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mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EV X-M+P vaccine) and explore its utility in proof-of-concept immunity studies in the settings of cancer and infectious disease. As a first example, we engineered EVs, natural nanoparticle carriers shed by all cells, to contain ovalbumin mRNA and protein (EV OvaM+P vaccine) to serve as cancer vaccine against ovalbumin-expressing melanoma tumors. EV OvaM+P administration to mice with established melanoma tumors resulted in tumor regression associated with effective humoral and adaptive immune responses. As a second example, we generated engineered EVs that contain Spike (S) mRNA and protein to serve as a combined mRNA and protein vaccine (EV SpikeM+P vaccine) against SARS-CoV-2 infection. EV SpikeM+P vaccine administration in mice and baboons elicited robust production of neutralizing IgG antibodies against RBD (receptor binding domain) of S protein and S protein specific T cell responses. Our proof-of-concept study describes a new platform with an ability for rapid development of combination mRNA and protein vaccines employing EVs for deployment against cancer and other diseases., Competing Interests: Declaration of competing interest MD Anderson Cancer Center and RK have filed patent applications and patents issued in the area of exosome biology, and some of them are licensed to PranaX, Inc. for non-cancer related use. MD Anderson and RK hold equity in PranaX and RK serves as an advisor on non-cancer related matters., (Copyright © 2024. Published by Elsevier B.V.)

A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes., (© 2024. The Author(s).)

Social information is a centerpiece of human experience. Despite a wealth of research into the way we understand social relationships and how aspects of social life might be supported by the brain, relatively little is known about how the brain represents individual people and their relationships with others. How do intrinsic networks in the brain track people and their connections in complex situations? Here, we sought to understand this issue using an open neuroimaging dataset in which people freely viewed "The Grand Budapest Hotel." Using support vector machine classification of fMRI activity patterns, we found that character identity could be decoded throughout subsystems of the brain's "Default Mode" Network, especially in regions of an Anterior Temporal and a Medial Prefrontal subsystem, as well as a Medial Temporal Network (MTN). We tested character relationships in two ways - onscreen co-occurrence and shared semantic information from an independent sample of character descriptions - and found evidence for these representations throughout the "Default Mode" Network, and the MTN. The extent to which each variant of character relationships fit neural patterns differed across networks, with abstract semantic relatedness being especially prominent in regions of Anterior Temporal and Medial Prefrontal Networks. These data show that subsystems of the brain's "Default Mode" Network and MTN carry information about individual people as well as their connections, and highlight a particularly strong role for the Anterior Temporal network in representing this information., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Solitary confinement and mental well-being has been researched extensively, with a significant increase in studies over the last ten years. These recent studies produce mixed evidence for whether placement in solitary confinement is associated with psychological distress. We advance our understanding of these relationships in two critical ways. First, we conduct both between- and within-person analyses within the same data to better understand the relationship of solitary confinement and mental well-being relative to the well-being of people in less restrictive prison settings. Second, we ask the men in our sample questions about their personality style, coping strategies, and interactions with staff, which allows us to explore how individual characteristics and prison experiences matter, alongside isolation, in understanding mental well-being., Methods: We gather data from interviews at three time points with 122 men in solitary confinement and 204 men in other conditions of confinement in Arizona from 2017 to 2019. We merge these interview data with administrative data on study sample and population sample to include critical measures such as mental health score, risk level, and visitation status. Our interviews contain a Global Severity Index (GSI), created from 90 self-reported psychopathological symptoms experienced, that we use to assess well-being. We estimate cross-classified multilevel models to assess between-person differences and within-person change in well-being over time., Results: There was a small relationship between solitary confinement and worsening well-bring (longitudinal, within-person) and a small relationship between solitary confinement and worse well-being (cross-sectional, between-person), with this between-person association reduced significantly upon inclusion of additional individual characteristics and prison experiences., Conclusions: Our results suggest that the incarceration experience, including conditions of confinement, is associated with mental well-being in different ways for different people. We believe that collective confinement and well-being could receive the same scholarly attention and public concern as solitary confinement., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The KRAS G12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS G12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRAS G12D , on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS G12D -driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRAS G12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8 + T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials., Competing Interests: Declaration of interests A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology, and this financial relationship is managed and monitored by the UTMDACC Conflict of Interest Committee. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection and serves as a consultant for Freenome and Tezcat Biosciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This chapter canvasses the current relevance of behavioral neuroscience to the law, especially to issues of criminal responsibility and competence. It begins with an explanation of the legal doctrines at stake. I then explore the source of the often-inflated claims for the legal relevance of neuroscience. The next section discusses the scientific status of behavioral neuroscience. Then, it addresses two radical challenges to current conceptions of criminal responsibility that neuroscience allegedly poses: determinism and the death of agency. The question of the specific relevance of neuroscience to criminal law doctrine, practice, and institutions is considered next. This is followed by a discussion of how neuroscience evidence is being used in criminal cases in five different countries, including the United States. The penultimate section points to some areas warranting modest optimism. A brief conclusion suggests that neuroscience is at present of limited legal relevance, and advances in the science might alter that judgment., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This paper clarifies the conceptual space of discussion of legal insanity by considering the virtues of the 'medical model' model that has been used in Norway for almost a century. The medical model identifies insanity exclusively with mental disorder, and especially with psychosis, without any requirement that the disorder causally influenced the commission of the crime. We explore the medical model from a transdisciplinary perspective and show how it can be utilised to systematise and reconsider the central philosophical, legal and medical premises involved in the insanity debate. A key concern is how recent transdiagnostic and dimensional approaches to psychosis can illuminate the law's understanding of insanity and its relation to mental disorder. The authors eventually raise the question whether the medical model can be reconstructed into a unified insanity model that is valid across the related disciplinary perspectives, and that moves beyond current insanity models., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Enhancers are cis -regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type-specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in the brain., Competing Interests: JL, LS, KC, TW, IZ, YW, KL, JH, SM, CC, TS, EC, VH, SM, HP, DQ, DS, DV, LB, AN No competing interests declared, (© 2021, Lambert et al.)

