Predictions and errors are distinctly represented across V1 layers.

Popular accounts of mind and brain propose that the brain continuously forms predictions about future sensory inputs and combines predictions with inputs to determine what we perceive.1,2,3,4,5,6 Under "predictive processing" schemes, such integration is supported by the hierarchical organization of the cortex, whereby feedback connections communicate predictions from higher-level deep layers to agranular (superficial and deep) lower-level layers.7,8,9,10 Predictions are compared with input to compute the "prediction error," which is transmitted up the hierarchy from superficial layers of lower cortical regions to the middle layers of higher areas, to update higher-level predictions until errors are reconciled.11,12,13,14,15 In the primary visual cortex (V1), predictions have thereby been proposed to influence representations in deep layers while error signals may be computed in superficial layers. Despite the framework's popularity, there is little evidence for these functional distinctions because, to our knowledge, unexpected sensory events have not previously been presented in human laminar paradigms to contrast against expected events. To this end, this 7T fMRI study contrasted V1 responses to expected (75% likely) and unexpected (25%) Gabor orientations. Multivariate decoding analyses revealed an interaction between expectation and layer, such that expected events could be decoded with comparable accuracy across layers, while unexpected events could only be decoded in superficial laminae. Although these results are in line with these accounts that have been popular for decades, such distinctions have not previously been demonstrated in humans. We discuss how both prediction and error processes may operate together to shape our unitary perceptual experiences.

Selenium Protects Mouse Hypothalamic Cells from Glucocorticoid-Induced Endoplasmic Reticulum Stress Vulnerability and Insulin Signaling Impairment.

The use of glucocorticoid medications is known to cause metabolic side effects such as overeating, excess weight gain, and insulin resistance. The hypothalamus, a central regulator of feeding behavior and energy expenditure, is highly responsive to glucocorticoids, and it has been proposed that it plays a role in glucocorticoid-induced metabolic defects. Glucocorticoids can alter the expression and activity of antioxidant enzymes and promote the accumulation of reactive oxygen species. Recent evidence indicates that selenium can counter the effects of glucocorticoids, and selenium is critical for proper hypothalamic function. This study sought to determine whether selenium is capable of protecting hypothalamic cells from dysfunction caused by glucocorticoid exposure. We treated mHypoE-44 mouse hypothalamic cells with corticosterone to study the effects on cellular physiology and the involvement of selenium. We found that corticosterone administration rendered cells more vulnerable to endoplasmic reticulum stress and the subsequent impairment of insulin signaling. Supplementing the cell culture media with additional selenium alleviated endoplasmic reticulum stress and promoted insulin signaling. These findings implicate a protective role of selenium against chronic glucocorticoid-induced hypothalamic dysfunction.

Fifteen years of shared care for paediatric oncology, haematology and palliative patients across Queensland: The role of Regional Case Managers.

OBJECTIVE: A shared care model was implemented in 2006 in Queensland to facilitate paediatric oncology, haematology and palliative care patients receiving care as close to home as possible. Following initial diagnosis, care planning and treatment at the tertiary children's hospital, appropriate local care was coordinated by Regional Case Managers (RCMs) established at each of 10 Shared Care Units (SCUs). This enabled safe and quality regional care supported by a statewide network providing clinical governance and education. This paper examines learnings from 15 years of this shared care. SETTING: Ten hospitals throughout Queensland facilitated a statewide model of shared care for paediatric oncology, haematology and palliative care patients, supported by a tertiary hub in Brisbane. PARTICIPANTS: Regional Case Managers in Shared Care Units and their supporting staff. DESIGN: Staff from SCUs were surveyed and focus group interviews conducted. RESULTS: The paper reviews the attributes, knowledge and experience required for RCMs. Standards of care were supported through education workshops, clinical placements, chemotherapy credentialing, guidelines and standards. RCMs facilitated communication and information sharing with the tertiary centre, advocated for their cohort of patients locally and streamlined and supported the family's experience of care. CONCLUSION: The RCM role provided invaluable clinical leadership for the care of paediatric oncology, haematology and palliative patients across Queensland. As new treatments evolve, the expertise and coordination provided by the RCMs will be even more critical. Achieving high-quality shared care outcomes is underpinned by the RCMs drive to achieve statewide safety and support for this cohort of children.

