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Background In search of innovative approaches to the challenge of uncontrolled hypertension, we assessed the association between preference for immediate gratification (i.e., high discounting rate), low medication adherence, and uncontrolled blood pressure (BP) in adults with hypertension. Methods Using a probability discounting model and the Collier–Williams hypothetical discount rate framework, participants in this cross-sectional study reported their preference for a smaller amount of money available immediately (high discount rate; immediate gratification preference) vs. a larger amount available 1 year later (low discount rate; delayed gratification preference). Multivariable Poisson regression was used to test the association of high discounting rates with low antihypertensive medication adherence using the validated 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4 score ≥1). Mediation of the association between high discounting rate and uncontrolled BP (systolic/diastolic BP ≥ 130/80 mm Hg) by low adherence was tested using the counterfactual approach. Results Among 235 participants (mean age 63.7 ± 6.7 years; 51.1% women; 41.9% Black), 50.6% had a high 1-year discount rate, 51.9% had low K-Wood-MAS-4 adherence, and 59.6% had uncontrolled BP. High discounting rates were associated with low adherence (adjusted prevalence ratio 1.58, 95% confidence interval (CI) 1.18, 2.12). Forty-three percent (95% CI 40.9%, 45.8%) of the total effect of high discount rate on uncontrolled BP was mediated by low adherence. Conclusions Adults with preference for immediate gratification had worse adherence; low adherence partially mediated the association of high discount rate with uncontrolled BP. These results support preference for immediate gratification as an innovative factor underlying low medication adherence and uncontrolled BP.

Background In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016. Methods In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available. Results A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%). Conclusions Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.

Auditory verbal hallucinations (AVH), also referred to as “hearing voices,” are vivid perceptions of speech that occur in the absence of any corresponding external stimulus but seem very real to the voice hearer. They are experienced by the majority of people with schizophrenia, less frequently in other psychiatric and neurological conditions, and are relatively rare in the general population. Because antipsychotic medications are not always successful in reducing the severity or frequency of AVH, a better understanding is needed of their neurobiological basis, which may ultimately lead to more precise treatment targets. What voices say and how the voices sound, or their phenomenology, varies widely within and across groups of people who hear them. In help-seeking populations, such as people with schizophrenia, the voices tend to be threatening and menacing, typically spoken in a non-self-voice, often commenting and sometimes commanding the voice hearers to do things they would not otherwise do. In psychotic populations, voices differ from normal inner speech by being unbidden and unintended, co-opting the voice hearer’s attention. In healthy voice-hearing populations, voices are not typically distressing nor disabling, and are sometimes comforting and reassuring. Regardless of content and valence, voices tend to activate some speech and language areas of the brain. Efforts to silence these brain areas with neurostimulation have had mixed success in reducing the frequency and salience of voices. Progress with this treatment approach would likely benefit from more precise anatomical targets and more precisely dosed neurostimulation. Neural mechanisms that may underpin the experience of voices are being actively investigated and include mechanisms enabling context-based predictions and distinctions between experiences coming from self and other. Both these mechanisms can be studied in non-human animal “models” and both can provide new anatomical targets for neurostimulation.

Negative symptoms are core contributors to vocational and social deficits in schizophrenia (SZ). Available antipsychotic medications typically fail to reduce these symptoms. The neurohormone oxytocin (OT) is a promising treatment for negative symptoms, given its role in complex social behaviors mediated by the amygdala. In sample 1, we used a double-blind, placebo-controlled, crossover design to test the effects of a single dose of intranasal OT on amygdala resting-state functional connectivity (rsFC) in SZ (n = 22) and healthy controls (HC, n = 24) using a whole-brain corrected approach: we identified regions for which OT modulated SZ amygdala rsFC, assessed whether OT-modulated circuits were abnormal in SZ relative to HC on placebo, and evaluated whether connectivity on placebo and OT-induced connectivity changes correlated with baseline negative symptoms in SZ. Given our modest sample size, we used a second SZ (n = 183) and HC (n = 178) sample to replicate any symptom correlations. In sample 1, OT increased rsFC between the amygdala and left middle temporal gyrus, superior temporal sulcus, and angular gyrus (MTG/STS/AngG) in SZ compared to HC. Further, SZ had hypo-connectivity in this circuit compared to HC on placebo. More severe negative symptoms correlated with less amygdala-to-left-MTG/STS/AngG connectivity on placebo and with greater OT-induced connectivity increases. In sample 2, we replicated the correlation between amygdala-left-MTG/STS/AngG hypo-connectivity and negative symptoms, finding a specific association with expressive negative symptoms. These data suggest intranasal OT can normalize functional connectivity in an amygdala-to-left-MTG/STS/AngG circuit that contributes to negative symptoms in SZ.

