Social-geographic disparities in suicidal ideations among methamphetamine users in the USA.

IMPORTANCE: Methamphetamine use is a growing public health concern nationwide. Suicide is the second leading cause of death in 2019 for US citizens aged 10-14 years and 25-34 years and is also a significant public health concern. Understanding the intersection of methamphetamine use and suicidal ideation (SI) is necessary to develop public health and policy solutions that mitigate these ongoing severe public health issues. OBJECTIVE: Our objective was to examine SI in methamphetamine users to allow us to determine prevalence and trends by age, sex, race, and geographical region. DESIGN, SETTINGS, AND PARTICIPANTS: Using data collected between 2008 and 2019 from the National Inpatient Sample (NIS) database, we identified hospital admissions (HA) of patients ≥18 years of age with a primary or secondary diagnosis of SI who were also diagnosed as methamphetamine users. Those who used other substances with methamphetamine were excluded from the analysis. MAIN OUTCOME AND MEASURES: To determine the trend and prevalence of hospital admissions due to SI and SI among methamphetamine users, we used trend weights to calculate the national estimates and performed design-based analysis to account for complex survey design and sampling weights on data collected between 2008 and 2019 in the US. RESULTS: The prevalence ratio (PR) of hospitalizations with concurrent SI and methamphetamine use increased 16-fold from 2008 to 2019. The most significant increase occurred between 2015 and 2016; the PR doubled from 6.07 to 12.14. The PR of hospitalizations with concurrent SI and methamphetamine use was highest in patients aged 26-40 (49.08%) and 41-64 (28.49%). Patients aged 41-64 showed the most significant increase from 2008 to 2019 (15.8-fold). While non-Hispanic White patients comprised most of these hospitalizations (77.02%), non-Hispanic Black patients showed the highest proportional increase (39.1-fold). The Southern and Western regions in the US showed the highest PR for these hospitalizations (34.86% and 34.31%, respectively). CONCLUSION AND RELEVANCE: Our findings indicate that SI in methamphetamine users has been increasing for some time and is likely to grow. In addition, our results suggest that these patients are demographically different. Both conditions are associated with a lesser likelihood of seeking and receiving care. Therefore, when addressing increased SI or methamphetamine use, learning more about patients who share both conditions is necessary to ensure proper care.

Exploring psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder.

Methamphetamine use disorder is a chronic relapsing condition associated with substantial mental, physical, and social harms and increasing rates of mortality. Contingency management and psychotherapy interventions are the mainstays of treatment but are modestly effective with high relapse rates, while pharmacological treatments have shown little to no efficacy. Psilocybin-assisted psychotherapy is emerging as a promising treatment for a range of difficult-to-treat conditions, including substance use disorders; however, no studies have yet been published looking at psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder. Here we review the rationale for psilocybin-assisted psychotherapy as a potential treatment for this indication, and describe practical considerations based on our early experience designing and implementing four separate clinical trials of psilocybin-assisted psychotherapy for methamphetamine use disorder.

Elevated plasma sulfides are associated with cognitive dysfunction and brain atrophy in human Alzheimer's disease and related dementias.

Emerging evidence indicates that vascular stress is an important contributor to the pathophysiology of Alzheimer's disease and related dementias (ADRD). Hydrogen sulfide (H2S) and its metabolites (acid-labile (e.g., iron-sulfur clusters) and bound (e.g., per-, poly-) sulfides) have been shown to modulate both vascular and neuronal homeostasis. We recently reported that elevated plasma sulfides were associated with cognitive dysfunction and measures of microvascular disease in ADRD. Here we extend our previous work to show associations between elevated sulfides and magnetic resonance-based metrics of brain atrophy and white matter integrity. Elevated bound sulfides were associated with decreased grey matter volume, while increased acid labile sulfides were associated with decreased white matter integrity and greater ventricular volume. These findings are consistent with alterations in sulfide metabolism in ADRD which may represent maladaptive responses to oxidative stress.

Social media use and body image issues among adolescents in a vulnerable Louisiana community.

