Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia.

Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80 mg daily for 3 days), in chronic stable patients with schizophrenia (n = 26 analyzed). We focused on 3 T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p < 0.0001) and anterior cingulate/paracingulate (p = 0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r = -0.42, p = 0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism, which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment toward specific populations.

In-person versus virtual administration of the American College of Rheumatology gold standard cognitive battery in systemic lupus erythematosus: Are they interchangeable?

OBJECTIVE: During the COVID-19 pandemic, many research studies were adapted, including our longitudinal study examining cognitive impairment (CI) in systemic lupus erythematosus (SLE). Cognitive testing was switched from in-person to virtual. This analysis aimed to determine if the administration method (in-person vs. virtual) of the ACR-neuropsychological battery (ACR-NB) affected participant cognitive performance and classification. METHODS: Data from our multi-visit, SLE CI study included demographic, clinical, and psychiatric characteristics, and the modified ACR-NB. Three analyses were undertaken for cognitive performance: (1) all visits, (2) non-CI group visits only and (3) intra-individual comparisons. A retrospective preferences questionnaire was given to participants who completed the ACR-NB both in-person and virtually. RESULTS: We analysed 328 SLE participants who had 801 visits (696 in-person and 105 virtual). Demographic, clinical, and psychiatric characteristics were comparable except for ethnicity, anxiety and disease-related damage. Across all three comparisons, six tests were consistently statistically significantly different. CI classification changed in 11/71 (15%) participants. 45% of participants preferred the virtual administration method and 33% preferred in-person. CONCLUSIONS: Of the 19 tests in the ACR-NB, we identified one or more problems with eight (42%) tests when moving from in-person to virtual administration. As the use of virtual cognitive testing will likely increase, these issues need to be addressed - potentially by validating a virtual version of the ACR-NB. Until then, caution must be taken when directly comparing virtual to in-person test results. If future studies use a mixed administration approach, this should be accounted for during analysis.

A meta-analysis of variability in conjunctival microvascular hemorheology metrics.

Conjunctival hemorheology has been used analytically to assess qualities of blood flow associated with various forms of cardiovascular disorders including diabetes mellitus, stroke, and sickle cell disease. Although conjunctival axial red blood cell velocity (Vax) has been demonstrated in varying disease states, benchmark measures of Vax are not well-defined. Due to various methodologic differences in assessment of Vax, interstudy consistency of hemorheological metrics is susceptible to both systematic and random error. Our study examines interstudy heterogeneity of Vax as measured in the conjunctival microvasculature of healthy subjects and assesses the overall perturbation of Vax based on disease state. Furthermore, our study aims to establish a potential range of normative Vax by comparing inter-study measurements in healthy patients. The most widely employed analytic approach to assess Vax was space-time analysis (n = 30). Using a meta-analytic approach, the prediction interval for Vax in healthy subjects among 20 studies ranged from 0.32-2.60 mm/s with a combined effect size of 0.52 ± 0.03 (CI: 0.46-0.59) mm/s. Inter-study comparison of Vax in healthy patients showed a high degree of variability (I2: 98.96%), due to studies with low measurement precision and/or dissimilar analytic methodology. Neither age nor diameter was a clinically significant moderator of Vax measurements in healthy patients. The combined effect size, defined as the composite Hedge's g of studies comparing healthy and disease state mean Vax, was 0.21 ± 0.13. High heterogeneity (I2: 80.48%) was observed in studies analyzing the difference between mean Vax in healthy and disease state patients. This heterogeneity was also observed when the difference in mean Vax between healthy and disease state patients was assessed in subgroups based on disease condition (I2: vascular disease 33%, sickle cell disease 62.22%, other 83.43%). Age was found to be a significant moderator (p = 0.048, ß = -0.40) of Hedge's g while diameter was not. No significant publication bias was observed in studies presenting healthy patient Vax or in studies comparing Vax between healthy and disease state patients. In summary, although homogeneity can be seen in healthy group Vax measurements, a high degree of statistical heterogeneity is found in Vax assessment comparing healthy and disease conditions that is not fully explained by methodologic variability.

Hierarchical data visualization of experimental erythrocyte aggregation employing cross correlation and optical flow applications.

