Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.

A distinct inferential mechanism for delusions in schizophrenia.

Delusions, a core symptom of psychosis, are false beliefs that are rigidly held with strong conviction despite contradictory evidence. Alterations in inferential processes have long been proposed to underlie delusional pathology, but previous attempts to show this have failed to yield compelling evidence for a specific relationship between inferential abnormalities and delusional severity in schizophrenia. Using a novel, incentivized information-sampling task (a modified version of the beads task), alongside well-characterized decision-making tasks, we sought a mechanistic understanding of delusions in a sample of medicated and unmedicated patients with schizophrenia who exhibited a wide range of delusion severity. In this novel task, participants chose whether to draw beads from one of two hidden jars or to guess the identity of the hidden jar, in order to minimize financial loss from a monetary endowment, and concurrently reported their probability estimates for the hidden jar. We found that patients with higher delusion severity exhibited increased information seeking (i.e. increased draws-to-decision behaviour). This increase was highly specific to delusion severity as compared to the severity of other psychotic symptoms, working-memory capacity, and other clinical and socio-demographic characteristics. Delusion-related increases in information seeking were present in unmedicated patients, indicating that they were unlikely due to antipsychotic medication. In addition, after adjusting for delusion severity, patients as a whole exhibited decreased information seeking relative to healthy individuals, a decrease that correlated with lower socioeconomic status. Computational analyses of reported probability estimates further showed that more delusional patients exhibited abnormal belief updating characterized by stronger reliance on prior beliefs formed early in the inferential process, a feature that correlated with increased information seeking in patients. Other decision-making parameters that could have theoretically explained the delusion effects, such as those related to subjective valuation, were uncorrelated with both delusional severity and information seeking among the patients. In turn, we found some preliminary evidence that subjective valuation (rather than belief updating) may explain group differences in information seeking unrelated to delusions. Together, these results suggest that abnormalities in belief updating, characterized by stronger reliance on prior beliefs formed by incorporating information presented earlier in the inferential process, may be a core computational mechanism of delusional ideation in psychosis. Our results thus provide direct empirical support for an inferential mechanism that naturally captures the characteristic rigidity associated with delusional beliefs.

Death effects of reveromycin A in normal and disease-associated cells of the joint.

Earlier work in our laboratory demonstrated that naturally occurring reveromycin A (Rev A) causes apoptosis in osteoclasts without accompanying necrosis. Rev A death effects in both normal and diseased joint cells were investigated in this study. A dose of 10 µM Rev A did not cause apoptosis nor necrosis in monolayer chondrocytes, even at pH 6.8, a pH mimicking that of an inflamed joint. In contrast, at the acidic pH Rev A did induce significant apoptosis (fourfold increase at 48 h of treatment, P < 0.005) in normal synoviocytes without accompanying necrosis. Western blot of the normal synoviocyte proteins revealed that cytochrome c levels were not significantly changed over the time course of treatment nor did caspase 8 activity increase; therefore, Rev A appears to exert this apoptotic effect through a mechanism independent of the classical intrinsic and extrinsic pathways. Fibroblast-like synoviocytes isolated from rheumatoid arthritis patients (RAFLS) as well as normal human fibroblast-like synoviocytes (NHFLS), cells known to play key roles in arthritic joint pathology, were also subjected to Rev A treatment at both physiologic and acidic pH's. Neither apoptosis nor necrosis was induced in either RAFLS or NHFLS. Parallel mitomycin C treatment of NHFLS induced both apoptosis and necrosis. Comparative structure-activity analyses of Rev A and mitomycin C revealed that Rev A is less likely to cross the cell membrane at near neutral pH. Collectively the data reveal that a physiological dose of Rev A under acidic conditions induces normal synoviocytes to undergo apoptosis while pathologic fibroblast-like synoviocytes are resistant to apoptosis and necrosis.

Predicting Complications in 153 Lumbar Pedicle Subtraction Osteotomies by a Single Surgeon Over a 6-Year Period.