Widespread concern has been expressed regarding unrealistic body image and adolescent eating disorder promoting content on social media (SM) platforms. Numerous research studies have examined the impact of SM on body image as well as social vulnerability on negative mental health outcomes. Despite this, few previous studies have examined the impact of SM on body image specifically in vulnerable, underserved, or predominantly minority communities. This study examines the impact of SM on body image issues (BII) in adolescents in a public school system where greater than 50% of the students live in impoverished households. In late 2019, high school student leaders in Northwest Louisiana developed a survey alongside Step Forward, a collective impact initiative. Questions investigated adolescent SM use and mental health in Caddo Parish, namely BII. Teachers within Caddo Parish Public School System administered the survey. Out of the 11,248 total high school students in the school system, nearly 50% were sampled for a sample size of 5,070. Hypotheses included: (1) females were more likely to use SM than males, (2) increasing time spent on SM would correlate with females reporting BII, with males remaining largely unaffected, and (3) highly visual social media (HVSM) platforms would be associated with greater reports of BII than non-HVSM platforms. Results showed females were more likely to use SM (p < 0.001) and report BII (p < 0.001) compared to males, while both sexes reported BII with increasing time spent on SM (p < 0.001). A diversity of platforms were associated with increased BII among SM users compared to non-users (p < 0.001): Pinterest, Reddit, Snapchat, TikTok, Twitter, and YouTube. This conclusion is tempered by the omission of race as a variable in the study design, the use of self-report, and the use of an unvalidated instrument. These findings suggest that the harmful association between SM use and BII may transcend culture and socioeconomic status for a broadly deleterious effect on adolescent mental wellbeing.

Teen Advisory Council Survey's Factors Associated With Self-Harming Thoughts.

Background: The evaluation of teens with self-harming thoughts (SHT) is a high-stakes task for physicians in community and emergency department (ED) settings. The lived experience of adolescents with stress and SHT provides an important source of insight for mental health professionals who evaluate and treat teens A snapshot of the lived experience of teens in northwest Louisiana was captured by the Step Forward Teen Advisory Council (TAC) in 2019. The TAC surveyed peers with the goal of identifying common stressors experienced by local teens in order to inform policy and practices in the local school system. The identification of stressors is a critical step in addressing SHT as adolescents who experience life stressors are at increased risk for self-harming thoughts (SHT), a known precursor to self-harm and suicide. Assessing youth for life stressors is a critical element of suicide prevention. Methods: Local teens queried 5,070 peers attending Caddo Parish schools to better understand the stressors faced by high school students in Northwest Louisiana using a student developed survey. Results were presented to peers at a virtual summit where teens developed action items to reduce stress and presented findings to local leaders. Their efforts ultimately lead to increased supports for students in local schools. Results: Over half of the teens surveyed reported stressors that negatively impacted their physical or emotional well-being. Students endorsing self-harming thoughts reported an average of 7.82 stressors as compared to 3.47 in peers without SHT. Teens with stressors at both home and school were more likely to experience SHT than teens with stressors in a single location. Conclusion: The Gen Z students who developed the TAC Survey identified stress as a major concern for teens in Northwest Louisiana. The TAC Survey data aligns local experience with established data regarding the association between stress, depression and SHT. Second, the results highlight the importance of diving deep to identify all stressors when assessing the risk of self-harm. Finally, the lived experience of local teens with SHT provides critical information for professionals to better understand risk for SHT and suicide in our region and beyond.

Transcranial Magnetic Stimulation for Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that causes significant functional impairment and is related to altered stress response and reinforced learned fear behavior. PTSD has been found to impact three functional networks in the brain: default mode, executive control, and salience. The executive control network includes the dorsolateral prefrontal cortex (DLPFC) and lateral PPC. The salience network involves the anterior cingulate cortex, anterior insula, and amygdala. This latter network has been found to have increased functional connectivity in PTSD. Transcranial Magnetic Stimulation (TMS) is a technique used in treating PTSD and involves stimulating specific portions of the brain through electromagnetic induction. Currently, high-frequency TMS applied to the left dorsolateral prefrontal cortex (DLPFC) is approved for use in treating major depressive disorder (MDD) in patients who have failed at least one medication trial. In current studies, high-frequency stimulation has been shown to be more effective in PTSD rating scales posttreatment than low-frequency stimulation. The most common side effect is headache and scalp pain treated by mild analgesics. Seizures are a rare side effect and are usually due to predisposing factors. Studies have been done to assess the overall efficacy of TMS. However, results have been conflicting, and sample sizes were small. More research should be done with larger sample sizes to test the efficacy of TMS in the treatment of PTSD. Overall, TMS is a relatively safe treatment. Currently, the only FDA- approved to treat refractory depression, but with the potential to treat many other conditions.

