by Measurement Location.

BACKGROUND: Cerebral perfusion pressure (CPP) is a key parameter in management of brain injury with suspected impaired cerebral autoregulation. CPP is calculated by subtracting intracranial pressure (ICP) from mean arterial pressure (MAP). Despite consensus on importance of CPP monitoring, substantial variations exist on anatomical reference points used to measure arterial MAP when calculating CPP. This study aimed to identify differences in CPP values based on measurement location when using phlebostatic axis (PA) or tragus (Tg) as anatomical reference points. The secondary study aim was to determine impact of differences on patient outcomes at discharge. METHODS: This was a prospective, repeated measures, multi-site national trial. Adult ICU patients with neurological injury necessitating ICP and CPP monitoring were consecutively enrolled from seven sites. Daily MAP/ICP/CPP values were gathered with the arterial transducer at the PA, followed by the Tg as anatomical reference points. RESULTS: A total of 136 subjects were enrolled, resulting in 324 paired observations. There were significant differences for CPP when comparing values obtained at PA and Tg reference points (p < 0.000). Differences remained significant in repeated measures model when controlling for clinical factors (mean CPP-PA = 80.77, mean CPP-Tg = 70.61, p < 0.000). When categorizing CPP as binary endpoint, 18.8% of values were identified as adequate with PA values, yet inadequate with CPP values measured at the Tg. CONCLUSION: Findings identify numerical differences for CPP based on anatomical reference location and highlight importance of a standard reference point for both clinical practice and future trials to limit practice variations and heterogeneity of findings.

Therapeutic Use of Music and Television in Neurocritical Care: A Practice Survey.

INTRODUCTION: Although health care providers often play music via radio, or play television, to calm and soothe patients, limited research is available to guide practice. METHOD: This study used a 17-item practice survey that was distributed electronically to neurocritical care society members in July 2014. Responses were collated and analyzed using SAS (Version 9.3). RESULTS: There were 118 completed responses, including from 71 attending physicians, 9 resident or fellow physicians, 30 nurses, and 8 affiliate professional members. The majority of respondents sometimes or always play music (65%) and agree that music is therapeutic (70%). However, there was no clear practice pattern regarding when or why music or TV should be used as an intervention in the neurocritical care unit. CONCLUSION: The use of music and TV is a common intervention in the neurocritical care unit but lacks a strong scientific foundation and is associated with a high practice variance.

Modalities for Visualization of Cortical Bone Remodeling: The Past, Present, and Future.

Bone's ability to respond to load-related phenomena and repair microdamage is achieved through the remodeling process, which renews bone by activating groups of cells known as basic multicellular units (BMUs). The products of BMUs, secondary osteons, have been extensively studied via classic two-dimensional techniques, which have provided a wealth of information on how histomorphology relates to skeletal structure and function. Remodeling is critical in maintaining healthy bone tissue; however, in osteoporotic bone, imbalanced resorption results in increased bone fragility and fracture. With increasing life expectancy, such degenerative bone diseases are a growing concern. The three-dimensional (3D) morphology of BMUs and their correlation to function, however, are not well-characterized and little is known about the specific mechanisms that initiate and regulate their activity within cortical bone. We believe a key limitation has been the lack of 3D information about BMU morphology and activity. Thus, this paper reviews methodologies for 3D investigation of cortical bone remodeling and, specifically, structures associated with BMU activity (resorption spaces) and the structures they create (secondary osteons), spanning from histology to modern ex vivo imaging modalities, culminating with the growing potential of in vivo imaging. This collection of papers focuses on the theme of "putting the 'why' back into bone architecture." Remodeling is one of two mechanisms "how" bone structure is dynamically modified and thus an improved 3D understanding of this fundamental process is crucial to ultimately understanding the "why."

Pediatric cardiac retransplantation: Waitlist mortality stratified by age and era.

