A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations.

BackgroundFood fortification has been recommended to improve a population's micronutrient status. Biofortification techniques modestly elevate the zinc content of cereals, but few studies have reported a positive impact on functional indicators of zinc status.ObjectiveWe determined the impact of a modest increase in dietary zinc that was similar to that provided by biofortification programs on whole-body and cellular indicators of zinc status.DesignEighteen men participated in a 6-wk controlled consumption study of a low-zinc, rice-based diet. The diet contained 6 mg Zn/d for 2 wk and was followed by 10 mg Zn/d for 4 wk. To reduce zinc absorption, phytate was added to the diet during the initial period. Indicators of zinc homeostasis, including total absorbed zinc (TAZ), the exchangeable zinc pool (EZP), plasma and cellular zinc concentrations, zinc transporter gene expression, and other metabolic indicators (i.e., DNA damage, inflammation, and oxidative stress), were measured before and after each dietary-zinc period.ResultsTAZ increased with increased dietary zinc, but plasma zinc concentrations and EZP size were unchanged. Erythrocyte and leukocyte zinc concentrations and zinc transporter expressions were not altered. However, leukocyte DNA strand breaks decreased with increased dietary zinc, and the level of proteins involved in DNA repair and antioxidant and immune functions were restored after the dietary-zinc increase.ConclusionsA moderate 4-mg/d increase in dietary zinc, similar to that which would be expected from zinc-biofortified crops, improves zinc absorption but does not alter plasma zinc. The repair of DNA strand breaks improves, as do serum protein concentrations that are associated with the DNA repair process. This trial was registered at clinicaltrials.gov as NCT02861352

Generalisability of and lessons learned from a mixed-methods study conducted in three low- and middle-income countries to identify care pathways for atrial fibrillation

BackgroundIdentifying existing care pathways is the first step for understanding how services can be improved to enable early diagnosis and effective follow-up care for non-communicable diseases (NCDs); however, evidence on how care pathways can and should be identified in low- and middle-income countries (LMICs) is lacking.ObjectiveTo describe generalisability and lessons learned from recruitment and data collection for the quantitative component of a mixed methods study designed to determine the care pathway for atrial fibrillation (AF) in Brazil, China and Sri Lanka.MethodsAdults (≥18 years) that spoke the local language and with an AF diagnosis were eligible. We excluded anyone with a hearing or cognitive impairment or ineligible address. Eligible participants were identified using electronic records in Brazil and China; in Sri Lanka, researchers attended the outpatient clinics to identify eligible participants. Data were collected using two quantitative questionnaires administered at least 2-months apart. A minimum sample size of 238 was required for each country.ResultsThe required sample size was met in Brazil (n = 267) and China (n = 298), but a large proportion of AF patients could not be contacted (47% and 27%, respectively) or refused to participate (36% and 38%, respectively). In Sri Lanka, recruitment was challenging, resulting in a reduced sample (n = 151). Mean age of participants from Brazil, China and Sri Lanka was 69 (SD = 11.3), 65 (SD = 12.8) and 58 (SD = 11.7), respectively. Females accounted for 49% of the Brazil sample, 62% in China and 70% in Sri Lanka.ConclusionsGeneralisability was an issue in Brazil and China, as was selection bias. Recruitment bias was highlighted in Sri Lanka. Additional or alternative recruitment methods may be required to ensure generalisability and reduce bias in future studies aimed at identifying NCD care pathways in LMICs

JGromacs: A Java Package for Analyzing Protein Simulations

UNLABELLED: In this paper, we introduce JGromacs, a Java API (Application Programming Interface) that facilitates the development of cross-platform data analysis applications for Molecular Dynamics (MD) simulations. The API supports parsing and writing file formats applied by GROMACS (GROningen MAchine for Chemical Simulations), one of the most widely used MD simulation packages. JGromacs builds on the strengths of object-oriented programming in Java by providing a multilevel object-oriented representation of simulation data to integrate and interconvert sequence, structure, and dynamics information. The easy-to-learn, easy-to-use, and easy-to-extend framework is intended to simplify and accelerate the implementation and development of complex data analysis algorithms. Furthermore, a basic analysis toolkit is included in the package. The programmer is also provided with simple tools (e.g., XML-based configuration) to create applications with a user interface resembling the command-line interface of GROMACS applications. AVAILABILITY: JGromacs and detailed documentation is freely available from http://sbcb.bioch.ox.ac.uk/jgromacs under a GPLv3 license

Insulin Sensitivity Is Reflected by Characteristic Metabolic Fingerprints - A Fourier Transform Mass Spectrometric Non-Targeted Metabolomics Approach

BACKGROUND: A decline in body insulin sensitivity in apparently healthy individuals indicates a high risk to develop type 2 diabetes. Investigating the metabolic fingerprints of individuals with different whole body insulin sensitivity according to the formula of Matsuda, et al. (ISI(Matsuda)) by a non-targeted metabolomics approach we aimed a) to figure out an unsuspicious and altered metabolic pattern, b) to estimate a threshold related to these changes based on the ISI, and c) to identify the metabolic pathways responsible for the discrimination of the two patterns. METHODOLOGY AND PRINCIPAL FINDINGS: By applying infusion ion cyclotron resonance Fourier transform mass spectrometry, we analyzed plasma of 46 non-diabetic subjects exhibiting high to low insulin sensitivities. The orthogonal partial least square model revealed a cluster of 28 individuals with alterations in their metabolic fingerprints associated with a decline in insulin sensitivity. This group could be separated from 18 subjects with an unsuspicious metabolite pattern. The orthogonal signal correction score scatter plot suggests a threshold of an ISI(Matsuda) of 15 for the discrimination of these two groups. Of note, a potential subgroup represented by eight individuals (ISI(Matsuda) value between 8.5 and 15) was identified in different models. This subgroup may indicate a metabolic transition state, since it is already located within the cluster of individuals with declined insulin sensitivity but the metabolic fingerprints still show some similarities with unaffected individuals (ISI >15). Moreover, the highest number of metabolite intensity differences between unsuspicious and altered metabolic fingerprints was detected in lipid metabolic pathways (arachidonic acid metabolism, metabolism of essential fatty acids and biosynthesis of unsaturated fatty acids), steroid hormone biosyntheses and bile acid metabolism, based on data evaluation using the metabolic annotation interface MassTRIX. CONCLUSIONS: Our results suggest that altered metabolite patterns that reflect changes in insulin sensitivity respectively the ISI(Matsuda) are dominated by lipid-related pathways. Furthermore, a metabolic transition state reflected by heterogeneous metabolite fingerprints may precede severe alterations of metabolism. Our findings offer future prospects for novel insights in the pathogenesis of the pre-diabetic phase

Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression

<p>Abstract</p> <p>Background</p> <p>Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain.</p> <p>Results</p> <p>Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes <it>homer1a</it>, <it>arc</it>, <it>zif268</it>, <it>ngfi-b </it>and c-<it>fos </it>in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues.</p> <p>Conclusion</p> <p>The results implicate correlated activity between the cortex and the striatum, especially the nucleus accumbens core and the basolateral amygdala, in the generation of a conditioned motivated state that may promote excessive food intake. The upregulation of a number of genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. As many of these genes play a role in plasticity, their upregulation within these circuits may also indicate the neuroanatomic and transcriptional correlates of extinction learning.</p

A Novel Protein Kinase-Like Domain in a Selenoprotein, Widespread in the Tree of Life

Selenoproteins serve important functions in many organisms, usually providing essential oxidoreductase enzymatic activity, often for defense against toxic xenobiotic substances. Most eukaryotic genomes possess a small number of these proteins, usually not more than 20. Selenoproteins belong to various structural classes, often related to oxidoreductase function, yet a few of them are completely uncharacterised

The impact of rate and rhythm control strategies on quality of life for patients with atrial fibrillation: a protocol for a systematic review

Abstract Background Atrial fibrillation (AF) is the most common heart arrhythmia globally and it adversely affects the quality of life (QoL). Available rate and rhythm control strategies equally reduce mortality but may impact QoL differently. A number of systematic reviews have focused on the impact of specific strategies on QoL, though a 2006 review synthesized the evidence on the effect of all strategies on QoL, allowing for a clinically important comparison between the types of strategies. Many trials have been published since the review undertook the search in 2005; therefore, an update is needed. This systematic review aims to provide an update to the 2006 review on the impact of all rate and rhythm control strategies on QoL in people with AF. Methods The following four databases and three clinical trial registries will be searched for primary studies: CENTRAL, MEDLINE, Embase, CINAHL, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and ClinicalTrialsRegister.eu. No language restriction will be applied. The search will be limited to 2004 or later publication year to allow overlap with the search conducted by the 2006 review authors. Any randomized control trial that reports the QoL of adult (≥ 18 years) AF patients following an eligible rate or rhythm control intervention will be eligible for inclusion. Eligible interventions (and comparators) include pacing, atrioventricular node junction and bundle of HIS ablation, pharmacological therapy, radio frequency catheter ablation, cryoablation, pulmonary vein isolation, maze operation, pace maker implantation, and defibrillator implantation. Two reviewers will independently screen for eligible studies, extract the data using a piloted tool, and assess bias by QoL outcome using the RoB 2 tool. The suitability of conducting a meta-analysis will be assessed by the clinical and methodology similarities of included studies. If it is feasible, standardized mean differences will be pooled using a random-effects model and assessed appropriately. Discussion The findings from this review will allow for meaningful comparisons between various rate and rhythm control strategies regarding their impact on QoL. This review will be useful for a wide range of stakeholders and will be crucial for optimizing the overall wellbeing of AF patients. Systematic review registration PROSPERO CRD42021290542 </jats:sec

Cardiovascular Health and Atrial Fibrillation or Flutter: A Cross-Sectional Study from ELSA-Brasil.

BackgroundThe association between ideal cardiovascular health (ICVH) status and atrial fibrillation or flutter (AFF) diagnosis has been less studied compared to other cardiovascular diseases.ObjectiveTo analyze the association between AFF diagnosis and ICVH metrics and scores in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).MethodsThis study analyzed data from 13,141 participants with complete data. Electrocardiographic tracings were coded according to the Minnesota Coding System, in a centralized reading center. ICVH metrics (diet, physical activity, body mass index, smoking, blood pressure, fasting plasma glucose, and total cholesterol) and scores were calculated as proposed by the American Heart Association. Crude and adjusted binary logistic regression models were built to analyze the association of ICVH metrics and scores with AFF diagnosis. Significance level was set at 0.05.ResultsThe sample had a median age of 55 years and 54.4% were women. In adjusted models, ICVH scores were not significantly associated with prevalent AFF diagnosis (odds ratio [OR]:0.96; 95% confidence interval [95% CI]:0.80-1.16; p=0.70). Ideal blood pressure (OR:0.33; 95% CI:0.15-0.74; p=0.007) and total cholesterol (OR:1.88; 95% CI:1.19-2.98; p=0.007) profiles were significantly associated with AFF diagnosis.ConclusionsNo significant associations were identified between global ICVH scores and AFF diagnosis after multivariable adjustment in our analyses, at least partially due to the antagonistic associations of AFF with blood pressure and total cholesterol ICVH metrics. Our results suggest that estimating the prevention of AFF burden using global ICVH scores may not be adequate, and ICVH metrics should be considered in separate

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