Blood glutamine synthetase signaling in alcohol use disorder and racial disparity.

As of 2018, 14.4 million adults ages 18 and older in the U.S had alcohol use disorder (AUD). However, only about 8% of adults who had AUD in the past year received treatment. Surveys have also shown racial disparities regarding AUD treatments. Thus, it is imperative to identify racial disparities in AUD patients, as it may indicate a specific underlying pathophysiology in an AUD subpopulation. To identify racial disparity in AUD, we enrolled 64 cohorts, including 26 AUD participants and 38 healthy controls, from Northwest Louisiana using community-based enrollment. Then, we used psychometric scales to assess alcohol drinking patterns and measured blood metabolites change using LC-MS/MS. Alcohol-related scales from the questionnaires did not differ between the Caucasian AUD participants and African-American AUD participants. From blood metabolomics analyses, we identified that 6 amino acids were significantly different by AUD status and or race. Interestingly, Caucasian AUD participants had a higher glutamate metabolism mediated by glutamine synthetase (GS). The correlation between blood glutamate/glutamine ratio and GS activity was only significant in the Caucasian AUD group whereas no changes were observed in African-American AUD group or controls. Taken together, our findings from this sample population demonstrate that blood GS is a potential biomarker associated with Caucasian AUD, which is an important step towards the application of a new pharmacological treatment for AUD.

Stimulant Drugs of Abuse and Cardiac Arrhythmias.

Nonmedical use of prescription and nonprescription drugs is a worldwide epidemic, rapidly growing in magnitude with deaths because of overdose and chronic use. A vast majority of these drugs are stimulants that have various effects on the cardiovascular system including the cardiac rhythm. Drugs, like cocaine and methamphetamine, have measured effects on the conduction system and through several direct and indirect pathways, utilizing multiple second messenger systems, change the structural and electrical substrate of the heart, thereby promoting cardiac dysrhythmias. Substituted amphetamines and cocaine affect the expression and activation kinetics of multiple ion channels and calcium signaling proteins resulting in EKG changes, and atrial and ventricular brady and tachyarrhythmias. Preexisting conditions cause substrate changes in the heart, which decrease the threshold for such drug-induced cardiac arrhythmias. The treatment of cardiac arrhythmias in patients who take drugs of abuse may be specialized and will require an understanding of the unique underlying mechanisms and necessitates a multidisciplinary approach. The use of primary or secondary prevention defibrillators in drug abusers with chronic systolic heart failure is both sensitive and controversial. This review provides a broad overview of cardiac arrhythmias associated with stimulant substance abuse and their management.

Paliperidone to Treat Psychotic Disorders.

PURPOSE OF REVIEW: This is a comprehensive review of the literature regarding the use of paliperidone in the treatment of schizophrenia and schizoaffective disorder. It covers the background and presentation of schizophrenia and schizoaffective disorder, as well as the mechanism of action and drug information for paliperidone. It covers the existing evidence of the use of paliperidone for the treatment of schizophrenia and schizoaffective disorder. RECENT FINDINGS: Schizophrenia and schizoaffective disorder lead to significant cognitive impairment. It is thought that dopamine dysregulation is the culprit for the positive symptoms of schizophrenia and schizoaffective disorder. Similar to other second-generation antipsychotics, paliperidone has affinity for dopamine D2 and serotonin 5-HT2A receptors. Paliperidone was granted approval in the United States in 2006 to be used in the treatment of schizophrenia and in 2009 for schizoaffective disorder. SUMMARY: Schizophrenia and schizoaffective disorder have a large impact on cognitive impairment, positive symptoms and negative symptoms. Patients with either of these mental illnesses suffer from impairments in everyday life. Paliperidone has been shown to reduce symptoms of schizophrenia and schizoaffective disorder.

Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly.

Biogenesis of high-density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density, driven by excess PL or membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol.

Molecular dynamics study of Zn(aß) and Zn(aß)2.