This essay considers the foundational rationale for why the law treats at least some mentally disordered people specially in a wide array of civil and criminal contexts. It suggests that non-responsible incapacity for rational behavior in specific contexts is the primary principle that warrants special legal treatment. It also considers the major distractions and confusions about why such special treatment is sometimes justifiable. It concludes with the reductionist challenge to conceptions of mental disorder and more broadly to the law that some advocate, usually based on the new neuroscience of brain imaging.

Background: Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo., Methods: To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2 V617F -driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2 V617F -driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis., Results: We found that JAK2 V617F -mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2 V617F -mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2 V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2 V617F -driven MPN., Conclusion: LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2 V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2 V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2 V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Patients with myeloproliferative neoplasms (MPN) have high levels of inflammatory cytokines, some of which drive many of the debilitating constitutional symptoms associated with the disease and may also promote expansion of the neoplastic clone. We report here that monocytes from patients with MPN have defective negative regulation of Toll-like receptor (TLR) signaling that leads to unrestrained production of the inflammatory cytokine tumor necrosis factor α (TNF-α) after TLR activation. Specifically, monocytes of patients with MPN are insensitive to the anti-inflammatory cytokine interleukin 10 (IL-10) that negatively regulates TLR-induced TNF-α production. This inability to respond to IL-10 is a not a direct consequence of JAK2 V617F , as the phenotype of persistent TNF-α production is a feature of JAK2 V617F and wild-type monocytes alike from JAK2 V617F -positive patients. Moreover, persistent TNF-α production was also discovered in the unaffected identical twin of a patient with MPN, suggesting it could be an intrinsic feature of those predisposed to acquire MPN. This work implicates sustained TLR signaling as not only a contributor to the chronic inflammatory state of MPN patients but also a potential predisposition to acquire MPN., (© 2019 by The American Society of Hematology.)

Although there is debate in the scientific and clinical literature about how much choice addicts have concerning the use of drugs and related activities, this article demonstrates that Anglo-American criminal law is most consistent with the position that addicts have substantial choice about engaging in crimes involving their addiction. It suggests that the criminal law's approach is consistent with plausible and reasonable current scientific and clinical understanding of addiction and is therefore defensible, but it also suggests that the law is unduly harsh and far from optimum.