Performance Comparisons on the Saint Louis University Mental Status Examination Between Black and White Veterans and Education Classification in a Large Outpatient Sample from the Southern United States.

OBJECTIVE: An increasing scientific literature recognizes that traditional cut-off scores for cognitive screeners may not be optimal for use in patients who differ in race/ethnicity from the screeners' normative/reference group. There is also literature on how racial/ethnic contextual factors, such as stereotype threat or perceived discrimination, may influence performance on cognitive testing. The current study examined the characteristics of SLUMS (a cognitive screening measure) performance in a large (n = 602) sample of Black (n = 229) and White (n = 373) veterans in a VA hospital located in the Southern United States. METHOD: SLUMS data were gathered from retrospective electronic chart review between January 2013 and February 2020. Race/ethnicity of veterans was gathered by chart review and race of hospital providers who administered the SLUMS by personal communication. RESULTS: Black veterans were 1.99 times more likely to be classified by total SLUMS score as being within the dementia range compared with White veterans. Differences in item level performance were only found between Black and White veterans with ≥ high school education. Race of clinical provider (i.e., Black or White) administering the SLUMS did not significantly impact veteran performance on the SLUMS. CONCLUSION: This is the first large sample study of differences in SLUMS performance between Black and White veterans. Findings replicate earlier research on Black and White performance differences on individual SLUMS items and provide an analysis of examiner-examinee racial discordance. This study underscores the importance of researching cognitive measures in groups who differ from the original normative/references samples.

Selenium in Bodily Homeostasis: Hypothalamus, Hormones, and Highways of Communication.

The ability of the body to maintain homeostasis requires constant communication between the brain and peripheral tissues. Different organs produce signals, often in the form of hormones, which are detected by the hypothalamus. In response, the hypothalamus alters its regulation of bodily processes, which is achieved through its own pathways of hormonal communication. The generation and transmission of the molecules involved in these bi-directional axes can be affected by redox balance. The essential trace element selenium is known to influence numerous physiological processes, including energy homeostasis, through its various redox functions. Selenium must be obtained through the diet and is used to synthesize selenoproteins, a family of proteins with mainly antioxidant functions. Alterations in selenium status have been correlated with homeostatic disturbances in humans and studies with animal models of selenoprotein dysfunction indicate a strong influence on energy balance. The relationship between selenium and energy metabolism is complicated, however, as selenium has been shown to participate in multiple levels of homeostatic communication. This review discusses the role of selenium in the various pathways of communication between the body and the brain that are essential for maintaining homeostasis.

New insights on selenoproteins and neuronal function.

Fifty years have passed since the discovery of the first selenoprotein by Rotruck and colleagues. In that time, the essential nature of selenium has come to light including the dependence of the brain on selenium to function properly. Animal models have shown that a lack of certain selenoproteins in the brain is detrimental for neuronal health, sometimes leading to neurodegeneration. There is also potential for selenoprotein-mediated redox balance to impact neuronal activity, including neurotransmission. Important insights on these topics have been gained over the past several years. This review briefly summarizes the known roles of specific selenoproteins in the brain while highlighting recent advancements regarding selenoproteins in neuronal function. Hypothetical models of selenoprotein function and emerging topics in the field are also provided.

Risk Factors and Outcomes After a Brief Resolved Unexplained Event: A Multicenter Study.