BACKGROUND: Targeted cognitive training (TCT) for schizophrenia is hypothesized to improve global cognitive functioning by driving plasticity in distributed frontal and temporal systems. While previous work has demonstrated that TCT evokes functional changes in prefrontal and temporal cortex, less is known about whether treatment response coincides with structural changes in these brain areas. In the current study, we examined whether changes in cognition in response to TCT (compared to a computer games control condition) correspond to changes in cortical thickness (CTh) in frontal and temporal cortices among patients with recent onset schizophrenia (SZ). Additionally, we determined whether baseline CTh predicted treatment response. METHODS: SZ patients were randomized to 40 hours of TCT of the auditory system (N=21) or computer games (CG; N=22). Before and after training, participants underwent MRI and cognitive testing. Freesurfer’s longitudinal pipeline was used to calculate CTh at baseline and follow up. Patients averaged 4.5 months to complete training. Using regions from the Desikan-Killiany Atlas, we created regions of interest (ROIs) from left and right frontal and temporal cortices and calculated CTh change scores. Next, we examined slope differences to determine whether the relationship between change in CTh and change in cognition differed between TCT and CG. Last, we determined whether baseline CTh in any sub-regions of the ROIs was predictive of treatment response in the TCT group. RESULTS: The relationship between change in CTh and global cognition differed between groups in the left frontal cortex (t=2.42; p=.02), characterized by a correlation in TCT (r=.50 p=.02), but no relationship in CG (r=-.18; p=.42). The same pattern was observed in the right frontal cortex (t=3.29 p=.002; TCT: r=.59; p=.004; CG: r=-.29 p=.18). We observed a similar pattern in the temporal cortex, with a significant slope difference in the left hemisphere (t=2.38 p=.02), characterized by a correlation in TCT (r=.58 p=.006) but not CG (r=-.13 p=.55). The same trend was observed in the right temporal cortex (t=1.93 p=.06), with a strong TCT correlation (r=.72 p=.0002), and no relationship in CG (r=.11 p=.61). We observed no significant group x time interactions on change in CTh. We conducted post-hoc analyses on sub-region ROIs that may be driving these relationships and identified numerous frontal and temporal regions showing a significant slope difference, including superior and middle frontal gyrus, as well as temporal pole, inferior, and middle temporal regions (all p’s

The U.S. military Standing Rules of Engagement (SROE) restrict the use of force in armed conflict to either self-defense or “mission-specific” rules of engagement, which refer to the use of force against members of enemy armed forces or organized armed groups that have been “declared hostile.” This bifurcation of authority works well in an international armed conflict, where the enemy force is uniformed and easily distinguished. In these circumstances, the overwhelming number of engagements are against identified hostile forces. In many non-international armed conflicts, however, combatants actively attempt to camouflage their status, and U.S. forces find themselves engaging enemy forces under a self-defense framework. This creates problems. Consider, for example, a situation where three individuals of unknown affiliation launch an attack against a U.S. military convoy in Afghanistan. After a short engagement, the attackers get in a van and speed away from the attack site. The U.S. convoy is disabled, but an unmanned aerial vehicle tracks the van as it retreats into the desert. Thirty minutes later an AH-64 Apache attack helicopter arrives on scene above the still-retreating van. Can the Apache attack the vehicle? The van is retreating and poses no threat, thus self-defense principles would not allow for the use of force, despite the fact that the occupants are clearly directly participating in hostilities. This chapter addresses three questions: Why are the SROE drafted in this manner? What is the basis in the law for the SROE’s approach to self-defense? What are the problems presented by this approach?

Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family-wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI.

