Mixed Mood State Behaviors and Circadian Dysfunction following Homocysteic Acid Treatment: Potential Animal Model for Bipolar Disorder

Bipolar disorder is a neuropsychiatric disease characterized by cyclical fluctuations of mood states between mania and depression. Circadian rhythm abnormalities and inconsistent sleep patterns are two common symptoms of bipolar disorder (Millar, Epsie, & Scott, 2004). Elevated levels of homocysteine, in the blood or cerebrospinal fluid, commonly occurs in patients with neuropsychiatric illnesses, including bipolar disorder (Bell et al., 1992; Boushey, Beresford, Omenn, & Motulsky, 1995). Homocysteic acid (HCA), an endogenous metabolite of homocysteine, has been implicated as a harmful neurotoxin and agonist of NMDA receptors. We have previously shown that postnatal administration of HCA (from postnatal day 3-21) in Sprague Dawley rats results in both mania-like and depressive-like behaviors, suggesting that this may serve as a novel animal model for bipolar disorder. The purpose of the present study was to characterize any circadian abnormalities that may be present in HCA-treated rats, as sleep and circadian dysfunction are common symptoms of bipolar disorder. In addition, we also characterized the developmental onset of the mania-like and depressive-like behaviors in this model. Prior to puberty, we found that HCA-treated rats exhibited no manic-like behaviors and only a trend toward depressive-like behaviors. After puberty, however, HCA-treated rats presented a mixed mood-state of both manic-like and depressive-like behaviors, along with significant dysfunction in the circadian clock. Specifically, both the free-running period and the amplitude of the rhythm were significantly reduced following HCA treatment. We are currently using microarray analyses to determine differences in circadian gene expression levels between HCA treated animals and controls. Additionally, we are examining the therapeutic role of lithium for reversing the circadian disruptions exhibited by the HCA-treated animals. Altogether, the findings of the present study provide strong evidence in support of the HCA model’s face validity for bipolar disorder, allowing us to better understand the mechanisms underlying the development of this disease

The Market for Organic Canned Corn in Germany and the United States

This market research paper has been prepared under the supervision of Prof. Dr. Wolfgang Veit of TH Köln and Prof. Dr. Carol Scovotti of University of Wisconsin-Whitewater in the course of the inter-university cross-border collaboration student research project “Export Opportunity Surveys (EOS)”. This study explores organic canned corn export opportunities to the German and US markets

The case for strategic international alliances to harness nutritional genomics for public and personal health

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countrie

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Transactional patterns of depressive symptoms between mothers and adolescents: The role of emotion regulation

BACKGROUND: Depression is a highly prevalent, debilitating disorder that runs in families. Yet, empirical support for bidirectional mechanisms linking mother-adolescent depression symptoms remains limited. This study examined longitudinal bidirectional relations among emotion regulation (ER) constructs and depressive symptoms among mother-adolescent dyads over time. Pathways for girls and boys were explored separately, given extant research on sex differences in the intergenerational transmission of depression. METHODS: Adolescent (n = 232; M = 15.02 years, SD = 0.95; 44% female)-mother dyads, drawn from a longitudinal study on the development of risky behaviors, completed annual assessments of depressive symptoms and facets of ER over 4 years. Panel modeling examined lagged and cross-lagged effects of mother-adolescent depressive symptoms and ER constructs over time, in a multigroup model of boys and girls. RESULTS: Among girls, higher baseline maternal depression scores predicted increased adolescent ER difficulties (std. est. = -.42, p \u3c .001) in turn, predicting increased adolescent depressive symptoms (std. est. = -.33, p = .002) and subsequent maternal ER difficulties (std. est. = .39, p = .002). The indirect effect of maternal depressive symptoms→adolescent ER→adolescent depressive symptoms→maternal ER was significant (ind. eff. = .10, 95% confidence interval [\u3e.001, .19]) for girls, but not boys. CONCLUSION: Implications for interrupting intergenerational cycles of depressive symptoms and emotion dysregulation are discussed

Manganese(I) Diamine Electrocatalysts: Electrochemical Carbon Dioxide Reduction to Carbon Monoxide

Novel organometallic complexes Mn(benzene-1,2-diamine)(CO)3Br, Mn-1, Mn(3-methylbenzene-1,2-diamine)(CO)3Br, Mn-2, and Re(benzene-1,2-diamine)(CO)3Cl, Re-1, have been synthesized and characterized by IR, UV/Vis, 1H-NMR, EA and HRMS. The structures of Mn-2 and Re-1 were confirmed by X-ray crystallography. The three novel compounds were studied for their electrocatalytic reduction of carbon dioxide to carbon monoxide using cyclic voltammetry in acetonitrile solutions. Controlled potential electrolysis was used to obtain information on faradaic yield, with product formation being confirmed by GC. Using earth-abundant manganese, compounds Mn-1 and Mn-2 display turnover frequencies of 108 s−1 and 82 s−1, respectively, amid selective production of carbon monoxide (faradaic yields ~85%), with minimal co-production of dihydrogen (Re-1, displays no activity as an electrocatalyst for carbon dioxide reduction under identical conditions

Clinical Consequences of Hepatitis B Surface Antigen Loss in Chronic Hepatitis B Infection: A Systematic Literature Review and Meta-Analysis

Background and Aims: Functional cure, which requires sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation, is currently the optimal treatment endpoint for chronic hepatitis B virus infection. We performed a systematic literature review (SLR) and meta-analyses to assess the association between HBsAg loss and long-term clinical outcomes. Methods: We performed a SLR of scientific literature published in Medline and Embase reporting the incidence of cirrhosis, hepatic decompensation (HD), hepatocellular carcinoma (HCC), liver-related mortality (LRM), and all-cause mortality (ACM) in relation to HBsAg status. Bayesian hierarchical commensurate prior meta-analyses synthesized evidence on the association between HBsAg loss and each outcome. Results: Thirty-eight studies, comprising 50,354 patients with 350,734 patient-years of follow-up, were included in the meta-analyses, reporting on cirrhosis (n = 12), HD (n = 12), HCC (n = 36), LRM (n = 12), and ACM (n = 16). Pooled incidence rate ratios (IRRs; vs HBsAg persistence) and respective credible intervals (Crls) were 0.28 (0.060–1.070) for cirrhosis, 0.13 (0.013–0.38) for HD, 0.27 (0.11–0.53) for HCC, 0.17 (0.028–0.61) for LRM, and 0.64 (0.24–1.17) for ACM. Single-predictor-adjusted IRRs remained consistent with those from the primary analyses for all outcomes except cirrhosis and LRM. Outcome incidence rates were modified by selected study, patient and infection characteristics, but trended in the same direction of reduced risk after loss. Conclusion: Overall, HBsAg loss was associated with a reduced risk of most clinically relevant outcomes. While the magnitude of the effect differed across subgroups, the direction of the association remained similar. Our results validate the need to develop new strategies to achieve HBsAg loss