A computational account of the development and evolution of psychotic symptoms.

The mechanisms of psychotic symptoms like hallucinations and delusions are often investigated in fully-formed illness, well after symptoms emerge. These investigations have yielded key insights, but are not well-positioned to reveal the dynamic forces underlying symptom formation itself. Understanding symptom development over time would allow us to identify steps in the pathophysiological process leading to psychosis, shifting the focus of psychiatric intervention from symptom alleviation to prevention. We propose a model for understanding the emergence of psychotic symptoms within the context of an adaptive, developing neural system. We will make the case for a pathophysiological process that begins with cortical hyperexcitability and bottom-up noise transmission, which engenders inappropriate belief formation via aberrant prediction error signaling. We will argue that this bottom-up noise drives learning about the (im)precision of new incoming sensory information because of diminished signal-to-noise ratio, causing an adaptive relative over-reliance on prior beliefs. This over-reliance on priors predisposes to hallucinations and covaries with hallucination severity. An over-reliance on priors may also lead to increased conviction in the beliefs generated by bottom-up noise and drive movement toward conversion to psychosis. We will identify predictions of our model at each stage, examine evidence to support or refute those predictions, and propose experiments that could falsify or help select between alternative elements of the overall model. Nesting computational abnormalities within longitudinal development allows us to account for hidden dynamics among the mechanisms driving symptom formation and to view established symptomatology as a point of equilibrium among competing biological forces.

Development of a Risk Stratification Model for Pre-liver-Transplant Screening Colonoscopy.

BACKGROUND AND AIMS: Colonoscopies are routinely obtained before liver transplantation, although their utility is a highly debated topic in the literature. We aimed to determine the risk factors in patients with decompensated cirrhosis (DC) for post-colonoscopy complications (PCC). MATERIALS AND METHODS: We performed a single-center retrospective study of patients with DC undergoing colonoscopy as part of their pre-liver-transplant evaluation. The primary composite outcome was defined as a complication occurring within 30 days of the colonoscopy. Complications included acute renal failure, new or worsening ascites or hepatic encephalopathy, gastrointestinal bleeding, or any cardiopulmonary or infectious complication. Logistic regression analysis was utilized to derive a risk score in predicting the primary composite outcome. RESULTS: The strongest predictors of post-colonoscopy complication were MELD-Na ≥21 [aOR 4.0026 ( P =0.0050)] and history of any infection in the 30 days before colonoscopy [aOR 8.4345 ( P =0.0093)]. The area under the receiver operating characteristic curve of the final model was 0.78. The predicted risk of any complication at the lowest quartile was 16.2% to 39.4%, and the observed risk was 30.6% (95% CI: 15.5-45.6%), while the predicted risk at the highest quartile was 71.9% to 97.1%, and the observed risk was 81.3% (95% CI: 67.7-95%). CONCLUSION: In this cohort of patients with DC undergoing colonoscopy for pre-liver-transplant evaluation, a history of ascites, spontaneous bacterial peritonitis, and MELD-Na were found to be predictive of PCC. This risk score may help to predict PCC in patients with DC undergoing a pre-transplant colonoscopy. External validation is recommended.

The Use and Perceptions of the Defense and Veterans Pain Rating Scale by Nursing Personnel.

BACKGROUND: In 2010, the Office of the US Army Surgeon General recommended the Veterans Administration (VA) assess pain using the Defense and Veterans Pain Rating Scale (DVPRS). One item in the DVPRS is for measuring pain intensity. This item contains a combination of five response metrics: categories, faces, colors, numbers, and functional descriptors. A few studies have supported patients' and health care providers' preferences for the DVPRS and its psychometric properties. However, they also left uncertainties about its usability and validity. AIMS: To advance our understanding of the DVPRS, this study examined the use and perceptions of the DVPRS' pain intensity item by nursing personnel during multi-modal care. DESIGN: A cross-sectional survey design was used. SETTING: VA Community Living Center. PARTICIPANTS: Nursing personnel. METHODS: Nursing personnel answered closed- and open-ended survey questions during a single session. RESULTS: Nursing personnel reported sufficient training before implementing the measure and that patients primarily used the numeric metric. When patients used a non-numeric metric, the nursing personnel responded in variable ways. In addition, the nursing personnel interpreted the functional descriptors differently. The nursing personnel also noted the need to supplement the pain intensity item with patients' pain duration and pain location. CONCLUSIONS: Results from this study inform the nursing community about the DVPRS' pain intensity item, which combines multiple response metrics. The results support the need for nursing units to generate and standardize procedures for using the item to measure multi-site pain and for interpreting and documenting patients' non-numeric responses. The effects of such procedures on the measure's usability and psychometric properties warrants additional investigation.