Background Methicillin-resistant Staphylococcus aureus (MRSA)is the most common nosocomial infection worldwide. Infection control measures using molecular tests [polymerase chain reaction (PCR) on nares swabs] aid to prevent hospital transmission of MRSA. Nares screening for MRSA has proven to be a valuable tool for antimicrobial stewardship programs (ASP) to de-escalate empiric anti-MRSA therapy in patients with pneumonia (community/nosocomial acquired) not nasally colonized with MRSA. In January 2016, an ASP was initiated at our institution with emphasis on rational use of antibiotics, decrease antibiotic duration and timely de-escalation of all empiric antibiotics, including IV vancomycin using nares PCR for MRSA. Methods We compared the vancomycin use at the Northport Veterans Affairs Medical center by days of therapy/1,000 patient-days from 2011–2015 to 2016–2019. Screening for MRSA is by DNA PCR (Cepheid GeneXpert Infinity). ASP reviewed all restricted antibiotic requests via electronic consults and rendered approval or disapproval. In addition, ASP requested empiric vancomycin to be discontinued for patients hospitalized for pneumonia, if PCR was negative for MRSA; PCR results were available within 24hours of admission. Results There were 21,330 admissions (including ICU) from March 1, 2011 to February 28, 2019. Since initiation of ASP in 2016, 4,021 total antibiotic approvals were requested and 483 were denied. 484 IV Vancomycin were requested and 43 were denied. There has been a statistically significant decrease in vancomycin use from 2011–2015 vs. 2016–2019, median by quarter (year divided in 4 quarters) 250 vs. 233, P = 0.012; Comparing the same time periods there has been a decrease in positive MRSA nares screening upon admission median annual rate 354 vs. 220, P = 0.011. There was no difference in vancomycin-resistant enterococci in clinical isolates, median 16 vs. 14.5, P = 0.465. Inpatient infectious diseases consultations increased by 30% since ASP was initiated. Conclusion Our ASP was successful in decreasing use of vancomycin through both disapproval of medication when a request was deemed inappropriate, and by promoting de-escalation of therapy by the use of MRSA nares screening in patients who were started empirically on MRSA antibiotic therapy for pneumonia. Disclosures All authors: No reported disclosures.

Highlight VvGuaS, a novel allele of the VvTPS24 gene, is responsible for the production of the rotundone precursor α-guaiene. Two specific polymorphisms distinguish VvGuaS from its non-guaiene-producing homologue VvPNSeInt., Rotundone was initially identified as a grape-derived compound responsible for the peppery aroma of Shiraz wine varieties. It has subsequently been found in black and white pepper and several other spices. Because of its potent aroma, the molecular basis for rotundone formation is of particular relevance to grape and wine scientists and industry. We have identified and functionally characterized in planta a sesquiterpene synthase, VvGuaS, from developing grape berries, and have demonstrated that it produces the precursor of rotundone, α-guaiene, as its main product. The VvGuaS enzyme is a novel allele of the sesquiterpene synthase gene, VvTPS24, which has previously been reported to encode VvPNSeInt, an enzyme that produces a variety of selinene-type sesquiterpenes. This newly discovered VvTPS24 allele encodes an enzyme 99.5% identical to VvPNSeInt, with the differences comprising just 6 out of the 561 amino acid residues. Molecular modelling of the enzymes revealed that two of these residues, T414 and V530, are located in the active site of VvGuaS within 4 Å of the binding-site of the substrate, farnesyl pyrophosphate. Mutation of these two residues of VvGuaS into the corresponding polymorphisms in VvPNSeInt results in a complete functional conversion of one enzyme into the other, while mutation of each residue individually produces an intermediate change in the product profile. We have therefore demonstrated that VvGuaS, an enzyme responsible for production of the rotundone precursor, α-guaiene, is encoded by a novel allele of the previously characterized grapevine gene VvTPS24 and that two specific polymorphisms are responsible for functional differences between VvTPS24 alleles.

Background: Individuals with schizophrenia (Sz) show abnormal functional connectivity between resting state networks (RSNs), yet the relation between disrupted connectivity and symptoms remains unclear. Using a combination of resting-state fMRI analyses – independent component analysis (ICA) and analysis of the mean amplitudes of low-frequency fluctuations (ALFF)—we probed the relation between cross-network communication, low frequency fluctuations and reported experience(s) of auditory hallucinations (AH) and visual hallucinations (VH) in Sz.