The aggregation of Aß-peptide (Aß) is widely considered to be the critical step in the pathology of Alzheimer's disease. Small, soluble Aß oligomers have been shown to be more neurotoxic than large, insoluble aggregates and fibrils. Recent studies suggest that biometal ions, including Zn(II), may play an important role in the aggregation process. Experimentally determining the details of the binding process is complicated by the kinetic lability of zinc. To study the dynamic nature of the zinc-bound Aß complexes and the potential mechanisms by which Zn(II) affects Aß oligomerization we have performed atomistic molecular dynamics (MD) simulations of Zn(Aß) and Zn(Aß)2. The models were based on NMR data and predicted coordination environments from previous density functional theory calculations. When modeled as 4-coordinate covalently bound Zn(Aß) n complexes (where n = 1 or 2), zinc imposes conformational changes in the surrounding Aß residues. Moreover, zinc reduces the helix content and increases the random coil content of the full peptide. Although zinc binds at the N-terminus of Aß, ß-sheet formation is observed exclusively at the C-terminus in the Zn(Aß) and most of the Zn(Aß)2 complexes. Furthermore, initial binding to zinc promotes the formation of intra-chain salt-bridges, while subsequent dissociation promotes the formation of inter-chain salt-bridges. These results suggest that Zn-binding to Aß accelerates the aggregation of Aß by unfolding the helical structure in Aß peptide and stabilizing the formation of vital salt-bridges within and between Aß peptides.

Suicidal and homicidal behaviors related to dextromethorphan abuse in a middle-aged woman.

Over-the-counter medications available without prescriptions are generally viewed safe for public consumption. However, when used in excess, these medications can lead to adverse consequences. There are multiple over-the-counter medications that have potential for abuse, and dextromethorphan is one such drug. We describe a case of a middle-aged woman who presented to the psychiatric emergency service after recent use of excessive amounts of dextromethorphan. The patient had developed severe psychotic symptoms and had attempted to kill both herself and her relative. This case highlights the importance of careful reviewing of both prescribed and nonprescribed medications that are being used by patients, especially in the emergency care setting.

The vascular morphology and in vivo muscle temperatures of thresher sharks (Alopiidae).

The thresher sharks comprise a single family (Alopiidae) of pelagic sharks most easily recognized by the elongate dorsal lobe of their caudal fin. Despite morphological similarities among the alopiids, the common thresher (Alopias vulpinus) is unique in that its red, aerobic myotomal muscle (RM) is medially positioned (i.e., closer to the vertebrae), its systemic blood is supplied through a lateral circulation which give rise to counter-current heat exchanging retia, and it is capable of regional RM endothermy. Despite this information, it remains unknown if the other two alopiid species (bigeye thresher, Alopias superciliosus and pelagic thresher, Alopias pelagicus) also possess some or all of the characteristics related to regional RM endothermy. Thus, this study aimed to 1) document the presence of vascular specializations necessary for heat retention and RM endothermy and 2) measure the in vivo muscle temperatures of all three alopiid species. Laboratory dissections of the thresher species showed that only A. vulpinus possesses the lateral branching of the dorsal aorta giving rise to a lateral subcutaneous circulation and retial system, and that RM temperatures are elevated relative to ambient temperature. By contrast, both A. pelagicus and A. superciliosus have a similar systemic blood circulation pathway, in which the dorsal aorta and postcardinal vein form the basis for the central circulation and in vivo RM temperature measurements closely matched those of the ambient temperature at which the sharks were captured. Collectively, the vascular anatomy and in vivo temperature data suggest that only one species of thresher shark (A. vulpinus) possesses the requisite vascular specializations (i.e., lateral subcutaneous vessels and retia mirabilia) that facilitate RM endothermy.

A CXCL8 receptor antagonist based on the structure of N-acetyl-proline-glycine-proline.