Posterior capsule edema in adhesive capsulitis: comparison with established non-contrast MRI findings and multivariable analysis.

OBJECTIVES: To evaluate posterior glenohumeral capsule edema compared to other MRI findings in adhesive capsulitis (AC). METHODS: This study was approved by the local Institutional Review Board and it is HIPAA compliant. A retrospective search identified subjects who received fluoroscopically guided intra-articular corticosteroid injections for AC and had an MRI within 6 months prior to injection. The study group was compared with an age-, sex-, and side-matched control group who underwent the same procedures but did not have AC. MRIs were evaluated for edema of posterior capsule, anterior capsule, axillary pouch, coracohumeral ligament (CHL) and rotator interval (RI), thickness of axillary pouch and CHL, thickness of anterior capsule, RI and subcoracoid fat replacement, and teres minor atrophy and edema. Multivariable analysis was performed. RESULTS: A total of 57 subjects with AC and 57 matched controls were studied: mean age 52 ± 7 (range 31-71) years, 37 female and 20 male, 22 right and 35 left. Posterior capsule edema was more common in the AC group vs. control group (66.7 vs 17.5%, p < 0.001). Multivariable analysis showed posterior capsule edema, CHL edema, and axillary pouch (glenoid) thickness (optimum cutoff = 4 mm) were significant independent predictors of AC. Simplified analysis using these three variables had an area under the curve of 0.860 (95%CI: 0.792-0.928). With all three variables present, the sensitivity and specificity for AC were 32% and 98%, respectively. CONCLUSIONS: Posterior joint capsule edema may be helpful to confirm AC. Posterior capsule edema, CHL edema, and axillary pouch (glenoid) thickness produce a strong model for distinguishing AC from controls. CLINICAL RELEVANCE STATEMENT: Edema involving the posterior shoulder joint capsule is an imaging marker of capsulitis and is useful in differentiating patients with adhesive capsulitis from those without in conjunction with other proven MRI findings. KEY POINTS: • Posterior capsule edema has a sensitivity of 66.7% and a specificity of 82.5% for the detection of adhesive capsulitis. • Posterior capsule edema, coracohumeral ligament (CHL) edema, and axillary pouch (glenoid) thickness were significant independent predictors of adhesive capsulitis, and combining these variables together produces a very strong model for distinguishing cases from controls (AUC = 0.860). • Optimal cutoff values for CHL, axillary pouch (humeral), axillary pouch (glenoid), and axillary pouch (total) thickness were 2.5, 2.6, 4, and 6.3 mm, respectively.

HLA-DPB1*13:01 associates with enhanced, and KIR2DS4*001 with diminished protection from developing severe COVID-19.

Extreme polymorphism of HLA and killer-cell immunoglobulin-like receptors (KIR) differentiates immune responses across individuals. Additional to T cell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that possession of the activating KIR2DS4*001 allotype is associated with severe disease, requiring hospitalization (OR = 1.48, 95% CI 1.20-1.85, pc = 0.017), and this effect is greater in individuals homozygous for KIR2DS4*001 (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from severe disease (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-α associated with COVID-19 severity were detected in 26% of 156 hospitalized patients tested. HLA-C*08:02 was more frequent in patients with IFN-α autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN-α antibodies. These findings suggest that KIR and HLA polymorphism is integral in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

Clinical and genetic predictors of cardiac dysfunction assessed by echocardiography in patients with hereditary hemochromatosis.

PURPOSE: Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. METHODS: In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. RESULTS: 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. CONCLUSION: We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF.

A review of uvulopalatopharyngoplasty for pediatric obstructive sleep apnea.

OBJECTIVES: To evaluate existing literature to understand the utility and safety of uvulopalatopharyngoplasty (UPPP) for treatment of pediatric obstructive sleep apnea (OSA). METHODS: A literature review was conducted by two authors to search for studies from the inception of two databases until March 1, 2023. Studies in which participants were under 18 years of age and underwent UPPP for OSA or upper airway obstruction were selected. Data on variables such as pre- and postoperative severity, efficacy, complications, and follow-up were collected from all studies. RESULTS: After applying inclusion criteria to the initial 91 abstracts that were screened, 26 studies remained that included 224 patients who underwent UPPP. Most children who underwent UPPP had neurologic impairment, developmental delay, craniofacial abnormalities, or were obese, and underwent several procedures for OSA treatment. Of the studies that reported outcomes, 85.6 % of patients had subjective improvement, and 25.6 % of patients had a reported complication. CONCLUSIONS: Most children who underwent UPPP had serious medical comorbidities with moderate or severe OSA and a multi-procedural treatment plan. Although most patients had subjective improvement and there were low complication rates, the heterogeneity of existing literature makes it difficult to draw conclusions. Future multi-center, prospective studies should be conducted to analyze the true safety and efficacy of UPPP in pediatric patients.