Background: The P300 event-related potential component is typically elicited during an “oddball” task by infrequent target stimuli (P3b) and infrequent novel distractor stimuli (P3a) that are randomly interspersed among frequent standard stimuli. Although standards do not generally elicit a P300, they can elicit a P3a when their appearance late in a local series of repeating standards is improbable. In a typical oddball task, local sequences of repeating standards end with the appearance of a deviant (target or novel) stimulus. Toward the end of such local sequences, the probability that a standard will appear decreases, and the probability that a deviant will appear increases. Previously, using an auditory oddball task, we showed that healthy subjects generated a P3a in response to late appearing standards within local sequences of repeating standards, suggesting that they implicitly recognized the conditional improbability of a standard following a local sequence of multiple repeating standards, likely in the service of predictive coding. However, chronic schizophrenia (SZ) patients failed to generate this P3a response to late appearing standards. Here, we examined whether similar P3a effects are present using a visual oddball task and whether similar deficits in P3a generation are evident early in the course of SZ.

Background: Error detection is a critical part of the self-monitoring functions that guide efficient, goal-directed behaviors. Error-monitoring deficits are well described in schizophrenia, but the extent to which error processing deficits and their associated functional neuroanatomy are evident in individuals at clinical high risk (CHR) for developing schizophrenia is not well characterized.

Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the "Total Toxicologist"; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives.

Deficits in the connectivity between brain regions have been suggested to play a major role in the pathophysiology of schizophrenia. A functional magnetic resonance imaging (fMRI) analysis of schizophrenia was implemented using independent component analysis (ICA) to identify multiple temporally cohesive, spatially distributed regions of brain activity that represent functionally connected networks. We hypothesized that functional connectivity differences would be seen in auditory networks comprised of regions such as superior temporal gyrus as well as executive networks that consisted of frontal-parietal areas. Eight networks were found to be implicated in schizophrenia during the auditory oddball paradigm. These included a bilateral temporal network containing the superior and middle temporal gyrus; a default-mode network comprised of the posterior cingulate, precuneus, and middle frontal gyrus; and multiple dorsal lateral prefrontal cortex networks that constituted various levels of between-group differences. Highly task-related sensory networks were also found. These results indicate that patients with schizophrenia show functional connectivity differences in networks related to auditory processing, executive control, and baseline functional activity. Overall, these findings support the idea that the cognitive deficits associated with schizophrenia are widespread and that a functional connectivity approach can help elucidate the neural correlates of this disorder.

Correlations of cognitive functioning with brain activation during a sternberg item recognition paradigm (SIRP) were investigated in patients with schizophrenia and in healthy controls studied at 8 sites. To measure memory scanning times, 4 response time models were fit to SIRP data. The best fitting model assumed exhaustive serial memory scanning followed by self-terminating memory search and involved one intercept parameter to represent SIRP processes not contributing directly to memory scanning. Patients displayed significantly longer response times with increasing memory load and differed on the memory scanning, memory search, and intercept parameters of the best fitting probability model. Groups differed in the correlation between the memory scanning parameter and linear brain response to increasing memory load within left inferior and left middle frontal gyrus, bilateral caudate, and right precuneus. The pattern of findings in these regions indicated that high scanning capacity was associated with high neural capacity among healthy subjects but that scanning speed was uncoupled from brain response to increasing memory load among schizophrenia patients. Group differences in correlation of the best fitting model's scanning parameter with a quadratic trend in brain response to increasing memory load suggested inefficient or disordered patterns of neural inhibition among individuals with schizophrenia, especially in the left perirhinal and entorhinal cortices. The results show at both cognitive and neural levels that disordered memory scanning contributes to deficient SIRP performance among schizophrenia patients.

Introduction: Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically “tuned” to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. Methods: At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. Results: Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. Discussion: Although “voices” are the anticipated sensory experience, it appears that even primary auditory cortex is “turned on” and “tuned in” to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample.

l-Ascorbate (vitamin C) has well-documented roles in many aspects of redox control and anti-oxidant activity in plant cells. This Botanical Briefing highlights recent developments in another aspect of l-ascorbate metabolism: its function as a precursor for specific processes in the biosynthesis of organic acids.The Briefing provides a summary of recent advances in our understanding of l-ascorbate metabolism, covering biosynthesis, translocation and functional aspects. The role of l-ascorbate as a biosynthetic precursor in the formation of oxalic acid, l-threonic acid and l-tartaric acid is described, and progress in elaborating the mechanisms of the formation of these acids is reviewed. The potential conflict between the two roles of l-ascorbate in plant cells, functional and biosynthetic, is highlighted.Recent advances in the understanding of l-ascorbate catabolism and the formation of oxalic and l-tartaric acids provide compelling evidence for a major role of l-ascorbate in plant metabolism. Combined experimental approaches, using classic biochemical and emerging 'omics' technologies, have provided recent insight to previously under-investigated areas.