Appraisal of microvascular erythrocyte velocity as well as aggregation are critical features of hemorheological assessment. Examination of erythrocyte velocity-aggregate characteristics is critical in assessing disorders associated with coagulopathy. Microvascular erythrocyte velocity can be assessed using various methodologic approaches; however, the shared assessment of erythrocyte velocity and aggregation has not been well described. The purpose of this study therefore is to examine three independent erythrocyte assessment strategies with and without experimentally induced aggregation in order to elucidate appropriate analytic strategy for combined velocity/aggregation assessment applicable to in-vivo capillaroscopy. We employed a hierarchical microfluidic model combined with Bland-Altman analysis to examine agreement between three methodologies to assess erythrocyte velocity appropriate for interpretation of cinematography of in-vivo microvascular hemorheology. We utilized optical and manual techniques as well as a technique which we term transversal temporal cross-correlation (TTC) to observe and measure both erythrocyte velocity and aggregation. In general, optical, manual and TTC agree in estimation of velocity at relatively low flow rate, however with an increase in infusion rate the optical flow method yielded the velocity estimates that were lower than the TTC and manual velocity estimates. We suggest that this difference was due to the fact that slower moving particles close to the channel wall were better illuminated than faster particles deeper in the channel which affected the optical flow analysis. Combined velocity/aggregation appraisal using TTC provides an efficient approach for estimating erythrocyte aggregation appropriate for in-vivo applications. We demonstrated that the optical flow and TTC analyses can be used to estimate erythrocyte velocity and aggregation both in ex-vivo microfluidics laboratory experiments as well as in-vivo recordings. The simplicity of TTC method may be advantageous for developing velocity estimate methods to be used in the clinic. The trade-off is that TTC estimation cannot capture features of the flow based on optical flow analysis of individually tracked particles.

Variable abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson's disease (PD) and parkinsonism features.

OBJECTIVES: Ascertain and quantify abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson's disease (PD) and parkinsonism features based on a statistical predictive modeling strategy for PLR classification. METHODS: Exploratory cohort analysis of pupillary kinetics in non-disease controls, PD subjects, and subjects with parkinsonism features using chromatic pupillometry. Receiver operating characteristic (ROC) curve interpretation of pupillary changes consistent with abnormality of intrinsically photosensitive retinal ganglion cells (ipRGCs) was employed using a thresholding algorithm to discriminate pupillary abnormality between study groups. RESULTS: Twenty-eight subjects were enrolled, including 17 PD subjects (age range 64-85, mean 70.65) and nine controls (age range 48-95, mean 63.89). Two subjects were described as demonstrating parkinsonism symptoms due to presumed Lewy body dementia and motor system atrophy (MSA) respectively. On aggregate analysis, PD subjects demonstrated abnormal but variable pupillary dynamics suggestive of ipRGC abnormality. Subjects with parkinsonism features did not demonstrate pupillary changes consistent with ipRGC abnormality. There was no relationship between levodopa equivalent dosage or PD severity and ipRGC abnormality. The pupillary test sensitivity in predicting PD was 0.75 and likelihood ratio was 1.2. CONCLUSIONS: ipRGC deficit is demonstrated in PD subjects; however, the degree and constancy of abnormality appear variable.

Longitudinal Development of Brain Iron Is Linked to Cognition in Youth.

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8-26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence.SIGNIFICANCE STATEMENT Brain tissue iron is essential to healthy brain function. Atypical basal ganglia tissue iron levels have been linked to impaired cognition in iron deficient children and adults with neurodegenerative disorders. However, the normative developmental trajectory of basal ganglia iron concentration during adolescence and its association with cognition are less well understood. In the largest study of tissue iron development yet reported, we characterize the developmental trajectory of tissue iron concentration across the basal ganglia during adolescence and provide evidence that diminished iron content is associated with poorer cognitive performance even in healthy youth. These results highlight the transition from adolescence to adulthood as a period of dynamic maturation of tissue iron concentration in the basal ganglia.

Core outcome set for surgical trials in gastric cancer (GASTROS study): international patient and healthcare professional consensus.