INTRODUCTION: Pedicle subtraction osteotomy (PSO) is a complex surgical procedure that provides correction of moderate sagittal imbalance. Surgical complications have adverse effects on patient outcomes and healthcare costs, making it imperative for clinical researchers to focus on minimizing complications. However, when it comes to risk modeling of PSO surgery, there is currently no consensus on which patient characteristics or measures should be used. This study aimed to describe complications and compare the performance of various sociodemographic characteristics, surgical variables, and established risk indices in predicting postoperative complications, infections, and readmissions after lumbar PSO surgeries. METHODS: A review was conducted on 191 patients who underwent PSO surgery at a single institution by a single fellowship-trained orthopaedic spine surgeon between January 1, 2018, and December 31, 2021. Demographic, intraoperative, and postoperative data within 30 days, 1 year, and 2 years of the index procedure were evaluated. Descriptive statistics, t -test, chi-squared analysis, and logistic regression models were used. RESULTS: Intraoperative complications were significantly associated with coronary artery disease (odds ratios [OR] 3.95, P = 0.03) and operating room time (OR 1.01, P = 0.006). 30-day complications were significantly cardiovascular disease (OR 2.68, P = 0.04) and levels fused (OR 1.10, P = 0.04). 2-year complications were significantly associated with cardiovascular disease (OR 2.85, P = 0.02). 30-day readmissions were significantly associated with sex (4.47, 0.04) and length of hospital stay (χ 2 = 0.07, P = 0.04). 2-year readmissions were significantly associated with age (χ 2 = 0.50, P = 0.03), hypertension (χ 2 = 4.64, P = 0.03), revision surgeries (χ 2 = 5.46, P = 0.02), and length of hospital stay (χ 2 = 0.07, P = 0.03). DISCUSSION: This study found that patients with coronary vascular disease and longer fusions were at higher risk of postoperative complications and patients with notable intraoperative blood loss were at higher risk of postoperative infections. In addition, physicians should closely follow patients with extended postoperative hospital stays, with advanced age, and undergoing revision surgery because these patients were more likely to be readmitted to the hospital.

Does Surgical Day of the Week Affect Hospital Course and Outcomes for Patients Undergoing Adult Spinal Deformity Surgery?

STUDY DESIGN: Retrospective Cohort Analysis. OBJECTIVES: Extended hospital length of stay (LOS) poses a significant cost burden to patients undergoing adult spinal deformity (ASD) surgery. The purpose of this study is to investigate the relationship between late-week surgery and LOS in patients undergoing ASD surgery. METHODS: 256 patients who underwent ASD surgery between January 2018 and December 2021 by a single fellowship-trained orthopedic spine surgeon comprised the patient sample. Demographics, intraoperative, and perioperative data were collected for the 256 patients who underwent ASD surgery. Patients were divided into two groups based on surgical day of the week: (1) Early-week (Monday/Tuesday) n = 126 and (2) Late-week (Thursday/Friday) n = 130. Descriptive statistics, T-tests, and linear and logistic regression models were used to analyze the data. RESULTS: Surgical details and sociodemographic characteristics did not differ between the groups. When controlling for TLIF/DLIF status and PSO status there was no difference in mean length of stay between the groups. The late-week group was associated with a greater risk of 30-day readmission, but there was no difference in complications, infections, or intraoperative complications. CONCLUSIONS: We found no difference in mean length of stay between surgeries performed early in the week vs late in the week. Although late-week surgeries had higher 30-day readmission risk, all other outcomes, including complication rates, showed no significant differences. When adequate weekend post-operative care is available, we do not advise restricting ASD surgeries to specific weekdays.

Generalizability and Out-of-Sample Predictive Ability of Associations Between Neuromelanin-Sensitive Magnetic Resonance Imaging and Psychosis in Antipsychotic-Free Individuals.

