Recent social stress and severity of auditory hallucinations.

BACKGROUND AND HYPOTHESIS: Hearing voices is a common and often distressing experience for people with psychosis, and many individuals experience medication-resistant auditory verbal hallucinations (AVH). Psychosocial interventions are often employed to address distress over hearing voices. However, although links have been made between adverse social experiences and psychosis broadly, no work has yet delineated the relationship between day-to-day social stress and hallucination severity. We aimed to define that relationship in both clinical and non-clinical voice-hearers. STUDY DESIGN: A sample of 278 participants with a history of hearing voices was selected from the Yale Control Over Perceptual Experiences (COPE) Project. They were administered self-report measures of recent stress and recent auditory experiences within a cross-sectional design. Regression models were used to evaluate whether self-reported aspects of recent stress-and social stress in particular-were related to recent frequency of and distress over hearing voices. Related demographics and clinical characteristics were included as covariates. STUDY RESULTS: A significant relationship was observed between recent social stress and both recent frequency of and distress over hearing voices. While other aspects of recent stress were also related to recent distress over voices, social stressors uniquely predicted distress over voice-hearing, beyond the influence of other stressors. Depressive symptom severity was also related to distress over voices. CONCLUSIONS: Results suggest that daily social stress may be an important consideration and a potential treatment target for individuals experiencing clinical distress over auditory hallucinations.

Preservation of the heart in ancient Egyptian mummies: A computed tomography investigation with focus on the myocardium.

The ancient Egyptians considered the heart to be the most important organ. The belief that the heart remained in the body is widespread in the archeological and paleopathological literature. The purpose of this study was to perform an overview of the preserved intrathoracic structures and thoracic and abdominal cavity filling, and to determine the prevalence and computed tomography (CT) characteristics of the myocardium in the preserved hearts of ancient Egyptian mummies. Whole-body CT examinations of 45 ancient Egyptian mummies (23 mummies from the Ägyptisches Museum und Papyrussammlung, Berlin, Germany, and 22 mummies from the Museo Egizio, Turin, Italy) were systematically assessed for preserved intrathoracic soft tissues including various anatomical components of the heart (pericardium, interventricular septum, four chambers, myocardium, valves). Additionally, evidence of evisceration and cavity filling was documented. In cases with identifiable myocardium, quantitative (measurements of thickness and density) and qualitative (description of the structure) assessment of the myocardial tissue was carried out. Heart structure was identified in 28 mummies (62%). In 33 mummies, CT findings demonstrated evisceration, with subsequent cavity filling in all but one case. Preserved myocardium was identified in nine mummies (five male, four female) as a mostly homogeneous, shrunken structure. The posterior wall of the myocardium had a mean maximum thickness of 3.6 mm (range 1.4-6.6 mm) and a mean minimum thickness of 1.0 mm (range 0.5-1.7 mm). The mean Hounsfield units (HU) of the myocardium at the posterior wall was 61 (range, 185-305). There was a strong correlation between the HU of the posterior wall of the myocardium and the mean HU of the muscles at the dorsal humerus (R = 0.77; p = 0.02). In two cases, there were postmortem changes in the myocardium, most probably due to insect infestation. To our knowledge, this is the first study to investigate the myocardium systematically on CT scans of ancient Egyptian mummies. Strong correlations between the densities of the myocardium and skeletal muscle indicated similar postmortem changes of the respective musculature during the mummification process within individual mummies. The distinct postmortem shrinking of the myocardium and the collapse of the left ventriclular cavity in several cases did not allow for paleopathological diagnoses such as myocardial scarring.

Different learning aberrations relate to delusion-like beliefs with different contents.