BACKGROUND: Surgery is the primary treatment that can offer potential cure for gastric cancer, but is associated with significant risks. Identifying optimal surgical approaches should be based on comparing outcomes from well designed trials. Currently, trials report different outcomes, making synthesis of evidence difficult. To address this, the aim of this study was to develop a core outcome set (COS)-a standardized group of outcomes important to key international stakeholders-that should be reported by future trials in this field. METHODS: Stage 1 of the study involved identifying potentially important outcomes from previous trials and a series of patient interviews. Stage 2 involved patients and healthcare professionals prioritizing outcomes using a multilanguage international Delphi survey that informed an international consensus meeting at which the COS was finalized. RESULTS: Some 498 outcomes were identified from previously reported trials and patient interviews, and rationalized into 56 items presented in the Delphi survey. A total of 952 patients, surgeons, and nurses enrolled in round 1 of the survey, and 662 (70 per cent) completed round 2. Following the consensus meeting, eight outcomes were included in the COS: disease-free survival, disease-specific survival, surgery-related death, recurrence, completeness of tumour removal, overall quality of life, nutritional effects, and 'serious' adverse events. CONCLUSION: A COS for surgical trials in gastric cancer has been developed with international patients and healthcare professionals. This is a minimum set of outcomes that is recommended to be used in all future trials in this field to improve trial design and synthesis of evidence.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Differential analysis of serum and urine S100 proteins in juvenile-onset systemic lupus erythematosus (jSLE).

Up to 80% of juvenile-onset systemic lupus erythematosus (jSLE) patients develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably diagnose LN, leaving kidney biopsies as the gold-standard. Calcium-binding S100 proteins are expressed by innate immune cells and epithelia and may act as biomarkers in systemic inflammatory conditions. We quantified S100 proteins in the serum and urine of jSLE patients, matched healthy and inflammatory (IgA vasculitis) controls. Serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients when compared to controls. Furthermore, serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients with active as compared to patients with inactive/no LN. No differences in S100A4 levels were seen between groups. This study demonstrates potential promise for S100A8/A9 and S100A12 as biomarkers for jSLE and active LN. Findings require to be confirmed and tested prospectively in independent and larger multi-ethnic cohorts.

Adverse pregnancy outcomes and subsequent development of connective tissue disease in the UK: an epidemiological study.

OBJECTIVE: This study assessed prevalence of connective tissue disease (CTDs), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) in women with previous adverse pregnancy outcome compared with uncomplicated livebirths. DESIGN: Retrospective case-control study. SETTING: UK Primary Care. POPULATION OR SAMPLE: Records of women, 18 years and older, within the Clinical Practice Research Datalink (CPRD) (1 January 2000-31 December 2013). METHODS: Clinical Practice Research Datalink was searched for pregnancy terms to identify adverse pregnancy outcome. Each identified case was matched to five livebirths. MAIN OUTCOME MEASURES: Diagnosis of SLE, CTD, APS or autoimmune antibodies. Poisson regression was performed to calculate relative risk ratios (RR), comparing adverse pregnancy outcome with livebirth cohorts. RESULTS: Clinical Practice Research Datalink identified 20 123 adverse pregnancy outcomes matched to 97 323 livebirths, with a total of 875 590 person-years follow up. Median follow up from study entry was 7.29 years (SD 4.39). Compared with women with an uncomplicated livebirth, women with adverse pregnancy outcome had an increased risk of developing CTD or autoimmune antibodies (RR 3.20, 95% CI 2.90-3.51). Risk was greatest following a stillbirth (RR 5.82, 95% CI 4.97-6.81). For CTD and SLE, the risk was greatest within the first 5 years of adverse pregnancy outcome. Risk for aPL and APS diagnosis was highest ≥5 years from adverse pregnancy outcome. CONCLUSIONS: Adverse pregnancy outcome is associated with increased risk of developing maternal CTD, including SLE. Either immunological factors predispose women to adverse pregnancy outcome and subsequent CTD diagnosis or, alternatively, adverse pregnancy outcome initiates autoimmune events which culminate in CTD in later life. TWEETABLE ABSTRACT: Stillbirth is associated with increased maternal risk of developing systemic lupus erythematosus (SLE).

A review of the physiology behind letrozole applications in infertility: are current protocols optimal?