Unraveling the Phenotypic States of Human innate-like T Cells: Comparative Insights with Conventional T Cells and Mouse Models.

The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity, having the ability to mount rapid responses following activation. In mice, this ability is acquired during thymic development. We explored the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single cell RNA sequencing and flow cytometry. We reveal that in human blood, the majority of Tinn cells, including iNKT, MAIT, and Vδ2+Vγ9+ T cells, share an effector program characterized by the expression of unique chemokine and cytokine receptors, and cytotoxic molecules. This program is driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type I/type III effector potential. To conduct a comprehensive cross-species analysis, we constructed a murine Tinn developmental atlas and uncovered additional species-specific distinctions, including the absence of type II Tinn cells in humans, which implies distinct immune regulatory mechanisms across species. The study provides insights into the development and functionality of Tinn cells, emphasizing their role in immune responses and their potential as targets for therapeutic interventions.

Contrasting allelic effects for pistachio salinity tolerance in juvenile and mature trees.

Breeding perennial tree crops often requires prediction of mature performance from juvenile data. To assess the utility of juvenile screens to predict salinity tolerance of mature pistachio trees, we compared performance of 3-month ungrafted seedlings and 4-year-old grafted rootstocks under salinity stress. The QTL allele associated with higher salt exclusion from seedling leaves conferred lower growth in saline field conditions, suggesting that mapping QTL in seedlings may be easier than discerning the optimal allele for field performance.

Challenges facing mental health systems arising from the COVID-19 pandemic: Evidence from 14 European and North American countries.

We assessed challenges that the COVID-19 pandemic presented for mental health systems and the responses to these challenges in 14 countries in Europe and North America. Experts from each country filled out a structured questionnaire with closed- and open-ended questions between January and June 2021. We conducted thematic analysis to investigate the qualitative responses to open-ended questions, and we summarized the responses to closed-ended survey items on changes in telemental health policies and regulations. Findings revealed that many countries grappled with the rising demand for mental health services against a backdrop of mental health provider shortages and challenges responding to workforce stress and burnout. All countries in our sample implemented new policies or initiatives to strengthen mental health service delivery - with more than two-thirds investing to bolster their specialized mental health care sector. There was a universal shift to telehealth to deliver a larger portion of mental health services in all 14 countries, which was facilitated by changes in national regulations and policies; 11 of the 14 participating countries relaxed regulations and 10 of 14 countries made changes to reimbursement policies to facilitate telemental health care. These findings provide a first step to assess the long-term challenges and re-organizational effect of the COVID-19 pandemic on mental health systems in Europe and North America.

Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells.

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8+ T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3+ T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.

Pituitary Adenomas as a Barometer for Health Care Access.

Introduction Expanding access to care has been shown to impact patient care and disease epidemiology for different disease states, but has not been studied in pituitary adenoma. We hypothesize that increasing access to care-which includes diagnostics-through the Affordable Care Act (ACA) and Medicaid expansion has increased identification of pituitary adenomas. Methods The National Cancer Institute's Surveillance, Epidemiology, and End Results database was utilized to identify patients with pituitary adenomas from 2007-to 2016 yielding 39,120 cases. Demographic, histologic, and insurance data were extracted. After stratification based on their insurance status, they were plotted to examine trends in insurance status after introduction of the ACA and Medicaid expansion. Magnetic resonance imaging (MRI) data was gathered from the Organization for Economic Co-operation and Development. A linear regression model was developed to describe the relationship between pituitary adenoma discovery and the number of MRI exams. Results Pituitary adenoma diagnoses (37.6%) and MRI examinations per 1,000 in the U.S. (32.3%) increased concurrently from 2007 to 2016. Linear regression analysis revealed a statistically significant relationship ( p = 0.0004). Those patients without insurance diagnosed with pituitary adenomas decreased 36.8% after Medicaid expansion ( p = 0.023). With respect to Medicaid utilization, significant increases of 28.5% ( p = 0.014) and 30.3% ( p = 0.00096) were noted after both the ACA enactment and Medicaid expansion, respectively. Conclusion The ACA has expanded health care access which has increased the ability to identify patients with pituitary adenomas. The present study also provides evidence that access to care is important for less prevalent diseases such as pituitary adenomas.