The prediction error account of delusions has had success. However, its explanation of delusions with different contents has been lacking. Persecutory delusions and paranoia are the common unfounded beliefs that others have harmful intentions towards us. Other delusions include believing that one's thoughts or actions are under external control, or that events in the world have specific personal meaning. We compare learning on two different cognitive tasks, probabilistic reversal learning (PRL) and Kamin blocking, that have relationships to paranoid and non-paranoid delusion-like beliefs, respectively. We find that Clinical High-Risk status alone does not result in different behavioral results on the PRL task but that an individual's level of paranoia is associated with excessive switching behavior. During the Kamin blocking task, paranoid individuals learned inappropriately about the blocked cue. However, they also had decreased learning about the control cue, suggesting more general learning impairments. Non-paranoid delusion-like belief conviction (but not paranoia) was associated with aberrant learning about the blocked cue but intact learning about the control cue, suggesting specific impairments in learning related to cue combination. We fit task-specific computational models separately to behavioral data to explore how latent parameters vary within individuals between tasks, and how they can explain symptom-specific effects. We find that paranoia is associated with low learning rates on the PRL task as well as the blocking task. Non-paranoid delusion-like belief conviction was instead related to parameters controlling the degree and direction of similarity between cue updating during simultaneous cue presentation. These results suggest that paranoia and other delusion-like beliefs involve dissociable deficits in learning and belief updating, which - given the transdiagnostic status of paranoia - may have differential utility in predicting psychosis.

Wilderness Medical Society Clinical Practice Guidelines for the Treatment of Acute Pain in Austere Environments: 2024 Update.

The Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the management of pain in austere environments. Recommendations are graded based on the quality of supporting evidence as defined by criteria put forth by the American College of Chest Physicians. This is an update of the 2014 version of the "WMS Practice Guidelines for the Treatment of Acute Pain in Remote Environments" published in Wilderness & Environmental Medicine 2014; 25:41-49.

TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in ALS/FTD and related disorders.

Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and fronto- temporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet, this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from RNA-seq (DaPars) tool to ALS/FTD transcriptome datasets, and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional significance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3'UTRs, resulting in greater transcript stability and elevated MARK3 protein levels, which promotes increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously unrecognized feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially novel mechanistic link between TDP-43 dysfunction and tau regulation.

On the proportion of patients who experience a prodrome prior to psychosis onset: A systematic review and meta-analysis.

BACKGROUND: Preventing or delaying the onset of psychosis requires identification of those at risk for developing psychosis. For predictive purposes, the prodrome - a constellation of symptoms which may occur before the onset of psychosis - has been increasingly recognized as having utility. However, it is unclear what proportion of patients experience a prodrome or how this varies based on the multiple definitions used. METHODS: We conducted a systematic review and meta-analysis of studies of patients with psychosis with the objective of determining the proportion of patients who experienced a prodrome prior to psychosis onset. Inclusion criteria included a consistent prodrome definition and reporting the proportion of patients who experienced a prodrome. We excluded studies of only patients with a prodrome or solely substance-induced psychosis, qualitative studies without prevalence data, conference abstracts, and case reports/case series. We searched Ovid MEDLINE, Embase (Ovid), APA PsycInfo (Ovid), Web of Science Core Collection (Clarivate), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, APA PsycBooks (Ovid), ProQuest Dissertation & Thesis, on March 3, 2021. Studies were assessed for quality using the Critical Appraisal Checklist for Prevalence Studies. Narrative synthesis and proportion meta-analysis were used to estimate prodrome prevalence. I2 and predictive interval were used to assess heterogeneity. Subgroup analyses were used to probe sources of heterogeneity. (PROSPERO ID: CRD42021239797). RESULTS: Seventy-one articles were included, representing 13,774 patients. Studies varied significantly in terms of methodology and prodrome definition used. The random effects proportion meta-analysis estimate for prodrome prevalence was 78.3% (95% CI = 72.8-83.2); heterogeneity was high (I2 97.98% [95% CI = 97.71-98.22]); and the prediction interval was wide (95% PI = 0.411-0.936). There were no meaningful differences in prevalence between grouped prodrome definitions, and subgroup analyses failed to reveal a consistent source of heterogeneity. CONCLUSIONS: This is the first meta-analysis on the prevalence of a prodrome prior to the onset of first episode psychosis. The majority of patients (78.3%) were found to have experienced a prodrome prior to psychosis onset. However, findings are highly heterogenous across study and no definitive source of heterogeneity was found despite extensive subgroup analyses. As most studies were retrospective in nature, recall bias likely affects these results. While the large majority of patients with psychosis experience a prodrome in some form, it is unclear if the remainder of patients experience no prodrome, or if ascertainment methods employed in the studies were not sensitive to their experiences. Given widespread investment in indicated prevention of psychosis through prospective identification and intervention during the prodrome, a resolution of this question as well as a consensus definition of the prodrome is much needed in order to effectively direct and organize services, and may be accomplished through novel, densely sampled and phenotyped prospective cohort studies that aim for representative sampling across multiple settings.