Letrozole is a targeted aromatase inhibitor which has primarily been used in post-menopausal women with breast cancer. Recently, it has been utilized in infertile pre-menopausal women because of its ability to enhance FSH production for ovulation induction. However, the ovarian follicle's response to FSH is only a part of the endocrine events occurring in a developing follicle. The health of the small antral follicles is driven primarily by androgens, which contribute to granulosa cell mitosis, sensitivity to FSH, and resistance to atresia. In contrast, elevated androgens in the late antral to pre-ovulatory follicle have a negative impact on follicle health and lead to atresia and cystic follicle formation. This ovarian physiologic data suggests that current applications of letrozole to infertility may be squandering some of the primary benefits available in using letrozole to promote follicle development. Four applications of letrozole to infertility that have appeared in the medical literature are reviewed. Androgen-related benefits are reviewed and various questions put forward about how letrozole could be more effectively used to help patients in these settings.

An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency.

Fragile X and fragile X-associated tremor-ataxia syndrome (FXTAS) are caused by mutations of the FMR1 gene. The mutations causing FXTAS can expand in a generation to a "full mutation" causing fragile X syndrome. The mutations causing FXTAS and the phenotype, fragile X-associated premature ovarian insufficiency (FXPOI), are referred to as the FMR1 premutation (PM). The objective of this paper was to formulate a theory to explain the Mechanism for FXPOI.Recent research on fragile X syndrome and FXTAS has led to sophisticated theories about the mechanisms underlying these diseases. It has been proposed that similar mechanisms underlie FXPOI. Utilizing recent research on FXTAS, but a more detailed application of ovarian physiology, we present a more ovarian specific theory as to the primary mechanism explaining the development of FXPOI.The FXPOI phenotype may best be viewed as derivative of the observation that fragile X PM carriers experience menopause an average of 5 years earlier than non-carriers. Women carrying the PM experience an earlier menopause because of an accelerated activation of their primordial follicle pool. This acceleration of primordial follicle activation occurs, in part, because of diminished AMH production. AMH production is diminished because of accelerated atresia of early antral follicles. This accelerated atresia likely occurs because the fragile X PM leads to a slowing of the rate of granulosa cell mitosis in some follicles.

Time Fractional Fisher-KPP and Fitzhugh-Nagumo Equations.

A standard reaction-diffusion equation consists of two additive terms, a diffusion term and a reaction rate term. The latter term is obtained directly from a reaction rate equation which is itself derived from known reaction kinetics, together with modelling assumptions such as the law of mass action for well-mixed systems. In formulating a reaction-subdiffusion equation, it is not sufficient to know the reaction rate equation. It is also necessary to know details of the reaction kinetics, even in well-mixed systems where reactions are not diffusion limited. This is because, at a fundamental level, birth and death processes need to be dealt with differently in subdiffusive environments. While there has been some discussion of this in the published literature, few examples have been provided, and there are still very many papers being published with Caputo fractional time derivatives simply replacing first order time derivatives in reaction-diffusion equations. In this paper, we formulate clear examples of reaction-subdiffusion systems, based on; equal birth and death rate dynamics, Fisher-Kolmogorov, Petrovsky and Piskunov (Fisher-KPP) equation dynamics, and Fitzhugh-Nagumo equation dynamics. These examples illustrate how to incorporate considerations of reaction kinetics into fractional reaction-diffusion equations. We also show how the dynamics of a system with birth rates and death rates cancelling, in an otherwise subdiffusive environment, are governed by a mass-conserving tempered time fractional diffusion equation that is subdiffusive for short times but standard diffusion for long times.

Prevention of stroke: a global perspective.

Along with the rising global burden of disability attributed to stroke, costs of stroke care are rising, providing the impetus to direct our research focus towards effective measures of stroke prevention. In this Series paper, we discuss strategies for reducing the risk of the emergence of disease (primordial prevention), preventing the onset of disease (primary prevention), and preventing the recurrence of disease (secondary prevention). Our focus includes global strategies and campaigns, and measurements of the effectiveness of worldwide preventive interventions, with an emphasis on low-income and middle-income countries. Our findings reveal that effective tobacco control, adequate nutrition, and development of healthy cities are important strategies for primordial prevention, whereas polypill strategies, use of mobile technology (mHealth), along with salt reduction and other dietary interventions, are effective in the primary prevention of stroke. An effective collaboration between various health-care sectors, government policies, and campaigns can successfully implement secondary prevention strategies, through surveillance and registries, such as the WHO's non-communicable diseases programmes, across high-income and low-income countries.