BACKGROUND: The accuracy of the risk criteria for brief resolved unexplained events (BRUEs) from the American Academy of Pediatrics (AAP) is unknown. We sought to evaluate if AAP risk criteria and event characteristics predict BRUE outcomes. METHODS: This retrospective cohort included infants <1 year of age evaluated in the emergency departments (EDs) of 15 pediatric and community hospitals for a BRUE between October 1, 2015, and September 30, 2018. A multivariable regression model was used to evaluate the association of AAP risk factors and event characteristics with risk for event recurrence, revisits, and serious diagnoses explaining the BRUE. RESULTS: Of 2036 patients presenting with a BRUE, 87% had at least 1 AAP higher-risk factor. Revisits occurred in 6.9% of ED and 10.7% of hospital discharges. A serious diagnosis was made in 4.0% (82) of cases; 45% (37) of these diagnoses were identified after the index visit. The most common serious diagnoses included seizures (1.1% [23]) and airway abnormalities (0.64% [13]). Risk is increased for a serious underlying diagnosis for patients discharged from the ED with a history of a similar event, an event duration >1 minute, an abnormal medical history, and an altered responsiveness (P < .05). AAP risk criteria for all outcomes had a negative predictive value of 90% and a positive predictive value of 23%. CONCLUSIONS: AAP BRUE risk criteria are used to accurately identify patients at low risk for event recurrence, readmission, and a serious underlying diagnosis; however, their use results in the inaccurate identification of many patients as higher risk. This is likely because many AAP risk factors, such as age, are not associated with these outcomes.

Improving management of fever in neutropenic children with cancer across multiple sites.

OBJECTIVE: To evaluate the effectiveness of a clinical pathway in achieving antibiotic administration in less than 60 minutes for children with cancer, presenting with fever and neutropenia. Secondary objectives were to determine association between time to antibiotics (TTA) and other variables including fever duration, location of care and intravenous access types. METHODS: Following introduction of the clinical pathway, we collected prospective data about management of all cases that did and did not use the pathway across multiple sites over 16 months. A follow-up audit was conducted after 12 months. RESULTS: We evaluated a total of 453 presentations. Use of the clinical pathway was significantly associated with achieving TTA in less than 60 minutes (RR 0.69, 95% CI 0.56-0.85, p = <0.001). Despite varying use of the pathway over time, the median time to antibiotics was achieved in both the initial study period (57 minutes) and sustained at follow-up (60 minutes). TTA was also associated with types of intravenous access device and location of care and with length of stay. We did not find any association between TTA and any other variables. CONCLUSION: Clinical pathways improve fever management in this patient cohort. Ongoing education and auditing to identify factors which impact processes of care are necessary.

Supernatants of intestinal luminal contents from mice fed high-fat diet impair intestinal motility by injuring enteric neurons and smooth muscle cells.

BACKGROUND: Damage to enteric neurons and impaired gastrointestinal muscle contractions cause motility disorders in 70% of diabetic patients. It is thought that enteric neuropathy and dysmotility occur before overt diabetes, but triggers of these abnormalities are not fully known. We tested the hypothesis that intestinal contents of mice with and without high-fat diet- (HFD-) induced diabetic conditions contain molecules that impair gastrointestinal movements by damaging neurons and disrupting muscle contractions. METHODS: Small and large intestinal segments were collected from healthy, standard chow diet (SCD) fed mice. Filtrates of ileocecal contents (ileocecal supernatants; ICS) from HFD or SCD mice were perfused through them. Cultured intact intestinal muscularis externa preparations were used to determine whether ICS and their fractions obtained by solid-phase extraction (SPE) and SPE subfractions collected by high-performance liquid chromatography (HPLC) disrupt muscle contractions by injuring neurons and smooth muscle cells. KEY RESULTS: ICS from HFD mice reduced intestinal motility, but those from SCD mice had no effect. ICS, aqueous SPE fractions and two out of twenty HPLC subfractions of aqueous SPE fractions from HFD mice blocked muscle contractions, caused a loss of nitrergic myenteric neurons through inflammation, and reduced smooth muscle excitability. Lipopolysaccharide and palmitate caused a loss of nitrergic myenteric neurons but did not affect muscle contractions. CONCLUSIONS & INFERENCES: Unknown molecules in intestinal contents of HFD mice trigger enteric neuropathy and dysmotility. Further studies are required to identify the toxic molecules and their mechanisms of action.