Importance: The link between psychosis and dopaminergic dysfunction is established, but no generalizable biomarkers with clear potential for clinical adoption exist. Objective: To replicate previous findings relating neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a proxy measure of dopamine function, to psychosis severity in antipsychotic-free individuals in the psychosis spectrum and to evaluate the out-of-sample predictive ability of NM-MRI for psychosis severity. Design, Setting, and Participants: This cross-sectional study recruited participants from 2019 to 2023 in the New York City area (main samples) and Mexico City area (external validation sample). The main samples consisted of 42 antipsychotic-free patients with schizophrenia, 53 antipsychotic-free individuals at clinical high risk for psychosis (CHR), and 52 matched healthy controls. An external validation sample consisted of 16 antipsychotic-naive patients with schizophrenia. Main Outcomes and Measures: NM-MRI contrast within a subregion of the substantia nigra previously linked to psychosis severity (a priori psychosis region of interest [ROI]) and psychosis severity measured using the Positive and Negative Syndrome Scale (PANSS) in schizophrenia and the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR. The cross-validated performance of linear support vector regression to predict psychosis severity across schizophrenia and CHR was assessed, and a final trained model was tested on the external validation sample. Results: Of the 163 included participants, 76 (46.6%) were female, and the mean (SD) age was 29.2 (10.4) years. In the schizophrenia sample, higher PANSS positive total scores correlated with higher mean NM-MRI contrast in the psychosis ROI (t37 = 2.24, P = .03; partial r = 0.35; 95% CI, 0.05 to 0.55). In the CHR sample, no significant association was found between higher SIPS positive total score and NM-MRI contrast in the psychosis ROI (t48 = -0.55, P = .68; partial r = -0.08; 95% CI, -0.36 to 0.23). The 10-fold cross-validated prediction accuracy of psychosis severity was above chance in held-out test data (mean r = 0.305, P = .01; mean root-mean-square error [RMSE] = 1.001, P = .005). External validation prediction accuracy was also above chance (r = 0.422, P = .046; RMSE = 0.882, P = .047). Conclusions and Relevance: This study provided a direct ROI-based replication of the in-sample association between NM-MRI contrast and psychosis severity in antipsychotic-free patients with schizophrenia. In turn, it failed to replicate such association in CHR individuals. Most critically, cross-validated machine-learning analyses provided a proof-of-concept demonstration that NM-MRI patterns can be used to predict psychosis severity in new data, suggesting potential for developing clinically useful tools.

Differences in Financial Conflicts of Interest Among Participants in a National Spine Conference.

STUDY: Retrospective Study. OBJECTIVE: At the North American Spine Society (NASS) conference, participants may influence spine surgery practices and patient care through their contributions. Therefore, their financial conflicts of interest are of notable interest. This study aims to compare the demographics and payments made to participating surgeons. METHODS: A list of 151 spine surgeons was created based on those who participated in the 2022 NASS conference. Demographic information was obtained from public physician profiles. General payments, research payments, associated research funding, and ownership interest were collected for each physician. Descriptive statistics and two-tailed t-tests were used. RESULTS: In 2021, 151 spine surgeon participants received industry payments, totaling USD 48 294 115. The top 10% of orthopedic surgeons receiving payments accounted for 58.7% of total orthopedic general value, while the top 10% of neurosurgeons accounted for 70.1%. There was no significant difference between these groups' general payment amounts. Surgeons with 21-30 years of experience received the most general funding. There was no difference in funding between surgeons in academic or private settings. For all surgeons, royalties accounted for the largest percentage of the general value exchanged, while food/beverage accounted for the largest percentage of transactions. CONCLUSIONS: Our study found that only years of experience had a positive association with general payments, and most monetary value belonged to a small handful of surgeons. These participants receiving significant money may promote techniques requiring products of companies providing their compensation. Future conferences may require disclosure policy changes so attendees understand the degree of funding participants receive.

Rethinking delusions: A selective review of delusion research through a computational lens.

Delusions are rigid beliefs held with high certainty despite contradictory evidence. Notwithstanding decades of research, we still have a limited understanding of the computational and neurobiological alterations giving rise to delusions. In this review, we highlight a selection of recent work in computational psychiatry aimed at developing quantitative models of inference and its alterations, with the goal of providing an explanatory account for the form of delusional beliefs in psychosis. First, we assess and evaluate the experimental paradigms most often used to study inferential alterations in delusions. Based on our review of the literature and theoretical considerations, we contend that classic draws-to-decision paradigms are not well-suited to isolate inferential processes, further arguing that the commonly cited 'jumping-to-conclusion' bias may reflect neither delusion-specific nor inferential alterations. Second, we discuss several enhancements to standard paradigms that show promise in more effectively isolating inferential processes and delusion-related alterations therein. We further draw on our recent work to build an argument for a specific failure mode for delusions consisting of prior overweighting in high-level causal inferences about partially observable hidden states. Finally, we assess plausible neurobiological implementations for this candidate failure mode of delusional beliefs and outline promising future directions in this area.