Fronto-parietal and temporal brain dysfunction in depression: A fMRI investigation of auditory mismatch processing.

Mismatch responses reflect neural mechanisms of early cognitive processing in the auditory domain. Disturbances of these mechanisms on multiple levels of neural processing may contribute to clinical symptoms in major depression (MD). A functional magnetic resonance imaging (fMRI) study was conducted to identify neurobiological foundations of altered mismatch processing in MD. Twenty-five patients with major depression and 25 matched healthy individuals completed an auditory mismatch paradigm optimized for fMRI. Brain activity during mismatch processing was compared between groups. Moreover, seed-based connectivity analyses investigated depression-specific brain networks. In patients, mismatch processing was associated with reduced activation in the right auditory cortex as well as in a fronto-parietal attention network. Moreover, functional coupling between the right auditory cortex and frontal areas was reduced in patients. Seed-to voxel analysis on the whole-brain level revealed reduced connectivity between the auditory cortex and the thalamus as well as posterior cingulate. The present study indicates deficits in sensory processing on the level of the auditory cortex in depression. Hyposensitivity in a fronto-parietal network presumably reflects altered attention mechanisms in depression. The observed impairments may contribute to psychopathology by reducing the ability of the affected individuals to orient attention toward important environmental cues.

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers.

Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including IL-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. To assess whether neutrophils directly influence the progression of autoreactivity in secondary lymphoid organs (SLOs), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus. Neutrophils accumulate in SLO over the course of lupus progression, preferentially localizing near T lymphocytes early in disease and B cells with advanced disease. RNA sequencing reveals that the splenic neutrophil transcriptional program changes significantly over the course of disease, with neutrophil expression of anti-inflammatory mediators peaking during early-stage and midstage disease, and evidence of neutrophil activation with advanced disease. To assess whether neutrophils exert predominantly protective or deleterious effects on loss of B cell self-tolerance in vivo, we depleted neutrophils at different stages of disease. Neutrophil depletion early in lupus resulted in a striking acceleration in the onset of renal disease, SLO germinal center formation, and autoreactive plasma cell production. In contrast, neutrophil depletion with more advanced disease did not alter systemic lupus erythematosus progression. These results demonstrate a surprising temporal and context-dependent role for neutrophils in restraining autoreactive B cell activation in lupus.

Respiratory complications of metabolic disease in the paediatric population: A review of presentation, diagnosis and therapeutic options.

Inborn errors of metabolism (IEMs) whilst individually rare, as a group constitute a field which is increasingly demands on pulmonologists. With the advent of new therapies such as enzyme replacement and gene therapy, early diagnosis and treatment of these conditions can impact on long term outcome, making their timely recognition and appropriate investigation increasingly important. Conversely, with improved treatment, survival of these patients is increasing, with the emergence of previously unknown respiratory phenotypes. It is thus important that pulmonologists are aware of and appropriately monitor and manage these complications. This review aims to highlight the respiratory manifestations which can occur. It isdivided into conditions resulting primarily in obstructive airway and lung disease, restrictive lung disease such as interstitial lung disease or pulmonary alveolar proteinosis and pulmonary hypertension, whilst acknowledging that some diseases have the potential to cause all three. The review focuses on general phenotypes of IEMs, their known respiratory complications and the basic metabolic investigations which should be performed where an IEM is suspected.

Serum vitamin A, zinc and visual function in children with moderate to severe persistent asthma.