Criminal convictions require proof that a prohibited act was performed in a statutorily specified mental state. Different legal consequences, including greater punishments, are mandated for those who act in a state of knowledge, compared with a state of recklessness. Existing research, however, suggests people have trouble classifying defendants as knowing, rather than reckless, even when instructed on the relevant legal criteria. We used a machine-learning technique on brain imaging data to predict, with high accuracy, which mental state our participants were in. This predictive ability depended on both the magnitude of the risks and the amount of information about those risks possessed by the participants. Our results provide neural evidence of a detectable difference in the mental state of knowledge in contrast to recklessness and suggest, as a proof of principle, the possibility of inferring from brain data in which legally relevant category a person belongs. Some potential legal implications of this result are discussed.

Transduction-transplantation is a quick and efficient way to model human hematologic malignancies in mice. This technique results in expression of the gene of interest in hematopoietic cells and can be used to study the gene's role in normal and/or malignant hematopoiesis. This protocol provides a detailed description on how to perform transduction-transplantation using calreticulin (CALR) mutations recently identified in myeloproliferative neoplasm (MPN) as an example. In this protocol whole bone marrow cells from 5-flurouracil (5-FU) treated donor mice are transduced with a retrovirus encoding mutant CALR and transplanted into lethally irradiated syngeneic hosts. Donor cells expressing mutant CALR are marked with green fluorescent protein (GFP). Transplanted mice develop an MPN phenotype including elevated platelets in the peripheral blood, expansion of megakaryocytes in the bone marrow, and bone marrow fibrosis. We provide a step-by-step account of how to generate retrovirus, calculate viral titer, transduce whole bone marrow cells, and transplant into irradiated recipient mice.

The individual and social protective factors that help break the cycle of violence are examined. Specifically, this study investigates (a) the individual and social protective factors that reduce violent offending among previously victimized children, and (b) whether certain protective factors are more or less important depending on the type and frequency of childhood victimization experienced. Data on young adults from Wave III of the National Longitudinal Study of Adolescent to Adult Health are used (N = 13,116). Negative binomial regression models are estimated to examine the protective factors that promote resiliency to violent offending among individuals who reported being physically and sexually victimized as children. Results indicate that a number of individual and social protective factors reduce violent offending in young adulthood. With a few exceptions, these factors are specific to the type, frequency, and comorbidity of abuse experienced. The results suggest a number of promising approaches to break the cycle of violence among previously victimized children. Future research should move beyond explaining the cycle of violence to examine how the cycle may be broken., (© The Author(s) 2016.)

A germline JAK2(V617I) point mutation results in hereditary thrombocytosis and shares some phenotypic features with myeloproliferative neoplasm, a hematologic malignancy associated with a somatically acquired JAK2(V617F) mutation. We established a mouse transduction-transplantation model of JAK2(V617I) that recapitulated the phenotype of humans with germline JAK2(V617I). We directly compared the phenotypes of JAK2(V617I) and JAK2(V617F) mice. The JAK2(V617I) mice had increased marrow cellularity with expanded myeloid progenitor and megakaryocyte populations, but this phenotype was less severe than that of JAK2(V617F) mice. JAK2(V617I) resulted in cytokine hyperresponsiveness without constitutive activation in the absence of ligand, whereas JAK2(V617F) resulted in constitutive activation. This may explain why JAK2(V617I) produces a mild myeloproliferative phenotype in the mouse model, as well as in humans with germline JAK2(V617I) mutations., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

A decline in long-term memory (LTM) formation is a common feature of the normal aging process, which corresponds with abnormal expression of memory-related genes in the aged hippocampus. Epigenetic modulation of chromatin structure is required for proper transcriptional control of genes, such as the brain-derived neurotrophic factor (Bdnf) and Zif268 in the hippocampus during the consolidation of new memories. Recently, the view has emerged that aberrant transcriptional regulation of memory-related genes may be reflective of an altered epigenetic landscape within the aged hippocampus, resulting in memory deficits with aging. Here, we found that baseline resting levels for tri-methylation of histone H3 at lysine 4 (H3K4me3) and acetylation of histone H3 at lysine 9 and 14 (H3K9,K14ac) were altered in the aged hippocampus as compared to levels in the hippocampus of young adult rats. Interestingly, object learning failed to increase activity-dependent H3K4me3 and di-methylation of histone H3 at lysine 9 (H3K9me2) levels in the hippocampus of aged adults as compared to young adults. Treatment with the LSD-1 histone demethylase inhibitor, t-PCP, increased baseline resting H3K4me3 and H3K9,K14ac levels in the young adult hippocampus, while young adult rats exhibited similar memory deficits as observed in aged rats. After environmental enrichment (EE), we found that object learning induced increases in H3K4me3 levels around the Bdnf, but not the Zif268, gene region in the aged hippocampus and rescued memory deficits in aged adults. Collectively, these results suggest that histone lysine methylation levels are abnormally regulated in the aged hippocampus and identify histone lysine methylation as a transcriptional mechanism by which EE may serve to restore memory formation with aging.