BACKGROUND: Waitlist mortality among children listed for primary heart transplant (HTx) has been well characterized, whereas limited data exist for cardiac retransplantation (CRTx) after pediatric primary HTx. We sought to characterize the population listed for CRTx and to determine the factors that affect waitlist mortality. METHODS: All individuals listed for CRTx >1 year after pediatric primary HTx between October 1, 1987, and October 14, 2012 were identified in the Organ Procurement and Transplantation Network database. Baseline characteristics and waitlist mortality were compared between age groups (< 11 years, 11-18 years, and > 18 years) and during 3 successive eras (1987-1999, 1999-2006, and 2006-2012). RESULTS: The cohort comprised 632 patients who were listed for CRTx > 1 year after pediatric primary HTx. Median age was 4 years at primary HTx and 14 years at relisting. Median time from primary HTx to relisting was 7.3 years. Median waiting time was 75.3 days. Overall mortality was 25.2% (159 of 632). The most frequent relisting diagnosis was related to graft vasculopathy (62.5%). The leading causes of death were chronic rejection and vasculopathy (52%). Waitlist mortality significantly decreased after 2006 (31% vs 17%; p < 0.01), despite a relatively constant CRTx rate (67% vs 65%). Univariate analysis showed era, age, listing status, and life support (mechanical circulatory support device, extracorporeal membrane oxygenation, mechanical ventilation) were significant predictors of mortality. Multivariate analyses showed that later era (2006-2012), ages 11 to 18 years, and United Network of Organ Sharing listing status 2 predicted decreased mortality, whereas life support increased mortality. CONCLUSIONS: Waitlist mortality for CRTx in children and young adults has decreased by almost 50% over time. Individuals relisted as adults have increased waitlist mortality.

Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers.

Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood-brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200 nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The P-gp ATPase assay suggested that the NP were not substrate for P-gp and would not be effluxed by P-gp present in the BBB. The in vitro release profile of the NP exhibited no initial burst release and showed sustained drug release. The proposed coated NP showed significantly higher cytotoxicity in RG2 cells compared with uncoated NP (p ≤ 0.05). Tubulin immunofluorescent study showed higher cell death by the NP due to increased microtubule stabilization. In vivo brain uptake study in mice showed higher brain uptake of the NP containing coumarin-6 compared with solution. The proposed brain-targeted NP delivery of paclitaxel could be an effective treatment for the brain cancers.

The role of suggestibility in determinations of Miranda abilities: a study of the Gudjonsson Suggestibility Scales.

Traditionally, high levels of suggestibility have been widely assumed to be linked with diminished Miranda abilities, especially in relationship to the voluntariness of waivers. The current investigation examined suggestibility on the Gudjonsson Suggestibility Scales in a multisite study of pretrial defendants. One important finding was the inapplicability of British norms to American jurisdictions. Moreover, suggestibility appeared unrelated to Miranda comprehension, reasoning, and detainees' perceptions of police coercion. In testing rival hypotheses, defendants with high compliance had significantly lower Miranda comprehension and ability to reason about exercising Miranda rights than their counterparts with low compliance. Implications of these findings to forensic practice are examined.

Development and initial validation of the Miranda vocabulary scale.

Miranda vocabulary forms the essential foundation for Miranda comprehension and subsequent decisions to exercise or waive Miranda rights. The purpose of the current study is the development of the Miranda Vocabulary Scale (MVS), designed to evaluate key vocabulary words found in Miranda warnings and waivers across American jurisdictions. A preliminary list of MVS words was refined by expert ratings and by each word's discriminability between failed and good Miranda comprehension. Miranda and other measures were collected at multiple sites on 376 pretrial defendants. With further refinements, the MVS is composed of 36 words with excellent scale homogeneity and interrater reliability (r = .99). It also demonstrated good convergent and discriminant validity for cognitive abilities and psychological impairment.

Functional trade-offs in white matter axonal scaling.