Size-dependent therapeutic efficiency of 223Ra-labeled calcium carbonate carriers for internal radionuclide therapy of breast cancer.

The size of drug carriers strongly affects their biodistribution, tissue penetration, and cellular uptake in vivo. As a result, when such carriers are loaded with therapeutic compounds, their size can influence the treatment outcomes. For internal α-radionuclide therapy, the carrier size is particularly important, because short-range α-emitters should be delivered to tumor volumes at a high dose rate without any side effects, i.e. off-target irradiation and toxicity. In this work, we aim to evaluate and compare the therapeutic efficiency of calcium carbonate (CaCO3) microparticles (MPs, >2 µm) and nanoparticles (NPs, <100 nm) labeled with radium-223 (223Ra) for internal α-radionuclide therapy against 4T1 breast cancer. To do this, we comprehensively study the internalization and penetration efficiency of these MPs and NPs, using 2D and 3D cell cultures. For further therapeutic tests, we develop and modify a chelator-free method for radiolabeling of CaCO3 MPs and NPs with 223Ra, improving their radiolabeling efficiency (>97%) and radiochemical stability (>97%). After intratumoral injection of 223Ra-labeled MPs and NPs, we demonstrate their different therapeutic efficiencies against a 4T1 tumor. In particular, 223Ra-labeled NPs show a tumor inhibition of approximately 85%, which is higher compared to 60% for 223Ra-labeled MPs. As a result, we can conclude that 223Ra-labeled NPs have a more suitable biodistribution within 4T1 tumors compared to 223Ra-labeled MPs. Thus, our study reveals that 223Ra-labeled CaCO3 NPs are highly promising for internal α-radionuclide therapy.

Surgical Safety Does Not Happen By Accident: Learning From Perioperative Near Miss Case Studies.

Adverse surgical events cause negative patient health outcomes and harm that can often overshadow the safe and effective patient care provided daily by nurses as members of interprofessional healthcare teams. Near misses occur far more frequently than adverse events and are less visible to nurse leaders because patient harm is avoided due to chance, prevention, or mitigation. However, near misses have comparable root causes to adverse events and exhibit the same underlying patterns of failure. Reviewing near misses provides nurses with learning opportunities to identify patient care weaknesses and build appropriate solutions to enhance care. As the operating room is one of the most complex work settings in healthcare, identifying potential weaknesses or sources for errors is vital to reduce healthcare-associated risks for patients and staff. The purpose of this manuscript is to educate, inform, and stimulate critical thinking by discussing perioperative near miss case studies and the underlying factors that lead to errors. Our authors discuss 15 near miss case studies occurring across the perioperative patient experience of care and discuss barriers to near miss reporting. Nurse leaders can use our case studies to stimulate discussion among perioperative and perianesthesia nurses in their hospitals to inform comprehensive risk reduction programs.

Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity.

Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacologic inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated that ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by cotargeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that noncanonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies. SIGNIFICANCE: ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment.