Background: Asthma is a common childhood disorder with complex pathobiologic components that may include aspects of nutritional deficit. The contribution of vitamin deficiency, specifically vitamin A, as part of the disease complex has not been well studied, particularly among at risk children. In this study, we examined the prevalence of vitamin A as well as zinc deficiency in conjunction with visual function among an urban pediatric population sample with moderate-severe persistent asthma. Methods: A cross-sectional case-control assessment of serum vitamin A, zinc and visual function among urban children with and without asthma was undertaken. Inclusion criteria involved (1) well-controlled pediatric asthmatic patients between the ages of 8-18 with corrected vision of at least 20/25 in each eye and (2) chronic use of a combination beta agonist-steroid inhaler. Visual function was assessed by Snellen visual acuity and Peli Robson contrast sensitivity assessment. Results: Overall, 24 patients were enrolled for study with body mass index and age matched between asthmatic and control groups. Median serum vitamin A and zinc levels among control subjects was statistically higher compared to asthmatics (p = 0.0303 and p = 0.0111, respectively). Based on age-based reference levels there was no evidence of vitamin A or zinc deficiency among asthmatics or controls. Serum vitamin A and zinc were found to directly correlate with body mass index (p = 0.0074 and p = 0.0474, respectively), but not age or measures of visual function. Contrast sensitivity was however significantly reduced among asthmatic subjects (p = 0.0003). Conclusions: Children with chronic asthma demonstrate reduced levels of vitamin A and zinc that may be related to disease pathobiology however, evidence of frank zinc or vitamin A deficiency was not demonstrated. Reduced contrast sensitivity found in the asthmatic group appears unrelated to serum vitamin A and/or zinc levels.

Computing the Social Brain Connectome Across Systems and States.

Social skills probably emerge from the interaction between different neural processing levels. However, social neuroscience is fragmented into highly specialized, rarely cross-referenced topics. The present study attempts a systematic reconciliation by deriving a social brain definition from neural activity meta-analyses on social-cognitive capacities. The social brain was characterized by meta-analytic connectivity modeling evaluating coactivation in task-focused brain states and physiological fluctuations evaluating correlations in task-free brain states. Network clustering proposed a functional segregation into (1) lower sensory, (2) limbic, (3) intermediate, and (4) high associative neural circuits that together mediate various social phenomena. Functional profiling suggested that no brain region or network is exclusively devoted to social processes. Finally, nodes of the putative mirror-neuron system were coherently cross-connected during tasks and more tightly coupled to embodied simulation systems rather than abstract emulation systems. These first steps may help reintegrate the specialized research agendas in the social and affective sciences.

Dosage considerations in the combined use of ocular-specific vitamins and nutrients and multivitamin products: A systemic review and analysis.

OBJECTIVES: To provide guidance for safe and appropriate vitamin and mineral supplementation regimens for patients who use vitamins marketed for ocular use concurrently with general-purpose multivitamin (MVI) supplementation. DATA SOURCES: Primary and tertiary evidence was compiled from secondary literature reference databases. STUDY SELECTION: Dosage exposure with the use of supplements marketed for the prevention of ocular disease, including those recommended by the Age-Related Eye Disease Studies (AREDS), when used in combination with conventional MVI/nutrient products was determined. An analysis of the data was performed to suggest appropriate supplement recommendations. DATA EXTRACTION: Combined dosages for single and duplicate ingredients found in ocular supplements and select MVI/nutrient supplements were compared with U.S. Food and Drug Administration--recommended daily value intake levels and the National Academy of Medicine recommendations on vitamin and nutrient tolerable upper intake levels (TUILs). RESULTS: With the exception of copper, all studied product components that conformed to AREDS guidelines for vitamin and nutrient levels far exceeded U.S. Food and Drug Administration--recommended daily value intake level limits. Furthermore, vitamin A and zinc exceeded the National Academies of Medicine TUIL when a multivitamin product was combined with an ocular-specific vitamin or nutrient that conformed with AREDS-recommended dosage levels. Several products marketed specifically for ocular use failed to provide AREDS-recommended vitamin or nutrient levels even when combined with MVI products. CONCLUSION: With the exception of vitamin A and zinc, the addition of typical multivitamin preparations to AREDS-recommended vitamin and nutrient regimens do not result in vitamin and mineral dosages that exceed TUIL as outlined by the National Academy of Medicine. However, combined AREDS and MVI regimens can create a substantial vitamin or mineral burden that is not appropriate for all older adult populations, particularly those with comorbidities, contributing to susceptibility of component toxicity.