A role for the collagen-derived tripeptide, N-acetyl proline-glycine-proline (NAc-PGP), in neutrophil recruitment in chronic airway inflammatory diseases, including COPD and cystic fibrosis, has recently been delineated. Due to structural similarity to an important motif for interleukin-8 (CXCL8) binding to its receptor, NAc-PGP binds to CXCR1/2 receptors, leading to neutrophil activation and chemotaxis. In an effort to develop novel CXCL8 antagonists, we describe the synthesis of four chiral isomers of NAc-PGP (NAc-L-Pro-Gly-L-Pro (LL-NAc-PGP), NAc-L-Pro-Gly-D-Pro (LD-NAc-PGP), NAc-D-Pro-Gly-L-Pro (DL-NAc-PGP), and NAc-D-Pro-Gly-D-Pro (DD-NAc-PGP)), characterize them by circular dichroism and NMR spectroscopy, compare their structures to the equivalent region of CXCL8, and test them as potential antagonists of ll-NAc-PGP and CXCL8. We find that LL-NAc-PGP superimposes onto the CXCR1/2 contacting E(29)S(30)G(31)P(32) region of CXCL8 (0.59A rmsd for heavy atoms). In contrast, DD-NAc-PGP has an opposing orientation of key functional groups as compared to the G(31)P(32) region of CXCL8. As a consequence, DD-NAc-PGP binds CXCR1/2, as demonstrated by competition with radiolabeled CXCL8 binding in a radioreceptor assay, yet acts as a receptor antagonist as evidenced by inhibition of CXCL8 and LL-NAc-PGP mediated neutrophil chemotaxis. The ability of DD-NAc-PGP to prevent the activation of CXC receptors indicates that DD-NAc-PGP may serve as a lead compound for the development of CXCR1/2 inhibitors. In addition, this study further proves that using a different technical approach, namely preincubation of NAc-PGP instead of simultaneous addition of NAc-PGP with radiolabeled CXCL8, the direct binding of NAc-PGP to the CXCL8 receptor is evident.

Early Detection of Brain Pathology Suggestive of Early AD Using Objective Evaluation of FDG-PET Scans.

The need for early detection of AD becomes critical as disease-modifying agents near the marketplace. Here, we present results from a study focused on improvement in detection of metabolic deficits related to neurodegenerative changes consistent with possible early AD with statistical evaluation of FDG-PET brain images. We followed 31 subjects at high risk or diagnosed with MCI/AD for 3 years. 15 met criteria for diagnosis of MCI, and five met criteria for AD. FDG-PET scans were completed at initiation and termination of the study. PET scans were read clinically and also evaluated objectively using Statistical Parametric Mapping (SPM). Using standard clinical evaluation of the FDG-PET scans, 11 subjects were detected, while 18 were detected using SPM evaluation. These preliminary results indicate that objective analyses may improve detection; however, early detection in at-risk normal subjects remains tentative. Several FDA-approved software packages are available that use objective analyses, thus the capacity exists for wider use of this method for MCI/AD.

Structures of discoidal high density lipoproteins: a combined computational-experimental approach.

Conversion of discoidal phospholipid (PL)-rich high density lipoprotein (HDL) to spheroidal cholesteryl ester-rich HDL is a central step in reverse cholesterol transport. A detailed understanding of this process and the atheroprotective role of apolipoprotein A-I (apoA-I) requires knowledge of the structure and dynamics of these various particles. This study, combining computation with experimentation, illuminates structural features of apoA-I allowing it to incorporate varying amounts of PL. Molecular dynamics simulated annealing of PL-rich HDL models containing unesterified cholesterol results in double belt structures with the same general saddle-shaped conformation of both our previous molecular dynamics simulations at 310 K and the x-ray structure of lipid-free apoA-I. Conversion from a discoidal to a saddle-shaped particle involves loss of helicity and formation of loops in opposing antiparallel parts of the double belt. During surface expansion caused by the temperature-jump step, the curved palmitoyloleoylphosphatidylcholine bilayer surfaces approach planarity. Relaxation back into saddle-shaped structures after cool down and equilibration further supports the saddle-shaped particle model. Our kinetic analyses of reconstituted particles demonstrate that PL-rich particles exist in discrete sizes corresponding to local energetic minima. Agreement of experimental and computational determinations of particle size/shape and apoA-I helicity provide additional support for the saddle-shaped particle model. Truncation experiments combined with simulations suggest that the N-terminal proline-rich domain of apoA-I influences the stability of PL-rich HDL particles. We propose that apoA-I incorporates increasing PL in the form of minimal surface bilayers through the incremental unwinding of an initially twisted saddle-shaped apoA-I double belt structure.

Changes in hippocampal metabolites after effective treatment for fibromyalgia: a case study.