This commentary on Zhong et al. begins by addressing the definition of remorse. It then primarily focuses on the relation between remorse and various justifications for punishment commonly accepted in Anglo-American jurisprudence and suggests that remorse cannot be used in a principled way in sentencing. It examines whether forensic psychiatrists have special expertise in evaluating remorse and concludes that they do not. The final section is a pessimistic meditation on sentencing disparities, which is a striking finding of Zhong et al.

This article, which is based on and expands on an amicus brief the authors submitted to the United States Supreme Court, first provides the moral argument in favor of the insanity defense. It considers and rejects the most important moral counterargument and suggests that jurisdictions have considerable leeway in deciding what test best meets their legal and moral policies. The article then discusses why the two primary alternatives to the insanity defense, the negation of mens rea and considering mental disorder at sentencing, are insufficient to achieve the goal of responding justly to severely mentally disordered offenders. The last section considers and rejects standard practical arguments in favor of abolishing the insanity defense.

Molecular mechanisms involved in the strengthening and formation of synapses include the activation and repression of specific genes or subsets of genes by epigenetic modifications that do not alter the genetic code itself. Chromatin modifications mediated by histone acetylation have been shown to be critical for synaptic plasticity at hippocampal excitatory synapses and hippocampal-dependent memory formation. Considering that brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity and behavioral adaptations, it is not surprising that regulation of this gene is subject to histone acetylation changes during synaptic plasticity and hippocampal-dependent memory formation. Whether the effects of BDNF on dendritic spines and quantal transmitter release require histone modifications remains less known. By using two different inhibitors of histone deacetylases (HDACs), we describe here that their activity is required for BDNF to increase dendritic spine density and excitatory quantal transmitter release onto CA1 pyramidal neurons in hippocampal slice cultures. These results suggest that histone acetylation/deacetylation is a critical step in the modulation of hippocampal synapses by BDNF. Thus, mechanisms of epigenetic modulation of synapse formation and function are novel targets to consider for the amelioration of symptoms of intellectual disabilities and neurodegenerative disorders associated with cognitive and memory deficits., (Copyright © 2011 Wiley Periodicals, Inc.)

Some believe that genetics threatens privacy and autonomy and will eviscerate the concept of human nature. Despite the astonishing research advances, however, none of these dire predictions and no radical transformation of the law have occurred. Advocates have tried to use genetic evidence to affect judgments of criminal responsibility. At present, however genetic research can provide little aid to assessments of criminal responsibility and it does not suggest a radical critique of responsibility., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

After beginning with a warm appreciation of Alan Stone's scholarship and character, this article argues that Stone's woeful characterization of forensic practice as a wasteland that has no genuine ethical guide to practice and little to contribute is vastly overstated. It claims that the basis for useful ethical practice is rooted in a proper understanding of the law's folk psychological model of behavior and criteria. Then it suggests the proper bounds of forensic practice, including an aspirational list of do's and don'ts. The view presented is deflationary and cautious compared to what the law permits and most practitioners do, but it still leaves forensic practitioners with a wide and important role in the legal system.

This article demonstrates that there is no free will problem in forensic psychiatry by showing that free will or its lack is not a criterion for any legal doctrine and it is not an underlying general foundation for legal responsibility doctrines and practices. There is a genuine metaphysical free will problem, but the article explains why it is not relevant to forensic practice. Forensic practitioners are urged to avoid all usage of free will in their forensic thinking and work product because it is irrelevant and spawns confusion., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Despite a large and growing interest in applying brain science to the ends of justice, the implications of neuroscience for the law are still unclear. But Stephen Morse argues that, unless discoveries about the brain radically change our conception of ourselves, they are unlikely to fundamentally alter legal doctrine. For most challenges the findings might raise to justice, equality, and liberty, he writes, the law has rich theoretical resources with which to address them. On the other hand, the author acknowledges, one can easily imagine substantial changes in particular doctrines.