Hemodynamic comparison of intravenous push diltiazem versus metoprolol for atrial fibrillation rate control.

OBJECTIVE: Intravenous push (IVP) diltiazem and metoprolol are commonly used for management of atrial fibrillation (AF) with rapid ventricular rate (RVR) in the emergency department (ED). This study's objective was to determine if there was a significant difference in blood pressure reduction between agents. METHODS: This was a single-center, retrospective study of adult patients initially treated with IVP diltiazem or metoprolol in the ED from 2008 to 2018. Primary endpoint was mean reduction in systolic blood pressure (SBP) from baseline to nadir during the study period. Study period was defined as time from first dose of IVP intervention to 30 min after last dose of IVP intervention or first dose of maintenance therapy, whichever came first. RESULTS: A total of 63 diltiazem patients and 45 metoprolol patients met eligibility criteria. Baseline characteristics were similar except for initial ventricular rate (VR) and home beta-blocker use. Median dose of initial intervention was 10 [10-20] mg and 5 [5-5] mg for diltiazem and metoprolol respectively. Mean SBP reduction was 18 ± 22 mmHg for diltiazem compared to 14 ± 15 mmHg for metoprolol (p = .33). Clinically relevant hypotension was similar between groups 14% vs. 16% (p = .86). Rate control was achieved in 35 (56%) of the diltiazem group and 16 (36%) of the metoprolol group (p = .04). CONCLUSION: IVP diltiazem and metoprolol caused similar SBP reduction and hypotension when used for initial management of AF with RVR in the ED. However, rate control was achieved more often with diltiazem.

High-fat diet-induced alterations to gut microbiota and gut-derived lipoteichoic acid contributes to the development of enteric neuropathy.

BACKGROUND: High-fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram-positive bacteria and short-chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility. METHODS: We fed germ-free (GF) and conventionally raised (CR) mice either a high-fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations. KEY RESULTS: High-fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF-HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram-positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons. CONCLUSIONS & INFERENCES: Gut microbial alterations induced increase in Gram-positive bacterial LTA may contribute to enteric neuropathy.

Addressing the barriers to optimal management of febrile neutropenia in children with cancer.

PURPOSE: Fever and associated neutropenia presentations are frequent occurrences for children with cancer. Prompt treatment is required to prevent adverse outcomes; however, delays are common. In Australia's vast landscape, presentations occur in both tertiary metropolitan sites and smaller regional sites. Management and experiences differ between sites. Our primary aim was to identify the barriers to optimal management of febrile neutropenia in children with cancer from patient/parent and clinician perspectives. METHODS: A mixed methods approach was used where quantitative data was supplemented by qualitative data. Data were prospectively collected from parents (n=81) and clinicians (n=42) about all children who presented with fever across multiple diverse hospital locations. A subset of parents (n=9) and clinicians (n=19) completed semi-structured interviews. RESULTS: Delays in assessment and treatment were reported by 31% of parents and up to 36% of clinicians. Four distinct time points where delays occurred were identified: 1) pre-presentation; 2) initial assessment; 3) blood collection and establishing intravenous access, and 4) preparation and administration of antibiotics. Although reasons for delay were diverse, they were primarily related to clinician's knowledge and awareness of fever management, and intravenous access device factors. Interventions were formulated to target these barriers and streamline processes. CONCLUSION: We identified multifactorial reasons for delays at different time points in care. Regional centres and families have unique needs which require considerations and tailored interventions. Ongoing education, monitoring compliance with initiation of practice changes and identifying and overcoming barriers as they arise are strategies for improving management of the febrile child with cancer.