Subanalysis of the CYP-GUIDES Trial: CYP2D6 Functional Stratification and Operational Timeline Selection.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients. CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients. We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

Clinical database of the CYP-guides trial: An open data resource on psychiatric hospitalization for severe depression.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support ) is a randomized controlled trial (RCT) of pharmacogenetic decision support in the psychotropic treatment of hospitalized patients with major depressive disorder or severe depression. Patients were treated according to their CYP2D6 functional status or empirically and compared for both their Length of Stay (LOS, primary outcome) at the hospital and Re-Admission Rate (RAR, secondary outcome) 30 days after discharge. The trial was conducted at the Institute of Living (Hartford Hospital, Hartford CT). CYP2D6 genotyping was implemented to infer the functional status of the CYP2D6 enzyme and classify it as sub-normal, normal or supra-normal. The electronic medical record (EMR) transmitted to the physician the indicated drug prescribing guidance. During the RCT, 1500 patients were recruited and 1459 genotyped for CYP2D6. A 1:2 randomization assigned 477 patients to standard therapy (Group S) and 982 to genetically-guided therapy (Group G). In Group S, standard empiric treatment was indicated for all patients. In Group G, medications primarily metabolized by the CYP2D6 enzyme were proscribed for patients with sub- or supra-normal CYP2D6 function. The clinical course, therapeutic guidance, and drug treatment for each patient are being published in this article and deposited in Mendeley Data. These data should be valuable to assess the impact of clinical decision support on utilization of psychiatric resources for treatment of severe depression requiring hospitalization.

Results of the CYP-GUIDES randomized controlled trial: Total cohort and primary endpoints.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) is a randomized controlled trial (RCT) comparing 2 outcomes in hospitalized patients with major depressive disorder (MDD) treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary outcome was the Re-Admission Rate (RAR) 30 days after discharge. The trial setting was the Institute of Living at Hartford Hospital. CYP2D6 genotyping was implemented to detect common polymorphisms resulting in an enzyme with sub-normal, normal or supra-normal function. The electronic medical record (EMR) was utilized to transmit clinically actionable drug prescribing guidance based on the patient's CYP2D6 genotype to the physician. The RCT recruited 1500 patients, genotyped CYP2D6 in 1459, and randomized 477 to standard therapy (Group S), for whom treatment-as-usual guidance was delivered without consideration of patient CYP2D6 genotype, and 982 to genetically-guided therapy (Group G) where CYP2D6-based treatment recommendations were provided via EMR to physicians. For inpatients in Group G whose CYP2D6 function was sub- or supra-normal, medications primarily metabolized by the CYP2D6 enzyme were proscribed. The RCT developed a database of potential benefit to the field. The genetic, pharmacologic and clinical information is being simultaneously published. Results did not reveal differences in LOS or RAR between Group G and Group S, but confounders may have obscured the effects of pharmacogenetic guidance. We present strategies to assess effects of pharmacogenetic guidance on the most vulnerable patients at either extreme of CYP2D6 function treated with multiple psychotropics.

Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations.

Aim: Variants of the MTHFR gene have been associated with a wide range of diseases. Materials & methods: The present study analyzed data from clinical genotyping of MTHFR 677C>T and 1298A>C in 1405 patients in urban primary care settings. Results: Striking differences in ethnogeographic frequencies of MTHFR polymorphisms were observed. African-Americans appear to be protected from MTHFR deficiency. Hispanics and Caucasians may be at elevated risk due to increased frequencies of 677C>T and 1298A>C, respectively. Conclusion: Individuals carrying mutations for both genes were rare and doubly homozygous mutants were absent, suggesting the TTcc is extremely rare in the greater population. The results suggest multilocus MTHFR genotyping may yield deeper insight into the ethnogeographic association between MTHFR variants and disease.

Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study.

Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.

Multiple routes of porcine circovirus type 2 transmission to piglets in the presence of maternal immunity.