The brains of large mammals have lower rates of metabolism than those of small mammals, but the functional consequences of this scaling are not well understood. An attractive target for analysis is axons, whose size, speed and energy consumption are straightforwardly related. Here we show that from shrews to whales, the composition of white matter shifts from compact, slow-conducting, and energetically expensive unmyelinated axons to large, fast-conducting, and energetically inexpensive myelinated axons. The fastest axons have conduction times of 1-5 ms across the neocortex and <1 ms from the eye to the brain, suggesting that in select sets of communicating fibers, large brains reduce transmission delays and metabolic firing costs at the expense of increased volume. Delays and potential imprecision in cross-brain conduction times are especially great in unmyelinated axons, which may transmit information via firing rate rather than precise spike timing. In neocortex, axon size distributions can account for the scaling of per-volume metabolic rate and suggest a maximum supportable firing rate, averaged across all axons, of 7 +/- 2 Hz. Axon size distributions also account for the scaling of white matter volume with respect to brain size. The heterogeneous white matter composition found in large brains thus reflects a metabolically constrained trade-off that reduces both volume and conduction time.

The language of Miranda warnings in American jurisdictions: a replication and vocabulary analysis.

Miranda warnings are remarkably heterogeneous in their language, length, and content. Past research has focused mostly on individual Miranda warnings. Lacking in generalizability, these studies have limited applicability to both public policy and professional practice. A large-scale survey by R. Rogers et al. [2007b, Law and Human Behavior, 31, 177-192] examined Miranda warnings from across the United States and documented striking differences in the length, content, and reading comprehension. In moving from single jurisdiction studies to nationally representative research, the replication of the Rogers et al. survey is essential. With an additional 385 general Miranda warnings, most of the original findings were confirmed; this replication allows Miranda researchers to use findings based upon nationally-representative warnings for their subsequent research. Beyond reading comprehension, the study makes an original contribution to the understanding of Miranda vocabulary that is often infused with abstruse words and legalistic terms. It provides the first analysis of sentence complexity, which affects both Miranda comprehension and retention. As a result of these analyses, preliminary guidelines are provided for increasing the comprehension and understanding of Miranda warnings.

Facets of psychopathy, Axis II traits, and behavioral dysregulation among jail detainees.

Forensic evaluations of offender populations often consider psychopathy as an integral component of these consultations. Vexing issues remain of whether psychopathic traits should be evaluated consistently irrespective of demographic characteristics (e.g. gender), comorbidity (e.g. other Axis II pathology), or setting (e.g. jail or community). The current study examined gender differences for psychopathy and Axis II traits in a nonreferred jail sample of predominantly nonviolent offenders. Participants with moderate to high levels of psychopathy evidenced substantial comorbidity, especially with Cluster B personality disorders. Facets of psychopathy and Axis II traits varied substantially across both genders. In addition, the research evaluated Lynam's Hyperactivity, Impulsivity, and Attention difficulties (HIA) model of psychopathy. These initial data found little support for the HIA model in this jail sample. In testing competing hypotheses, the HIA model was substantially better at predicting Cluster B traits than psychopathy per se.

Synthesis and structure-activity relationship of a novel, non-hydroxamate series of TNF-alpha converting enzyme inhibitors.

A novel series of TNF-alpha converting enzyme (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds use a triazolethione moiety as the zinc binding ligand and exhibit IC50 values from 1.5 to 100 nM in a porcine TACE assay. They also have excellent selectivities over other MMPs.

Axis I screens and suicide risk in jails: a comparative analysis.

Mental health professionals conducting screenings in jail settings face formidable challenges in identifying inmates at risk for major depression and suicide. Psychologists often rely on correctional staff to provide initial appraisals of those inmates requiring further evaluation. In a sample of 100 jail detainees, the effectiveness of two specialized screens (the Referral Decision Scale and Mental Disability/Suicide Intake Screen or MDSIS) and one general screen (Personality Assessment Screener or PAS) was evaluated. For suicidal ideation, the MDSIS composite score evidenced promise (sensitivity = 1.00; specificity = 0.71). In ruling out major depression, the PAS Negative Affect subscale was useful for the inmate participants.

Knowing and intelligent: a study of Miranda warnings in mentally disordered defendants.