Racial Disparity in Tympanostomy Tube Placement in Inpatient Pediatric Admissions.

This study aims to evaluate if race and ethnicity affect rates of tympanostomy tube (TT) placement during inpatient pediatric admissions in children with otologic conditions. A review of the 2016 Kids' Inpatient Database was conducted based on the International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM) codes for common otologic conditions. Among 85 827 weighted pediatric inpatient discharges with ICD-10-CM codes for common otologic conditions, 213 underwent TT placement. Odds ratios (ORs) for children of Hispanic ethnicity and Asian or Pacific Islander race undergoing TT placement when compared to other ethnicities and races were 0.60 (P = .011) and 0.21 (P = .040), respectively. Multiple logistic regression showed Hispanic ethnicity was associated with lower rates of TT placement when compared to non-Hispanic white children (OR = 0.62; 95% confidence interval = 0.40-0.96). Future studies should assess why these differences exist and if these differences are associated with racial/ethnic bias or attributed to patient/family preference.

Symptom-imaging correlation in lumbar spine pain.

Lumbar spine MRI is associated with a high prevalence of morphological abnormalities in both symptomatic and asymptomatic individuals. A difficult challenge, therefore, is distinguishing the relevant findings causing symptoms from incidental findings. The accurate diagnosis of pain generator is important because misdiagnosis can negatively impact patient management and outcome. Spine physicians use clinical symptoms and signs to interpret lumbar spine MRI and make treatment decisions. Symptom-MRI correlation enables the targeted inspection of images for pain generator. Radiologists can also use clinical information to improve diagnostic confidence and the value of dictated reports. Because high-quality clinical information may be difficult to obtain, radiologists often generate lists of lumbar spine abnormalities that are otherwise difficult to rank as pain generators. Based on the literature review, this article attempts to distinguish the MRI abnormalities that may represent incidental findings from the abnormalities that are more commonly associated with lumbar spine-related symptoms.

Proposed dietary recommendations for iron overload: a guide for physician practice.

PURPOSE OF REVIEW: Iron overload disorders such as hemochromatosis involve unregulated absorption of dietary iron, leading to excessive iron accumulation in multiple organs. Phlebotomy is the standard of care for removal of excess iron, but dietary modification is not standardized in practice. The purpose of this article is to help standardize hemochromatosis diet counseling based on commonly asked patient questions. RECENT FINDINGS: The clinical benefit regarding dietary modification in iron overload patients is limited due to lack of large clinical trials, but preliminary results are promising. Recent studies suggest diet modification could reduce iron burden in hemochromatosis patients resulting in less annual phlebotomy as supported through small patient studies, concepts of physiology, and animal studies. SUMMARY: This article is a guide for physicians to counsel hemochromatosis patients based on commonly asked questions such as foods to avoid, foods to consume, use of alcohol, and use of supplements. The goal of this guide is to help standardize hemochromatosis diet counseling to reduce phlebotomy amount in patients. Standardization of diet counseling could help facilitate future patient studies to analyze the clinical significance.

Complete sequences of six major histocompatibility complex haplotypes, including all the major MHC class II structures.

Accurate and comprehensive immunogenetic reference panels are key to the successful implementation of population-scale immunogenomics. The 5Mbp Major Histocompatibility Complex (MHC) is the most polymorphic region of the human genome and associated with multiple immune-mediated diseases, transplant matching and therapy responses. Analysis of MHC genetic variation is severely complicated by complex patterns of sequence variation, linkage disequilibrium and a lack of fully resolved MHC reference haplotypes, increasing the risk of spurious findings on analyzing this medically important region. Integrating Illumina, ultra-long Nanopore, and PacBio HiFi sequencing as well as bespoke bioinformatics, we completed five of the alternative MHC reference haplotypes of the current (GRCh38/hg38) build of the human reference genome and added one other. The six assembled MHC haplotypes encompass the DR1 and DR4 haplotype structures in addition to the previously completed DR2 and DR3, as well as six distinct classes of the structurally variable C4 region. Analysis of the assembled haplotypes showed that MHC class II sequence structures, including repeat element positions, are generally conserved within the DR haplotype supergroups, and that sequence diversity peaks in three regions around HLA-A, HLA-B+C, and the HLA class II genes. Demonstrating the potential for improved short-read analysis, the number of proper read pairs recruited to the MHC was found to be increased by 0.06%-0.49% in a 1000 Genomes Project read remapping experiment with seven diverse samples. Furthermore, the assembled haplotypes can serve as references for the community and provide the basis of a structurally accurate genotyping graph of the complete MHC region.