Porcine circovirus 2 (PCV2), the cause of porcine circovirus-associated disease (PCVAD), is widespread in swine farms throughout the United States with vaccine controlling disease, but not eliminating infection. We examined the PCV2 virological and immunological status of sows, pre-suckling piglets, and the farrowing environment of sow farms to determine PCV2 exposure risks, transmission dynamics, and immunological impacts at the time of farrowing. PCV2 was widely distributed in animals and the farrowing environment of 6 midwestern US sow farms irrespective of sow vaccination status. High levels of PCV2 capsid-specific antibodies were observed in sow serum and colostrum and had no apparent effect on PCV2 transmission to and infection in piglets. In 281 pre-suckling piglets from 59 sows, PCV2 DNA was detected in 63% of serum samples and on 93% of axillary skin swabs. PCV2 was present in one or more samples from 58 of 59 sows and in the farrowing environment. Isolated infectious virus samples from sows, presuckling piglets, and the environment were shown by sequencing to be genetically similar from all farms. In conclusion, piglets are readily infected with PCV2 in utero and are under constant challenge by PCV2 through contact with infected sows and a contaminated farrowing environment. However, maternal immunity did not affect PCV2 transmission to piglets or the viral load in sows. These findings illustrate the importance of maternal infection, despite robust anti-PCV2 immunity, in early infection of newborn piglets, and the need to develop appropriate infection models for elucidation of mechanisms of protective immunity.

Discrepancy between admission and discharge diagnoses as a predictor of hospital length of stay.

CONTEXT: The addition of clinical data or present on admission (POA) codes to administrative databases improves the accuracy of predicting clinical outcomes, such as inpatient mortality. Other POA information may also explain variation in hospital outcomes, such as length of stay (LOS), but this potential has not been previously explored. OBJECTIVES: To assess whether a discrepancy between the diagnosis coded at the time of admission and the diagnoses coded at discharge independently explains variation in LOS for general internal medicine patients. DESIGN, SETTING, AND PATIENTS: A retrospective data review of patients age 18 years and older admitted to general internal medicine units at a large, urban academic medical center between July 2005 and June 2006. A generalized linear regression model was constructed to adjust for patient factors known to be associated with LOS. OUTCOME MEASURE: Average LOS among patients with a discrepancy between the admitting and discharge diagnosis codes versus those patients without a discrepancy. MAIN RESULTS: The average LOS for patients without a discrepancy between the admitting and discharge diagnosis codes, adjusted for comorbid conditions, was 3.4 days compared to 4.2 days with a discrepancy (0.76-day increase; P < 0.01). CONCLUSIONS: Diagnosis discrepancy is associated with longer LOS. Diagnosis discrepancy on admission may be a marker of diagnosis uncertainty or poor patient assessment/documentation. Further research is needed to understand the underlying reasons for this discrepancy and its association with LOS, and, potentially, clinical outcomes.

Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function.

CD4(+)CD25+ T regulatory (Treg) cells have been shown to critically regulate self and allograft tolerance in mice. Studies of human Treg cells have been hindered by low numbers present in peripheral blood and difficult purification. We found that cord blood was a superior source for Treg-cell isolation and cell line generation compared with adult blood. Cord blood CD4(+)CD25+ cells were readily purified and generated cell lines that consistently exhibited potent suppressor activity, with more than 95% suppression of allogeneic mixed lymphocyte reactions (MLRs) (29 of 30 donors). Cultured Treg cells blocked cytokine accumulation in MLRs, with a less robust inhibition of chemokine production. These cell lines uniformly expressed CD25, CD62L, CCR7, CD27, and intracellular cytotoxic T-lymphocyte antigen-4 (CTLA4). FoxP3 protein, but not mRNA, was specifically expressed. Upon restimulation with anti-CD3/CD28 beads, the cultured Treg cells produced minimal cytokines (interleukin-2 [IL-2], interferon-gamma [IFN-gamma], and IL-10) and preferentially expressed tumor growth factor-beta (TGF-beta) latency associated protein. Cytokine production, however, was restored to normal levels by restimulation with phorbol myristate acetate (PMA)/ionomycin. Cord blood-derived cultured suppressor cell function was predominantly independent of IL-10 and TGF-beta. These results demonstrate cord blood contains a significant number of Treg precursor cells capable of potent suppressor function after culture activation. Banked cord blood specimens may serve as a readily available source of Treg cells for immunotherapy.