A conservative estimate is that 695,000 mentally disordered offenders are arrested and Mirandized annually in the United States. Past research has focused almost exclusively on cognitive factors affecting the comprehension of Miranda rights. The current study broadens the scope by including diagnostic variables and by extending the investigation to basic elements of Miranda reasoning. A sample of 107 mentally disordered defendants was administered two research measures, the Miranda Statements Scale (MSS) and Miranda Rights Scale (MRS), in addition to standardized tests. Most defendants lacked good comprehension of all but the simplest (Flesch-Kincaid<6th grade) Miranda warnings. Defendants with the poorest understanding (i.e., comprehending about 25% of the warnings) had marked deficits in multiple domains including cognitive abilities (intelligence and comprehension) and general adjustment. Different background and clinical variables predicted defendants' abilities to generate reasons either to exercise or waive their Miranda rights.

An analysis of Miranda warnings and waivers: comprehension and coverage.

Miranda warnings enshrine the constitutional rights of custodial suspects against self-incrimination. However, the wording and sentence complexity of Miranda warnings and waivers vary dramatically from jurisdiction to jurisdiction. This study is the first extensive investigation of Miranda warning variations examining 560 Miranda warnings from across the United States. With Flesch-Kincaid reading comprehension as a useful metric, Miranda warnings varied from very simple comprehension (i.e., grade 2.8) to requiring postgraduate education. Miranda warnings are composed of five components (e.g., silence and evidence against you); marked variations were also observed in the comprehensibility of individual components. On average, the Miranda warning component on "continuing rights" requires a reading comprehension level six grades higher than the comparatively simple expression of the right to silence. Similar analyses were conducted on Miranda waivers. The content of these warnings differed on such issues as communicating (a) when access to an attorney would be granted (e.g., 45.9% specified only "during questioning") and (b) explicitly that indigent legal services were free (e.g., 31.8% directly informed suspects). Finally, the study identified representative Miranda components at different levels of reading comprehension as a template for further research.

The MMPI-2 Restructured Clinical Scales: a paradigmatic shift in scale development.

Tellegen et al. (2003) proposed fundamental changes in MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) scale development by discarding empirical scale development in favor of construct validation via Jackson's (1970) sequential system of scale development. As a result of their efforts, a general distress factor (Demoralization) was identified and 8 Restructured Clinical (RC) Scales were developed. Using 7,330 clinical cases from Caldwell's (1997) data set, in this study, we sought to cross-validate the MMPI-2 RC Scales. Scale homogeneity was confirmed with high alpha coefficients and interitem correlations in the expected range. We also achieved a major objective of reducing interscale correlations. In replicating Tellegen et al.'s principal components analysis, we achieved a high concordance for 6 of the 8 RC Scales. We critically examine these results in light of Jackson's construct validation. We discuss the clinical usefulness of the MMPI-2 RC Scales within the context of current and future research.

An examination of the ECST-R as a screen for feigned incompetency to stand trial.

Psychological assessments of competency-to-stand-trial (CST) referrals must consider whether the defendants' impairment is genuine or feigned. This study addressed feigning on the Evaluation of Competency to Stand Trial--Revised (ECST-R), a standardized interview designed for assessing dimensions of CST and screening for feigned CST. In particular, this study examined the effectiveness of the ECST-R's Atypical Presentation (ATP) scales as screens for feigned incompetency. It examined ATP scales for (a) jail detainees (n=96) in simulation and control conditions and (b) inpatient competency cases (n=56) in clinical comparison and probable malingering groups. Comparisons of ATP scales yielded very large effect sizes for feigners when compared with jail controls (mean d=2.50) and genuine inpatient competency cases (mean d=1.83). Several cut scores were established with very few false negatives and robust sensitivity estimates. In summary, the ECST-R ATP scales appear to be homogenous scales with established clinical use as feigning screens in CST evaluations.

A critical review of published competency-to-confess measures.

The development of standardized assessments for competency-to-confess evaluations has remained largely neglected for the last several decades. Groundbreaking research was conducted on Miranda waivers during the late 1970s, but researchers have failed to sustain programmatic research. This critical review focuses on four published Miranda measures (Comprehension of Miranda Rights, Comprehension of Miranda Rights-Recognition, Comprehension of Miranda Vocabulary, and Function of Rights in Interrogation). When evaluated by contemporary standards, the validation of these measures is very limited. Major improvements are needed for interrater reliability, test-retest reliability, content validity, construct validity, and criterion-related validity.