Pharmacotherapy considerations for long-term management of patients with left ventricular assist devices.

PURPOSE: Current guidelines and research pertaining to pharmacotherapy considerations for management of patients with left ventricular assist devices (LVADs) are reviewed. SUMMARY: LVADs are being used more frequently to sustain patients with end-stage heart failure who are on a waitlist or ineligible for heart transplantation. The devices significantly impact patient physiology leading to unique medical complications and pharmacotherapy considerations. Pharmacists can play a vital role in understanding and relaying relevant medication concerns to the interdisciplinary healthcare team. Although optimal treatment regimens for some complications are still unclear, evolving research provides key information to incorporate into decisions. The introduction of an LVAD requires antithrombotic therapy in the absence of contraindications to prevent thrombosis. Warfarin with a device-dependent International Normalized Ratio (INR) goal is preferred. The baseline INR goal is usually 2-3 but can be adjusted for recurrent thrombosis or refractory bleeding. When infection is suspected, cultures should be obtained, covering likely pathogens with consideration of resistance in long-standing infections. Chronic antimicrobial suppression may be warranted. Elimination rate constant and volume of distribution may be altered. LVAD implantation may improve glycemic control. Doppler probe is preferred to monitor blood pressure, with a goal mean arterial pressure of ≤80 mm Hg. CONCLUSION: Many pharmacotherapy considerations are necessary for the long-term management of patients with an LVAD. Awareness of LVAD structure, pathophysiologic alterations after LVAD implantation, and pharmacologic considerations will help pharmacists provide better recommendations.

Nicotinic alpha7- or beta2-containing receptor knockout: effects on radial-arm maze learning and long-term nicotine consumption in mice.

Classically, it has been thought that high-affinity nicotinic receptors-containing beta2 subunits are the most important receptor subtypes for nicotinic involvement in cognitive function and nicotine self-administration, while low affinity alpha7-containing nicotinic receptors have not been thought to be important. In the current study, we found that knockout of either beta2 or alpha7 subunits caused significant deficits in spatial discrimination in mice. The character of the impairment in the two knockouts was different. The beta2 knockout preferentially impaired cognition in males while the alpha7 caused impairment regardless of sex. Both beta2- and alpha7-containing nicotinic receptors also are important for nicotine self-administration, also in different ways. Most animal model studies of nicotine self-administration are relatively short-term whereas the problem of tobacco addiction is considerably longer-term. To better model the impact of nicotinic receptor subtypes on nicotine self-administration over the long-term, we studied the impact of genetic knockout of low affinity alpha7 receptors vs. high-affinity beta2-containing nicotinic receptors. Mice with knockouts of either of these receptors and their wildtype counter parts were given free access to a choice of nicotine-containing and nicotine-free solution in their home cages on a continuous basis over a period of 5 months. During the first few weeks, the beta2-containing nicotinic receptor knockout mice showed a significant decrease in nicotine consumption relative to wildtype mice, whereas the alpha7 knockout mice did not significantly differ from wildtype controls at the beginning of their access to nicotine. Interestingly, in the longer-term after the first few weeks of nicotine access, the beta2 knockout mice returned to wildtype mouse levels of nicotine consumption, whereas the alpha7 knockout mice developed an emergent decrease in nicotine consumption. The alpha7 receptor knockout-induced decrease in nicotine consumption persisted for the 5-month period of the study. Both alpha7- and beta2-containing nicotinic receptors play critical roles in cognitive function and nicotine self-administration. Regarding cognitive function, beta2-containing receptors are important for maintaining normal sex differences in spatial learning and memory, whereas alpha7 receptors are important for cognitive function regardless of sex. Regarding nicotine self-administration high-affinity beta2-containing nicotinic receptors are important for consumption during the initial phase of nicotine access, but it is the alpha7 nicotinic receptors that are important for the longer-term regulation of nicotine consumption.