BACKGROUND: Fibromyalgia has been associated with disrupted hippocampal brain metabolite ratios by studies using single voxel magnetic resonance spectroscopy (1H-MRS). Exposure to stress is considered a risk factor for the development and exacerbation of fibromyalgia symptoms. Basic science has demonstrated the hippocampus to be exquisitely sensitive to the effects of stressful experience, which results in changes including alterations in metabolite content and frank atrophy. METHODS: This report details the case of a 47-year-old woman with fibromyalgia who was originally found to have a profound depression of the ratio of N-acetylaspartate to creatine in her right hippocampus during participation in a study to assess brain metabolite disturbances in fibromyalgia utilizing single voxel proton magnetic resonance spectroscopy. An individualized treatment strategy was developed based both on physiological abnormalities associated with the disorder and symptoms that characterized the patient's unique clinical profile. RESULTS: Clinical and spectroscopic evaluation following nine months of treatment demonstrated both an improvement in her clinical profile and normalization of the NAA/Cr ratio within her right hippocampus. DISCUSSION: Therapeutic strategies aimed at demonstrable lesions associated with fibromyalgia appear to represent rational targets for pharmacological intervention. The rationale for development of novel pharmacotherapies for this unusual disorder is discussed.

Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism.

UNLABELLED: Fibromyalgia (FM) has been associated with alterations in brain morphometry and abnormal dopaminergic neurotransmission. Evidence from preclinical models has demonstrated that dopamine plays a role in promoting neuronal integrity. We therefore sought to confirm previous findings of reduced gray matter density in subjects with FM and to determine whether variations in dopamine metabolism might affect gray matter density. Voxel-based morphometry was used to evaluate anatomical magnetic resonance imaging data from 30 female FM subjects in comparison with 20 age- and gender-matched healthy control subjects. In addition, data from a subset of subjects from both groups who had previously participated in our positron emission tomography study using radiolabeled DOPA (n = 14; 6 FM subjects and 8 control subjects) was used to determine whether correlation might exist between gray matter density and dopamine metabolism. We found a significant reduction in gray matter density within the bilateral parahippocampal gyri, right posterior cingulate cortex, and left anterior cingulate cortex. In addition, a positive correlation was demonstrated between an index of dopamine metabolism from the ventral tegmental area wherein cell bodies of corticolimbic projection neurons originate and gray matter density, specifically in the bilateral parahippocampal gyri and left pregenual cortex. The current results confirm our previous findings that FM is associated with altered brain morphometry. Alterations in dopamine metabolism might contribute to the associated changes in gray matter density. PERSPECTIVE: Fibromyalgia is associated with reductions in gray matter density within brain regions ostensibly involved in phenomena related to the disorder, including enhanced pain perception, cognitive dysfunction, and abnormal stress reactivity. Given mounting evidence of abnormal dopaminergic neurotransmission associated with the disorder, the strong correlation between dopamine metabolism and gray matter density provides insight as to the pathophysiology that might contribute to these changes.

Thermal stability of apolipoprotein A-I in high-density lipoproteins by molecular dynamics.

Apolipoprotein (apo) A-I is an unusually flexible protein whose lipid-associated structure is poorly understood. Thermal denaturation, which is used to measure the global helix stability of high-density lipoprotein (HDL)-associated apoA-I, provides no information about local helix stability. Here we report the use of temperature jump molecular dynamics (MD) simulations to scan the per-residue helix stability of apoA-I in phospholipid-rich HDL. When three 20 ns MD simulations were performed at 500 K on each of two particles created by MD simulations at 310 K, bilayers remained intact but expanded by 40%, and total apoA-I helicity decreased from 95% to 72%. Of significance, the conformations of the overlapping N- and C-terminal domains of apoA-I in the particles were unusually mobile, exposing hydrocarbon regions of the phospholipid to solvent; a lack of buried interhelical salt bridges in the terminal domains correlated with increased mobility. Nondenaturing gradient gels show that 40% expansion of the phospholipid surface of 100:2 particles by addition of palmitoyloleoylphosphatidylcholine exceeds the threshold of particle stability. As a unifying hypothesis, we propose that the terminal domains of apoA-I are phospholipid concentration-sensitive molecular triggers for fusion/remodeling of HDL particles. Since HDL remodeling is necessary for cholesterol transport, our model for remodeling has substantial biomedical implications.