Wilderness Medical Society Clinical Practice Guidelines for Prevention and Management of Avalanche and Nonavalanche Snow Burial Accidents: 2024 Update.

To provide guidance to the general public, clinicians, and avalanche professionals about best practices, the Wilderness Medical Society convened an expert panel to revise the evidence-based guidelines for the prevention, rescue, and resuscitation of avalanche and nonavalanche snow burial victims. The original panel authored the Wilderness Medical Society Practice Guidelines for Prevention and Management of Avalanche and Nonavalanche Snow Burial Accidents in 2017. A second panel was convened to update these guidelines and make recommendations based on quality of supporting evidence.

Inorganic polyphosphate regulates functions of thymocytes via activation of P2X purinoreceptors.

Inorganic polyphosphate (polyP) is an ancient polymer, which was proven to be a signalling molecule in the mammalian brain, mediating the communication between astrocytes via activation of P2Y1 purinoreceptors and modulating the activity of neurons. There is very limited information regarding the ability of polyP to transmit the information as an agonist of purinoreceptors in other cells and tissues. Here, we show that application of polyP to the suspension of primary thymocytes increases the concentration of intracellular calcium. PolyP evoked calcium signal was dependent on the presence of P2X inhibitors but not P2Y1 inhibitor. PolyP dependent increase in intracellular calcium concentration caused mild mitochondrial depolarization, which was dependent on inhibitors of purinoreceptors, extracellular calcium and inhibitor of mitochondrial calcium uniporter but wasn't dependent on cyclosporin A. Application of polyP modulated cell volume regulation machinery of thymocytes in calcium dependent manner. Molecular docking experiments revealed that polyP can potentially bind to several types of P2X receptors with binding energy similar to ATP - natural agonist of P2X purinoreceptors. Further molecular dynamics simulations with P2X4 showed that binding of one molecule of polyP dramatically increases permeability of this receptor-channel for water molecules. Thus, in this research we for the first time showed that polyP can interact with P2X receptors in thymocytes and modulate physiological processes.

Periop 101: Improving Perioperative Nursing Knowledge and Competence in Labor and Delivery Nurses Through an Evidence-Based Education and Training Program.

INTRODUCTION: To reach the highest levels of health care quality, all nurses providing intraoperative care to surgical patients should have a firm grasp of the complex knowledge, skills, and guidelines undergirding the perioperative nursing profession. In military treatment facilities, either perioperative registered nurses or labor and delivery (L&D) nurses provide skilled intraoperative nursing care for cesarean deliveries. However, L&D and perioperative nurses occupy vastly different roles in the continuum of care and may possess widely differing levels of surgical training and experience. MATERIALS AND METHODS: The purpose of this project was to improve surgical care quality by standardizing and strengthening L&D nurse perioperative training, knowledge, and competence. Our population, intervention, comparative, and outcome question was, "For labor and delivery nurses of a regional military medical center (P), does implementing an evidence-based training program (I), as compared to current institutional nursing practices (C), increase nursing knowledge and perioperative nursing competence (O)?" We implemented Periop 101: A Core Curriculum-Cesarean Section training for 17 L&D nurses, measured knowledge using product-provided testing, and assessed competence using the Perceived Perioperative Competence Scale-Revised. RESULTS: We found that perioperative nursing knowledge and competence significantly improved and were less varied among the nurses after completing the training program. Nurses demonstrated the greatest knowledge area improvements in scrubbing, gowning, and gloving; wound healing; and sterilization and disinfection, for which median scores improved by more than 100%. Nurses reported significantly greater perceived competence across all six domains of the Perioperative Competence Scale-Revised, with the largest improvements realized in foundational skills and knowledge, leadership, and proficiency. CONCLUSIONS: We recommend that health care leaders develop policies to standardize perioperative education, training, and utilization for nurses providing intraoperative care to reduce clinician role ambiguity, decrease inefficiencies, and enhance care.