Thinking about addictions has been dominated by two models: the medical model, which treats addiction as a disease and related behaviors as signs and symptoms, and the moral model, which views addiction and related behaviors as indications of moral failure. This article describes both models and their implications, with special emphasis on the moral model. The meaning of compulsion or coercion caused by internal psychological states, such as craving, is explored to determine if addicts may fairly be held morally and legally responsible for their behavior, such as seeking and using substances. It is argued that diminished rationality better explains than compulsion why addicts might be excused for their behavior, but it is concluded that most addicts can be held responsible for most addiction-related behavior. Nonetheless, both models have desirable characteristics, and sound public policy should not be based solely on either. The implications for criminal justice of employing both models to guide policy are explored.

Objective: To compare the lipid-altering effect of roasted salted almonds and roasted almond butter with that of raw almonds, as part of a plant-based diet., Methods: Thirty-eight free-living, hypercholesterolemic men (n = 12) and women (n = 26) with a mean total serum cholesterol (TC) of 245 + 29 mg/dL (mean + SD) followed a heart-healthy diet including 100g of one of three forms of almonds: roasted salted almonds, roasted almond butter or raw almonds for four weeks. Measurements of serum TC, triglycerides (TG), selected lipoproteins and blood pressure were taken at baseline and after four weeks., Results: All three forms of almonds in the context of a heart-healthy diet significantly lowered low-density lipoprotein-cholesterol (LDL) from baseline to the completion of the study. Both raw and roasted almonds significantly lowered TC, whereas the decrease by almond butter (in a smaller cohort) did not reach statistical significance. High-density lipoprotein-cholesterol (HDL) did not significantly change with raw or roasted almonds but slightly increased with almond butter. At the end of the study, blood pressure did not change significantly from baseline values for any of the groups., Conclusion: These results suggest that unblanched almonds-whether raw, dry roasted, or in roasted butter form-can play an effective role in cholesterol-lowering, plant-based diets.

This article addresses whether the state has the right to medicate involuntarily a defendant who is incompetent either to plead guilty or to stand trial for the purpose of restoring legal competence. It first presents the constitutional background concerning incompetence and the right of prisoners generally to refuse psychotropic medication. Then the article examines the individual and state interests that must be considered to decide specifically whether the state may involuntarily medicate a criminal defendant solely for the purpose of restoring competence. Although the individual interests are strong, the article contends that the state does have a right to medicate involuntarily defendants charged with most crimes to restore trial competence, and that adequate remedies are available to ensure that medicated defendants receive a fair trial., (Copyright 2003 John Wiley & Sons, Ltd.)

This article addresses why mental disorder is relevant to criminal responsibility. It begins by considering the meaning of criminal responsibility because it is impossible to understand the relevance of mental disorder unless one understands responsibility clearly. The next section provides a theoretical account of responsibility and excuse in general and addresses common misconceptions about these topics. The third section examines in detail why mental disorder can sometimes produce either a complete or partial excusing condition, such as legal insanity or "partial responsibility," and whether the U.S. Constitution requires the provision of an excuse based on mental disorder. The section proposes that mental disorder should produce an excusing condition in appropriate cases. The next section considers the relation of mental disorder to mens rea, the mental state "element" that is a definitional criterion of most crimes, and whether the U.S. Constitution requires that defendants be permitted to use evidence of mental disorder to negate mental state elements of the crime charged. This section argues that mental disorder rarely negates mens rea, but in those cases in which a plausible claim for negation could be made, defendants should be allowed to make this claim., (Copyright 1999 John Wiley & Sons, Ltd.)

This article addresses the law's concept of the person and its relation to responsibility and the excusing conditions. It demonstrates that causation of behavior in general, even pathological biological causation, is not itself and excuse and suggests that the incapacity for rationality is the genuline basis of moral and legal excuse. The paper concludes by applying its theses to the case of Spyder Cystkopf, a man with a confirmed subarachnoid cyst, who killed his wife during a heated argument with her.

This article first addresses the persistent confusion between causation and excuse. It demonstrates that causation is not the equivalent of compulsion and that causation per se is not an excusing condition. Then the article examines the conceptual and practical difficulties presented by the excuse that is variously labeled "compulsion," "involuntariness," "volitional problems," "irresistible impulse," and the like. It concludes that this excuse, when produced by internal causes, is far less well understood and assessed than forensic clinicians usually assume and that most such excusing conditions are better understood and assessed in terms of rationality problems.